Methods of increasing lifespan in dogs

Abstract

Disclosed herein are methods of using SGLT2 inhibitors for increasing lifespan, promoting metabolic health and longevity, and / or preventing, reducing the severity of, or delaying the onset of, various age-associated diseases or conditions in dogs.

Description

WSGR Docket No. 58989-730.601METHODS OF INCREASING LIFESPAN IN DOGSCROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 755,644 filed February 7, 2025, which is hereby incorporated by reference in its entirety.BACKGROUND

[0002] Throughout history, products and methods that promote longevity and extend lifespan have been eagerly sought. Generally, these products and methods have proven to be ineffective and / or unsafe. Accordingly, there remains an unmet need for safe and effective products and methods that promote longevity and extend lifespan.SUMMARY

[0003] In an aspect, provided herein is a method of reducing or delaying mortality due to an age-associated disease or condition in a dog, the method comprising administering to the dog an effective amount of an SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof. In some embodiments, the age-associated disease or condition comprises an age-associated metabolic disease or age-associated diminished quality of life. In some embodiments, the age-associated metabolic disease comprises metabolic dysfunction, metabolic syndrome, or obesity-related metabolic disease. In some embodiments, the age-associated metabolic disease comprises an increase in serum glucose, an increase in serum insulin, a decrease in fat metabolism, or a decrease in serum beta-hydroxybutyrate level. In some embodiments, the age-associated diminished quality of life comprises frailty, sarcopenia, sarcopenic obesity, osteoporosis, pain, functional impairment, locomotor impairment, diminished energy or mood, or cognitive decline.

[0004] In some embodiments, the dog has an age of four years or older. In some embodiments, the dog has a weight of six pounds or more. In some embodiments, the SGLT2 inhibitor is selected from the group consisting of atigliflozin, bexagliflozin, canagliflozin, dapagliflozin, empagliflozin, enavogliflozin, ertugliflozin, henagliflozin, ipragliflozin, janagliflozin, licogliflozin, luseogliflozin, mizagliflozin, remogliflozin etabonate, rongliflozin, sergliflozin etabonate, sotagliflozin, tofogliflozin, velagliflozin, and wanpagliflozin, or a pharmaceutically acceptable salt thereof. In some embodiments, the SGLT2 inhibitor is selected from the group consisting of canagliflozin, dapagliflozin, empagliflozin, and velagliflozin, or a pharmaceutically acceptable salt thereof. In someWSGR Docket No. 58989-730.601embodiments, the SGLT2 inhibitor is dapagliflozin, or a pharmaceutically acceptable salt thereof.

[0005] In some embodiments, the effective amount is about 0.1 to about 5.0 mg / kg. In some embodiments, the effective amount is about 0.3 to about 3.0 mg / kg. In some embodiments, the effective amount is about 1.0 mg / kg. In some embodiments, preventing the age-associated disease or condition of the dog. In some embodiments, the effective amount is administered daily. In some embodiments, the effective amount is directed to be administered once daily for a period of at least seven days. In some embodiments, the effective amount is directed to be administered once daily for a period of at least two weeks. In some embodiments, the effective amount is directed to be administered once daily for a period of at least four weeks. In some embodiments, the effective amount is directed to be administered once daily for a period of at least one year. In some embodiments, the effective amount is directed to be administered for a period of at least seven days. In some embodiments, the effective amount is directed to be administered for a period of at least two weeks. In some embodiments, the effective amount is directed to be administered for a period of at least four weeks. In some embodiments, the effective amount is directed to be administered for a period of at least one year.

[0006] In some embodiments, the age-associated disease or condition is or comprises impaired hepatic function (including liver disease, steatosis, non-alcoholic steatohepatitis, nonalcoholic fatty liver disease, or other hepatitis), impaired renal function (including kidney failure, chronic kidney disease), impaired metabolic function, elevated blood glucose, or inflammatory conditions (including neuroinflammation, chronic inflammation, inflammaging, senescence, and senescence-associated secretory phenotype). In some embodiments, the age- associated disease or condition is or comprises an obesity-related metabolic disease or inflammation. In some embodiments, the age-associated disease or condition is or comprises metabolic syndrome. In some embodiments, the age-associated disease or condition is or comprises hyperlipidemia, hyperinsulinemia, and / or hyperglycemia. In some embodiments, the age-associated disease or condition is or comprises multimorbidity or mortality associated with accumulated functional impairments.

[0007] In some embodiments, the reducing or delaying mortality due to the age-associated metabolic disease comprises delaying progression of subclinical age-associated metabolic disease. In some embodiments, the frailty is or comprises decreased bone density, decreased musculoskeletal function, decreased locomotion, chronic inflammation, decreased appetite, acute vascular problems, incontinence, osteoarthrosis, decreased activity, hearing impairment,WSGR Docket No. 58989-730.601reduced cognitive ability, cardiomyopathy, reduced vitality, chronic respiratory disease, weakness during exercise, hepatopathy, congenital defects, neurological deficits, oral disease, weight loss (not due to diet or exercise), visual impairment, chronic digestive disease, epilepsy, disease of the hematopoietic system, episodes of disorientation, dermatological disease, chronic infectious disease, or chronic kidney disease.

[0008] In some embodiments, the reducing or delaying mortality due to the age-associated diminished quality of life comprises evaluating the quality of life of the dog via a health survey. In some embodiments, the evaluating the quality of life of the dog via the health survey is performed before, and within about a year of, the administering the effective amount of the SGLT2 inhibitor, or the pharmaceutically acceptable salt thereof, to the dog. In some embodiments, the evaluating the quality of life of the dog via the health survey is performed after, and within about a year of, the administering the effective amount of the SGLT2 inhibitor, or the pharmaceutically acceptable salt thereof, to the dog. In some embodiments, the health survey comprises an assessment of quality of life, functional impairment, disease burden, or frailty. In some embodiments, the age-associated diminished quality of life is evaluated by use of a health survey (e.g., a health survey evaluating the frailty and / or quality of life of the dog) or a measurement of a presence or level of an age-associated biomarker.

[0009] In some embodiments, the age-associated biomarker comprises a measurement or quantification of blood glucose levels, serum insulin levels, serum adiponectin levels, serum beta-hydroxybutyrate levels, or free fatty acid levels. In some embodiments, the age-associated biomarker comprises a measurement or quantification of fasted blood glucose levels, fasted serum insulin levels, fasted serum adiponectin levels, fasted serum beta-hydroxybutyrate levels, or fasted free fatty acid levels.

[0010] In some embodiments, the reducing or delaying mortality due to the age-associated disease or condition further comprises reducing reabsorption of glucose of the dog, or increasing glucose excretion of the dog. In some embodiments, the reducing or delaying mortality due to the age-associated disease or condition further comprises reducing insulin secretion of the dog, increasing insulin sensitivity of the dog, increasing glucagon / insulin ratio of the dog, increasing ketogenesis of the dog, or increasing fatty acid oxidation of the dog. In some embodiments, the reducing or delaying mortality due to the age-associated disease or condition further comprises improving the energy, mobility, or cognitive function of the dog; or reducing panting, polydipsia, or polyuria of the dog.

[0011] In some embodiments, the reducing or delaying mortality due to the age-associated disease or condition further comprises administering a restricted diet to the dog. In someWSGR Docket No. 58989-730.601embodiments, the restricted diet comprises a caloric restriction, low-fat diet, high-fat diet, high-fructose diet, high-fat / high-fructose diet, high-protein diet, or ketogenic diet. In some embodiments, the administering of the SGLT2 inhibitor, or the pharmaceutically acceptable salt thereof, is in combination with a normal or unrestricted diet.

[0012] In some embodiments, the reducing or delaying mortality due to the age-associated disease or condition further comprises increasing lifespan, wherein the increasing lifespan comprises an at least 5% increase in lifespan relative to the expected or median lifespan of a dog of the same breed. In some embodiments, the increasing lifespan comprises increasing lifespan by at least 10% relative to the expected or median lifespan of a dog of the same breed.

[0013] In some embodiments, the reducing or delaying mortality due to the age-associated disease or condition comprises mitigating or reversing insulin resistance, or increasing insulin sensitivity by at least 5% measured by an oral glucose tolerance testing assay or by measuring fasting insulin blood levels. In some embodiments, the reducing or delaying mortality due to the age-associated disease or condition comprises decreasing serum insulin levels of the dog by at least 5%. In some embodiments, the reducing or delaying mortality due to the age-associated disease or condition comprises increasing beta-hydroxybutyrate (BHB) blood concentration of the dog by at least 5%. In some embodiments, the reducing or delaying mortality due to the age-associated disease or condition comprises increasing adiponectin blood concentration of the dog by at least 5%. In some embodiments, the reducing or delaying mortality due to the age-associated disease or condition comprises mitigating or reversing an elevation of fatty acids of the dog by at least 5%.

[0014] In some embodiments, the Cmaxand / or AUC0-inf of the dog does not vary by more than 10%, 20%, 30%, or 40% when the SGLT2 inhibitor is administered to the dog in a fed state or in a fasted state. In some embodiments, the Cmaxand / or AUC0-inf does not vary by more than 30% when the SGLT2 inhibitor is administered to the dog in a fed state or in a fasted state. In some embodiments, the Cmaxand / or AUC0-inf are determined at 0.5h, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 24 hours, 48 hours, or 72 hours after the administering. In some embodiments, the Cmaxand / or AUC0-inf are determined at 0.5 to 2 hours after the administering.

[0015] In some embodiments, the administering provides a Cmaxof about 300 to about 5,000 ng / mL when the SGLT2 inhibitor is administered to the dog in a fed state or in a fasted state. In some embodiments, the administering provides a Cmaxof about 300 ng / mL to 500 ng / mL when the SGLT2 inhibitor is administered to the dog in a fed state or in a fasted state at a dose of about 0.3 mg / kg. In some embodiments, the administering provides a Cmaxof about 900WSGR Docket No. 58989-730.601ng / mL to 2000 ng / mL when the SGLT2 inhibitor is administered to the dog in a fed state or in a fasted state at a dose of about 1.0 mg / kg. In some embodiments, the administering provides a Cmaxof about 3000 ng / mL to 5000 ng / mL when the SGLT2 inhibitor is administered to the dog in a fed state or in a fasted state at a dose of about 3.0 mg / kg.

[0016] In some embodiments, the administering provides a T1 / 2 of about 9 hours to about 15 hours when the SGLT2 inhibitor is administered to the dog in a fed state or in a fasted state. In some embodiments, the administering provides a T1 / 2 of about 12 hours when the SGLT2 inhibitor is administered to the dog in a fed state or in a fasted state. In some embodiments, the dog has reached maturity.

[0017] In some embodiments, the dog is at least 7 years old. In some embodiments, the dog is at least 10 years old. In some embodiments, the SGLT2 inhibitor is administered to the dog in a fed state. In some embodiments, the SGLT2 inhibitor is administered to the dog in a fasted state. In some embodiments, the SGLT2 inhibitor is administered in combination with an additional veterinary medicine or medicament.

[0018] Also provided herein is a pharmaceutical or nutraceutical composition comprising an effective amount of an SGLT2 inhibitor for use in the reduction or delay of mortality due to an age-associated disease or disorder in a dog. In some embodiments, provided herein is a pharmaceutical or nutraceutical composition comprising an effective amount of an SGLT2 inhibitor for use in reducing or delaying mortality due to signs of aging of a dog. In some embodiments, provided herein is a pharmaceutical or nutraceutical composition comprising an effective amount of an SGLT2 inhibitor for use in extending a lifespan or a healthspan of a dog, treating or preventing an age-associated disease or condition of a dog, reducing or delaying frailty and / or mortality of a dog, or treating an age-associated diminished quality of life of a dog.

[0019] In some embodiments, the SGLT2 inhibitor is selected from the group consisting of atigliflozin, bexagliflozin, canagliflozin, dapagliflozin, empagliflozin, enavogliflozin, ertugliflozin, henagliflozin, ipragliflozin, janagliflozin, licogliflozin, luseogliflozin, mizagliflozin, remogliflozin etabonate, rongliflozin, sergliflozin etabonate, sotagliflozin, tofogliflozin, velagliflozin, and wanpagliflozin, or a pharmaceutically acceptable salt thereof. In some embodiments, the SGLT2 inhibitor is selected from the group consisting of canagliflozin, dapagliflozin, empagliflozin, and velagliflozin, or a pharmaceutically acceptable salt thereof. In some embodiments, the SGLT2 inhibitor is dapagliflozin, or a pharmaceutically acceptable salt thereof. In some embodiments, the effective amount is about 0.1 to about 5.0 mg / kg.WSGR Docket No. 58989-730.601

[0020] In some embodiments, the SGLT2 inhibitor is administered once daily for at least two weeks. In some embodiments, the SGLT2 inhibitor is administered once daily for at least four weeks. In some embodiments, the age-associated disease or condition comprises an age-associated metabolic disease.

[0021] An aspect of the present disclosure is a method of prolonging lifespan or healthspan of a dog comprising administering to the dog an effective amount of an SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof. Unless otherwise stated, the lifespan is the time from which the dog is born until the dog dies; and the healthspan is the time from which the dog is born until the dog is diagnosed with a terminal and / or degenerative disease, and / or is diagnosed or categorized as frail (e g., according to a canine frailty index or health-related quality of life index).

[0022] Another aspect relates to a method of treating or preventing an age-associated disease or condition in a dog comprising administering to the dog an effective amount of a SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof. In some embodiments, the age- associated disease or condition is or comprises an age-associated metabolic disease or age-associated diminished quality of life. In some embodiments, the age-associated metabolic disease comprises metabolic dysfunction, metabolic syndrome, or obesity-related metabolic disease. In some embodiments, the age-associated metabolic disease comprises an increase in serum glucose, an increase in serum insulin, a decrease in fat metabolism, or a decrease in serum beta-hydroxybutyrate level. In some embodiments, the age-associated diminished quality of life comprises frailty, sarcopenia, sarcopenic obesity, osteoporosis, pain, functional impairment, locomotor impairment, diminished energy or mood, or cognitive decline.

[0023] In some embodiments, the age-associated disease or condition can be or comprise, for example, loss of playfulness, loss of appetite, diminished energy or mood, joint pain, cognitive decline, frailty (e.g., sarcopenia, sarcopenic obesity, decreased bone density, decreased musculoskeletal function, decreased locomotion), and / or death by euthanasia. In some embodiments, the age-associated disease or condition is or comprises hypertension, cardiac disease, renal impairment, and / or cancer. Additional examples of age-associated diseases or conditions include impaired hepatic function (including liver disease, steatosis, non-alcoholic steatohepatitis, nonalcoholic fatty liver disease, or other hepatitis), impaired renal function (including kidney failure, chronic kidney disease), impaired metabolic function, elevated blood glucose, and inflammatory conditions (including neuroinflammation, chronic inflammation, inflammaging, senescence, and senescence-associated secretory phenotype). In some embodiments, the age-associated disease or condition is or comprises an obesity-relatedWSGR Docket No. 58989-730.601metabolic disease or inflammation. In some embodiments, the age-associated disease or condition is or comprises metabolic syndrome. In some embodiments, the age-associated disease or condition is or comprises hyperlipidemia, hyperinsulinemia, and / or hyperglycemia. In some embodiments, the method further comprises preventing the age-associated disease or condition of the dog, comprising administering to the dog a prophylactically effective amount of an SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof.

[0024] Also provided herein is a method of delaying frailty and / or mortality in a dog comprising administering to the dog an effective amount of an SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof. In some embodiments, frailty is or comprises decreased bone density, decreased musculoskeletal function, decreased locomotion, chronic inflammation, decreased appetite, acute vascular problems, incontinence, osteoarthrosis, decreased activity, hearing impairment, reduced cognitive ability, cardiomyopathy, reduced vitality, chronic respiratory disease, weakness during exercise, hepatopathy, congenital defects, neurological deficits, oral disease, weight loss (not due to diet or exercise), visual impairment, chronic digestive disease, epilepsy, disease of the hematopoietic system, episodes of disorientation, dermatological disease, chronic infectious disease, or chronic kidney disease. In some embodiments, mortality is or comprises death by euthanasia. In some embodiments, mortality is or comprises all-cause mortality. In some embodiments, mortality is or comprises death by non-cardiac and / or non-metabolic causes.

[0025] In another aspect, provided herein is a method of treating an age-associated decline in quality of life, comprising administering to the dog an effective amount of a SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof. In some embodiments, the age-associated decline in quality of life is evaluated by use of a health survey or a measurement of a presence or level of an age-associated biomarker, for example, fasting blood glucose, fasting insulin levels, adiponectin levels, and / or free fatty acid levels.

[0026] According to any one of the foregoing methods, the dog may be, for example, a healthy dog. For example, in some instances, the healthy dog is a dog that is not diagnosed with obesity and / or cardiac disease, and / or cancer. The healthy dog may be, for example, 4 years of age or older. In some embodiments, the dog has reached maturity. In some embodiments, the dog is at least 4 years old and / or has a body weight of at least about 6 pounds. In some embodiments, the dog is at least 7 years old. In some embodiments, the dog is at least 7 years old, and / or has a body weight of at least about 10 pounds. In some embodiments, the dog is at least 10 years old. In some embodiments, the dog is at least 10 years old and / or has a body weight of at least about 14 pounds. In some embodiments, theWSGR Docket No. 58989-730.601SGLT2 inhibitor is Atigliflozin, Bexagliflozin, Canagliflozin, Dapagliflozin, Empagliflozin, Enavogliflozin, Ertugliflozin, Henagliflozin, Ipragliflozin, Janagliflozin, Licogliflozin, Luseogliflozin, Mizagliflozin, Remogliflozin etabonate, Rongliflozin, Sergliflozin etabonate, Sotagliflozin, Tofogliflozin, Velagliflozin, or Wanpagliflozin, or a pharmaceutically acceptable salt thereof. In some embodiments, the SGLT2 inhibitor is selected from the group consisting of canagliflozin, dapagliflozin, empagliflozin, and velagliflozin, or a pharmaceutically acceptable salt thereof. For example, the SGLT2 inhibitor may be dapagliflozin, or a pharmaceutically acceptable salt thereof.

[0027] In some embodiments, the effective amount is a therapeutically or prophylactically effective amount. In some embodiments, the effective amount is about 1 to about 100 μg / kg. In some embodiments, the effective amount is about 0.1 to about 5.0 mg / kg. In some embodiments, the effective amount is about 1.0 to about 5.0 mg / kg. In some embodiments, the prophylactically effective amount is about 80% or less of a minimum effective dose for therapeutic activity. In some embodiments, the effective amount is provided in a dosage form of about 0.5 to about 4.5 mg. In some embodiments, the effective amount is provided in a dosage form of about 4 mg or less. In some embodiments, the effective amount is provided in a dosage form of about 3 mg or less. In some embodiments, the effective amount is administered with a frequency of: (a) once daily, (b) once every two to seven days, (c) once weekly, (d) once every 8 to 28 days, (e) once monthly, (f) once every 6 to 12 weeks, or (g) once every 3 to 6 months. In some embodiments, the effective amount is directed to be administered once daily. In some embodiments, the effective amount is directed to be administered once daily for a period of at least seven days. In some embodiments, the effective amount is directed to be administered once daily for a period of at least two weeks. In some embodiments, the effective amount is directed to be administered once daily for a period of at least three weeks. In some embodiments, the effective amount is directed to be administered once daily for a period of at least four weeks. In some embodiments, the effective amount is directed to be administered once daily for a period of at least two months, three months, six months, or twelve months. In some embodiments, the effective amount is directed to be administered once daily for a period of at least one year.

[0028] In some embodiments, the age-associated disease or condition is or comprises impaired hepatic function (including liver disease, steatosis, non-alcoholic steatohepatitis, nonalcoholic fatty liver disease, or other hepatitis), impaired renal function (including kidney failure, chronic kidney disease), impaired metabolic function, elevated blood glucose, or inflammatory conditions (including neuroinflammation, chronic inflammation, inflammaging,WSGR Docket No. 58989-730.601senescence, and senescence-associated secretory phenotype). In some embodiments, the age-associated disease or condition is or comprises an obesity-related metabolic disease or inflammation. In some embodiments, the age-associated disease or condition is or comprises metabolic syndrome. In some embodiments, the age-associated disease or condition is or comprises hyperlipidemia, hyperinsulinemia, and / or hyperglycemia. In some embodiments, the age-associated disease or condition is or comprises multimorbidity or mortality associated with accumulated functional impairments. In some embodiments, the treating or preventing the age-associated metabolic disease comprises delaying progression of subclinical age-associated metabolic disease. In some embodiments, frailty is or comprises decreased bone density, decreased musculoskeletal function, decreased locomotion, chronic inflammation, decreased appetite, acute vascular problems, incontinence, osteoarthrosis, decreased activity, hearing impairment, reduced cognitive ability, cardiomyopathy, reduced vitality, chronic respiratory disease, weakness during exercise, hepatopathy, congenital defects, neurological deficits, oral disease, weight loss (not due to diet or exercise), visual impairment, chronic digestive disease, epilepsy, disease of the hematopoietic system, episodes of disorientation, dermatological disease, chronic infectious disease, or chronic kidney disease.

[0029] Any one of the aforementioned methods may, in some embodiments, further comprise evaluating the frailty and / or quality of life of the dog by use of a health survey. In some embodiments, any one of the preceding methods may further comprise evaluating the frailty and / or quality of life of the dog by use of a health survey before and within about a year of, the administering of the effective amount of the SGLT2 inhibitor to the dog. In some embodiments, any one of the preceding methods may further comprise evaluating the frailty and / or quality of life of the dog by use of a health survey after, and within about a year of, the administering of the effective amount of the SGLT2 inhibitor to the dog.

[0030] In some embodiments, the health survey is administered within a year, within six months, within three months, within six weeks, within one month, within a week, or within a day, of the administering of the SGLT2 inhibitor – before and / or after. In some embodiments, the health survey is a canine frailty index survey or health-related quality of life survey.

[0031] In some embodiments, prolonging lifespan or healthspan comprises slowing, stopping, or reversing one or more signs of aging. In some embodiments, the signs of aging are selected from the group consisting of: decreased bone density, decreased musculoskeletal function, decreased locomotion, chronic inflammation, decreased appetite, acute vascular problems, incontinence, osteoarthrosis, decreased activity, hearing impairment, reduced cognitive ability, cardiomyopathy, reduced vitality, chronic respiratory disease, weaknessWSGR Docket No. 58989-730.601during exercise, hepatopathy, congenital defects, neurological deficits, oral disease, weight loss (not due to diet or exercise), visual impairment, chronic digestive disease, epilepsy, disease of the hematopoietic system, episodes of disorientation, dermatological disease, chronic infectious disease, or chronic kidney disease.

[0032] In some embodiments, a method provided herein further comprises the element of reducing reabsorption of glucose of the dog; and / or increasing glucose excretion of the dog; and / or improving the energy, mobility, or cognitive function of the dog; and / or reducing panting, polydipsia, and / or polyuria of the dog. In some embodiments, a method provided herein further comprises reducing insulin secretion of the dog, increasing insulin sensitivity and / or reducing insulin resistance of the dog, increasing glucagon / insulin ratio of the dog, increasing ketogenesis of the dog, and / or increasing fatty acid P-oxidation of the dog. In some embodiments, the treating or preventing the age-associated disease or condition further comprises reducing insulin secretion of the dog, increasing insulin sensitivity of the dog, increasing glucagon / insulin ratio of the dog, increasing ketogenesis of the dog, or increasing fatty acid oxidation of the dog. In some embodiments, a method provided herein further comprises administering a restricted diet (e.g., a caloric restriction, low-fat diet, high-fat diet, high-fructose diet, high-fat / high-fructose diet, high-protein diet, or ketogenic diet) to the dog within a period of about a year before, during, and / or within a period of about a year after administering the SGLT2 inhibitor. In some embodiments, the period of about a year is a period of about six months, a period of about three months, a period of about two months, a period of about one month, a period of about a week, or a period of about a day.

[0033] In some embodiments, the age-associated diminished quality of life is evaluated by use of a health survey (e.g., a health survey evaluating the frailty and / or quality of life of the dog) or a measurement of a presence or level of an age-associated biomarker. In some embodiments, the age-associated biomarker comprises a measurement or quantification of blood glucose levels, serum insulin levels, serum adiponectin levels, serum betahydroxybutyrate levels, or free fatty acid levels. In some embodiments, the administering of the SGLT2 inhibitor, or the pharmaceutically acceptable salt thereof, increases lifespan, wherein the increasing lifespan comprises an at least 5% increase in lifespan relative to the expected or median lifespan of a dog of similar species, strain, or breed. In some embodiments, increasing lifespan comprises an at least 10%, at least 15%, at least 20%, or at least 25% increase in lifespan. In some embodiments, the method further comprises mitigating or reversing insulin resistance, or increasing insulin sensitivity (by at least 5% measured by anWSGR Docket No. 58989-730.601oral glucose tolerance testing assay or by measuring fasting insulin blood levels). In some embodiments, the insulin resistance occurs from an aging process.

[0034] In some embodiments, the age-associated disease state is metabolic syndrome, insulin resistance, obesity, type II diabetes, cardiovascular disease, kidney disease, hepatic steatosis, atherosclerosis, or sarcopenia.

