Dapagliflozin for use in treating prediabetes or reducing the risk of developing type 2 diabetes

Abstract

The present disclosure relates to a method of reducing the risk of developing type 2 diabetes and / or treating prediabetes in a patient in need thereof, the method comprising administering to the patient an effective amount of a sodium glucose cotransporter type 2 (SGLT2) inhibitor, wherein the patient has an HbA1c of 5.7%-6.4%, and / or a fasting glucose of 100-125 mg / dl.

Description

[Technical field]

[0001] Prediabetes is a serious health condition that increases the risk of type 2 diabetes (T2D), micro- and macrovascular complications including CV, and renal complications. In 2021, it was estimated that 10.6% of the world's adult population (541 million people) had prediabetes; the prevalence was projected to increase to 11.4% of the world's population (730 million people) by 2045 (International Diabetes Federation. IDF Diabetes Atlas 2021). In the United States, there are more people living with prediabetes than with diabetes (88 million adults vs. 34 million adults) (Centers for Disease Control and Prevention Diabetes and Prediabetes 2020).

[0002] Despite the severity of the condition, the majority of affected individuals (90%) are unaware that they have prediabetes. As it progresses to T2D, the risk of complications increases substantially. In 2021, it was estimated that 6.7 million deaths in adults aged 20-79 years worldwide were due to diabetes and its complications (International Diabetes Federation IDF Diabetes Atlas 2021). [Background technology]

[0003] In the United States, there are no drug products approved for the treatment of prediabetes. Lifestyle changes, such as adjustments to diet and exercise, are recommended for people with prediabetes. (Non-Patent Document 1). The National Diabetes Prevention Program was created to address the growing burden of prediabetes and T2D in the United States. (Centers for Disease Control and Prevention. Diabetes and Prediabetes 2020.) The key message of the National Diabetes Prevention Program is that prediabetes can be reversed by taking an active role and engaging in a long-term lifestyle change program that includes a healthy diet and physical activity. However, lifestyle changes are difficult to maintain over the long term (Diabetes Prevention Program Research Group 2009).

[0004] In summary, the ADA recognizes the difficulty of maintaining lifestyle changes and recommends pharmacotherapy (e.g., metformin) for the prevention of T2D (Non-Patent Document 1). However, it is also recognized that long-term side effects and safety are important considerations (e.g., gastrointestinal intolerance and vitamin B12 deficiency with long-term use of metformin) and that other options are needed (Id.; Non-Patent Document 2).

[0005] Thus, in the United States, there is an unmet need, from an individual and societal perspective, for pharmacological options to reduce the risk of progression to T2D and to reduce the risk of micro- and macrovascular complications in people with prediabetes. Dapagliflozin is a potent, highly selective, orally active inhibitor of human renal SGLT2. The chemical structure of dapagliflozin is: [ka] It is.

[0006] The present disclosure relates to methods of reducing the risk of developing type 2 diabetes and treating pre-diabetes with SGLT2 inhibitors, such as dapagliflozin. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] American Diabetes Association.3.Prevention or delay of type 2 diabetes.Diabetes Care.2021;44(Suppl 1):S34-9

[0008] [Non-Patent Document 2] Bonnet F and Scheen A.Understanding and overcoming metformin gastrointestinal intolerance.Diabetes Obes Metab.2017;19(4):473-8 Summary of the Invention [Means for solving the problem]

[0009] The present disclosure relates to methods for reducing the risk of developing type 2 diabetes in a patient in need thereof. In some embodiments, the methods include administering an effective amount of a sodium glucose cotransporter type 2 (SGLT2) inhibitor to the patient, wherein the patient has an HbA1c of 5.7%-6.4% and / or a fasting glucose of 100-125 mg / dl.

[0010] Also disclosed are methods of treating prediabetes in a patient in need thereof. In some embodiments, the methods include administering an effective amount of an SGLT2 inhibitor to the patient, wherein the patient has an HbA1c of 5.7%-6.4% and / or a fasting glucose of 100-125 mg / dl.

[0011] In some embodiments of the methods disclosed herein, the patient has type 1 diabetes (T1D). In some embodiments, the patient has type 2 diabetes (T2D). In some embodiments, the patient does not have T1D or T2D. In some embodiments, the patient has not previously been administered prescription medication for diabetes. In some embodiments, the patient does not have chronic kidney disease (CKD) and / or heart