[0035] In some embodiments, the SGLT2 inhibitor is administered in combination with a second veterinary medicine or medicament. In some embodiments, the SGLT2 inhibitor is administered in combination with dog food (e.g., dry animal feed grade pellets, or kibble; or wet animal feed grade food, or canned food). In some embodiments, the SGLT2 inhibitor is administered in combination with a high-fat diet (e.g., comprising at least 10%, at least 15%, at least 20%, or at least 25% calories from fat), and optionally further comprising dog food (e.g., kibble or canned meat product comprising cooked meat, grain gluten, protein gels, and / or veterinary nutraceutical products).

[0036] Also provided herein is a pharmaceutical or nutraceutical composition comprising an effective amount of an SGLT2 inhibitor for use in the treatment or prevention of a disease or disorder in a dog. Another aspect provided herein is a pharmaceutical or nutraceutical composition comprising an effective amount of an SGLT2 inhibitor for use in promoting longevity of a dog, and / or in treating or preventing signs of aging of a dog.

[0037] In another aspect, provided herein are pharmaceutical or nutraceutical compositions comprising an effective amount of an SGLT2 inhibitor for use in a method of the prolonging lifespan or healthspan of a dog, preventing an age-associated disease or condition of a dog, delaying frailty and / or mortality of a dog, or treating an age-associated decline in quality of life.BRIEF DESCRIPTION OF THE DRAWINGS

[0038] FIG. 1 shows changes in urine glucose in dogs treated with placebo or SGLT2 inhibitor at baseline, day 7, and day 13.

[0039] FIG. 2 shows changes in serum glucose AUC in dogs treated with placebo or SGLT2 inhibitor at baseline, day 7, and day 13.

[0040] FIG. 3 shows serum insulin AUC in dogs treated with placebo or SGLT2 inhibitor at baseline, day 7, and day 13.

[0041] FIG. 4 shows beta-hydroxybutyrate levels in dogs treated with placebo or SGLT2 inhibitor at baseline, day 7, and day 13.WSGR Docket No. 58989-730.601

[0042] FIG. 5 shows changes in serum adiponectin in dogs treated with placebo or SGLT2 inhibitor at baseline and day 1.

[0043] FIG. 6 shows changes in urinary glucose levels in dogs treated with vehicle or varying doses of dapagliflozin at day 14 and day 28 of a four-week daily treatment.

[0044] FIG. 7 shows changes in serum glucose in dogs treated with vehicle or varying doses of dapagliflozin at days 0, 7, 14, 21, and 28 of a 28-day daily dosing study.

[0045] FIG. 8 shows glucose AUC in dogs treated with vehicle or varying doses of dapagliflozin at week 0 and week 4 of a 4-week daily dosing study.

[0046] FIG. 9 shows changes in serum insulin in dogs treated with vehicle or varying doses of dapagliflozin at days 0, 7, 14, 21, and 28 of a 28-day daily dosing study.

[0047] FIG. 10 shows insulin AUC in dogs treated with vehicle or varying doses of dapagliflozin at week 0 and week 4 of a 4-week daily dosing study.

[0048] FIG. 11 shows changes in serum beta-hydroxybutyrate (BHB) in dogs treated with vehicle or varying doses of dapagliflozin at days 0, 7, 14, 21, and 28 of a 28-day daily dosing study.

[0049] FIG. 12 shows changes in serum adiponectin in dogs treated with vehicle or varying doses of dapagliflozin at days 0, 7, 14, 21, and 28 of a 28-day daily dosing study.

[0050] FIG. 13 shows exposure (AUC) to dapagliflozin after varying doses administered to dogs in a fed state.

[0051] FIG. 14 shows exposure (AUC) to dapagliflozin after varying doses administered to dogs in a fasted state.

[0052] FIG. 15 shows urinary glucose in both fed and fasted dogs for 24 hours following varying doses of dapagliflozin.

[0053] FIG. 16 shows serum glucose in both fed and fasted dogs for 4 hours following varying doses of dapagliflozin.

[0054] FIG. 17 shows serum insulin in both fed and fasted dogs for 4 hours following varying doses of dapagliflozin.

[0055] FIG. 18 shows BHB levels in both fed and fasted dogs for 72 hours following varying doses of dapagliflozin.

[0056] FIG. 19 shows changes in fat mass, lean mass, fat mass percentage, and lean mass percentage, before and after treatment with vehicle or dapagliflozin at 4 doses.WSGR Docket No. 58989-730.601DETAILED DESCRIPTION

[0057] The present disclosure is directed, at least in part, to the discovery of compositions and methods that increase lifespan, promote longevity, and / or prevent, reduce the severity of, or delay the onset of various age-associated conditions in a dog. The compositions and methods may further improve the healthspan of the dog, which includes treating and / or preventing, reducing the severity of, or delaying the onset of an age-associated disease (particularly metabolic, inflammatory, and / or cardiovascular diseases).

[0058] Advanced age is a major risk factor for nearly every major cause of morbidity and mortality in living organisms, including dogs. Even in the absence of observable disease, the physiology of organ systems and tissues progressively declines throughout life. However, the aging process is malleable, and some interventions have been identified that can delay mortality and promote healthy lifespan (shortened herein as the term “healthspan”).

[0059] The first compelling evidence of a specific intervention that resulted in increased lifespan was the observation that reduced caloric intake significantly increased lifespan in rodents. This finding has been reproduced in dogs and in many other species including yeast, nematodes, fish, flies, and nonhuman primates. Not only is the lifespan of many organisms increased under caloric restriction, but healthspan is also improved, as measured by the reduced incidence of many age-associated morbidities. Subsequent genetic and pharmacological studies have identified specific genes and protein targets in nutrient sensing pathways that mediate the lifespan promoting benefits of reduced caloric intake.

[0060] High levels of insulin resistance and hyperinsulinemia are risk factors for age- associated disease in humans, whereas decreased levels of fasting insulin and insulin sensitivity are associated with extended lifespan. In caloric restriction (CR) studies in rodents, the CR group had less adiposity, lower fasting insulin and were more insulin sensitive. This improvement in fasting insulin and insulin sensitivity was associated with increased lifespan and healthspan. Early preclinical studies in rodents targeting insulin action and sensitivity have been shown to have a healthspan benefit while extending lifespan.

[0061] Compounds modulating nutrient-sensing pathways have been suggested to reproduce part of the beneficial effect of caloric restriction on aging. Sodium-glucose cotransporter 2 inhibitors (SGLT2) are a class of drugs that block glucose reabsorption in the kidney, resulting in higher glucose excretion through urine and lower circulating blood glucose. The lowering of blood glucose drives a metabolic shift that favors utilization of ketones and fatty acids as glucose-alternative substrates. This metabolic shift is also associated with a shift in the inflammatory pathways proposed to drive aging, overall resembling majorWSGR Docket No. 58989-730.601features of caloric restriction. Accordingly, SGLT2 inhibitors may be used to promote glucose excretion in the urine, lowering circulating blood glucose and simulating the calorically restricted state associated with increased healthspan. As a secondary effect, lowering circulating glucose levels leads to improvements in insulin sensitivity. For example, human patients receiving 10 mg of the SGLT2 inhibitor dapagliflozin for 2 weeks experienced both lower fasting plasma glucose by -24%, and lower fasting insulin by -50%.

[0062] Some animals, including dogs, have the unique ability to maintain euglycemia in the face of severe metabolic dysfunction, which is not the case in humans. The regulation of glucose homeostasis is a dynamic physiological process that can break down leading to impaired fasting glucose, pre-diabetes, and even type II diabetes in humans. One would anticipate that because SGLT2 inhibitors rely on a glucose-excretion based mechanism to mimic caloric restriction, such usage would not be effective in animals that generally do not develop hyperglycemia, such as dogs. Additionally, dogs generally do not develop the pathologies associated with hyperglycemia and those that SGLT2 inhibitors are indicated for in human populations (i.e. type 2 diabetes, coronary artery disease, diabetic nephropathy). To the contrary, it is a surprising aspect of the present invention that SGLT2 inhibitors such as dapagliflozin promote metabolic function and insulin sensitivity in dogs, leading to extended lifespan and healthspan, despite dogs not being susceptible to the hyperglycemia that the drug is proposed to target. By decreasing insulin resistance and mimicking caloric restriction in dogs (e.g., euglycemic dogs), metabolic health can be preserved and restored, resulting in fewer metabolic, inflammatory, or cardiac symptoms associated with advanced age. In some regards, a dog’s lifespan or healthy lifespan may be extended by restoring metabolic function (i.e., reducing fasting insulin, improved insulin sensitivity) and / or reducing the duration of poor metabolic health at the end of a dog’s life. In some embodiments, a dog’s lifespan or healthy lifespan may be extended by improving cardiac health (i.e., reducing cardiovascular disease or heart failure) and / or reducing the duration of poor cardiac health at the end of a dog’s life.

[0063] An aspect of the present disclosure is a method of prolonging lifespan or healthspan, promoting longevity, or delaying frailty and / or mortality of a dog, the method comprising administering to the dog an effective amount of an SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof. Another aspect of the present disclosure is a method of treating or preventing an age-associated disease or condition, treating or preventing one or more signs of aging, and / or treating or preventing an age-associated decline in the quality of life of a dog, the method comprising administering to the dog an effective amount of an SGLT2 inhibitor,WSGR Docket No. 58989-730.601or a pharmaceutically acceptable salt thereof. In some embodiments, the age-associated disease is associated with increased fasting insulin or increased insulin resistance.Definitions

[0064] The terminology used herein is for the purpose of describing particular cases only and is not intended to be limiting.

[0065] The terms “about” and “approximately” mean an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the terms “about” and “approximately” mean within 1, 2, 3, or 4 standard deviations. In certain embodiments, the terms “about” and “approximately” mean within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range. Unless otherwise specified, “about” can be interpreted as within plus or minus 10% of the value. For example, the range “about 1 to about 10 mg / kg,” may be interpreted as being as little as 0.9 mg / kg and as much as 11 mg / kg.

[0066] As used herein, unless otherwise specified, the term “all-cause mortality” may refer to the mortality rate for a population across all causes.

[0067] As used herein, the term “alkyl,” may refer to a branched or straight chain aliphatic hydrocarbon group. Whenever it appears herein, a numerical range such as “1 to 12” refers to each integer in the given range; e.g., “1 to 12 carbon atoms” means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 12 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, an alkyl is a Ci-Ce alkyl. In one aspect the alkyl is methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or t-butyl.

[0068] An “alkylene” group refers to a branched or straight chain divalent alkyl radical. Any of the above mentioned monovalent alkyl groups may be an alkylene by abstraction of a second hydrogen atom from the alkyl. In some embodiments, an alkylene is a Ci-Ce alkylene. In other embodiments, an alkylene is a C1-C4 alkylene. Typical alkylene groups include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and the like. In some embodiments, an alkylene is -CH2-. In some instances, an alkylene group is substituted by one or more substituents, in which case one or more substituents replaces the equivalent number of hydrogen atoms to complete the valency and saturation of the alkylene group.

[0069] An “alkoxy” group may refer to a -O(alkyl) group, where alkyl is as defined herein (or is C1-6 alkyl if not otherwise specified). Examples of alkoxy groups include -OCH3, -OCH2CH3, -OCH(CH3)2, -OCH2CH2CH3, -OC(CH3)3, and the like.WSGR Docket No. 58989-730.601

[0070] As used herein, the term “aryl,” may refer to a monocyclic aromatic group and / or polycyclic monovalent aromatic group that contains at least one aromatic hydrocarbon ring. In certain embodiments, the aryl has from 6 to 20 (C6-20), from 6 to 15 (C6-15), or from 6 to 10 (Ce-io) ring atoms. Examples of aryl groups include, but are not limited to, phenyl and naphthyl. Aryl also refers to bicyclic or tricyclic carbon rings, where one of the rings is aromatic and the others of which may be saturated, partially unsaturated, or aromatic, for example, dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl.

[0071] As used herein, unless otherwise specified, the term “canine frailty index” or “CFI” may refer to a model or calculated score for predicting mortality risk in dogs based on perceived frailty or disease burden. Lower CFI scores (approaching zero) indicated fewer health deficits and lower frailty, while higher CFI scores (approaching one) indicated more health deficits or higher frailty.

[0072] As used herein, unless otherwise specified, the term “dapagliflozin” may refer to the compound named “(2S,3R,4R,5S,6R)-2-(3-(4-Ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyl-tetrahydro-2H-pyran-3,4,5-triol,” or “BMS-512148,” and assigned chemical abstract service number (CAS No.) 461432-26-8. Pharmaceutically acceptable salts and solvates of the compound (e g., dapagliflozin propanediol monohydrate) are considered within the scope of the term “dapagliflozin.” The chemical structure of dapagliflozin is:H (dapagliflozin).

[0073] The terms “halo” or “halogen” as used herein, may refer to fluorine, bromine, chlorine, and / or iodine.

[0074] The term “haloalkyl,” as used herein, may refer to a linear or branched alkyl chain substituted with one or more halogen groups in place of hydrogens along the hydrocarbon chain. Examples of halogen groups suitable for substitution in the haloalkyl group include fluorine, bromine, chlorine, and iodine. Haloalkyl groups may include substitution with multiple halogen groups in place of hydrogens in an alkyl chain, wherein said halogen groups can be attached to the same carbon or to another carbon in the alkyl chain. Examples include -CH2F, -CHF2, -CF3, -CH2CI, etc.

[0075] As used herein, the term “heteroaryl” may refer to a monovalent, monocyclic or polycyclic ring structure that contains at least one ring heteroatom selected from N, O, or S (i.e., a heterocycle), and at least one fully aromatic ring: i.e., they contain 4n+2 pi electronsWSGR Docket No. 58989-730.601within the monocyclic or polycyclic ring system. The term “heteroaryl” includes bicyclic, tricyclic, and tetracyclic groups in which any of the above heteroaromatic rings is fused to one or more, aryl or carbocyclic rings, e.g., a phenyl ring or a cyclohexane ring. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrazolyl, imidazolyl, thiazolyl, indolyl, quinolinyl, tetrahydroquinolinyl, benzoimidazolyl, benzothiazolyl, benzothiophenyl, benzodioxanyl, benzopyranyl, benzoxazolyl, chromanyl. In some embodiments, the heteroaryl is any mono- or bi-cyclic group composed of 5 to 10 ring members, having at least one aromatic moiety and containing from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen (including quaternary nitrogens). The term “heteroarylene” refers to a bivalent heteroaryl group, which is substituted at two positions. By extension, the term “heteroaryltriene” refers to a trivalent heteroaryl group, which is substituted at three positions.

[0076] As used herein, the term “heterocycloalkyl,” may refer to a monovalent monocyclic, bicyclic or polycyclic ring system, which may be bridged, fused or spirocyclic, wherein at least one ring is non-aromatic and contains one, two, three, or four ring heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. Examples of heterocycloalkyl groups include pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl. Unless otherwise specified, a heterocycloalkyl group may have between 3 to 30 ring atoms. In some embodiments, a heterocycloalkyl group is a 5- or 6-membered (e.g., monocyclic) heterocycloalkyl.

[0077] As used herein, unless otherwise specified, the terms “effective amount” or “therapeutically effective amount,” may refer to a sufficient amount of an agent or a compound being administered that will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition including a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate “effective amount” in any individual case may be determined using techniques such as a dose escalation study. The term “therapeutically effective amount” includes, for example, a prophylactically effective amount. An “effective amount” of a compound disclosed herein is an amount effective to achieve a desired pharmacologic effect or therapeutic improvement. It is understood that “an effective amount” or “a therapeutically effective amount” can vary from subject to subject, due to variation in metabolism of the SGLT2 inhibitor, age, weight, general condition of the subject, theWSGR Docket No. 58989-730.601condition being treated, the severity of the condition being treated, and the judgment of the prescribing physician or veterinarian.

[0078] As used herein, unless otherwise specified, the term “frailty” may refer to a medical status or categorization wherein the subject is markedly below the median level of physical fitness for an otherwise healthy subject. Frailty may refer to a loss of muscle mass, increase of adipose tissue, decrease of respiratory, circulatory, and / or metabolic function, increase in inflammation and / or pain, or any combination thereof. Frailty generally increases with age, however its onset and severity may be modulated by use of the methods and compositions provided herein. Examples of conditions that may be encompassed by the term frailty include, but are not limited to, sarcopenia, sarcopenic obesity, decreased bone density, decreased musculoskeletal function, and / or decreased locomotion.

[0079] As used herein, unless otherwise specified, the term “Health survey” may refer to a survey, questionnaire, examination, or analysis configured to (and preferably validated for) assessing the health of a subject such as a dog. Health surveys may be administered by a medical professional, a caregiver, family member, or other qualified evaluator of the subject’s health, for example, a pet owner. Exemplary health surveys include but are not limited to the Canine Frailty Index (CFI) and Health-Related Quality of Life (HRQL) surveys described more fully herein.

[0080] As used herein, the term “functional impairment” may refer to a decline or loss of physical, sensory, and cognitive abilities that negatively impacts a dog’s daily quality of life, independence, and interaction with their environment. These changes may be manifest as a decrease in activity levels, mobility, and sensory perception (vision, hearing, smell), which may progress from normal aging to, or coexist with, chronic disease, such as osteoarthritis or canine cognitive dysfunction syndrome (CDS). Functional impairment may comprise physical deficits including decreased mobility; pain or difficulty standing, sitting, walking, or laying down; incontinence or decreased bladder control; confusion or disorientation; or diminished mood or energy. In some instances, a functional impairment may refer to an inability to perform a particular task or function. In some instances, a functional impairment may refer to an increased difficulty to perform a particular task or function.

[0081] As used herein, the term “healthspan” may refer to the part of a subject’s life during which they are generally in good health, and / or free from chronic diseases and disabilities and conditions of aging. The healthspan may be, for example, the duration of life during which the subject (e.g., a dog) is not frail and / or suffering from an age-associated disease. Accordingly, a herein-disclosed composition or method that treats, prevents, reduces the severity of, and / orWSGR Docket No. 58989-730.601delay the onset of various aging-associated conditions, as mentioned above, improves the healthspan of a mammal. In some embodiments, improving the healthspan of a mammal comprises a reduction in the incidence and / or severity of one or more age-associated diseases.

[0082] As used herein, unless otherwise specified, the term “healthy” may refer to a combination of medical status and physical fitness, wherein the subject is free from debilitating diseases and / or conditions; and wherein the subject is capable of performing physical tasks (e.g., running, climbing stairs, sitting, standing, passing waste, etc.) without hinderance or pain. In some embodiments, “healthy” refers to the fitness level of an average subject within a species or breed during youth or early adulthood, which timing may differ based on the subject. A healthy subject is neither ill nor frail.

[0083] As used herein, the term “inflammaging” may refer to the elevated levels (i.e., 1%, 2%, 3%, 4%, 5%, 10% or more) of proinflammatory biomarkers that carries high susceptibility to chronic morbidity, disability, frailty, and premature death. Inflammaging is a risk factor for cardiovascular diseases (CVDs), chronic kidney disease, diabetes mellitus, cancer, depression, dementia, and sarcopenia. Examples of proinflammatory biomarkers indicative of inflammaging include, for example, C-reactive protein (CRP), erythrocyte sedimentation rate, plasma viscosity, procalcitonin, fibrinogen, serum amyloid A, cytokines (including MCP-1, TNFa, IL-ip, IL-6, IL-8, IL-10, and IL-12).

[0084] As used herein, the term “mature” or “maturity” may refer to a mammal that is capable of sexual reproduction and / or a mammal that has achieved the height, length, and / or body mass characteristic of a dog of the same species or breed.

[0085] As used herein, the term “multimorbidity” may refer to the co-occurrence of two or more diseases (e.g., chronic diseases or long-term health conditions) within a single dog at the same time. The combination of diseases may result in premature or avoidable death, either by succumbing to one or more of the diseases, or by euthanasia. Multimorbidity may be characterized by an age-dependent accumulation of diverse pathological conditions — including but not limited to metabolic, musculoskeletal, neoplastic, and neurodegenerative disorders. The presence of multiple conditions may exert a cumulative negative impact on the subject's functional capacity and mortality risk. Multimorbidity may refer to the broad, holistic burden of multiple concurrent chronic ailments, either clinical or sub-clinical, present as a dog progresses through its geriatric life stages. Risk of multimorbidity or mortality may be assessed using a health survey such as the HRQL or CFI disclosed herein, or other health surveys suitable for assessing risk factors and quantifying disease burden. It may also be quantified byWSGR Docket No. 58989-730.601measuring one or more biomarkers of aging (including, but not limited to serum glucose, urinary glucose, serum insulin, adiponectin, beta-hydroxybutyrate, etc.).

[0086] As used herein, the term “pharmaceutically acceptable excipient” or “excipient” generally refers to an inert substance added to a pharmaceutical composition to further facilitate administration of an active ingredient, including carriers, diluents, and / or adjuvants. Formulations for parenteral administration can, for example, contain excipients such as sterile water or saline, polyalkylene glycols such as polyethylene glycol, vegetable oils, or hydrogenated naphthalene. Other exemplary excipients include, but are not limited to, calcium bicarbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, ethylene-vinyl acetate co-polymer particles, and surfactants, including, for example, polysorbate 20.

[0087] As used herein, unless otherwise specified, the terms “prevent,” “preventing,” and “prevention” generally refer to a method of delaying and / or precluding the onset of a disorder, disease, or condition, and / or its attendant symptoms; barring a subject from acquiring a disorder, disease, or condition; or reducing a subject’s risk of acquiring a disorder, disease, or condition.

[0088] As used herein, unless otherwise specified, the term “SGLT” refers to sodium-dependent glucose cotransporters (or sodium-glucose linked transporter), which are a family of glucose transporter that includes SGLT1 (found in the intestinal mucosa of the small intestine) and SGLT2 (found in the proximal renal tubule). SGLT1 and SGLT2 contribute to renal glucose reabsorption, and inhibitors of SGLT block glucose reabsorption (leading to glucose elimination via urine).

[0089] As used herein, unless otherwise specified, the term “SGLT2 inhibitor” refers to any inhibitor of SGLT2, which may be a selective inhibitor or a SGLT1 / 2 inhibitor. In some embodiments, the SGLT2 inhibitor is a gliflozin drug. In some embodiments, the SGLT2 inhibitor is atiglitlozin, bexagliflozin, canagliflozin, dapagliflozin, empagliflozin, enavogliflozin, ertugliflozin, henagliflozin, ipragliflozin, janagliflozin, licogliflozin, luseogliflozin, mizagliflozin, remogliflozin etabonate, rongliflozin, sergliflozin etabonate, sotagliflozin, tofogliflozin, velagliflozin, or wanpagliflozin, or a pharmaceutically acceptable salt thereof.

[0090] As used herein, unless otherwise specified, the terms “treat,” “treating,” “treated,” and “treatment” generally refer to therapeutic treatment, wherein the object is to prevent or slow (lessen) an undesired physiological condition, disorder, or disease, or to obtain beneficial or desired clinical results. For the purposes described herein, beneficial or desired clinicalWSGR Docket No. 58989-730.601results include, but are not limited to, alleviation of symptoms; diminishment of the extent of the condition, disorder or disease; stabilization (i.e., not worsening) of the state of the condition, disorder or disease; delay in onset or slowing of the progression of the condition, disorder or disease; amelioration of the condition, disorder or disease state; and remission (whether partial or total), whether detectable or undetectable, or enhancement or improvement of the condition, disorder or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment.Methods

[0091] One aspect of the disclosure is a method of using an SGLT2 inhibitor for promoting, maintaining, or restoring health in a dog. For example, in some embodiments, provided herein is a method of prolonging lifespan or healthspan of a dog comprising administering to the dog an effective amount of an SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof. Also provided herein is a method of treating or preventing (preferably preventing) an age-associated disease or condition in a dog comprising administering to the dog an effective amount of an SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a method of delaying frailty and / or mortality in a dog comprising administering to the dog an effective amount of an SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a method of treating an age- associated decline in quality of life of a dog, comprising administering to the dog an effective amount of an SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof.

[0092] In some embodiments, provided herein is a method of increasing lifespan in dogs by reducing or delaying mortality due to age-associated diseases, comprising administering to the dog an effective amount of an SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a method of increasing lifespan in dogs 10 years of age and older, by reducing or delaying mortality due to age-associated diseases. In some embodiments, provided herein is a method of increasing lifespan in dogs 10 years of age and older, and 14 pounds or heavier body weight by reducing or delaying mortality due to age- associated diseases. In some embodiments, provided herein is a method of increasing lifespan in dogs 10 years of age and older, and 14 pounds or heavier by reducing or delaying mortality due to age-associated diseases, comprising administering to the dog an effective amount of an SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a method of increasing lifespan or healthspan in a dog comprisingWSGR Docket No. 58989-730.601administering to the dog an effective amount of an SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a method of reducing or delaying mortality due to age-associated diseases in a dog comprising administering to the dog an effective amount of an SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a method of mimicking caloric restriction in a dog comprising administering to the dog an effective amount of an SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a method of pharmacologically inducing a caloric deficit via urinary glucose excretion in a dog independent of dietary compliance, comprising administering to the dog an effective amount of an SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a method of pharmacologically inducing a caloric deficit in a dog without inducing significant appetite suppression or weight loss comprising administering to the dog an effective amount of an SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a method of inducing diet-independent caloric restriction in a dog comprising administering to the dog an effective amount of an SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof.

[0093] In any one of the aforementioned methods, the dog may be a healthy dog (i.e., the dog does not have cancer, heart conditions, obesity, metabolic disorders, inflammatory disease, frailty, sarcopenia, or any number of other diseases disclosed herein). For example, in some embodiments, the healthy dog is not diagnosed with or suspected of having obesity and / or cardiac disease and / or cancer. In some embodiments, a “healthy” dog refers to a dog not diagnosed with cardiac disease, renal disease, hypertension, and / or metabolic disorder. In some embodiments, a “healthy” dog refers to a dog that does not have, or is not suspected of having, cardiac disease, renal disease, hypertension, and / or metabolic disorder. In some embodiments, the dog is diagnosed with or suspected of having one or more conditions disclosed herein.

[0094] In some embodiments, provided herein is a method of prolonging lifespan or healthspan of a dog comprising administering to the dog an effective amount of an SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof, wherein the lifespan is the time from which the dog is born until the dog dies; and wherein the healthspan is the time from which the dog is born until the dog is diagnosed with a terminal and / or degenerative disease, and / or is diagnosed or categorized as frail (e g., according to a canine frailty index or health-related quality of life index). In some embodiments, the age-associated decline in quality of life is measured or characterized according to one or more of the following diminished quality of life metrics:WSGR Docket No. 58989-730.6011. Assistance when standing up 18. Chronic inflammation2. Decreased appetite 19. Acute vascular problems3. Assistance when eating 20. Cancer4. Incontinence 21. Diabetes5. Assistance when climbing stairs 22. Osteoarthrosis6. Decreased activity over the last year 23. Hearing impairment7. Reduced cognitive ability 24. Cardiomyopathy8. Reduced vitality over the last year 25. Chronic respiratory disease9. Weakness during exercise 26. Hepatopathy10. Congenital defects 27. Neurological deficits11. Weight loss (not due to diet or exercise) 28. Disease of the oral cavity12. Signs or symptoms of pain 29. Visual impairment13. Chronic therapies 30. Chronic digestive disease14. Epilepsy 31. Disease of the hematopoietic system 15. Episodes of disorientation 32. Dermatological disease16. Chronic infectious disease 33. Chronic kidney disease17. Endocrine disease

[0095] In some embodiments, the quality of life of a dog is measured or evaluated on a numeric scale, or as a positive / negative response. In some embodiments, the methods provided herein comprise improving or reversing one or more metrics of diminished quality of life, or preventing an increase of one or more metrics of diminished quality of life. In some embodiments, an improvement in the quality of life of the dog (i.e., as determined by one or more of the quality-of-life metrics provided herein or known in the field) is directly correlated with an increase in the lifespan or healthspan of the dog. In some embodiments, provided herein is a method of extending heathy years of life of a dog comprising improving one or more quality of life metrics of the dog (e.g., as reported by an owner or clinician via a tool such as a health survey).

[0096] In some embodiments, the age-associated decline in quality of life, or the age- associated disease or condition, comprises one or more functional impairments. In some embodiments, the functional impairment comprises a necessity for assistance when standing up, necessity for assistance when eating, necessity for assistance with urination or defecation, necessity' for assistance with walking or climbing stairs, decreased activity over the past year, reduced cognitive ability, reduced vitality, weakness, pain, disorientation, inflammation, hearing impairment, visual impairment, or neurological deficits. In some embodiments, theWSGR Docket No. 58989-730.601method comprises minimizing or mitigating effects of pathological aging. In some embodiments, the method comprises slowing or preventing physiological decline associated with aging. In some embodiments, the effects of pathological aging include cancer, dementia, canine cognitive decline, musculoskeletal diseases such as osteoarthritis, chronic kidney disease, cardiovascular disease, metabolic disorders, sensory defects, neurological disorders, or chronic gastrointestinal disorders.

[0097] In some embodiments, provided herein is a method of treating or preventing (preferably preventing) an age-associated disease or condition in a dog comprising administering to the dog an effective amount of an SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof, wherein the age-associated disease or condition is or comprises loss of playfulness, loss of appetite, diminished energy or mood, joint pain, cognitive decline (e.g., forgetfulness, confusion), frailty (e.g., sarcopenia, sarcopenic obesity, decreased bone density, decreased musculoskeletal function, decreased locomotion), and / or death by euthanasia. In some embodiments, the age-associated disease or condition is or comprises frailty (e.g., sarcopenia, sarcopenic obesity, decreased bone density, decreased musculoskeletal function, decreased locomotion), and / or death by euthanasia. In some embodiments, the age-associated disease or condition is or comprises sarcopenia, sarcopenic obesity, or osteoporosis. In some embodiments, the age-associated disease or condition is or comprises hypertension, cardiac disease, renal impairment, and / or cancer.

[0098] In some embodiments, the age-associated disease or condition is or comprises impaired hepatic function (including liver disease, steatosis, non-alcoholic steatohepatitis, nonalcoholic fatty liver disease, or other hepatitis), impaired renal function (including kidney failure, chronic kidney disease), impaired metabolic function, elevated blood glucose, or inflammatory conditions (including neuroinflammation, chronic inflammation, inflammaging, senescence, and senescence-associated secretory phenotype). In some embodiments, the age-associated disease or condition is or comprises impaired metabolic function, elevated blood glucose, or inflammatory conditions. In some embodiments, the age-associated disease or condition is or comprises neuroinflammation, chronic inflammation, inflammaging, senescence, and senescence-associated secretory phenotype. In some embodiments, the age- associated disease or condition is or comprises neuroinflammation. In some embodiments, the age-associated disease or condition is or comprises chronic inflammation. In some embodiments, the age-associated disease or condition is or comprises inflammaging. In some embodiments, the age-associated disease or condition is or comprises senescence. In some embodiments, the age-associated disease or condition is or comprises senescence-associatedWSGR Docket No. 58989-730.601secretory phenotype. In some embodiments, the age-associated disease or condition is or comprises an obesity-related metabolic disease or inflammation. In some embodiments, the age-associated disease or condition is or comprises heart and / or kidney aging. In some embodiments, the age-associated disease or condition is or comprises heart and / or kidney aging.

[0099] In some embodiments, the age-associated disease or condition is or comprises metabolic syndrome. In some embodiments, the age-associated disease or condition is or comprises hyperlipidemia, hyperinsulinemia, and / or hyperglycemia. In some embodiments, the age-associated disease or condition is or comprises hyperlipidemia. In some embodiments, the age-associated disease or condition is or comprises hyperinsulinemia. In some embodiments, the age-associated disease or condition is or comprises hyperglycemia. In some embodiments, the age-associated disease or condition is a metabolic disease or disorder wherein the subject is euglycemic. In some embodiments, the metabolic disease or disorder is obesity, type II diabetes, hyperinsulinemia, or insulin resistance. In some embodiments, the age-associated disease or condition is or comprises an age-associated metabolic disease. In some embodiments, the age-associated metabolic disease comprises an increase in serum glucose (e.g., an increase in serum glucose as a function or result of aging). In some embodiments, the age-associated metabolic disease comprises an increase in serum insulin (e.g., an increase in serum insulin as a function or result of aging). In some embodiments, the age-associated metabolic disease comprises a decrease in insulin sensitivity (e.g., a decrease in insulin sensitivity as a function or result of aging). In some embodiments, the age-associated metabolic disease comprises a decrease in insulin sensitivity (e.g., a decrease in insulin sensitivity as a function or result of aging). In some embodiments, the age-associated metabolic disease comprises a decrease in fat oxidation or ketosis (e.g., a decrease in fat oxidation or ketosis as a function or result of aging). In some embodiments, the age-associated metabolic disease comprises a decrease in serum levels of beta-hydroxybutyrate (BHB) (e.g., a decrease in BHB levels as a function or result of aging).

[0100] In some embodiments, provided herein is a method of promoting ketosis or fat oxidation in a dog, the method comprising administering to the dog an effective amount of an SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof. In some embodiments, the method of promoting ketosis or fat oxidation comprises increasing serum levels of beta-hydroxybutyrate (BHB). In some embodiments, provided herein is a method of increasing lifespan or reducing / delaying mortality due to age-associated diseases, comprising increasing serum levels of beta-hydroxybutyrate (BHB). In some embodiments, provided herein is aWSGR Docket No. 58989-730.601method of increasing lifespan or reducing / delaying mortality due to age-associated diseases, comprising increasing serum levels of beta-hydroxybutyrate (BHB) by administration of an SGLT2 inhibitor.

[0101] In some embodiments, provided herein is a method of delaying frailty and / or mortality in a dog comprising administering to the dog an effective amount of an SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof, wherein the frailty is or comprises decreased bone density, decreased musculoskeletal function, decreased locomotion, chronic inflammation, decreased appetite, acute vascular problems, incontinence, osteoarthrosis, decreased activity, hearing impairment, reduced cognitive ability, cardiomyopathy, reduced vitality, chronic respiratory disease, weakness during exercise, hepatopathy, congenital defects, neurological deficits, oral disease, weight loss (not due to diet or exercise), visual impairment, chronic digestive disease, epilepsy, disease of the hematopoietic system, episodes of disorientation, dermatological disease, chronic infectious disease, or chronic kidney disease.

[0102] In some embodiments, the mortality is or comprises death by euthanasia. In some embodiments, the mortality is or comprises all-cause mortality. In some embodiments, the mortality is or comprises death by non-cardiac and / or non-metabolic causes. In some embodiments, provided herein is a method of promoting cardioprotective effects, reducing cardiac or cardiovascular disease, reducing heart failure, or increasing cardiac / cardiovascular health in a dog, the method comprising administering to the dog an SGLT2 inhibitor provided herein. In some embodiments, the method further comprises any one or more of promoting diuresis and / or natriuresis, reducing blood pressure, promoting erythropoiesis, improving cardiac energy metabolism, reducing inflammation, inhibiting sympathetic nervous system activity, preventing adverse cardiac remodeling, preventing ischemia and / or reperfusion injury, inhibiting Na+ / H+-exchange, inhibiting SGLT1, reducing hyperuricemia, increasing autophagy and lysosomal degradation, decreasing epicardial fat mass, increasing erythropoietin levels, increasing circulating pro-vascular progenitor cells, decreasing oxidative stress, and / or improving vascular function. In some embodiments, the promoting cardioprotective effects comprises reducing blood pressure or improving vascular function of the dog. In some embodiments, the method comprises reducing blood pressure of the dog. In some embodiments, the method comprises reducing vascular function of the dog. In some embodiments, the reducing blood pressure of the dog comprises reducing the blood pressure by about 1% to about 35%, 1% to about 30%, 1% to about 25%, 1% to about 20%, 1% to about 15%, 1% to about 10%, 1% to about 9%, 1% to about 8%, 1% to about 7%, 1% to about 6%, or 1% to about 5%. In some embodiments, the reducing blood pressure of the dog comprisesWSGR Docket No. 58989-730.601reducing the blood pressure by about 5% to about 35%, about 5% to about 30%, about 5% to about 25%, about 5% to about 20%, about 5% to about 15%, about 5% to about 10%, about 10% to about 35%, about 10% to about 30%, about 10% to about 25%, about 10% to about 20%, about 10% to about 15%, about 15% to about 35%, 15% to about 30%, or about 15% to about 25%. In some embodiments, the reducing blood pressure comprises reducing the blood pressure to a clinically appropriate level for the age and breed or size of the dog.

[0103] In some embodiments, provided herein is a method of preventing, delaying, halting, reversing, or treating renal disease in a dog, the method comprising administering to the dog an effective amount of an SGLT2 inhibitor compound provided herein. In some embodiments, the renal disease is kidney failure or chronic kidney disease (CKD). In some embodiments, the renal disease is selected from renal dysplasia, glomerulopathy, polycystic kidney disease, amyloidosis, tubulo-nephritis / tubulointerstitial nephritis (TIN), acute kidney disease, and chronic kidney disease. In some embodiments, the method comprises reducing mortality and / or morbidity due to renal dysfunction.

[0104] In any of the preceding embodiments, the SGLT2 inhibitor may be from the ‘flozin class of drugs. For example, in some embodiments, the method comprises administering an effective amount of an SGLT2 inhibitor that is Atigliflozin, Bexagliflozin, Canagliflozin, Dapagliflozin, Empagliflozin, Enavogliflozin, Ertugliflozin, Henagliflozin, Ipragliflozin, Janagliflozin, Licogliflozin, Luseogliflozin, Mizagliflozin, Remogliflozin etabonate, Rongliflozin, Sergliflozin etabonate, Sotagliflozin, Tofogliflozin, Velagliflozin, or Wanpagliflozin, or a pharmaceutically acceptable salt thereof, to a dog. In some embodiments, the SGLT2 inhibitor is Canagliflozin. In some embodiments, the SGLT2 inhibitor is Dapagliflozin. In some embodiments, the SGLT2 inhibitor is Empagliflozin.

[0105] In any of the preceding embodiments, the effective amount may be a therapeutically or prophylactically effective amount.

[0106] In some embodiments, provided herein is a method of preventing an age-associated disease or condition in a dog comprising administering to the dog a prophylactically effective amount of the SGLT2 inhibitor, or the pharmaceutically acceptable salt thereof.

[0107] In some embodiments, the effective amount is about 1 μg / kg to about 5.0 mg / kg. In some embodiments, the effective amount is about 1 to about 100 μg / kg. In some embodiments, the effective amount is about 20 to about 100 μg / kg. In some embodiments, the effective amount is about 50 to about 100 μg / kg. In some embodiments, the effective amount is about 0.1 to about 1.0 mg / kg. In some embodiments, the effective amount is about 0.1 to about 2.0 mg / kg. In some embodiments, the effective amount is about 0.1 to about 3.0 mg / kg. In someWSGR Docket No. 58989-730.601embodiments, the effective amount is about 0.1 to about 4.0 mg / kg. In some embodiments, the effective amount is about 0.1 to about 5.0 mg / kg. In some embodiments, the effective amount is about 0.3 mg / kg to about 1.0 mg / kg. In some embodiments,> the effective amount is about 0.3 mg / kg to about 2.0 mg / kg. In some embodiments, the effective amount is about 0.3 mg / kg to about 3.0 mg / kg. In some embodiments, the effective amount is about 0.3 mg / kg to about 4.0 mg / kg. In some embodiments, the effective amount is about 0.3 mg / kg to about 5.0 mg / kg. In some embodiments, the effective amount is about 0.5 mg / kg to about 1.0 mg / kg. In some embodiments, the effective amount is about 0.5 mg / kg to about 1.5 mg / kg. In some embodiments, the effective amount is about 0.5 mg / kg to about 2.0 mg / kg. In some embodiments, the effective amount is about 0.5 mg / kg to about 2.5 mg / kg. In some embodiments, the effective amount is about 0.5 mg / kg to about 3.0 mg / kg. In some embodiments,effective amount is about 0.5 mg / kg to about 4.0 mg / kg. In some embodiments, the effective amount is about 0.5 mg / kg to about 5.0 mg / kg.

[0108] In some embodiments, the effective amount is about 0.1 mg / kg. In some embodiments, the effective amount is about 0.3 mg / kg. In some embodiments, the effective amount is about 0.5 mg / kg. In some embodiments, the effective amount is about 1.0 mg / kg. In some embodiments, the effective amount is about 2.0 mg / kg. In some embodiments, the effective amount is about 3.0 mg / kg. In some embodiments, the effective amount is about 4.0 mg / kg. In some embodiments, the effective amount is about 5.0 mg / kg. In some embodiments, the effective amount is about 1.0 mg / kg to about 2.0 mg / kg. In some embodiments, the effective amount is about 1.0 mg / kg to about 3.0 mg / kg. In some embodiments, the effective amount is about 1.0 mg / kg to about 4.0 mg / kg. In some embodiments, the effective amount is about 1.0 mg / kg to about 5.0 mg / kg. In some embodiments, the effective amount is at least about 5.0 mg / kg. In some embodiments, the effective amount is about 0.1 mg / kg to about 20 mg / kg. In some embodiments, the effective amount is about 1 mg / kg to about 5 mg / kg. In some embodiments, the effective amount is about 1 mg / kg to about 10 mg / kg. In some embodiments, the effective amount is about 10 mg / kg to about 20 mg / kg. In some embodiments, the effective amount is about 5 mg / kg to about 50 mg / kg.

[0109] In some embodiments, the prophylactically effective amount is about 80% or less of a minimum effective dose for therapeutic activity.

[0110] In some embodiments, the effective amount is provided in a dosage form of about 0.5 to about 4.5 mg. In some embodiments, the effective amount is provided in a dosage form of about 0.5 to about 4.0 mg. In some embodiments, the effective amount is provided in a dosage form of about 0.5 to about 3.5 mg. In some embodiments, the effective amount is provided inWSGR Docket No. 58989-730.601a dosage form of about 0.5 to about 3.0 mg. In some embodiments, the effective amount is provided in a dosage form of about 0.5 to about 2.5 mg. In some embodiments, the effective amount is provided in a dosage form of about 0.5 to about 2.0 mg. In some embodiments, the effective amount is provided in a dosage form of about 0.5 to about 1.5 mg. In some embodiments, the effective amount is provided in a dosage form of about 0.5 to about 1.0 mg.

[0111] In some embodiments, the effective amount is provided in a dosage form of about 1 mg to about 5 mg. In some embodiments, the effective amount is provided in a dosage form of about 1 mg to about 4 mg. In some embodiments, the effective amount is provided in a dosage form of about 1 mg to about 3 mg. In some embodiments, the effective amount is provided in a dosage form of about 1 mg to about 2 mg. In some embodiments, the effective amount is provided in a dosage form of about 1 mg. In some embodiments, the effective amount is provided in a dosage form of about 2 mg to about 5 mg. In some embodiments, the effective amount is provided in a dosage form of about 2 mg to about 4 mg. In some embodiments, the effective amount is provided in a dosage form of about 2 mg to about 3 mg. In some embodiments, the effective amount is provided in a dosage form of about 2 mg. In some embodiments, the effective amount is provided in a dosage form of about 4 mg or less. In some embodiments, the effective amount is provided in a dosage form of about 3 mg or less. In some embodiments, the effective amount is provided in a dosage form of at least about 0.1 mg. In some embodiments, the effective amount is provided in a dosage form of at least about 1.0 mg. In some embodiments, the effective amount is provided in a dosage form of at least about 2.0 mg.

[0112] In some embodiments, the effective amount is administered once daily. In some embodiments, the effective amount is administered once every' other day. In some embodiments, the effective amount is administered once every 3 days. In some embodiments, the effective amount is administered once every 4 days. In some embodiments, the effective amount is administered once every 5 days. In some embodiments, the effective amount is administered once weekly. In some embodiments, the effective amount is administered once every’ 8 to 28 days. In some embodiments, the effective amount is administered once every 8 days. In some embodiments, the effective amount is administered once every' 10 days. In some embodiments, the effective amount is administered once every 14 days. In some embodiments, the effective amount is administered once every 21 days. In some embodiments, the effective amount is administered once every 28 days. In some embodiments, the effective amount is administered once monthly. In some embodiments, the effective amount is administered once every 6 weeks. In some embodiments, the effective amount is administered once every 12WSGR Docket No. 58989-730.601weeks. In some embodiments, the effective amount is administered once every 3 months. In some embodiments, the effective amount is administered once every 6 months. In some embodiments, the effective amount is administered once every year. In some embodiments, the effective amount is administered via a controlled or extended release drug delivery formulation or device. In some embodiments, the effective amount of the SGLT2 inhibitor is administered over a period of about seven days to about six months from an extended-release formulation, controlled release formulation, or implantable drug delivery device. In some embodiments, the effective amount of the SGLT2 inhibitor is administered over a period of at least about 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, or more. In some embodiments, the effective amount of the SGLT2 inhibitor is administered over a period of at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or more. In some embodiments, the effective amount of the SGLT2 inhibitor is administered over a period of at least about 2 weeks or more. In some embodiments, the effective amount of the SGLT2 inhibitor is administered over a period of at least about 4 weeks or more. In some embodiments, the effective amount of the SGLT2 inhibitor is administered over a period of at least about 6 weeks or more. In some embodiments, the effective amount of the SGLT2 inhibitor is administered over a period of at least about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, or more. In some embodiments, the effective amount of the SGLT2 inhibitor is administered over a period of at least about 1 month or more. In some embodiments, the effective amount of the SGLT2 inhibitor is administered over a period of at least about 2 months or more. In some embodiments, the effective amount of the SGLT2 inhibitor is administered over a period of at least about 3 months or more. In some embodiments, the effective amount of the SGLT2 inhibitor is administered over a period of at least about 6 months or more. In some embodiments, the effective amount of the SGLT2 inhibitor is administered over a period of at least about a year, or more. In some embodiments, the effective amount of the SGLT2 inhibitor is administered over a period of at least about 2 years, or more. In some embodiments, the effective amount of the SGLT2 inhibitor is administered over a period of at least about 3 years, or more. In some embodiments, the effective amount of the SGLT2 inhibitor is administered over a period of at least about 4 years, or more. In some embodiments, the effective amount of the SGLT2 inhibitor is administered over a period of at least about 5 years, or more. In some embodiments, the effective amount of the SGLT2 inhibitor is administered over a period of atWSGR Docket No. 58989-730.601least about 8 years, or more. In some embodiments, the effective amount of the SGLT2 inhibitor is administered over a period of at least about 10 years, or more.

[0113] In some embodiments, provided herein is a method of prolonging lifespan or healthspan of a dog; treating or preventing an age-associated disease or condition in a dog; delaying frailty and / or mortality in a dog; or treating an age-associated decline in quality of life of a dog; the method comprising administering to the dog an effective amount of an SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a health survey. In some embodiments, the health survey is administered before the administering of the effective amount of the SGLT2 inhibitor. In some embodiments, the health survey is administered after the administering of the effective amount of the SGLT2 inhibitor. In some embodiments, the health survey is administered both before and after the administering of the effective amount of the SGLT2 inhibitor. In some embodiments, the health survey is administered within about a year of the administering of the effective amount of the SGLT2 inhibitor.

[0114] In some embodiments, the method comprises evaluating the frailty and / or quality of life of the dog by use of a health survey. In some embodiments, the method comprises evaluating the frailty and / or quality of life of the dog by use of a health survey before and within about a year of the administering of the effective amount of the SGLT2 inhibitor to the dog. In some embodiments, the method comprises evaluating the frailty and / or quality of life of the dog by use of a health survey after, and within about a year of, the administering of the effective amount of the SGLT2 inhibitor to the dog.

[0115] In some embodiments, the methods disclosed herein comprise evaluating the frailty and / or quality of life of the dog by use of a health survey within about a year of (before and / or after), the administering of the effective amount of the SGLT2 inhibitor to the dog. In some embodiments, the method comprises evaluating the frailty and / or quality of life of the dog by use of a health survey within about six months of (before and / or after) the administering of the effective amount of the SGLT2 inhibitor to the dog. In some embodiments, the method comprises evaluating the frailty and / or quality of life of the dog by use of a health survey within about three months of (before and / or after) the administering of the effective amount of the SGLT2 inhibitor to the dog. In some embodiments, the method comprises evaluating the frailty and / or quality of life of the dog by use of a health survey within about six weeks of (before and / or after) the administering of the effective amount of the SGLT2 inhibitor to the dog. In some embodiments, the method comprises evaluating the frailty and / or quality of life of the dog by use of a health survey within about a month of (before and / or after) the administering of the effective amount of the SGLT2 inhibitor to the dog. In some embodiments, the methodWSGR Docket No. 58989-730.601comprises evaluating the frailty and / or quality of life of the dog by use of a health survey within about a week of (before and / or after) the administering of the effective amount of the SGLT2 inhibitor to the dog. In some embodiments, the method comprises evaluating the frailty and / or quality of life of the dog by use of a health survey within about one to 28 days of (before and / or after) the administering of the effective amount of the SGLT2 inhibitor to the dog. In some embodiments, the health survey is administered within a year, within six months, within three months, within six weeks, within one month, within a week, or within a day of the administering of the SGLT2 inhibitor - before and / or after. In some embodiments, the health survey is a canine frailty index survey or health-related quality of life survey.

[0116] In some embodiments, provided herein is a method of treating an age-associated decline in quality of life of a dog comprising administering to the dog an effective amount of an SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof, wherein the age-associated decline in quality of life is evaluated by use of a health survey or a measurement of a presence or level of an age-associated biomarker.

[0117] In some embodiments, provided herein is a method of treating an age-associated decline in quality of life of a dog comprising administering to the dog an effective amount of an SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof, wherein the age-associated decline in quality of life is evaluated by use of a health survey evaluating the frailty and / or quality of life of the dog. In some embodiments, provided herein is a method of treating an age-associated decline in quality of life of a dog comprising administering to the dog an effective amount of an SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof, wherein the age-associated decline in quality of life is evaluated by use of a measurement of a presence or level (amount, concentration) of an age-associated biomarker. In some embodiments, provided herein is a method of treating an age-associated decline in quality of life of a dog comprising administering to the dog an effective amount of an SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof, wherein the age-associated decline in quality of life is evaluated by use of a measurement of an amount or concentration of fasting blood glucose, fasting insulin levels, adiponectin levels, and / or free fatty acid levels. In some embodiments, the age-associated decline in quality of life is evaluated by measurement of an amount or concentration of fasting insulin levels. In some embodiments, the age-associated decline in quality of life is evaluated by measurement of an amount or concentration of fasting blood glucose. In some embodiments, the age-associated decline in quality of life is evaluated by measurement of an amount or concentration of adiponectin. In some embodiments, the age-WSGR Docket No. 58989-730.601associated decline in quality of life is evaluated by measurement of an amount or concentration of fatty acid levels.

[0118] In some embodiments, provided herein is a method of prolonging lifespan or healthspan of a dog comprising administering to the dog an effective amount of an SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof, wherein the prolonging lifespan or healthspan comprises slowing, stopping, or reversing one or more signs of aging. Signs of aging include, for example, decreased bone density or osteoporosis, decreased musculoskeletal function, decreased locomotion, chronic inflammation, decreased appetite, acute vascular problems, incontinence, osteoarthrosis, decreased activity, hearing impairment, reduced cognitive ability, cardiomyopathy, reduced vitality, chronic respiratory disease, weakness during exercise, hepatopathy, congenital defects, neurological deficits, oral disease, weight loss (not due to diet or exercise), visual impairment, chronic digestive disease, epilepsy, disease of the hematopoietic system, episodes of disorientation, dermatological disease, chronic infectious disease, or chronic kidney disease. In some embodiments, the one or more signs of aging is osteoporosis, osteoarthrosis, sarcopenia, or sarcopenic obesity.

[0119] Any one of the preceding methods may further comprise reducing reabsorption of glucose of the dog; and / or increasing glucose excretion of the dog; and / or improving the energy, mobility, or cognitive function of the dog; and / or reducing panting, polydipsia, and / or polyuria of the dog. In some embodiments, any one of the preceding methods may further comprise reducing reabsorption of glucose of the dog; and / or increasing glucose excretion of the dog. In some embodiments, any one of the preceding methods may further comprise improving the energy, mobility, or cognitive function of the dog.

[0120] Any one of the preceding methods may further comprise reducing insulin secretion of the dog, increasing insulin sensitivity and / or reducing insulin resistance of the dog. In some embodiments, the method comprises reducing insulin secretion of the dog. In some embodiments, the administering of the SGLT2 inhibitor, or the pharmaceutically acceptable salt thereof, increases insulin sensitivity of the dog. In some embodiments, the administering of the SGLT2 inhibitor, or the pharmaceutically acceptable salt thereof, reduces insulin resistance of the dog.

[0121] Any one of the preceding methods may further comprise increasing glucagon / insulin ratio of the dog, increasing ketogenesis of the dog, and / or increasing fatty acid P-oxidation of the dog. In some embodiments, provided herein is a method of using an SGLT2 inhibitor for treating dogs as disclosed herein, further comprising increasing ketogenesis of the dog. In someWSGR Docket No. 58989-730.601embodiments, the administering of the SGLT2 inhibitor, or the pharmaceutically acceptable salt thereof, increases glucagon / insulin ratio of the dog.

[0122] In some embodiments, any one of the preceding methods may further comprise administering a restricted diet to the dog. In some embodiments, the restricted diet is administered within a period of about a year before the administering of the SGLT2 inhibitor. In some embodiments, the restricted diet is administered within a period of about a year after the administering of the SGLT2 inhibitor. In some embodiments, the restricted diet is administered concurrently with the administering of the SGLT2 inhibitor. In some embodiments, the restricted diet comprises a calorically restricted diet, low-fat diet, high-fat diet, high-fructose diet, high-fat / high-fructose diet, high-protein diet, or ketogenic diet. In some embodiments, the restricted diet comprises a calorically restricted diet. In some embodiments, the restricted diet comprises a high-fat diet. In some embodiments, the restricted diet comprises a high-fat / high-fructose diet. In some embodiments, the restricted diet comprises a high-protein diet. In some embodiments, the restricted diet comprises a ketogenic diet.

[0123] In some embodiments, provided herein is a method disclosed herein further comprising administering a restricted diet within a period of about six months, before the administering of the SGLT2 inhibitor. In some embodiments, the restricted diet is administered within a period of about three months, a period of about two months, a period of about one month, a period of about a week, or a period of about a day before the administering of the SGLT2 inhibitor.

[0124] Any one of the preceding methods may further comprise increasing lifespan, wherein the increasing lifespan comprises an at least 5% increase in lifespan relative to the expected or median lifespan of a dog of similar species, strain, or breed. In some embodiments, increasing lifespan comprises an at least 10%, at least 15%, at least 20%, or at least 25% increase in lifespan relative to the expected or median lifespan of a dog of similar species, strain, or breed. In some embodiments, increasing lifespan comprises an at least 1%, 2%, 3%, or 4% increase in lifespan relative to the expected or median lifespan of a dog of similar species, strain, or breed.

[0125] Any one of the preceding methods may further comprise mitigating or reversing insulin resistance in the dog. In some embodiments, the insulin resistance occurs from an aging process. In some embodiments, the insulin resistance is age-induced insulin resistance in dogs.

[0126] In some embodiments, any one of the preceding methods may further comprise mitigating or reversing an elevation of fatty acids in the dog. In some embodiments, the elevation of fatty acids comprises an elevation of free fatty acid levels in plasma. In someWSGR Docket No. 58989-730.601embodiments, the elevation of fatty acids is associated with an age-associated disease state. In some embodiments, the age-associated disease state is metabolic syndrome, insulin resistance, obesity, type II diabetes, cardiovascular disease, kidney disease, hepatic steatosis, atherosclerosis, or sarcopenia.

[0127] In some embodiments, provided herein is a method of treating and / or preventing metabolic syndrome, insulin resistance, obesity, type II diabetes, cardiovascular disease, kidney disease, hepatic steatosis, atherosclerosis, or sarcopenia in a dog, the method comprising administering to the dog an effective amount of an SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of an SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a method of treating and / or preventing metabolic syndrome, insulin resistance, obesity, obesity-related metabolic disease, atherosclerosis, or sarcopenia in a dog, the method comprising administering to the dog an effective amount of an SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of an SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof. In some embodiments, the SGLT2 inhibitor is a gliflozin compound, or a pharmaceutically acceptable salt thereof. In some embodiments, the SGLT2 inhibitor is canagliflozin, dapagliflozin, empagliflozin, or velagliflozin, or a pharmaceutically acceptable salt thereof. In some embodiments, the SGLT2 inhibitor is dapagliflozin, or a pharmaceutically acceptable salt thereof.

[0128] In some embodiments, the SGLT2 inhibitor has the structure of Formula (I):R4Formula (I)or a pharmaceutically acceptable salt, solvate, or salt of a solvate, wherein:m is 0, 1, 2, 3, or 4;ring B is C6aryl or 5- to 10-membered heterocyclyl (i.e., heteroaryl or heterocycloalkyl);X is -O- or -S-;Rlais -Ci-3 hydroxyalkyl or -SCH3;each of Rlb, R2, R3, and R4is independently hydrogen, halogen, -CN, or -OR7;WSGR Docket No. 58989-730.601or Rlband R2together form a 5 -membered heterocycloalkyl ring, and R3and R4are each independently hydrogen, halogen, -CN, or -OR7;or R1b, and R2are each independently hydrogen, halogen, -CN, or -OR7, and R3and R4together form a 5-membered heterocycloalkyl ring;or Rlb, and R4are each independently hydrogen, halogen, -CN, or -OR7, and R2and R3together form a 5-membered heterocycloalkyl ring;R5is hydrogen, halogen, -CN, C1-3 alkyl, C1-3 haloalkyl, C1-3 deuteroalkyl, or C1-3 alkoxy;R6is hydrogen, halogen, -CN, OR7, C1-3 alkyl, C3-6 cycloalkyl, Ce aryl, 5-membered heterocycloalkyl, or 5- or 6-membered heteroaryl; or, two R6on adjacent atoms form a C3-6 cycloalkyl, Ce aryl, 5- or 6-membered heterocycloalkyl, or a 5- or 6- membered heteroaryl; wherein each C1-3 alkyl, C3-6 cycloalkyl, Ce aryl, 5- membered heterocycloalkyl, or 5- or 6-membered heteroaryl is optionally substituted with 1, 2, 3, or 4 R8;R7is hydrogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 deuteroalkyl, C3-6 cycloalkyl, -C1-3 alkylene-O-Ci-3 alkyl or -C1-3 alkylene-O-Cs-e cycloalkyl; andR8is halogen, -CN, -OH, -C1-3 alkoxy, C1-3 alkyl, or two R8together form a C3-6 cycloalkyl or 5- or 6-membered heterocycloalkyl.

[0129] In some embodiments, the SGLT2 inhibitor has the structure of Formula (I), or a pharmaceutically acceptable salt, solvate, or salt of a solvate, wherein:m is 0, 1, or 2;ring B is phenyl, thiophenyl, benzothiophenyl, or benzodioxanyl;X is -O- or -S-;Rlais -CH2OH, -CH(CH3)OH or -SCH3;each of Rlb, R2, R3, and R4is independently hydrogen, halogen, -CN, or -OR7; or Rlband R2together form a 5 -membered heterocycloalkyl ring, and R3and R4are each hydrogen;or Rlband R2are each hydrogen, and R3and R4together form a 5 -membered heterocycloalkyl ring;or R,band R4are each hydrogen, and R2and R3together form a 5 -membered heterocycloalkyl ring;R’ is hydrogen, halogen, -CN, or C1-3 alkyl;WSGR Docket No. 58989-730.601R6is hydrogen, halogen, -CN, OR7, C1-3 alkyl, C3-6 cycloalkyl, or C6 aryl; or, two R6on adjacent atoms form a C3-6 cycloalkyl, Ce aryl, 5- or 6-membered heterocycloalkyl, or a 5- or 6-membered heteroaryl;R7is hydrogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 deuteroalkyl, C3-6 cycloalkyl, -C1-3 alkylene-O-C1-3 alkyl or -C1-3 alkylene-O-C3-6 cycloalkyl.

[0130] In some embodiments, the SGLT2 inhibitor (e.g., of Formula (I)) is:(empagliflozin),WSGR Docket No. 58989-730.601(henagliflozin),WSGR Docket No. 58989-730.601

[0131] In some embodiments, the SGLT2 inhibitor is selected from the group consisting of atigliflozin, mizagliflozin, remogliflozin, sergliflozin, and wanpagliflozin, or a pharmaceutically acceptable salt thereof. In some embodiments, the SGLT2 inhibitor isHO' ' ''OHH (remogliflozin), or a pharmaceutically acceptable salt thereof.

[0132] In some embodiments, the SGLT2 inhibitor is administered in combination with a second veterinary medicine or medicament. In some embodiments, the SGLT2 inhibitor is administered in combination with dog food. In some embodiments, the SGLT2 inhibitor is administered in combination with dog food comprising dry animal feed grade pellets, or kibble. In some embodiments, the SGLT2 inhibitor is administered in combination with dog food comprising wet animal feed grade food, or canned food.

[0133] In some embodiments, the SGLT2 inhibitor is administered in combination with a high-fat diet (e.g., comprising at least 10%, at least 15%, at least 20%, or at least 25% calories from fat), and optionally further comprising dog food (e.g., kibble or canned meat product comprising cooked meat, grain gluten, protein gels, and / or veterinary nutraceutical products).

[0134] In some embodiments, provided herein is a method of pharmacologically inducing a caloric deficit in a dog, comprising administering to the dog an effective amount of an SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof. In some embodiments, the caloric deficit comprises a metabolic shift in a dog from glucosuria to ketones / β-oxidation. In some embodiments, the method comprises inducing an about 5% or more caloric deficit. For example, in some embodiments, the caloric deficit comprises an about 5% or more caloric deficit, an about 6% or more caloric deficit, an about 7% or more caloric deficit, an about 8% or more caloric deficit, an about 9% or more caloric deficit, an about 10% or more caloric deficit, an about 12% or more caloric deficit, an about 15% or more caloric deficit, an about 20% or more caloric deficit, an about 25% or more caloric deficit, or an about 30% or more caloric deficit. In some embodiments, the caloric deficit is evaluated based on blood glucose (e.g., fasting blood glucose), urinary glucose, serum triglycerides, serum fatty acids, serum insulin, or serum beta-hydroxybutyrate. In some embodiments, the metabolic shift comprisesWSGR Docket No. 58989-730.601a shift (i.e., increasing or decreasing) in blood glucose (e.g., fasting blood glucose), urinary glucose, serum triglycerides, serum fatty acids, serum insulin, serum adiponectin, or serum beta-hydroxybutyrate toward metabolic resilience (e.g., decreased blood glucose, increased urinary glucose, decreased serum triglycerides, decreased free fatty acids, decreased serum insulin, increased serum adiponectin, or increased serum BHB), in an amount that is about 5% or more relative to an untreated (placebo) subject. In some embodiments, the metabolic shift comprises a shift of blood glucose, urinary glucose, triglycerides, fatty acids, adiponectin, or BHB toward metabolic resilience in an amount that is about 5% to about 15% compared to placebo. In some embodiments, the metabolic shift comprises a shift of blood glucose, urinary glucose, triglycerides, fatty acids, adiponectin, or BHB toward metabolic resilience in an amount that is about 5% to about 25%, 5% to about 30%, 5% to about 35%, 5% to about 40%, 7% to about 25%, 7% to about 30%, 7% to about 35%, 7% to about 40%, 10% to about 25%, 10% to about 30%, 10% to about 35%, 10% to about 40%, 15% to about 25%, 15% to about 30%, 15% to about 35%, 15% to about 40%, 20% to about 25%, 20% to about 30%, 20% to about 35%, or 20% to about 40%, compared to placebo.

[0135] In some embodiments, provided herein is a method of pharmacologically inducing a caloric deficit in a dog without significantly reducing food intake or without causing significant net weight loss, comprising administering to the dog an effective amount of an SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof. In some embodiments, the significantly reducing food intake comprises reducing food intake by 3% or more. In some embodiments, the significantly reducing food intake comprises reducing food intake by 5% or more. In some embodiments, the significantly reducing food intake comprises reducing food intake by 10% or more. In some embodiments, the dog’s food intake is not reduced by more than about 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, 25%, 30%, or more. In some embodiments, the dog’s food intake is not reduced by more than about 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10%. In some embodiments, the dog’s food intake is increased or unaffected. In some embodiments, the dog’s food intake is reduced by about 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10% or less. In some embodiments, the dog’s food intake is reduced by about 10%, 12%, 15%, 16%, 17%, 18%, 19%, 20% or less. In some embodiments, significant weight loss comprises at least about 5% weight loss. In some embodiments, significant weight loss comprises at least about 6%, 7%, 8%, 9%, 10%, 12%, 15%, 20% weight loss or more. In some embodiments, significant weight loss comprises about 5% to about 7%, 5% to about 8%, 5% to about 9%, 5% to about 10%, 5% to about 12%, 5% to about 15%, or 5% to about 20% weight loss. In some embodiments, the methodWSGR Docket No. 58989-730.601comprises no reduction in the dog’s weight. In some embodiments, the method comprises inducing no more than about a 1% net weight loss. In some embodiments, the method comprises inducing no more than about a 2% net weight loss. In some embodiments, the method comprises inducing no more than about a 3% net weight loss. In some embodiments, the method comprises inducing no more than about a 5% net weight loss. In some embodiments, the method comprises inducing no more than about a 10% net weight loss. In some embodiments, the method comprises inducing no more than about a 15% net weight loss. In some embodiments, the method comprises inducing no more than about a 20% net weight loss. In some embodiments, the method comprises inducing no more than about a 25% net weight loss. In some embodiments, the dog’s weight is not significantly affected.

[0136] In some embodiments, the dog’s weight is not decreased from its pretreatment weight within 2 months of treatment. In some embodiments, the dog’s weight is not decreased from its pretreatment weight within 3 months of treatment. In some embodiments, the dog’s weight is not decreased from its pretreatment weight within 6 months of treatment. In some embodiments, the dog’s weight is not decreased from its pretreatment weight within 12 months of treatment. In some embodiments, the dog’s weight is decreased by about 1% to about 5% of its pretreatment weight within 2 months of treatment. In some embodiments, the dog’s weight is decreased by about 1% to about 5% of its pretreatment weight within 3 months of treatment. In some embodiments, the dog’s weight is decreased by about 1% to about 5% of its pretreatment weight within 6 months of treatment. In some embodiments, the dog’s weight is decreased by about 1% to about 5% of its pretreatment weight within 12 months of treatment. In some embodiments, the dog’s weight is decreased by about 1% to about 10% of its pretreatment weight within 3 months of treatment. In some embodiments, the dog’s weight is decreased by about 1% to about 10% of its pretreatment weight within 6 months of treatment. In some embodiments, the dog’s weight is decreased by about 1% to about 10% of its pretreatment weight within 12 months of treatment. In some embodiments, the dog’s weight is decreased by about 1% to about 15% of its pretreatment weight within 3 months of treatment. In some embodiments, the dog’s weight is decreased by about 1% to about 15% of its pretreatment weight within 6 months of treatment. In some embodiments, the dog’s weight is decreased by about 1% to about 15% of its pretreatment weight within 12 months of treatment.

[0137] In some embodiments, provided herein is a method of (significantly) decreasing fat mass (kg) or fat mass percentage (%) relative to overall body mass in a dog, comprising administering to the dog an effective amount of an SGLT2 inhibitor, or a pharmaceuticallyWSGR Docket No. 58989-730.601acceptable salt thereof. In some embodiments, fat mass percentage is unaffected. In some embodiments, the fat mass percentage is decreased by 1% - 5% within the first 3 months of treatment with the SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof. In some embodiments, the fat mass percentage is decreased by 1% - 10% within the first 3 months of treatment with the SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof. In some embodiments, the fat mass percentage is decreased by 1% - 10% within the first 6 months of treatment with the SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof. In some embodiments, the fat mass percentage is decreased by 1% - 10% within the first 12 months of treatment with the SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof. In some embodiments, the fat mass percentage is decreased by 1% - 15% within the first 3 months of treatment with the SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof. In some embodiments, the fat mass percentage is decreased by 1% - 15% within the first 6 months of treatment with the SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof. In some embodiments, the fat mass percentage is decreased by 1% - 15% within the first 12 months of treatment with the SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof. In some embodiments, the fat mass percentage is decreased by 1% - 20% within the first 3 months of treatment with the SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof. In some embodiments, the fat mass percentage is decreased by 1% - 20% within the first 6 months of treatment with the SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof. In some embodiments, the fat mass percentage is decreased by 1% - 20% within the first 12 months of treatment with the SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof.

[0138] In some embodiments, provided herein is a method of increasing lean mass percentage (%) relative to overall body mass in a dog, comprising administering to the dog an effective amount of an SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof. In some embodiments, the lean mass percentage is decreased by about 1% to about 5%, or by about 5% to about 10%, or by about 5% to about 15%. In some embodiments, the lean mass percentage is decreased by no more than 3% following the administering of the effective amount of the SGLT2 inhibitor, or the pharmaceutically acceptable salt thereof. In some embodiments, the lean mass percentage is decreased by no more than 5% following the administering of the effective amount of the SGLT2 inhibitor, or the pharmaceutically acceptable salt thereof. In some embodiments, the lean mass percentage is decreased by no more than 10% following the administering of the effective amount of the SGLT2 inhibitor, or the pharmaceutically acceptable salt thereof. In some embodiments, the lean mass percentage is decreased by no more than 15% following the administering of the effectiveWSGR Docket No. 58989-730.601amount of the SGLT2 inhibitor, or the pharmaceutically acceptable salt thereof. In some embodiments, the lean mass percentage is not decreased following the administering of the effective amount of the SGLT2 inhibitor, or the pharmaceutically acceptable salt thereof.

[0139] In some embodiments, the lean mass percentage is increased by at least about 3% following the administering of the effective amount of the SGLT2 inhibitor, or the pharmaceutically acceptable salt thereof. In some embodiments, the lean mass percentage is increased by at least about 5% following the administering of the effective amount of the SGLT2 inhibitor, or the pharmaceutically acceptable salt thereof. In some embodiments, the lean mass percentage is increased by at least about 3% within about 3 months, within about 6 months, within about 12 months, or within about 2, 3, 4, 5, 6, 7, 8, 9, 10, or more years following the administering of the effective amount of the SGLT2 inhibitor, or the pharmaceutically acceptable salt thereof. In some embodiments, the lean mass percentage is increased by at least about 5% within about 3 months following the administering of the effective amount of the SGLT2 inhibitor, or the pharmaceutically acceptable salt thereof. In some embodiments, the lean mass percentage is increased by at least about 5% within about 6 months following the administering of the effective amount of the SGLT2 inhibitor, or the pharmaceutically acceptable salt thereof. In some embodiments, the lean mass percentage is increased by at least about 5% within about 12 months following the administering of the effective amount of the SGLT2 inhibitor, or the pharmaceutically acceptable salt thereof. In some embodiments, the lean mass percentage is increased by at least about 10% within about 3 months following the administering of the effective amount of the SGLT2 inhibitor, or the pharmaceutically acceptable salt thereof. In some embodiments, the lean mass percentage is increased by at least about 15% within about 3 months following the administering of the effective amount of the SGLT2 inhibitor, or the pharmaceutically acceptable salt thereof. In some embodiments, the lean mass percentage is increased by at least about 15% within about 6 months following the administering of the effective amount of the SGLT2 inhibitor, or the pharmaceutically acceptable salt thereof. In some embodiments, the lean mass percentage is increased by at least about 25% within about 6 months following the administering of the effective amount of the SGLT2 inhibitor, or the pharmaceutically acceptable salt thereof. In some embodiments, the lean mass percentage is increased by at least about 25% within about 12 months following the administering of the effective amount of the SGLT2 inhibitor, or the pharmaceutically acceptable salt thereof.

[0140] In some embodiments, provided herein is a method of replacing fat mass with lean mass in a dog, comprising administering to the dog an effective amount of an SGLT2WSGR Docket No. 58989-730.601inhibitor, or a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises pharmacologically inducing a caloric deficit in the dog. In some embodiments, the method comprises pharmacologically inducing a caloric deficit in the dog without inducing significant appetite suppression or weight loss. In some embodiments, the significant appetite suppression comprises a decrease in food intake of about 5% or more. In some embodiments, the significant appetite suppression comprises a decrease in food intake of about 5% or more over a period of about 2 months. In some embodiments, the significant appetite suppression comprises a decrease in food intake of about 5% or more over a period of about 3 months. In some embodiments, the significant appetite suppression comprises a decrease in food intake of about 5% or more over a period of about 6 months. In some embodiments, the significant appetite suppression comprises a decrease in food intake of about 5% or more over a period of about 12 months. In some embodiments, the significant appetite suppression comprises a decrease in food intake of about 10% or more. In some embodiments, the significant appetite suppression comprises a decrease in food intake of about 10% or more over a period of about 3 months. In some embodiments, the significant appetite suppression comprises a decrease in food intake of about 10% or more over a period of about 6 months. In some embodiments, the significant appetite suppression comprises a decrease in food intake of about 10% or more over a period of about 12 months.

[0141] In some embodiments, provided herein is a method of pharmacologically inducing a fasting-mimetic metabolic shift in a dog, comprising administering to the dog an effective amount of an SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a method of pharmacologically inducing a metabolic shift in a dog from glucosuria to ketones / β-oxidation, comprising administering to the dog an effective amount of an SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof. In some embodiments, the administering of the SGLT2 inhibitor, or the pharmaceutically acceptable salt thereof, increases β-oxidation by at least about 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, or more. In some embodiments, the administering increases β-oxidation by at least about 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, or more, within about 3 months of administering the SGLT2 inhibitor. In some embodiments, the administering increases β-oxidation by about 5%-15%, 5%-20%, 5%-25%, 5%-30%, 5%-40%, 10%-15%, 10%-20%, 10%-30%, 10%-40%, 15%-25%, 15%-30%, or 20%-40%. In some embodiments, the administering increases β-oxidation by at least about 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, or more. In some embodiments, the administering increases β-oxidation by at least about 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%,WSGR Docket No. 58989-730.60135%, or more, within about 3 months of administering the SGLT2 inhibitor. In some embodiments, the administering increases β-oxidation by about 5%-15%, 5%-20%, 5%-25%, 5%-30%, 5%-40%, 10%-15%, 10%-20%, 10%-30%, 10%-40%, 15%-25%, 15%-30%, or 20%-40%.

[0142] In some embodiments, provided herein is a method of pharmacologically inducing metabolic resilience in a dog, or age-associated diseases associated with metabolic dysfunction, comprising administering to the dog an effective amount of an SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof.

[0143] In some embodiments, the dog’s food intake is not reduced by more than about 3%. In some embodiments, the dog’s food intake is not reduced by more than about 4%. In some embodiments, the dog’s food intake is not reduced by more than about 5%. In some embodiments, the dog’s food intake is not reduced by more than about 6%. In some embodiments, the dog’s food intake is not reduced by more than about 7%. In some embodiments, the dog’s food intake is not reduced by more than about 8%. In some embodiments, the dog’s food intake is not reduced by more than about 9%. In some embodiments, the dog’s food intake is not reduced by more than about 10%. In some embodiments, the dog’s food intake is not reduced by more than about 15%. In some embodiments, the dog’s food intake is not reduced by more than about 20%. In some embodiments, the dog’s food intake is not reduced by more than about 25%. In some embodiments, the dog’s food intake is not reduced by more than about 30%. In some embodiments, the dog’s food intake is not reduced by more than about 35%. In some embodiments, the dog’s food intake is not reduced by more than about 40%. In some embodiments, the dog’s food intake is not reduced by more than about 5% to about 10%. In some embodiments, the dog’s food intake is not reduced by more than about 15% to about 10%. In some embodiments, the dog’s food intake is not reduced by more than about 5% to about 20%. In some embodiments, the dog’s food intake is not reduced by more than about 5% to about 25%. In some embodiments, the dog’s food intake is not reduced by more than about 10% to about 20%.

[0144] In some embodiments, the administering of the SGLT2 inhibitor, or the pharmaceutically acceptable salt thereof, produces no change in the dog’s diet. In some embodiments, the administering produces no change in the dog’s appetite. In some embodiments, the administering produces no change in the dog’s food intake. In some embodiments, the administering produces no change in the dog’s body fat or fat mass. In some embodiments, the administering produces no change in the dog’s body fat percentage.WSGR Docket No. 58989-730.601In some embodiments, the administering produces no change in the dog’s body mass. In some embodiments, the administering produces a decrease in the dog’s body fat percentage. In some embodiments, the administering produces an increase in the dog’s lean mass to fat mass ratio.

[0145] In some embodiments, the dog’s food intake is not reduced by more than about 5% over a period of about a month or more. In some embodiments, the dog’s food intake is not reduced by more than about 5% over a period of about 2 months, or more. In some embodiments, the dog’s food intake is not reduced by more than about 5% over a period of about 3 months, or more. In some embodiments, the dog’s food intake is not reduced by more than about 5% over a period of about 6 months, or more. In some embodiments, the dog’s food intake is not reduced by more than about 5% over a period of about a year, or more. In some embodiments, the dog’s food intake is not reduced by more than about 5% over a period of about 2 years, or more. In some embodiments, the dog’s food intake is not reduced by more than about 5% over a period of about 3 years, or more.

[0146] In some embodiments, the dog’s food intake is not reduced by more than about 10% over a period of about a month or more. In some embodiments, the dog’s food intake is not reduced by more than about 10% over a period of about 2 months, or more. In some embodiments, the dog’s food intake is not reduced by more than about 10% over a period of about 3 months, or more. In some embodiments, the dog’s food intake is not reduced by more than about 10% over a period of about 6 months, or more. In some embodiments, the dog’s food intake is not reduced by more than about 10% over a period of about a year, or more. In some embodiments, the dog’s food intake is not reduced by more than about 10% over a period of about 2 years, or more. In some embodiments, the dog’s food intake is not reduced by more than about 10% over a period of about 3 years, or more.

[0147] In some embodiments, the dog’s food intake is not reduced by more than about 20% over a period of about a month or more. In some embodiments, the dog’s food intake is not reduced by more than about 20% over a period of about 2 months, or more. In some embodiments, the dog’s food intake is not reduced by more than about 20% over a period of about 3 months, or more. In some embodiments, the dog’s food intake is not reduced by more than about 20% over a period of about 6 months, or more. In some embodiments, the dog’s food intake is not reduced by more than about 20% over a period of about a year, or more. In some embodiments, the dog’s food intake is not reduced by more than about 20% over a period of about 2 years, or more. In some embodiments, the dog’s food intake is not reduced by more than about 20% over a period of about 3 years, or more.WSGR Docket No. 58989-730.601

[0148] In some embodiments, the method comprises no significant change in fat mass following treatment. In some embodiments, the method comprises no more than a 5%, 10%, or 15% decrease in fat mass following treatment. In some embodiments, the method comprises a decrease in fat mass (kg) of about 5 to about 15% following treatment with the SGLT2 inhibitor. In some embodiments, the method comprises a decrease in fat mass (kg) of about 10 to about 15% following treatment. In some embodiments, the method comprises a decrease in fat mass (kg) of about 10 to about 15% within about two weeks, three weeks, four weeks, five weeks, six weeks, eight weeks, ten weeks, or twelve weeks following treatment with the SGLT2 inhibitor. In some embodiments, the method comprises a decrease in fat mass (kg) of about 5% to about 15% (e.g., about 10% to about 15%) within about four weeks following treatment with the SGLT2 inhibitor. In some embodiments, the method comprises a decrease in fat mass (kg) of about 5% to about 15% (e.g., about 10% to about 15%) for up to about two weeks, three weeks, four weeks, five weeks, six weeks, eight weeks, ten weeks, or twelve weeks after treatment with the SGLT2 inhibitor. In some embodiments, the method comprises a decrease in fat mass (kg) of about 5% to about 15% (e.g., about 10% to about 15%) for at least about two weeks, three weeks, four weeks, five weeks, six weeks, eight weeks, ten weeks, or twelve weeks after treatment with the SGLT2 inhibitor. In some embodiments, the method comprises a decrease in fat mass (kg) of up to (e.g., no more than) about 12%, 15%, 17%, or 20% following treatment. In some embodiments, the method comprises a decrease in fat mass (kg) of at least about 5%, 6%, 7%, 8%, 9%, or 10% following treatment.

[0149] In some embodiments, the method comprises no significant change in fat mass percentage following treatment. In some embodiments, the method comprises no more than a 5% increase (or no more than a 10% increase) in fat percentage following treatment. In some embodiments, the method comprises no more than a 5%, 10%, or 15% decrease in fat mass percentage following treatment. In some embodiments, the method comprises a decrease in fat mass percentage of at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% following treatment with the SGLT2 inhibitor. In some embodiments, the method comprises a decrease in fat mass percentage of about 2% to about 12% (e.g., about 3% to about 10%) following treatment with the SGLT2 inhibitor. In some embodiments, the method comprises a decrease in fat mass percentage of about 2% to about 12% following treatment. In some embodiments, the method comprises a decrease in fat mass percentage of about 3% to about 10% within about two weeks, three weeks, four weeks, five weeks, six weeks, eight weeks, ten weeks, or twelve weeks following treatment with the SGLT2 inhibitor. In some embodiments, theWSGR Docket No. 58989-730.601method comprises a decrease in fat mass percentage of about 3% to about 10% within about four weeks following treatment with the SGLT2 inhibitor. In some embodiments, the method comprises a decrease in fat mass percentage of about 3% to about 10% for up to about two weeks, three weeks, four weeks, five weeks, six weeks, eight weeks, ten weeks, or twelve weeks after treatment with the SGLT2 inhibitor. In some embodiments, the method comprises a decrease in fat mass percentage of about 3% to about 10% for at least about two weeks, three weeks, four weeks, five weeks, six weeks, eight weeks, ten weeks, or twelve weeks after treatment with the SGLT2 inhibitor. In some embodiments, the method comprises a decrease in fat mass percentage of up to (e.g., no more than) about 8%, 10%, 12%, or 15% following treatment. In some embodiments, the method comprises a decrease in fat mass percentage of at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% following treatment.

[0150] In some embodiments, the method comprises no significant change in lean mass percentage following treatment. In some embodiments, the method comprises no more than a 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% decrease in lean mass percentage following treatment. In some embodiments, the method comprises an increase in lean mass percentage of at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% following treatment with the SGLT2 inhibitor. In some embodiments, the method comprises an increase in lean mass percentage of no more than about 10%, 15%, or 20% following treatment. In some embodiments, the method comprises an increase in lean mass percentage of about 2% to about 12% (e.g., about 3% to about 10%; about 3.5% to about 9%, or about 4% to about 8%) following treatment with the SGLT2 inhibitor. In some embodiments, the method comprises an increase in lean mass percentage of about 2% to about 10% following treatment. In some embodiments, the method comprises an increase in lean mass percentage of about 3% to about 10% within about two weeks, three weeks, four weeks, five weeks, six weeks, eight weeks, ten weeks, or twelve weeks following treatment with the SGLT2 inhibitor. In some embodiments, the method comprises an increase in lean mass percentage of about 3% to about 10% within about four weeks following treatment with the SGLT2 inhibitor. In some embodiments, the method comprises an increase in lean mass percentage of about 3% to about 10% for up to about two weeks, three weeks, four weeks, five weeks, six weeks, eight weeks, ten weeks, or twelve weeks after treatment with the SGLT2 inhibitor. In some embodiments, the method comprises an increase in lean mass percentage of about 3% to about 10% for at least about two weeks, three weeks, four weeks, five weeks, six weeks, eight weeks, ten weeks, or twelve weeks after treatment with the SGLT2 inhibitor. In someWSGR Docket No. 58989-730.601embodiments, the method comprises an increase in lean mass percentage of up to (e.g., no more than) about 8%, 10%, 12%, or 15% following treatment. In some embodiments, the method comprises an increase in lean mass percentage of at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% following treatment.

[0151] In some embodiments, the method comprises no significant change in lean mass following treatment. In some embodiments, the method comprises no more than a 5%, 10%, or 15% decrease in lean mass following treatment. In some embodiments, the method comprises a decrease in lean mass (kg) of about 1% to about 5% following treatment with the SGLT2 inhibitor. In some embodiments, the method comprises an increase in lean mass (kg) of about 1% to about 5% following treatment with the SGLT2 inhibitor. In some embodiments, the method comprises an increase in lean mass (kg) of about 1% to about 5% within about two weeks, three weeks, four weeks, five weeks, six weeks, eight weeks, ten weeks, or twelve weeks following treatment with the SGLT2 inhibitor. In some embodiments, the method comprises an increase in lean mass (kg) of less than about 5% after about two weeks, three weeks, four weeks, five weeks, six weeks, eight weeks, ten weeks, or twelve weeks following treatment with the SGLT2 inhibitor. In some embodiments, the method comprises a decrease in lean mass (kg) of less than about 5% after about two weeks, three weeks, four weeks, five weeks, six weeks, eight weeks, ten weeks, or twelve weeks following treatment with the SGLT2 inhibitor.

[0152] In some embodiments, provided herein is a method of improving one or more biomarkers of aging or quality of life metrics in a dog, comprising administering to the dog an effective amount of an SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a method of improving one or more biomarkers of aging or quality of life metrics in a dog, without inducing clinically significant weight loss, comprising administering to the dog an effective amount of an SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof. In some embodiments, the one or more biomarkers of aging is selected from serum glucose, serum insulin, BHB, adiponectin, fatty acids, or triglycerides. In some embodiments, the one or more quality of life metrics comprises frailty, sarcopenia, sarcopenic obesity, osteoporosis, pain, functional impairment, locomotor impairment, diminished energy or mood, or cognitive decline. In some embodiments, the one or more quality of life metrics comprises necessity for assistance when standing up, necessity for assistance when eating, necessity for assistance with urination or defecation, necessity for assistance with walking or climbing stairs, decreased activity over the past year, reducedWSGR Docket No. 58989-730.601cognitive ability, reduced vitality, weakness, pain, disorientation, inflammation, hearing impairment, visual impairment, or neurological deficits.

[0153] In some embodiments, provided herein is a method of maintaining a dog’s approximate weight while improving quality of life, lifespan, or healthspan comprising administering to the dog an effective amount of an SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof.

[0154] In some embodiments, the clinically significant weight loss is more than 5% weight loss over 1 month. In some embodiments, the clinically significant weight loss is more than 5% weight loss over 2 months. In some embodiments, the clinically significant weight loss is more than 5% weight loss over 3 months. In some embodiments, the clinically significant weight loss is more than 5% weight loss over 4 months. In some embodiments, the clinically significant weight loss is more than 5% weight loss over 6 months. In some embodiments, the clinically significant weight loss is more than 5% weight loss over 12 months.

[0155] In some embodiments, the clinically significant weight loss is more than 7% weight loss over 1 month. In some embodiments, the clinically significant weight loss is more than 7% weight loss over 2 months. In some embodiments, the clinically significant weight loss is more than 7% weight loss over 3 months. In some embodiments, the clinically significant weight loss is more than 7% weight loss over 4 months. In some embodiments, the clinically significant weight loss is more than 7% weight loss over 6 months. In some embodiments, the clinically significant weight loss is more than 7% weight loss over 12 months.

[0156] In some embodiments, the clinically significant weight loss is more than 8% weight loss over 1 month. In some embodiments, the clinically significant weight loss is more than 8% weight loss over 2 months. In some embodiments, the clinically significant weight loss is more than 8% weight loss over 3 months. In some embodiments, the clinically significant weight loss is more than 8% weight loss over 4 months. In some embodiments, the clinically significant weight loss is more than 8% weight loss over 6 months. In some embodiments, the clinically significant weight loss is more than 8% weight loss over 12 months.

[0157] In some embodiments, the clinically significant weight loss is more than 10% weight loss over 1 month. In some embodiments, the clinically significant weight loss is more than 10% weight loss over 2 months. In some embodiments, the clinically significant weight loss is more than 10% weight loss over 3 months. In some embodiments, the clinically significant weight loss is more than 10% weight loss over 4 months. In some embodiments, the clinically significant weight loss is more than 10% weight loss over 6 months. In someWSGR Docket No. 58989-730.601embodiments, the clinically significant weight loss is more than 10% weight loss over 12 months.

[0158] In some embodiments, the clinically significant weight loss is more than 12% weight loss over 3 months. In some embodiments, the clinically significant weight loss is more than 12% weight loss over 6 months. In some embodiments, the clinically significant weight loss is more than 12% weight loss over 12 months. In some embodiments, the clinically significant weight loss is more than 15% weight loss over 3 months. In some embodiments, the clinically significant weight loss is more than 15% weight loss over 6 months. In some embodiments, the clinically significant weight loss is more than 15% weight loss over 12 months. In some embodiments, the clinically significant weight loss is about 5% to about 10% weight loss over 3 months. In some embodiments, the clinically significant weight loss is about 5% to about 10% weight loss over 6 months. In some embodiments, the clinically significant weight loss is about 5% to about 10% weight loss over 12 months.

[0159] In some embodiments, the method comprises maintaining or increasing a level of playfulness and / or appetite (e.g., as measured by a health survey) in the dog. In some embodiments, the method comprises maintaining or increasing a level of playfulness and / or appetite (e.g., as measured by a health survey) in the dog within about two weeks, three weeks, a month, two months, three months, four months, six months, or a year of starting treatment with the SGLT2 inhibitor. In some embodiments, the method comprises maintaining or increasing a level of playfulness and / or appetite (e.g., as measured by a health survey) in the dog for at least about three months, six months, a year, two years, three years, four years, five years, six years, or more. In some embodiments, the method comprises maintaining or increasing a level of playfulness and / or appetite in the dog for up to two years, three years, four years, five years, six years, seven years, eight years, ten years, or longer. In some embodiments, the maintaining or increasing a level of playfulness and / or appetite comprises an increased reported level of playfulness on a health survey. In some embodiments, the maintaining or increasing a level of playfulness and / or appetite comprises an increased food intake. In some embodiments, the method prevents or reduces an age-associated decrease in playfulness and / or appetite (e.g., as measured by a health survey).

[0160] In some embodiments, the method of administering described herein has no observable food effect.WSGR Docket No. 58989-730.601Pharmaceutical Compositions

[0161] The compositions of the present disclosure are formulated to be suitable for in vivo administration to a mammal. Such compositions can optionally comprise a suitable amount of a pharmaceutically acceptable excipient so as to provide the form for proper administration. Pharmaceutical excipients can be liquids, such as water or saline. In addition, auxiliary, stabilizing, thickening, lubricating, and coloring agents can be used. The pharmaceutically acceptable excipients are sterile when administered to a subject. Water is a useful excipient when any composition described herein is administered intravenously. In some embodiments, the compositions described herein are suspended in a saline buffer (including, without limitation Ringer’s, TBS, PBS, HEPES, HBSS, and the like). Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid excipients, specifically for injectable solutions. Suitable pharmaceutical excipients also include starch, glucose, lactose, sucrose, glycerol monostearate, mannitol, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. Any composition described herein, if desired, can also comprise pH buffering agents. As used herein, the terms “composition” or “pharmaceutical composition” may be used interchangeably to encompasses any composition suitable (non-lethal, preferably non-toxic or minimally toxic) for use in a living subject. The subject may be a human or a non-human. Accordingly, the term “pharmaceutical composition” encompasses compositions for both human use and veterinary use. Unless otherwise specified, the pharmaceutical compositions disclosed herein are suitable for use in any organism, particularly a mammal, preferably a dog.

[0162] One aspect of the present invention is a pharmaceutical composition comprising an effective amount of an SGLT2 inhibitor and a pharmaceutically acceptable excipient.

[0163] In some embodiments, provided herein is a pharmaceutical or nutraceutical composition comprising an effective amount of an SGLT2 inhibitor for use in the treatment or prevention of a disease or disorder in a dog.

[0164] In some embodiments, provided herein is a pharmaceutical or nutraceutical composition comprising an effective amount of an SGLT2 inhibitor for use in promoting longevity of a dog, and / or in treating or preventing signs of aging of a dog. In some embodiments, the composition is a pharmaceutical composition. In some embodiments, the composition is a nutraceutical composition. In some embodiments, the pharmaceutical or nutraceutical composition comprises an effective amount of an SGLT2 inhibitor for use in the treatment or prevention of a disease or disorder in a dog.WSGR Docket No. 58989-730.601

[0165] In some embodiments, provided herein is a pharmaceutical or nutraceutical composition comprising an effective amount of an SGLT2 inhibitor and a pharmaceutically acceptable excipient, for use in the treatment and / or prevention of age-associated diseases or disorders in dogs. In some embodiments, the pharmaceutical composition comprises an effective amount of an SGLT2 inhibitor for use in dogs, and further comprising a vitamin, nutraceutical, probiotic, medicine, or medicament for use in dogs (i.e., veterinary medicines or supplements). In some embodiments, provided herein is a pharmaceutical composition comprising an SGLT2 inhibitor, wherein the pharmaceutical composition is provided or administered in combination with dog food (e.g., dry animal feed grade pellets, or kibble; or wet animal feed grade food, or canned food).

[0166] In some embodiments, provided herein is a pharmaceutical or nutraceutical composition comprising an effective amount of an SGLT2 inhibitor for use in a method of prolonging the lifespan or healthspan of a dog, preventing an age-associated disease or condition of a dog, delaying frailty and / or mortality of a dog, or treating an age-associated decline in quality of life. In some embodiments, the effective amount is about 1 to about 90 μg / kg. In some embodiments, the effective amount is about 1 to about 100 μg of SGLT2 inhibitor per kg bodyweight of the subject receiving the composition (i.e., μg / kg). In some embodiments, the effective amount is about 0.1 to about 1.0 mg of SGLT2 inhibitor per kg bodyweight of the subject receiving the composition (i.e., mg / kg). In some embodiments, the effective amount is about 0.1 to about 1.0 mg of SGLT2 inhibitor per kg bodyweight of the subject receiving the composition (i.e., mg / kg). In some embodiments, the prophylactically effective amount is about 80% or less than a therapeutically effective amount.

[0167] In some embodiments, the effective amount of the SGLT2 inhibitor is about 10 mg. In some embodiments, provided herein is a pharmaceutical or nutraceutical composition comprising about 10 mg of an SGLT2 inhibitor. In some embodiments, the effective amount of the SGLT2 inhibitor is about 5 mg. In some embodiments, provided herein is a pharmaceutical or nutraceutical composition comprising about 5 mg of an SGLT2 inhibitor. In some embodiments, the effective amount of the SGLT2 inhibitor is about 0.5 to about 4.5 mg. In some embodiments, provided herein is a pharmaceutical or nutraceutical composition comprising about 0.5 to about 4.5 mg of an SGLT2 inhibitor. In some embodiments, the effective amount of the SGLT2 inhibitor is about 4 mg or less. In some embodiments, provided herein is a pharmaceutical or nutraceutical composition comprising about 4 mg or less of an SGLT2 inhibitor. In some embodiments, the effective amount of the SGLT2WSGR Docket No. 58989-730.601inhibitor is about 3 mg or less. In some embodiments, provided herein is a pharmaceutical or nutraceutical composition comprising about 3 mg or less of an SGLT2 inhibitor.

[0168] In some embodiments, the SGLT2 inhibitor is dapagliflozin, or a pharmaceutically acceptable salt thereof. In some embodiments, the SGLT2 inhibitor is dapagliflozin. In some embodiments, provided herein is a pharmaceutical or nutraceutical composition comprisingan effective amount of dapagliflozin:or a pharmaceutically acceptable salt thereof, for use in dogs (i.e., the treatment and / or prevention of diseases or disorders in dogs, such as age-associated diseases or disorders disclosed herein).Dosage Forms

[0169] The pharmaceutical compositions described herein can be formulated for administration to a mammal via any conventional means including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, or intramuscular), buccal, intranasal, rectal, or transdermal administration routes. As used herein, the term “subject” or “individual” is used to mean a dog. The terms individual, patient and subject may be used interchangeably.

[0170] In some embodiments,, the pharmaceutical compositions described herein, which include dapagliflozin or a pharmaceutically acceptable salt thereof, can be formulated into any suitable dosage form, including but not limited to, solid oral dosage forms tablets, powders, and capsules.

[0171] Pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipients with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If desired, disintegrating agents may be added, such as the cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.WSGR Docket No. 58989-730.601

[0172] Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. All formulations for oral administration should be in dosages suitable for such administration.

[0173] In some embodiments, the solid dosage forms disclosed herein may be in the form of a tablet, a powder (including a sterile packaged powder, a dispensable powder, or an effervescent powder) a capsule multiparticulate dosage forms, pellets, or granules. In other embodiments, the pharmaceutical formulation is in the form of a powder. In still other embodiments, the pharmaceutical formulation is in the form of a pill or tablet.Subjects

[0174] In some embodiments, the subject is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, rabbit, sheep, or non-human primate, such as a monkey, chimpanzee, or baboon. In some embodiments, the subject is a companion animal. In some embodiments, the subject is a canine (e.g., a dog, a fox, a coyote, a wolf, etc.). In some embodiments, the subject is a dog. In other embodiments, the subject is a human.

[0175] In some embodiments, the subject has a mass of about 0.5 kg to about 150 kg. In some embodiments, the subject is a companion animal having a mass of about 0.5 kg to about 150 kg. In some embodiments, the companion animal is a dog having a mass of about 0.5 kg to about 150 kg. In some embodiments, the subject is a small or tiny dog. In some embodiments, the dog is a dog having a mass of about 2 kg to about 12 kg (i.e., a tiny or small dog breed). In some embodiments, the subject is a tiny dog (e.g., having a mass of about 2 kg to about 5 kg (or about 4 lbs to about 10 lbs)). In some embodiments, the subject is a small dog (e.g., having a mass of about 5 kg to about 12 kg (or about 10 lbs to about 25 lbs)). In some embodiments, the dog is a dog having a mass of about 13 kg to about 26 kg (i.e., a medium dog breed). In some embodiments, the dog is a dog having a mass of about 26 kg to about 45 kg (i.e., a large dog breed). In some embodiments, the dog is a dog having a mass of about 45 kg or more (i.e., a giant dog breed). In certain embodiments, the dog is a large or giant dog breed, having a mass of about 26 kg to about 150 kg. In some embodiments, the subject is a dog having a mass of at least 5 lbs. In some embodiments, the subject is a dog having a mass of at least 6 lbs. In some embodiments, the subject is a dog having a mass of at least 7 lbs. In some embodiments, the subject is a dog having a mass of at least 8 lbs. In some embodiments, the subject is a dog having a mass of at least 9 lbs. In some embodiments, theWSGR Docket No. 58989-730.601subject is a dog having a mass of at least 10 lbs. In some embodiments, the subject is a dog having a mass of at least 11 lbs. In some embodiments, the subject is a dog having a mass of at least 12 lbs. In some embodiments, the subject is a dog having a mass of at least 13 lbs. In some embodiments, the subject is a dog having a mass of at least 14 lbs. In some embodiments, the subject is a dog having a mass of at least 15 lbs. In some embodiments, the subject is a dog having a mass of at least 16 lbs. In some embodiments, the dog is at least 4 years old. In some embodiments, the dog is at least 5 years old. In some embodiments, the dog is at least 6 years old. In some embodiments, the dog is at least 7 years old. In some embodiments, the dog is at least 8 years old. In some embodiments, the dog is at least 9 years old. In some embodiments, the dog is at least 10 years old. In some embodiments, the dog is at least 11 years old. In some embodiments, the dog is at least 12 years old. In some embodiments, the dog is about 10-16 years old.

[0176] In some embodiments, the dog is a dog having a mass of about 18 kg to about 120 kg. In some embodiments, the dog is a dog having a mass of about 18 kg or more. In some embodiments, the subject is a dog whose breed is associated with a lifespan of about 12 years or less. In some embodiments, the subject is a dog whose breed is associated with a lifespan of about 10 years or less. In some embodiments, the subject is a dog whose breed is associated with a lifespan of about 8 years or less. In some embodiments, the subject is a dog whose breed is associated with high levels of a biomarker (e.g., a biomarker selected from insulin (e.g., fasting insulin), insulin sensitivity, fasting plasma glucose, and / or fatty acid concentrations (e.g., palmitic acid, oleic acid, linoleic acid, free fatty acids, saturated fatty acids)). In some embodiments, the subject has reached maturity.

[0177] In some embodiments, the subject is administered a herein-disclosed composition as it is nearing or once it has reached halfway to its expected lifespan for the mammal’s species, strain, breed, sex, and / or age. The subject may have reached an age that is at least 60%, 70%, 80%, 90%, or 100% of its expected lifespan for the mammal’s species, strain, breed, sex, and / or age.

[0178] It is known that small dog breeds (e.g., Chihuahua) have longer expected lifespans than large or giant dog breeds (e.g., an English Mastiff, Great Dane, Newfoundland, St. Bernard, or Irish Wolfhound). Accordingly, a Chihuahua, which has an expected lifespan of 15 years, will reach halfway to its expected lifespan at about 7 years (or earlier); thus, a Chihuahua may be administered a composition beginning around 7 years of age. On the other hand, a Great Dane, which has an expected lifespan of 7 years, will reach halfway to its expected lifespan at about 3 years; thus, a Great Dane may be administered a compositionWSGR Docket No. 58989-730.601beginning around 3 years of age (or earlier). As disclosed herein, a mammal may be administered a composition once it has reached maturity; thus, either dog breed may be administered a composition at about its first-year birthday.

[0179] In some embodiments, the dog has an age of about 1 year or more (e.g., about 1 to about 20 years, about 1 to about 18 years, about 1 to about 15 years, about 1 to about 12 years, about 1 to about 10 years, about 1 to about 8 years, about 1 to about 7 years, about 1 to about 6 years, about 1 to about 5 years, about 1 to about 4 years, about 1 to about 3 years, or about 1 to about 2 years). In some embodiments, the dog has an age of about 2 years or more (e.g., about 2 to about 20 years, about 2 to about 18 years, about 2 to about 15 years, about 2 to about 12 years, about 2 to about 10 years, about 2 to about 8 years, about 2 to about 7 years, about 2 to about 6 years, about 2 to about 5 years, about 2 to about 4 years, or about 2 to about 3 years). In some embodiments, the dog has an age of about 3 years or more (e.g., about 3 to about 20 years, about 3 to about 18 years, about 3 to about 15 years, about 3 to about 12 years, about 3 to about 10 years, about 3 to about 8 years, about 3 to about 7 years, about 3 to about 6 years, about 3 to about 5 years, or about 3 to about 4 years).

[0180] In some embodiments, the dog has an age of about 4 years or more (e.g., about 4 to about 20 years, about 4 to about 18 years, about 4 to about 15 years, about 4 to about 12 years, about 4 to about 10 years, about 4 to about 8 years, about 4 to about 7 years, about 4 to about 6 years, or about 4 to about 5 years). In some embodiments, the dog has an age of about 5 years or more (e.g., about 5 to about 20 years, about 5 to about 18 years, about 5 to about 15 years, about 5 to about 12 years, about 5 to about 10 years, about 5 to about 8 years, about 5 to about 7 years, or about 5 to about 6 years).

[0181] In some embodiments, the dog has an age of about 7 years or more (e.g., about 7 to about 20 years, about 7 to about 18 years, about 7 to about 15 years, about 7 to about 12 years, or about 7 to about 10 years). In some embodiments, the dog has an age of about 8 years or more (e.g., about 8 to about 20 years, about 8 to about 18 years, about 8 to about 15 years, about 8 to about 12 years, or about 8 to about 10 years). In some embodiments, the dog has an age of about 10 years or more (e.g., about 10 to about 20 years, about 10 to about 18 years, or about 10 to about 15 years). In some embodiments, the dog has an age of about 12 years or more (e.g., about 12 to about 20 years, about 12 to about 18 years, or about 12 to about 15 years). In some embodiments, the dog has an age of about 15 years or more (e.g., about 15 to about 20 years, or about 15 to about 18 years).

[0182] The dog may have a combination of age and weight that make it a candidate for particularly effective treatment with one of the compositions disclosed herein. For example, aWSGR Docket No. 58989-730.601dog may have an age of about 1 or more years and a mass of about 18 kg or more. In some embodiments, the dog has an age of about 2 or more years (e.g., 3 or more years, 4 or more years, 5 or more years, etc.) and a mass of about 18 kg or more. In some embodiments, the dog has an age of about 7 or more years and a mass of about 18 kg or more. In some embodiments, the dog has an age of about 3 or more years and a mass of about 26 kg or more. In some embodiments, the dog has an age of about 3 or more years and a mass of about 45 kg or more. In some embodiments, the dog has an age of about 5 or more years and a mass of about 18 kg or more. In some embodiments, the dog has an age of about 5 or more years and a mass of about 26 kg or more. In some embodiments, the dog has an age of about 5 or more years and a mass of about 45 kg or more. In some embodiments, the dog has an age of about 7 or more years and a mass of about 18 kg or more. In some embodiments, the dog has an age of about 7 or more years and a mass of about 26 kg or more. In some embodiments, the dog has an age of about 7 or more years and a mass of about 45 kg or more.

[0183] Any dog breed can be administered a composition of the present disclosure and treated by a herein-described method. Illustrative common dog breeds include Retrievers (Labrador), German Shepherd Dogs, Retrievers (Golden), French Bulldogs, Bulldogs, Beagles, Poodles, Rottweilers, Pointers (German Shorthaired), Yorkshire Terriers, Boxers, Dachshunds, Pembroke Welsh Corgis, Siberian Huskies, Australian Shepherds, Great Danes, Doberman Pinschers, Cavalier King Charles Spaniels, Miniature Schnauzers, Shih Tzu, Boston Terriers, Bernese Mountain Dogs, Pomeranians, Havanese, Shetland Sheepdogs, Brittanys, Spaniels (English Springer), Pugs, Mastiffs, Spaniels (Cocker), Vizslas, Cane Corso, Chihuahuas, Miniature American Shepherds, Border Collies, Weimaraners, Maltese, Collies, Basset Hounds, and Newfoundlands.

[0184] In some embodiments, the dog is a healthy dog (e.g., non-diabetic, and / or free of cancer or cancerous tumor diseases. In some embodiments, the dog is a healthy, non-diabetic dog. In some embodiments, the dog is a euglycemic dog. In some embodiments, the dog is a healthy, non-diabetic, euglycemic dog.

[0185] In some embodiments, the dog has a metabolic disease or disorder (e.g., type II diabetes, obesity-related metabolic disease), or has an elevated risk of developing a metabolic disease or disorder based on its age (e.g., 7 years or older) and / or size (e.g., 18 kg or more). In some embodiments, the dog does not have a metabolic disease or disorder (e g., type II diabetes, obesity-related metabolic disease), but has an elevated risk of developing a metabolic disease or disorder based on its age (e.g., 4 years or older) and / or size (e.g., 6 lbs or more).WSGR Docket No. 58989-730.601

[0186] The herein-disclosed compositions and methods treat, prevent, reduce the severity of, and / or delay the onset of various aging-associated conditions in a mammal (i.e., a human or a dog), e.g., cellular senescence, chronic diseases and disabilities / conditions of aging. Illustrative aging-associated conditions include age-associated macular degeneration (AMD), Alzheimer’s disease, arthritis, atherosclerosis and cardiovascular disease, benign prostatic hyperplasia (BPH), bone atrophy, cancer, cardiovascular decline, cataracts, constipation, decrease in visual acuity, decrease in overall energy, delirium, dementia, depression, diminished peripheral vision, greater risk of heat stroke or hypothermia, hearing loss, hypertension, increased inflammation, increased susceptibility to infection (including influenza and pneumonia), kidney disease, memory loss, metabolic syndrome, muscle atrophy, osteoporosis, reduced metabolism (including increased risk for obesity), reduced reflexes and coordination including difficulty with balance, respiratory disease, shingles, type 2 diabetes, urologic changes (including incontinence), whitening or graying of hair, and wrinkling and sagging skin (including loss of skin elasticity). Aged non-human subjects experience similar, homologous, and / or equivalent aging-associated conditions.Health Surveys

[0187] Another aspect of the present invention is the use of a composition disclosed herein for improving not only the health of a subject, but also the perception of health by a companion of the subject. For example, it is known that one of the leading causes of death for dogs, particularly in old age, is death by euthanasia. A key driver of death by euthanasia is poor health, or the perception of poor health by an owner of the dog. Therefore, not only is it critical that the compositions provided herein improve the healthspan of a dog, but also that the dog is perceived as being healthy (i.e., free of pain and / or chronic or degenerative diseases). As described herein, the VetMetrica Health Related Qualify of Life (HRQL) questionnaire is a health survey designed to measure owner perceptions of the quality of life of their dog. It therefore follows that improvements in the HRQL (i.e., improved perceptions of quality of life) correlate to decreased death by euthanasia. In some embodiments, provided herein is a method of preventing, delaying, or reducing death by euthanasia of a subject, the method comprising administering to the subject a composition disclosed herein, thereby improving the HRQL score of the subject and preventing, delaying, or reducing death by euthanasia.

[0188] Another health survey described herein is the Canine Frailty Index (CFI), described in detail by T. Banzato et. al in “A Frailty Index based on clinical data to quantify mortality risk in dogs.” (Sci Rep. 2019 Nov 14; 9(1 ): 16749). The CFI is a validated predictor of mortalityWSGR Docket No. 58989-730.601risk in dogs. It is a survey administered to the owner of the dog to assess the perceived frailty of the dog, which also correlates to disease burden associated with advanced age. The CFI scores are based on the medical history and physical examination of the dog participants, performed by a veterinarian. CFI can be calculated by summing the response scores and dividing by the total number of questions. A frailty index of 0 denotes a dog that is not at all frail, whereas a score of 1 denotes a maximally frail dog according to the scoring system. Lower frailty scores indicated fewer health deficits and lower frailty, while higher frailty scores indicated more health deficits or higher frailty.Biomarkers

[0189] Methods of the present disclosure may further comprise detecting (e.g., detecting the presence, amount, or level of) one or more biomarkers in a first blood sample, wherein the first blood sample is obtained from the dog before administering the pharmaceutical composition. In some embodiments, the methods further comprise detecting one or more biomarkers in a second blood sample, wherein the second blood sample is obtained from the dog after administering the pharmaceutical composition. In some embodiments, the methods disclosed herein modulate (e.g., increase or decrease, e.g., by about 5%, 10%, 15%, 20% or more) one of the biomarkers disclosed herein. In some embodiments, the methods disclosed herein prevent an age-associated increase or decrease (e.g., by about 5%, 10%, 15%, 20% or more) of the biomarkers disclosed herein.

[0190] As used herein, a change in a biomarker may be an increase in the biomarker in a second sample obtained from a mammal relative to a first sample or relative to a historical control. The terms increased or increase, and the like, are used herein to generally mean an increase by any measurable amount. In some embodiments, an increase may be by a statistically significant amount. In some embodiments, the terms increased or increase means an increase of at least 10% as compared to a reference level, for example an increase of at least about 10%, at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% increase, or a greater increase, as compared to a reference level, e.g., an earlier-collected sample from a subject (e.g., before administration of a composition of the present disclosure), standard, or control, including historical control. Other examples of increase include an increase of at least 2-fold, at least 5-fold, at least 10-fold, at least 20-fold, at least 50-fold, at least 100-fold, at least 1000-fold or as compared to a reference level, e.g.,WSGR Docket No. 58989-730.601an earlier-collected sample from a subject (e.g., before administration of a composition of the present disclosure), standard, or control, including historical control.

[0191] Alternately, a change in a biomarker may be a decrease in the biomarker in a second sample obtained from a mammal relative to a first sample or relative to a historical control. The terms decreased, or decrease, and the like, are used herein generally to mean a decrease by any measurable amount. In some embodiments, a decrease may be by a statistically significant amount. In some embodiments, decreased or decrease means a reduction by at least 10% as compared to a reference level, for example a decrease by at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% decrease, as compared to a reference level, e.g., an earlier-collected sample from a subject (e.g., before administration of a composition of the present disclosure), standard, or control, including historical control.

[0192] As used herein, a historical control is where previous-obtained data is used to compare with new data. Information, e.g., the standard, median, normal, or pre-treatment serum amount / level / concentration of a biomarker, is essentially borrowed from historical data. The historical data is usually from a subject with the same characteristics, e.g., species, strain, breed, sex, age, weight, size, health, and / or disease status.

[0193] Another aspect of the invention is a method of:increasing lifespan or healthspan of a subject,increasing quality of life of a subject,maintaining healthy function of a subject,delaying mortality of a subject due to age-associated diseases,preventing, delaying, or reducing frailty of a subject,preventing, delaying, or reducing death by euthanasia of a subject, or- treating an aging-induced insulin resistance of a subject;wherein the method further comprises reducing the amount or concentration of one or more biomarkers in the serum of the subject by an effective amount (e.g., by about 5% to about 99%), by administering to the subject any one of the compositions disclosed herein (e.g., a pharmaceutical composition comprising an effective amount of an SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof). In some embodiments, the one or more biomarkers comprises insulin (e.g., fasting insulin), insulin sensitivity (or resistance), glucose, and / or fatty acid concentrations (e.g., palmitic acid, oleic acid, linoleic acid, free fatty acids, saturated fatty acids). In some embodiments, the one or more biomarkers comprises insulin. In someWSGR Docket No. 58989-730.601embodiments, the one or more biomarkers comprises fasting insulin. In some embodiments, the one or more biomarkers is blood glucose. In some embodiments, the one or more biomarkers is insulin-like growth factor-1 (IGF-1). In some embodiments, the one or more biomarkers is a fatty acid concentration (e.g., palmitic acid, oleic acid, linoleic acid, free fatty acids, and / or saturated fatty acids). For example, the methods disclosed herein may further comprise reducing the serum concentration of palmitic acid, oleic acid, or linoleic acid. In some embodiments, the methods disclosed herein may further comprise reducing the serum concentration of free fatty acids and / or saturated fatty acids.

[0194] In some embodiments, the administering increases urinary glucose levels of the dog by at least 5%, 10%, 15%, 20%, 30%, 50%, or more. In some embodiments, the administering increases urinary glucose levels of the dog by at least 5,000% at 24 hours after the administering. In some embodiments, the administering increases urinary glucose levels of the dog by at least 8,000% at 24 hours after the administering. In some embodiments, the administering increases urinary glucose levels of the dog by at least 9,000% at 24 hours after the administering. In some embodiments, the administering increases urinary glucose levels of the dog by at least 10,000% at 24 hours after the administering. In some embodiments, the administering increases urinary glucose levels of the dog by 5,000% to 15,000% at 24 hours after the administering. In some embodiments, the method comprises administering the SGLT2 inhibitor to the dog at fed state. In some embodiments, the method comprises administering the SGLT2 inhibitor to the dog at fasted state.

[0195] In some embodiments, the administering increases urinary glucose levels of the dog by at least 5,000% within 4 hours of the administering. In some embodiments, the administering increases urinary glucose levels of the dog by at least 8,000% within 4 hours of the administering. In some embodiments, the administering increases urinary glucose levels of the dog by at least 9,000% within 4 hours of the administering. In some embodiments, the administering increases urinary glucose levels of the dog by at least 10,000% within 4 hours of the administering. In some embodiments, the administering increases urinary glucose levels of the dog by 5,000% to 15,000% at 4 hours after the administering. In some embodiments, the method comprises administering the SGLT2 inhibitor to the dog at fed state. In some embodiments, the method comprises administering the SGLT2 inhibitor to the dog at fasted state. In some embodiments, the administering increases urinary glucose levels of the dog by at least 5,000% within 2 hours of the administering. In some embodiments, the administering increases urinary glucose levels of the dog by about 8,000% to about 20,000%. In some embodiments, the administering increases urinary glucose levels of the dog by about 8,000%WSGR Docket No. 58989-730.601to about 20,000% within about an hour, about two hours, about three hours, about four hours, about six hours, about six hours, about six hours, about six hours, or less of administering the SGLT2 inhibitor. In some embodiments, the administering of the SGLT2 inhibitor, or the pharmaceutically acceptable salt thereof, increases urinary glucose levels of the dog by at least 8,000% to about 20,000% within about four hours of the administering. In some embodiments, the administering increases urinary glucose levels of the dog by about 8,000% to about 20,000% within about four hours, or less, of administering the SGLT2 inhibitor. In some embodiments, the administering increases urinary glucose levels of the dog by about 8,000% to about 20,000% for at least about four weeks, or more, after administering the SGLT2 inhibitor

[0196] In some embodiments, the administering increases urinary glucose levels of the dog by at least 8,000% within 2 hours of the administering. In some embodiments, the administering increases urinary glucose levels of the dog by about 5,000% to about 15,000% within 2 hours of the administering. In some embodiments, the administering increases urinary glucose levels of the dog by about 5,000% to about 15,000% within 2 hours of the administering, and wherein the dog is in a fasted state.

[0197] In some embodiments, the administering increases urinary glucose levels of the dog by about 20,000% to about 100,000%. In some embodiments, the administering increases urinary glucose levels of the dog by about 20,000% to about 100,000% within about a day, about two days, about three days, about four days, about five days, about a week, about two weeks, about three weeks, about four weeks, or more of administering the SGLT2 inhibitor. In some embodiments, the administering increases urinary glucose levels of the dog by at least 20,000% to about 100,00% for up to about a day, two days, three days, four days, five days, six days, seven days, ten days, thirteen days, two weeks, three weeks, four weeks, six weeks, two months, three months, or more. In some embodiments, the administering increases urinary glucose levels of the dog by about 20,000% to about 100,000% within about two weeks, or less, of administering the SGLT2 inhibitor. In some embodiments, the administering increases urinary glucose levels of the dog by about 20,000% to about 100,000% for at least about four weeks, or more, after administering the SGLT2 inhibitor.

[0198] In some embodiments, the administering decreases serum glucose levels of the dog by at least 5%. In some embodiments, the administering decreases serum glucose levels of the dog by about 5% to about 15%. In some embodiments, the administering decreases serum glucose levels of the dog by about 5% to about 15% within about four hours of administering the SGLT2 inhibitor to the dog. In some embodiments, the administering decreases serumWSGR Docket No. 58989-730.601glucose levels of the dog by up to about 15% in a fed dog. In some embodiments, the administering decreases serum glucose levels of the dog by up to about 5% in a fasted dog. In some embodiments, the method comprises decreasing serum glucose levels of the dog by up to about 10% in a fasted dog. In some embodiments, the administering decreases serum glucose levels of the dog by about 1% to about 10% in a fasted dog. In some embodiments, the administering decreases serum glucose levels of the dog by about 1% to about 20% (e.g., about 1% to about 15%, about 5% to about 20%, about 5% to about 15%, about 1% to about 10%, or about 5% to about 10%) compared to a pre-dose reference serum glucose level. In some embodiments, the method comprises administering the SGLT2 inhibitor to the dog at fed state. In some embodiments, the method comprises administering the SGLT2 inhibitor to the dog at fasted state. In some embodiments, the serum glucose level is determined at 0.5, 1, 2, or 4 hours after the administering. In some embodiments, the serum glucose level is determined at 1 hour after the administering. In some embodiments, the serum glucose level is determined at 2 hours after the administering.

[0199] In some embodiments, the administering decreases serum glucose levels of the dog by about 5% to about 15% within about a day, two days, three days, four days, five days, six days, seven days, ten days, thirteen days, two weeks, three weeks, four weeks, six weeks, two months, or three months of administering the SGLT2 inhibitor to the dog. In some embodiments, the administering decreases serum glucose levels of the dog by about 5% to about 15% for about a day, two days, three days, four days, five days, six days, seven days, ten days, thirteen days, two weeks, three weeks, four weeks, six weeks, two months, or three months after administering the SGLT2 inhibitor to the dog. In some embodiments, the administering decreases serum glucose levels of the dog by about 5% to about 15% for about seven days after administering the SGLT2 inhibitor to the dog. In some embodiments, the administering decreases serum glucose levels of the dog by about 5% to about 15% for about thirteen days after administering the SGLT2 inhibitor to the dog. In some embodiments, the administering decreases serum glucose levels of the dog by about 5% to about 15% for about up to about three weeks, four weeks, six weeks, two months, or three months after administering (or beginning to administer) the SGLT2 inhibitor to the dog.

[0200] In some embodiments, the administering decreases serum glucose levels of the dog by at least 5% within 4 hours of the administering. In some embodiments, the administering decreases serum glucose levels of the dog by at least 8% within 4 hours of the administering. In some embodiments, the administering decreases serum glucose levels of the dog by at leastWSGR Docket No. 58989-730.60110% within 4 hours of the administering. In some embodiments, the administering decreases serum glucose levels of the dog by at least 12% within 4 hours of the administering.

[0201] In some embodiments, the administering decreases serum glucose levels of the dog by at least 5% within 0.5 hours of the administering. In some embodiments, the administering decreases serum glucose levels of the dog by at least 5% within 1 hour of the administering. In some embodiments, the administering decreases serum glucose levels of the dog by at least 5% within 2 hours of the administering.

[0202] In some embodiments, the administering decreases serum glucose levels of the dog by at least 8% within 0.5 hours of the administering. In some embodiments, the administering decreases serum glucose levels of the dog by at least 8% within 1 hour of the administering. In some embodiments, the administering decreases serum glucose levels of the dog by at least 8% within 2 hours of the administering.

[0203] In some embodiments, the administering decreases serum glucose levels of the dog by at least 10% within 4 hours of the administering, wherein the dog is in a fed or fasted state. In some embodiments, the administering decreases serum glucose levels of the dog by at least 10% within 2 hours of the administering, wherein the dog is in a fed state.

[0204] In some embodiments, the administering decreases serum glucose levels of the dog by 2% to about 20% at 4 hours after the administering. In some embodiments, the administering decreases serum glucose levels of the dog by 3% to about 15% at 4 hours after the administering. In some embodiments, the administering decreases serum glucose levels of the dog by 5% to about 15% at 4 hours after the administering. In some embodiments, the administering decreases serum glucose levels of the dog by 10% to about 15% at 4 hours after the administering. In some embodiments, the method comprises administering the SGLT2 inhibitor to the dog at fed state. In some embodiments, the method comprises administering the SGLT2 inhibitor to the dog at fasted state. In some embodiments, the administering decreases serum glucose levels of the dog by 2% to about 10% at 4 hours after the administering, wherein the dog is in a fasted state. In some embodiments, the administering decreases serum glucose levels of the dog by 10% to about 15% at 4 hours after the administering, wherein the dog is in a fed state.

[0205] In some embodiments, the administering decreases serum glucose levels of the dog by 2% to about 10% after three weeks of the administering the SGLT2 inhibitor to the dog. In some embodiments, the administering decreases serum glucose levels of the dog by 2% to about 10% after four weeks of the administering the SGLT2 inhibitor to the dog. In some embodiments, the administering decreases serum glucose levels of the dog by at least aboutWSGR Docket No. 58989-730.6015% after four weeks of the administering the SGLT2 inhibitor to the dog. In some embodiments, the administering decreases serum glucose levels of the dog by at least about 6% after four weeks of the administering. In some embodiments, the administering decreases serum glucose levels of the dog by at least about 7% after four weeks of the administering. In some embodiments, the administering decreases serum glucose levels of the dog by up to about 10% after four weeks of the administering.

[0206] In some embodiments, the administering decreases serum glucose AUC of the dog by up to about 2% after four weeks of the administering. In some embodiments, the administering decreases serum glucose AUC of the dog by up to about 3% after four weeks of the administering. In some embodiments, the administering decreases serum glucose AUC of the dog by up to about 4% after four weeks of the administering. In some embodiments, the administering decreases serum glucose AUC of the dog by up to about 5% after four weeks of the administering. In some embodiments, the administering decreases serum glucose AUC of the dog by up to about 8% after four weeks of the administering.

[0207] In some embodiments, the administering decreases serum insulin levels of the dog by at least 5%. In some embodiments, the administering decreases serum insulin levels of the dog by at least 10%, at least 15%, at least 20%, or at least 25%. In some embodiments, the administering decreases serum insulin levels of the dog by up to about 30%, up to about 40%, up to about 50%, up to about 60%, up to about 65%, up to about 70%, or up to about 75%. In some embodiments, the administering decreases serum insulin levels of the dog by about 15% to about 75%. In some embodiments, the administering decreases serum insulin levels of the dog by about 20% to about 60% (e.g., about 30% to about 60%, about 40% to about 60%, or about 50% to about 60%). In some embodiments, the administering decreases serum insulin levels of the dog by about 15% to about 75% within about an hour, two hours, or four hours of administering the SGLT2 inhibitor. In some embodiments, the administering decreases serum insulin levels of the dog by about 40% to about 60%. In some embodiments, the administering decreases serum insulin levels of the dog by about 35% to about 65%. In some embodiments, the administering decreases serum insulin levels of the dog by about 30% to about 70%. In some embodiments, the administering decreases serum insulin levels of the dog by about 50% to about 70%.

[0208] In some embodiments, the administering decreases serum insulin levels of the dog by about 5% to about 30% for about a day, two days, three days, four days, five days, six days, seven days, ten days, thirteen days, two weeks, three weeks, four weeks, six weeks, two months, or three months after administering the SGLT2 inhibitor to the dog. In someWSGR Docket No. 58989-730.601embodiments, the administering decreases serum insulin levels of the dog by about 5% to about 30% for about seven days after administering the SGLT2 inhibitor to the dog. In some embodiments, the administering decreases serum insulin levels of the dog by about 5% to about 30% for about thirteen days after administering the SGLT2 inhibitor to the dog. In some embodiments, the administering decreases serum insulin levels of the dog by about 10% to about 30% for up to about three weeks, four weeks, six weeks, two months, or three months after administering (or beginning to administer) the SGLT2 inhibitor to the dog. In some embodiments, the administering decreases serum insulin levels of the dog by about 20% to about 40% for up to about three weeks, four weeks, six weeks, two months, or three months after administering (or beginning to administer) the SGLT2 inhibitor to the dog. In some embodiments, the administering decreases serum insulin levels of the dog by up to about 30% for up to about one, two, three, or more weeks after administering (or beginning to administer) the SGLT2 inhibitor to the dog.

[0209] In some embodiments, the administering decreases serum insulin levels of the dog by at least 20% within an hour of the administering. In some embodiments, the administering decreases serum insulin levels of the dog by at least 20% within two hours of the administering. In some embodiments, the administering decreases serum insulin levels of the dog by at least 30% within 4 hours of the administering. In some embodiments, the administering decreases serum insulin levels of the dog by at least 40% within 4 hours of the administering. In some embodiments, the administering decreases serum insulin levels of the dog by at least 50% within 4 hours of the administering.

[0210] In some embodiments, the administering decreases serum insulin levels of the dog by 20% or more, at 4 hours after the administering. In some embodiments, the administering decreases serum insulin levels of the dog by 30% or more, at 4 hours after the administering. In some embodiments, the administering decreases serum insulin levels of the dog by 40% or more, at 4 hours after the administering. In some embodiments, the administering decreases serum insulin levels of the dog by 50% or more, at 4 hours after the administering. In some embodiments, the administering decreases serum insulin levels of the dog by 60% or more, at 4 hours after the administering. In some embodiments, the administering decreases serum insulin levels of the dog by 70% or more, at 4 hours after the administering.

[0211] In some embodiments, the administering decreases serum insulin levels of the dog by 15% to about 70%, within the first 4 hours of the administering. In some embodiments, the administering decreases serum insulin levels of the dog by 30% to about 65%, within the firstWSGR Docket No. 58989-730.6014 hours of the administering. In some embodiments, the administering decreases serum insulin levels of the dog by up to 80%, within 4 hours of the administering.

[0212] In some embodiments, the administering decreases serum insulin levels of the dog by at least 10% after the first week of the administering of the SGLT2 inhibitor, or the pharmaceutically acceptable salt thereof. In some embodiments, the administering decreases serum insulin levels of the dog by at least 10% after the two weeks of the administering. In some embodiments, the administering decreases serum insulin levels of the dog by at least 10% after three weeks of the administering. In some embodiments, the administering decreases serum insulin levels of the dog by at least 10% after four weeks of the administering. In some embodiments, the administering decreases serum insulin levels of the dog by at least 10% after five, six, seven, eight, ten, twelve, or more weeks of the administering. In some embodiments, the administering decreases serum insulin levels of the dog by at least 20% after four weeks of the administering. In some embodiments, the administering decreases serum insulin levels of the dog by at least 30% after four weeks of the administering. In some embodiments, the administering decreases serum insulin levels of the dog by at least 40% after four weeks of the administering.

[0213] In some embodiments, the administering decreases serum insulin levels of the dog by up to about 60% after four weeks of the administering. In some embodiments, the administering decreases serum insulin levels of the dog by up to about 50% after four weeks of the administering. In some embodiments, the administering decreases serum insulin levels of the dog by up to about 40% after four weeks of the administering. In some embodiments, the administering decreases serum insulin levels of the dog by up to about 30% after four weeks of the administering. In some embodiments, the administering decreases serum insulin levels of the dog by about 20% to about 60% within the first four weeks of the administering. In some embodiments, the administering decreases serum insulin levels of the dog by about 30% to about 60% within the first four weeks of the administering. In some embodiments, the administering decreases serum insulin levels of the dog by about 30% to about 50% within the first four weeks of the administering.

[0214] In some embodiments, the administering of the SGLT2 inhibitor, or the pharmaceutically acceptable salt thereof, increases adiponectin blood concentration of the dog by at least 5%. In some embodiments, the administering increases adiponectin blood concentration of the dog by at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more. In some embodiments, the administering increases adiponectin blood concentration of the dog by at least 100%, 200%, 300%, 400%, 500%, 1000%, 2000%,WSGR Docket No. 58989-730.6015000%, 10,000%, or more. In some embodiments, the administering increases adiponectin blood concentration of the dog by about 1% to about 10%, by about 1% to about 20%, by about 1% to about 30%, by about 1% to about 40%, or by about 1% to about 50%. In some embodiments, the administering increases adiponectin blood concentration of the dog by about 2% to about 10%, about 3% to about 10%, about 4% to about 10%, or by about 5% to about 10%. In some embodiments, the administering increases adiponectin blood concentration of the dog by about 2% to about 15%, about 3% to about 15%, about 4% to about 15%, or by about 5% to about 15%. In some embodiments, the administering increases adiponectin blood concentration of the dog by at least 1%. In some embodiments, the administering increases adiponectin blood concentration of the dog by 0% to about 10%, or by 0% to about 15%. In some embodiments, serum adiponectin levels of the dog are not significantly changed.

[0215] In some embodiments, the administering of the SGLT2 inhibitor, or the pharmaceutically acceptable salt thereof, increases beta-hydroxybutyrate (BHB) blood concentration of the dog by at least 5%. In some embodiments, the administering increases beta-hydroxybutyrate (BHB) blood concentration of the dog by at least 10%. In some embodiments, the administering increases beta-hydroxybutyrate (BHB) blood concentration of the dog by up to 200%. In some embodiments, the administering increases beta-hydroxybutyrate (BHB) blood concentration of the dog by about 10% to about 200%. In some embodiments, the administering increases beta-hydroxybutyrate (BHB) blood concentration of the dog by about 40% to about 160% (e.g., about 50% to about 150%). In some embodiments, the administering increases beta-hydroxybutyrate (BHB) blood concentration of the dog by about 40% to about 160% (e.g., about 50% to about 150%) for about a day, two days, three days, four days, five days, six days, seven days, ten days, thirteen days, two weeks, three weeks, four weeks, six weeks, two months, or three months after administering the SGLT2 inhibitor to the dog.

[0216] In some embodiments, the administering increases beta-hydroxybutyrate (BHB) blood concentration of the dog by about 40% to about 160% (e.g., about 50% to about 150%) within about a day, two days, three days, four days, five days, six days, seven days, ten days, thirteen days, two weeks, three weeks, four weeks, six weeks, two months, or three months of administering the SGLT2 inhibitor to the dog. In some embodiments, the administering increases the BHB blood concentration of the dog by at least about 25% after a week of the administering. In some embodiments, the administering increases the BHB blood concentration of the dog by at least about 25% after two weeks of the administering. In some embodiments, the administering increases the BHB blood concentration of the dog by at leastWSGR Docket No. 58989-730.601about 25% after three weeks of the administering. In some embodiments, the administering increases the BHB blood concentration of the dog by at least about 25% after four weeks of the administering.

[0217] In some embodiments, the administering increases the BHB blood concentration of the dog by at least about 30% after four weeks of the administering. In some embodiments, the administering increases the BHB blood concentration of the dog by at least about 40% after four weeks of the administering. In some embodiments, the administering increases the BHB blood concentration of the dog by at least about 50% after four weeks of the administering. In some embodiments, the administering increases the BHB blood concentration of the dog by at least about 60% in the first four weeks after the administering. In some embodiments, the administering increases the BHB blood concentration of the dog by about 30% to about 120% in the first four weeks after the administering. In some embodiments, the administering increases the BHB blood concentration of the dog by about 30% to about 120% in the two first weeks after the administering. In some embodiments, the administering increases the BHB blood concentration of the dog by about 30% to about 120% in the first week after the administering. In some embodiments, the about 30% to about 120% is further defined as about 40% to about 120%, about 50% to about 120%, about 60% to about 120%, or about 80% to about 120%. In some embodiments, the administering increases BHB levels of the dog by up to 130% within (or after) a week, two weeks, three weeks, or four weeks of the administering.

[0218] In some embodiments, the administering increases beta-hydroxybutyrate (BHB) blood concentration of the dog by about 40% to about 160% (e.g., about 50% to about 150%) for about a day, two days, three days, four days, five days, six days, seven days, ten days, thirteen days, two weeks, three weeks, four weeks, six weeks, two months, or three months after administering the SGLT2 inhibitor to the dog.

[0219] In some embodiments, the BHB blood concentration is determined at 24 hours after the administering. In some embodiments, the BHB blood concentration is determined at 72 hours after the administering.

[0220] In some embodiments, the method comprises administering the SGLT2 inhibitor to the dog at fed state. In some embodiments, the method comprises administering the SGLT2 inhibitor to the dog at fasted state.

[0221] In some embodiments, the Cmaxand / or AUC0-inf of the dog does not vary by more than 10%, 20%, 30%, or 40% when the SGLT2 inhibitor is administered to the dog in a fed state or in a fasted state.WSGR Docket No. 58989-730.601

[0222] In some embodiments, the Cmaxand / or AUC0-inf does not vary by more than 30% when the SGLT2 inhibitor is administered to the dog in a fed state or in a fasted state. In some embodiments, the Cmaxand / or AUC0-inf are determined at 0.5h, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 24 hours, 48 hours, or 72 hours after the administering. In some embodiments, the Cmaxand / or AUC0-inf are determined at 0.5 to 2 hours after the administering.

[0223] In some embodiments, the administering provides a Cmaxof about 300 ng / mL to about 5,000 ng / mL when the SGLT2 inhibitor is administered to the dog in a fed state or in a fasted state.

[0224] In some embodiments, the administering provides a Cmaxof about 300 ng / mL to 500 ng / mL when the SGLT2 inhibitor is administered to the dog in a fed state or in a fasted state at a dose of about 0.3 mg / kg. In some embodiments, the administering provides a Cmaxof at least about 300 ng / mL when the SGLT2 inhibitor is administered to the dog in a fed state or in a fasted state at a dose of about 0.3 mg / kg. In some embodiments, the administering provides a Cmaxof about 900 ng / mL to 2000 ng / mL when the SGLT2 inhibitor is administered to the dog in a fed state or in a fasted state at a dose of about 1.0 mg / kg. In some embodiments, the administering provides a Cmaxof about 3000 ng / mL to 5000 ng / mL when the SGLT2 inhibitor is administered to the dog in a fed state or in a fasted state at a dose of about 3.0 mg / kg.

[0225] In some embodiments, the administering provides a T1 / 2 of about 9 hours to about 15 hours when the SGLT2 inhibitor is administered to the dog in a fed state or in a fasted state. In some embodiments, the administering provides a T1 / 2 of at least about 6 hours. In some embodiments, the administering provides a T1 / 2 of at least about 8 hours. In some embodiments, the administering provides a T1 / 2 of at least about 9 hours. In some embodiments, the administering provides a T1 / 2 of at least about 10 hours. In some embodiments, the administering provides a T1 / 2 of at least about 12 hours. In some embodiments, the administering provides a T1 / 2 of at least about 13 hours. In some embodiments, the administering provides a T1 / 2 of up to 14 hours. In some embodiments, the administering provides a T1 / 2 of about 8 hours to about 14 hours. In some embodiments, the administering provides a T1 / 2 of about 9 hours to about 15 hours. In some embodiments, the administering provides a T1 / 2 of about 12 hours when the SGLT2 inhibitor is administered to the dog in a fed state or in a fasted state.

[0226] In some embodiments, the administering of the SGLT2 inhibitor, or the pharmaceutically acceptable salt thereof, decreases a concentration of a biomarker of the dog by at least 5%, wherein the biomarker is selected from IL-6 and TNFa. In some embodiments, the method further comprises mitigating or reversing an elevation of fatty acids in the dog. InWSGR Docket No. 58989-730.601some embodiments, the elevation of fatty acids comprises an elevation of free fatty acid levels in plasma. In some embodiments, the elevation of fatty acids is associated with an age-associated disease state.EXAMPLES

[0227] The following examples are given for the purpose of illustrating various embodiments of the invention and are not meant to limit the present invention in any fashion. The present examples, along with the methods described herein are presently representative of preferred embodiments, are exemplary, and are not intended as limitations on the scope of the invention. Changes therein and other uses which are encompassed within the spirit of the invention as defined by the scope of the claims will occur to those skilled in the art.Example 1. Subchronic Dosing Study in Beagle Dogs

[0228] A subchronic dosing study in twenty-five (25) healthy Beagle dogs assessed different biomarkers of metabolic function using multiple SGLT2 inhibitors, which included the following: dapagliflozin, empagliflozin, canagliflozin, and bexagliflozin. The dogs were randomized by body weight and age. Dogs were dosed orally for 14 days with a given SGLT2 inhibitor in either the fasted or fed prandial state. Serum and urinary glucose levels were measured over the course of the first 24 hours post dosing and periodically throughout the study (See FIG. 1 and FIG. 2). Serum insulin (FIG. 3), P-hydroxybutyrate (BHB) (FIG.4), and serum adiponectin (FIG. 5) were measured at baseline and weekly throughout the study. Serum glucose, urinary glucose, and P-hydroxybutyrate (BHB) were quantified with an AU680 clinical chemistry analyzer. Serum insulin was quantified by radioactive immunoassay (RIA). Serum adiponectin samples were collected and analyzed with a commercially available sandwich enzyme-linked immunoassay (ELISA). Body composition, measured by quantitative magnetic resonance (QMR), was assessed at baseline and the conclusion of the study by placing animals into a plexiglass kennel within a magnet bore and scanned using EchoMRI-D technology. The following Tables 1-8 contain the data from these studies.

[0229] As shown in FIG. 1 and Table 1, all SGLT2i treatments significantly increased glucose disposal from baseline by Day 7. Increased urinary' glucose was sustained through Day 14 of the study. The data demonstrate pharmacokinetic efficacy in the dog populations tested, across all SGLT2 inhibitors. Canagliflozin produced the greatest positive increase in urinary glucose at days 7 and 14, though all were significantly above placebo.WSGR Docket No. 58989-730.601Table 1. Percent Change in Urinary Glucose from BaselinePercent Change in Urinary Glucose from BaselineDose Day Change p-vatuePlacebo 7 -1.89 0.91913 -1.89 0.919Dapaglifiozhl 7 +81,303.08 <0.00113 +135,127.69 <0.001EmpagUftozm 7 +36,140.24 <0.00113 +82,110.29 <0.001Canagliftozin 7 +189,383.97 <0.00113 +169,073.06 <0.001Velaglifiozin 7 +137,700.17 <0.00113 +159,179.84 <0.001

[0230] The data provided in FIG. 2 and Table 2 also indicate that all SGLT2i treatments significantly reduced serum glucose during a food challenge test after two weeks of dosing. The data suggest an improvement in glucose homeostasis across all SGLT2 inhibitors tested. Canagliflozin also produced the most significant decrease in serum glucose across all SGLT2 inhibitors.Table 2. Percent Change in Serum Glucose AUC from BaselinePercent Change in Serum Glucose AUC from BaselineDose Day Percent Change p-valuePlacebo 7 +1.49 0.58713 -3.29 0.221Dapagliflozin 7 -4.34 0.10713 -8.60 0.002Empagliflozin 7 -4.17 0.12213 -6.82 0.012Canagliflozin 7 -7.52 0.00613 -14.04 <0.001Velagliflozin 7 -5.90 0.03013 -8.46 0.002

[0231] As depicted in FIG. 3 and Table 3, all SGLT2 inhibitors treatments produced serum insulin levels less than that of placebo. Moreover, all SGLT2 inhibitors but dapagliflozin demonstrated significant or trending decreases in serum insulin during the food challenge test. Additionally, the data in Table 4 show that dogs treated with dapagliflozin and other SGLT2i treatments had trending lower insulin than the placebo by Day 7, indicating an improvement in metabolic function across all tested dog populations.WSGR Docket No. 58989-730.601Table 3. Percent Change in Serum Insulin AUC from BaselinePercent Change in Serum insulin AUC from BaselineDose Day Percent Change (%) p-valuePlacebo 7 +24.56 0.06813 +22.65 0.089Dapagliflozin 7 -1.27 0.91413 +9.37 0.448Empagliflozin 7 -20.77 0.05413 12.60 0.256Canagliflozin 7 -29.50 0.00513 -28.92 0.008Velagliflozin 7 -22.02 0.04013 -2.56 0.826Table 4. Difference in Serum Insulin AUC from PlaceboDifference in Serum insulin AUC from PlaceboAbsolute DifferenceDose Day (uUL / mL*min) p-valueDapagliflozin Baseline -890.87 0.1657 -1,820.32 0.01713 -1,457.98 0.057Empagliflozin Baseline +507.68 0.5087 -1,248.60 0.11513 -840.27 0.296Canagliflozin Baseline +870.43 0.2837 -1,355.09 0.08513 -1,259.43 0.105Velagliflozin Baseline +286.22 0.7007 -1,473.40 0.05913 -639.29 0.435

[0232] The data in FIG. 4 and Table 5 show that all SGLT2 inhibitor treatments tested significantly increased P-Hydroxybutyrate relative to placebo after two weeks of dosing. Increased levels of P-Hydroxybutyrate (BHB) in the blood generally correlate with and suggest increased hepatic fatty acid oxidation, a marker of metabolic improvement. BHB is a ketone body produced in the liver through the oxidation of fatty acids, particularly when carbohydrate availability is low. Elevated BHB signifies that the body is relying more on fat for fuel, often via ketogenesis.WSGR Docket No. 58989-730.601Table 5. Percent Change in β-Hydroxybutyrate (BHB) from BaselinePercent Change in BHB from BaselineDose Day Change (%) p-vatuePlacebo 7 +11.03 0.62513 -9.71 0.633Dapagliflozin 7 +91.60 0.00413 +60.14 0.032Empagliflozin 7 +42.45 0.10413 +61.99 0.029Canagliflozin 7 +68.23 0.01913 *156.34 <0.001Velagliflozin 7 +62.47 0.02813 *119.88 <0.001

[0233] Data presented in FIG. 5 and Table 6 show no significant changes in adiponectin levels after two weeks of treatment with either placebo or SGLT2 inhibitor, at the doses and durations tested.Table 6. Percent Change in Adiponectin from BaselinePercent Change in Adiponectin from BaselineDose Day Change (%) p-valuePlacebo 13 +4.15 0.628Dapagliflozin 13 +7.63 0.384Empagliflozin 13 -3.37 0.683Canagliflozin 13 +8.32 0.345Velagliflozin 13 +0.90 0.915

[0234] Data in Table 7 indicate that treatment with empagliflozin caused a significant increase in lean mass by day 13 of treatment, while canagliflozin caused a comparable decrease in lean mass. The Table 8 data showed no significant changes in body fat after two weeks of treatment with any of the SGLT2 inhibitor treatments.Table 7. Percent Change in Lean Mass from BaselinePercent Change in Lean Mass from BaselineDose Day Change (%) p-valuePlacebo 13 +2.37 0.431Dapagliflozin 13 +1.37 0.646Empagliflozin 13 +6.77 0.036Canagliflozin 13 -6,17 0.041Velagliflozin 13 +0.72 0.809WSGR Docket No. 58989-730.601Table 8. Percent Change in Fat Mass from BaselinePercent Change in Fat Mass from BaselineDose Day Change p-valuePlacebo 13 +4.91 0.228Dapagliflozin 13 +1.14 0.772Empagliflozin 13 +2.19 0.579Canagliflozin 13 +5.54 0.177Velagliflozin 13 +2.81 0.480Example 2. Effects of Dapagliflozin on Glucose Homeostasis and Insulin Sensitivity

[0235] Dapagliflozin is an SGLT2 inhibitor, which decreases blood glucose concentration by blocking renal glucose reabsorption. It is hypothesized that dapagliflozin could prevent or reverse impairments in hyperinsulinemia and insulin sensitivity induced by chronic HFD feeding. Interventions that reduce blood glucose levels and insulin resistance (i.e., caloric restriction) increase the health-span (the years of life spent disease-free) and lifespan of several model organisms, including rodents, dogs and monkeys. This study aims to provide evidence that dapagliflozin is metabolically protective (i.e., mitigates the development of clinical manifestations of insulin resistance) when used as an intervention after HFD-induced metabolic dysfunction had already occurred.

[0236] This study was used to determine whether dapagliflozin can prevent the development of hyperinsulinemia and insulin resistance compared to vehicle / placebo treated dogs fed HFD for at least 5 weeks. Fifty (50) male beagle, mongrel or mixed beagle / mongrel dogs were utilized in a parallel matched group design. Prior to Day 0, subjects were randomized and allocated into one of two treatment groups: Group 1 (HFD + Placebo) or Group 2 (HFD + dapagliflozin). The Group 2 dapagliflozin doses were in the amounts of 0.3 mg / kg, 1.0 mg / kg, 2.0 mg / kg, and 3.0 mg / kg. Groups were randomized by age, sex, cohort, and body weight as the primary factors. Fasting glucose, insulin, and insulin sensitivity were measured by oral glucose tolerance test (OGTT) in the baseline period while being maintained on their normal chow diet.

[0237] On Day 0, both groups of dogs were switched from their normal chow diet to a HFD containing 74% fat for the following selected duration of study (5 weeks). Concurrently, dogs were dosed orally every day with either a placebo (Group 1) or dapagliflozin (Group 2) for the duration of the HFD. After 4 weeks, repeated measurement of fasted plasma glucose, insulin, and insulin sensitivity were measured by OGTT to determine if dapagliflozin preserves insulin sensitivity compared to placebo when challenged with an HFD. AdditionalWSGR Docket No. 58989-730.601pre-treatment and post-treatment plasma, serum, and urine samples were taken for other exploratory analyses. Additional analyses were carried out as part of the study, measuring biomarkers of metabolic health / metabolic resilience, including: urinary glucose (FIG. 6 and Table 9), serum glucose (FIG. 7 and Table 10), OGTT glucose (FIG. 8 and Table 11), serum insulin (FIG. 9 and Table 12), OGTT insulin (FIG. 10 and Table 13), serum P-hydroxybutyrate (FIG. 11 and Table 14), and serum adiponectin (FIG. 12 and Table 16). Body composition analyses were also conducted before and after the treatment (FIG. 19), with each of the treatment groups achieving reductions in fat mass and fat mass percentage, and increases in lean mass percentage. The simultaneous decrease in fat mass percentage and increase in lean mass percentage, paired with reductions in serum glucose and serum insulin, indicate a shift away from insulin resistance and / or obesity, and toward metabolic resilience. Serum glucose, urinary glucose, and P-hydroxybutyrate (BHB) were quantified with an AU680 clinical chemistry analyzer. Serum insulin was quantified by radioactive immunoassay (RIA). Serum adiponectin samples were collected and analyzed with a commercially available sandwich enzyme-linked immunoassay (ELISA). Improvements in these biomarkers are associated with reduced or delayed mortality in dogs by treating, preventing, or delaying progression of subclinical metabolic disease, age-associated metabolic dysfunction, and / or frailty.

[0238] Clinical examinations and body weight measurements were conducted throughout the study to monitor the health of the animals. Daily general health observations and fecal examinations were also performed for the duration of the study.

[0239] Animals were fed their daily food ration (g) as a split ration. Each feeding (AM or PM) consisted of approximately half the animal’s daily food ration and were offered approximately 4 hours apart. Dogs were given approximately 2 hours to consume each ration and any remaining food was weighed back for each feeding.

[0240] Baseline or Pre-Treatment readings for all parameters (blood tests, body weight, food consumption, OGTT, body composition / energy expenditure) were established per animal and per group and these results were compared to Treatment results. Individual and summary statistics, arithmetic means, percentage change and within and between group comparisons were carried out. The fasted glucose measurements and fasted insulin measurements for each group of subjects were analyzed.

[0241] Baseline readings for all parameters (blood tests, body weight, food consumption, OGTT) were established per animal and per group and these results were compared to treatment results. Individual and summary7statistics, arithmetic means, percentage change andWSGR Docket No. 58989-730.601within and between group comparisons were carried out. The fasted glucose measurements and fasted insulin measurements for each group of subjects were analyzed.Table 9. Ratio of Urinary Glucose Levels in Treated Dogs Compared to Vehicle Ratio of Urinary Glucose Levels in Treated Dogs Compared to VehicleDose Day Ratio (%) p-value0.3mg / kg 14 +89,646.13 <8,89128 +25,225.63 <8,801l. Omg / fcg 14 -'80,494.69 <8,80128 +55.065.01 <9.8012.0mg / kg 14 +67.996.71 <9.60128 +48,096.60 <0.0013.0mg / kg 14 +57,871.73 <00128 +36,449.33 <0.601

[0242] All doses of dapagliflozin resulted in significantly increased urinary glucose levels, suggesting pharmacokinetic efficacy.Table 10. Percent Change in Serum Glucose from BaselinePercent Change in Serum Glucose from BaselineDose Day Change (%) p-valueVehicle 7 +2.29 0.37014 -1.85 0.46021 -1.14 0.65028 -5.99 0.0400.3mg / kg 7 +1.96 0.44414 -6.44 0.00921 -3.33 0.18128 -3.47 0.1641.0mg / kg 7 -2.19 0.38214 -7.42 0.00421 -5.30 0.03228 -6.30 0.0112.0 mg / kg 7 -0.01 0.99614 -3.02 0.22621 -2.77 0.26728 -4.84 0.0513.0 mg / kg 7 -2.38 0.34114 -5.96 0.01621 -8.82 <0.00128 -7.62 0.002

[0243] All doses of dapagliflozin resulted in a significant or trending decrease to serum glucose by four weeks of dosing, which suggests an improvement in glucose homeostasis.WSGR Docket No. 58989-730.601Table 11. Percent Change in Glucose (AUC) from BaselinePercent Change in Glucose (AUC) from BaselineDose Week Change (%) p-valueVehicle 4 -1.84 0.4710.3 mg / kg 4 +0.56 0.8271.0 mg / kg 4 -0.91 0.7222.0 mg / kg 4 ”3.54 0.1653.0 mg / kg 4 -7.41 0.004

[0244] During an oral glucose tolerance test (metabolic challenge test), glucose release was suppressed by dapagliflozin treatment at 3.0 mg / kg dose.Table 12. Percent Change in Serum Insulin from BaselinePercent Change in Serum Insulin from BaselineDose Day Change (%) p-valueVehicle 7 +2.77 0.87814 -6.81 0.69521 +16.28 0.38828 -22.75 0.1400.3 mg / kg 7 -23.79 0.12114 -10.85 0.51121 -29.20 0.05728 -18.58 0.2401.0 mg / kg 7 -35.43 0.01314 -34.15 0.02121 -45.88 <8.08128 -36.69 0.0092.0 mg / kg 7 -4.63 0.79314 +5.99 0.74721 -16.93 0.30428 -1.18 0.9483.0 mg / kg 7 -37.87 0.00714 -24.30 0.11221 -43.11 0.00128 -24.59 0.107

[0245] A dose of 1.0 mg / kg of dapagliflozin was the most effective at lowering insulin over four weeks of dosing.WSGR Docket No. 58989-730.601Table 13. Percent Change in Insulin (AUC) from BaselinePercent Change in Insulin (AUC) from BaselineDose Week Change p- valueVehicle 4 -12.06 0.2350.3 mg / kg 4 -0.54 0.9601.0 mg / kg 4 +0.04 0.9972.0 mg / kg 4 ’21.04 0.0323.0 mg / kg 4 +3.45 0.752

[0246] During an oral glucose tolerance test (metabolic challenge test), insulin release was not affected by dapagliflozin treatment except for in the 2.0 mg / kg group.Table 14. Percent Change in p-Hydroxybutyrate from BaselinePercent Change in p-hydroxybutyratefrom BaselineDose Day Change (%) p-valueVehicle 7 0.00 1.00014 -8.38 0.55621 -0.64 0.96528 +0.77 0.9590.3 mg / kg 7 +94.14 <0.00114 +48.91 0.00821 +50.26 0.00728 +45.35 0.0131.0 mg / kg 7 +120.83 <0.00114 +108.74 <0.00121 +100.64 <0.00128 +112.05 <0.0012.0 mg / kg 7 +85.66 <0.00114 +33.90 0.05121 +84.09 <0.00128 +59.17 0.0023.0 mg / kg 7 +106.69 <0.00114 +47.01 0.01021 +69.80 <0.00128 +42.49 0.018

[0247] Treatment with dapagliflozin resulted in a trending or significant rise in P~ hydroxybutyrate with all doses, which suggests a metabolic improvement with increased fat oxidation.WSGR Docket No. 58989-730.601Table 15. Percent Change in Adiponectin from BaselinePercent C h a n ge i n Adiponectin from BaselineDose Day Change (%) p-valueVehicle 7 +6.09 0.58314 -4.43 0.67421 -5.05 0.63028 -19.24 0.0490.3 mg / kg 7 +18.14 0.12314 -7.32 0.48121 +21.77 0.06928 +11.58 0.3101.0 mg / kg 7 +10.84 0.34014 +14.35 0.21421 +10.58 0.35128 -11.56 0.2712.0 mg / kg 7 +2.35 0.83014 +21.15 0.07621 +20.77 0.10428 +7.36 0.5103.0 mg / kg 7 -6.63 0.52414 -6.58 0.52821 -4.48 0.67128 -10.00 0.329

[0248] No significant changes in adiponectin levels were found after four weeks of treatment with dapagliflozin.Example 3. Food Effects on Tolerability, Efficacy, and Pharmacokinetics

[0249] A four-week study in healthy Beagle dogs assessed different biomarkers of tolerability, efficacy, and pharmacokinetics following three tested doses of dapagliflozin (0.3, 1.0, and 3.0 mg / kg). Dogs were randomized by body weight. Dogs were dosed orally with dapagliflozin in either the fasted or fed prandial state. Dapagliflozin exposure concentrations were measured over the course of the first 72 hours after dosing for groups given a single dose of dapagliflozin at the three different strengths and analyzed (see FIG. 13, FIG. 14, and Table 16). Dapagliflozin exposure concentrations were determined by liquid chromatography / tandem mass spectrometry (LC-MS / MS). There was not a significant food effect observed, however urinary glucose and other measured biomarkers showed efficacy and tolerability throughout the study.

[0250] Urinary glucose levels were measured pre-dose and over the first 24 hours after dosing for groups given a single dose of dapagliflozin at different strengths (0.3, 1.0, and 3.0WSGR Docket No. 58989-730.601mg / kg) and analyzed (FIG. 15 and Table 17). Serum glucose and serum insulin levels were collected pre-dose and over the first 4 hours after dosing for groups given a single dose of dapagliflozin at different strengths (0.3, 1.0, and 3.0 mg / kg) and analyzed (See FIGs. 16 and 17, and Tables 18 and 19, respectively). Serum P-hydroxybutyrate (BHB) levels also were measured pre-dose and over the first 72 hours after dosing for groups given a single dose of dapagliflozin at different strengths (0.3, 1.0, and 3.0 mg / kg) and analyzed (FIG. 18 and Table 20). Serum glucose, urinary glucose, and P-hydroxybutyrate (BHB) were quantified with an AU680 clinical chemistry analyzer. Serum insulin was quantified by radioactive immunoassay (RIA).

[0251] Dapagliflozin exposure concentrations were found to be similar within doses in groups treated with dapagliflozin both in the fasted and fed prandial state. All doses of dapagliflozin resulted in significantly increased urinary glucose (FIG. 15). Serum glucose levels decreased at 0.3, 1.0, and 3.0 mg / kg for groups in the fed state, consistent with an improvement in glucose homeostasis (FIG. 16). Serum insulin levels decreased across all doses tested, in both fed and fasted states (FIG. 17), suggesting improvements in insulin resistance, or increased insulin sensitivity. P-hydroxybutyrate (BHB) levels increased in all groups but only reached significance within a 0.3 and 3.0 mg / kg dose in the fed state and at a 3.0 mg / kg dose in the fasted state, suggesting an increase in fat oxidation (FIG. 18).

[0252] As shown in Table 16, exposure to dapagliflozin was found to be similar within doses both in the fasted and fed prandial state.Table 16. Pharmacokinetics of Dapagliflozin in Fed and Fasted StatesPharmacokinetic Parameters Fed Fasted 0.3 mg / kg 1.0 mg / kg 3.0 mg / kg 0.3 mg / kg 1.0 mg / kg 3.0 mg / kg C_max (ng / mL) 341 ± 142 1,020 + 85 3,470 ± 410 451 ± 82 1,560 ± 397 4,390 ± 121 Tmax(hr) 1.7 ± 1.4 1.6 ± 1.3 0.9 ± 0.2 1.2 ± 0.8 1.0 ± 0.6 0.8 ± 0.3 AUC0-inf(ng*hr / mL) 4,550 ± 1,920 14,200 ± 3,150 43,100 ± 11,200 4,420 ± 1,570 15,100 ± 3,840 50,400 ± 11,600T1 / 2(hr) 11.4 ± 2.6 12.5 ± 3.7 10.7 ± 0.8 11.2 ± 2.6 11.3 ± 1.4 13.3 ± 3.7 Table 17. Percent Change in Urinary Glucose at 24 Hours Post-DosePercent Change in Urinary Glucose at 24 Hours Post-DoseFed FastedDose Percent Change (%) p-value Percent Change (%) p-value 0.3 mg / kg +10,828.59 <0.001 +11,527.97 <0.001 1.0 mg / kg +9,813.86 <0.001 +8,011.14 <0.001 3.0 mg / kg +8,417.1 <0.001 +12,708.64 <0.001WSGR Docket No. 58989-730.601Table 18. Percent Change in Serum GlucosePercent Change In Serum GlucoseFed FastedLtDose ' Percent Change (%) p-value Percent Change (%) p-value Dose0.3 mg / kg 0.5 -3.54 0.812 -1.44 0.9161.0 -7.37 0.084 -1.78 0.871 2.0 -12.94 <0.001 -5.52 0.010 4.0 -11.70 0.035 -8.89 <0.001 1.0 mg / kg 0.5 -7.86 0.005 -0.03 1.0001.0 -11.23 0.004 -1.14 0.845 2.0 -12.18 <0.001 -2.15 0.472 4.0 -8.39 0.082 -1.61 0.828 3.0 mg / kg 0.5 -8.93 0.006 +5.27 0.2181.0 -8.75 0.180 -5.02 0.268 2.0 -11.82 0.024 -4.10 0.397 4.0 -13.28 0.104 -4.58 0.600 Table 19. Percent Change in Serum InsulinPercent Change in Serum InsulinFed FastedLi reDose Percent Change (%) p-value Percent Change (%) p-value Dose0.3 mg / kg 0.5 -27.11 0.750 -16.81 0.7291.0 -43.67 <0.001 -58.66 0.028 2.0 -55.58 0.046 -47.09 0.388 4.0 -49.79 0.050 -50.34 0.106 1.0 mg / kg 0.5 -38.65 0.247 -33.94 0.3161.0 -41.18 0.065 -61.48 <0.001 2.0 -39.26 <0.001 -55.41 0.062 4.0 -16.10 0.949 -48.23 0.005 3.0 mg / kg 0.5 -23.72 0.616 -28.09 0.8361.0 -33.08 0.253 -56.57 0.030 2.0 -31.08 0.485 -59.74 0.106 4.0 -57.69 0.215 -65.84 0.011 Table 20. Percent Change in P-HydroxybutyratePercent Change in p-hydroxybutyrateFed FastedDose Hrs Post-Dose Percent Change (%) p-value Percent Change (%) p-value 0.3 mg / kg 24 +130.44 0.004 +16.93 0.76072 +38.19 0.187 +35.86 0.670 l. Omg / kg 24 +30.81 0.130 +27.63 0.46572 +26.77 0.150 +49.34 0.082 3.0mg / kg 24 +112.71 0.009 +113.53 <0.00172 +61.80 0.179 +83.96 0.247WSGR Docket No. 58989-730.601Example 4. Obesity-Related Metabolic Dysfunction

[0253] A 12-week high-fat diet (HFD) design was designed to determine whether dapagliflozin reverses obesity related metabolic dysfunction. This study will be conducted on 2 groups of 12 Beagle dogs each. All dogs are fed ad libitum “normal diet” (ND), for example, consisting of about 55% fat for all baseline measurements prior to the study start. Prior to the study start, dogs are placed on HFD (consisting of about 74% fat), on which they remain for approximately 12 weeks. After 42 days (6 weeks) of HFD-feeding, Placebo will be administered daily by mouth to Group 1 while dapagliflozin (Img / kg / day) is to be administered daily by mouth to Group 2.

[0254] Clinical examinations and body weights will be conducted throughout the study to monitor the health of the animals. Daily general health observations and fecal examinations will be also performed for the duration of the study. Blood collections for Chemistry, Haematology, Triglycerides, Cholesterol, Metabolomics and Lipidomics, efficacy Biomarkers (fasting insulin, ketones, adiponectin), and pharmacokinetics, are performed throughout the study to assess the diet and drug-related effects on markers of safety and metabolic function.

[0255] Baseline and Pre-Treatment) readings of each parameter will be compared to Treatment (Day 57) measurements. OGTTs will be performed during the baseline and Treatment phases to assess glucose and insulin kinetics and insulin sensitivity. OGTTs will be carried out as described herein:

[0256] Briefly, dogs will be fasting overnight prior to conducting the procedure. Blood will be sampled and serum and plasma separated at -20 and 0 minutes pre-glucose bolus to establish fasting glucose and insulin values. At 0 minutes (t=0), a glucose bolus (0.9 g / kg, p.o.) is to be delivered. Blood will be collected at 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 120, 180 and 240 minutes post-glucose bolus. Serum will be then analyzed for glucose and plasma will be analyzed for insulin levels at each time point.& *

Claims

WSGR Docket No. 58989-730.601CLAIMSWe claim:

1. A method of reducing or delaying mortality due to an age-associated disease or condition in a dog, the method comprising administering to the dog an effective amount of an SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the age-associated disease or condition compri ses an age-associated metabolic disease or age-associated diminished quality of life.

3. The method of claim 2, wherein the age-associated metabolic disease comprises metabolic dysfunction, metabolic syndrome, or obesity-related metabolic disease.

4. The method of claim 2, wherein the age-associated metabolic disease comprises an increase in serum glucose, an increase in serum insulin, a decrease in fat metabolism, or a decrease in serum beta-hydroxybutyrate level.

5. The method of claim 2, wherein the age-associated diminished quality of life comprises frailty, sarcopenia, sarcopenic obesity, osteoporosis, pain, functional impairment, locomotor impairment, diminished energy or mood, or cognitive decline.

6. The method of any one of claims 1 to 5, wherein the dog has an age of four years or older.

7. The method of any one of claims 1 to 6, wherein the dog has a weight of six pounds or more.

8. The method of any one of claims 1 to 7, wherein the SGLT2 inhibitor is selected from the group consisting of atigliflozin, bexagliflozin, canagliflozin, dapagliflozin, empagliflozin, enavogliflozin, ertugliflozin, henagliflozin, ipragliflozin, janagliflozin, licogliflozin, luseogliflozin, mizagliflozin, remogliflozin etabonate, rongliflozin, sergliflozin etabonate, sotagliflozin, tofogliflozin, velagliflozin, and wanpagliflozin, or a pharmaceutically acceptable salt thereof.

9. The method of claim 8, wherein the SGLT2 inhibitor is selected from the group consisting of canagliflozin, dapagliflozin, empagliflozin, and velagliflozin, or a pharmaceutically acceptable salt thereof.

10. The method of claim 8, wherein the SGLT2 inhibitor is dapagliflozin, or a pharmaceutically acceptable salt thereof.

11. The method of any one of claims 1 to 10, wherein the effective amount is about 0.1 to about 5.0 mg / kg.

12. The method of claim 11, wherein the effective amount is about 0.3 to about 3.0 mg / kg.

13. The method of claim 11, wherein the effective amount is about 1.0 mg / kg.WSGR Docket No. 58989-730.60114. The method of any one of claims 1 to 13, comprising preventing the age-associated disease or condition of the dog.

15. The method of any one of claims 1 to 14, wherein the effective amount is administered daily.

16. The method of any one of claims 1 to 15, wherein the effective amount is directed to be administered once daily for a period of at least seven days.

17. The method of claim 16, wherein the effective amount is directed to be administered once daily for a period of at least two weeks.

18. The method of claim 16, wherein the effective amount is directed to be administered once daily for a period of at least four weeks.

19. The method of claim 16, wherein the effective amount is directed to be administered once daily for a period of at least one year.

20. The method of any one of claims 1 to 19, wherein the age-associated disease or condition is or comprises impaired hepatic function (including liver disease, steatosis, non-alcoholic steatohepatitis, nonalcoholic fatty liver disease, or other hepatitis), impaired renal function (including kidney failure, chronic kidney disease), impaired metabolic function, elevated blood glucose, or inflammatory conditions (including neuroinflammation, chronic inflammation, inflammaging, senescence, and senescence- associated secretory phenotype).

21. The method of any one of claims 1 to 19, wherein the age-associated disease or condition is or comprises an obesity-related metabolic disease or inflammation.

22. The method of any one of claims 1 to 19, wherein the age-associated disease or condition is or comprises metabolic syndrome.

23. The method of any one of claims 1 to 19, wherein the age-associated disease or condition is or comprises hyperlipidemia, hyperinsulinemia, and / or hyperglycemia.

24. The method of any one of claims 1 to 19, wherein the age-associated disease or condition is or comprises multimorbidity or mortality associated with accumulated functional impairments.

25. The method of any one of claims 1 to 24, wherein the reducing or delaying mortality due to the age-associated metabolic disease comprises delaying progression of subclinical age-associated metabolic disease.

26. The method of any one of claims 5 to 25, wherein the frailty is or comprises decreased bone density, decreased musculoskeletal function, decreased locomotion, chronic inflammation, decreased appetite, acute vascular problems, incontinence, osteoarthrosis,WSGR Docket No. 58989-730.601decreased activity, hearing impairment, reduced cognitive ability, cardiomyopathy, reduced vitality, chronic respiratory disease, weakness during exercise, hepatopathy, congenital defects, neurological deficits, oral disease, weight loss (not due to diet or exercise), visual impairment, chronic digestive disease, epilepsy, disease of the hematopoietic system, episodes of disorientation, dermatological disease, chronic infectious disease, or chronic kidney disease.

27. The method of any one of claims 1 to 26, wherein the reducing or delaying mortality due to the age-associated diminished quality of life comprises evaluating the quality of life of the dog via a health survey.

28. The method of claim 27, wherein the evaluating the quality of life of the dog via the health survey is performed before, and within about a year of, the administering the effective amount of the SGLT2 inhibitor, or the pharmaceutically acceptable salt thereof, to the dog.

29. The method of claim 27, wherein the evaluating the quality of life of the dog via the health survey is performed after, and within about a year of, the administering the effective amount of the SGLT2 inhibitor, or the pharmaceutically acceptable salt thereof, to the dog.

30. The method of claim 27, wherein the health survey comprises an assessment of quality of life, functional impairment, disease burden, or frailty.

31. The method of any one of claims 2 to 30, wherein the age-associated diminished quality of life is evaluated by use of a health survey (e.g., a health survey evaluating the frailty and / or quality of life of the dog) or a measurement of a presence or level of an age- associated biomarker.

32. The method of claim 31, wherein the age-associated biomarker comprises a measurement or quantification of blood glucose levels, serum insulin levels, serum adiponectin levels, serum beta-hydroxybutyrate levels, or free fatty acid levels.

33. The method of claim 31, wherein the age-associated biomarker comprises a measurement or quantification of fasted blood glucose levels, fasted serum insulin levels, fasted serum adiponectin levels, fasted serum beta-hydroxybutyrate levels, or fasted free fatty acid levels.

34. The method of any one of claims 1 to 33, wherein the reducing or delaying mortality due to the age-associated disease or condition further comprises reducing reabsorption of glucose of the dog, or increasing glucose excretion of the dog.WSGR Docket No. 58989-730.60135. The method of any one of claims 1 to 34, wherein the reducing or delaying mortality due to the age-associated disease or condition further comprises reducing insulin secretion of the dog, increasing insulin sensitivity of the dog, increasing glucagon / insulin ratio of the dog, increasing ketogenesis of the dog, or increasing fatty acid oxidation of the dog.

36. The method of any one of claims 1 to 35, wherein the reducing or delaying mortality due to the age-associated disease or condition further comprises improving the energy, mobility, or cognitive function of the dog; or reducing panting, polydipsia, or polyuria of the dog.

37. The method of any one of claims 1 to 36, wherein the reducing or delaying mortality due to the age-associated disease or condition further comprises administering a restricted diet to the dog.

38. The method of claim 37, wherein the restricted diet comprises a caloric restriction, low- fat diet, high-fat diet, high-fructose diet, high-fat / high-fructose diet, high-protein diet, or ketogenic diet.

39. The method of any one of claims 1 to 38, wherein the reducing or delaying mortality due to the age-associated disease or condition further comprises increasing lifespan, wherein the increasing lifespan comprises an at least 5% increase in lifespan relative to the expected or median lifespan of a dog of the same breed.

40. The method of claim 39, wherein the increasing lifespan comprises increasing lifespan by at least 10% relative to the expected or median lifespan of a dog of the same breed.

41. The method of any one of claims 1 to 40, wherein the reducing or delaying mortality due to the age-associated disease or condition comprises mitigating or reversing insulin resistance, or increasing insulin sensitivity by at least 5% measured by an oral glucose tolerance testing assay or by measuring fasting insulin blood levels.

42. The method of any one of claims 1 to 41, wherein the reducing or delaying mortality due to the age-associated disease or condition comprises decreasing serum insulin levels of the dog by at least 5%.

43. The method of any one of claims 1 to 42, wherein the reducing or delaying mortality due to the age-associated disease or condition comprises increasing beta¬ hydroxybutyrate (BHB) blood concentration of the dog by at least 5%.

44. The method of any one of claims 1 to 43, wherein the reducing or delaying mortality due to the age-associated disease or condition comprises increasing adiponectin blood concentration of the dog by at least 5%.WSGR Docket No. 58989-730.60145. The method of any one of claims 1 to 44, wherein the reducing or delaying mortality due to the age-associated disease or condition comprises mitigating or reversing an elevation of fatty acids of the dog by at least 5%.

46. The method of any one of claims 1 to 45, wherein the Cmaxand / or AUC0-inf of the dog does not vary by more than 10%, 20%, 30%, or 40% when the SGLT2 inhibitor is administered to the dog in a fed state or in a fasted state.

47. The method of any one of claims 1 to 45, wherein the Cmaxand / or AUC0-inf does not vary by more than 30% when the SGLT2 inhibitor is administered to the dog in a fed state or in a fasted state.

48. The method of claim 46 or 47, wherein the Cmaxand / or AUC0-inf are determined at 0.5h, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 24 hours, 48 hours, or 72 hours after the administering.

49. The method of claim 46 or 47, wherein the Cmaxand / or AUC0-inf are determined at 0.5 to 2 hours after the administering.

50. The method of any one of claims 1 to 49, wherein the administering provides a Cmaxof about 300 to about 5,000 ng / mL when the SGLT2 inhibitor is administered to the dog in a fed state or in a fasted state.

51. The method of any one of claims 1 to 49, wherein the administering provides a Cmaxof about 300 ng / mL to 500 ng / mL when the SGLT2 inhibitor is administered to the dog in a fed state or in a fasted state at a dose of about 0.3 mg / kg.

52. The method of any one of claims 1 to 49, wherein the administering provides a Cmaxof about 900 ng / mL to 2000 ng / mL when the SGLT2 inhibitor is administered to the dog in a fed state or in a fasted state at a dose of about 1.0 mg / kg.

53. The method of any one of claims 1 to 49, wherein the administering provides a Cmaxof about 3000 ng / mL to 5000 ng / mL when the SGLT2 inhibitor is administered to the dog in a fed state or in a fasted state at a dose of about 3.0 mg / kg.

54. The method of any one of claims 1 to 49, wherein the administering provides a T1 / 2 of about 9 hours to about 15 hours when the SGLT2 inhibitor is administered to the dog in a fed state or in a fasted state.

55. The method of any one of claims 1 to 49, wherein the administering provides a T1 / 2 of about 12 hours when the SGLT2 inhibitor is administered to the dog in a fed state or in a fasted state.WSGR Docket No. 58989-730.60156. The method of any one of claims 1 to 55, wherein the age-associated disease or condition comprises metabolic syndrome, insulin resistance, obesity, type II diabetes, cardiovascular disease, kidney disease, hepatic steatosis, atherosclerosis, or sarcopenia.

57. The method of any one of claims 1 to 56, wherein the dog has reached maturity.

58. The method of any one of claims 1 to 56, wherein the dog is at least 7 years old.

59. The method of any one of claims 1 to 56, wherein the dog is at least 10 years old.

60. The method of any one of claims 1 to 59, wherein the SGLT2 inhibitor is administered to the dog in a fed state.

61. The method of any one of claims 1 to 59, wherein the SGLT2 inhibitor is administered to the dog in a fasted state.

62. The method of any one of claims 1 to 61, wherein the SGLT2 inhibitor is administered in combination with an additional veterinary medicine or medicament.

63. A pharmaceutical or nutraceutical composition comprising an effective amount of an SGLT2 inhibitor for use in the reduction or delay of mortality due to an age-associated disease or disorder in a dog.

64. A pharmaceutical or nutraceutical composition comprising an effective amount of an SGLT2 inhibitor for use in reducing or delaying mortality due to signs of aging of a dog.

65. A pharmaceutical or nutraceutical composition comprising an effective amount of an SGLT2 inhibitor for use in extending a lifespan or a healthspan of a dog, treating or preventing an age-associated disease or condition of a dog, reducing or delaying frailty and / or mortality of a dog, or treating an age-associated diminished quality of life of a dog.

66. The pharmaceutical or nutraceutical composition of any one of claims 63 to 65, wherein the SGLT2 inhibitor is selected from the group consisting of atigliflozin, bexagliflozin, canagliflozin, dapagliflozin, empagliflozin, enavogliflozin, ertugliflozin, henagliflozin, ipragliflozin, janagliflozin, licogliflozin, luseogliflozin, mizagliflozin, remogliflozin etabonate, rongliflozin, sergliflozin etabonate, sotagliflozin, tofogliflozin, velagliflozin, and wanpagliflozin, or a pharmaceutically acceptable salt thereof67. The pharmaceutical or nutraceutical composition of claim 66, wherein the SGLT2 inhibitor is selected from the group consisting of canagliflozin, dapagliflozin, empagliflozin, and velagliflozin, or a pharmaceutically acceptable salt thereof.

68. The pharmaceutical or nutraceutical composition of claim 66, wherein the SGLT2 inhibitor is dapagliflozin, or a pharmaceutically acceptable salt thereof.WSGR Docket No. 58989-730.60169. The pharmaceutical or nutraceutical composition of any one of claims 63 to 68, wherein the effective amount is about 0.1 to about 5.0 mg / kg.

70. The pharmaceutical or nutraceutical composition of any one of claims 63 to 69, wherein the SGLT2 inhibitor is admini stered once daily for at least two weeks.

71. The pharmaceutical or nutraceutical composition of any one of claims 63 to 69, wherein the SGLT2 inhibitor is administered once daily for at least four weeks.

72. The pharmaceutical or nutraceutical composition of any one of claims 63 to 71, wherein the age-associated disease or condition comprises an age-associated metabolic disease.

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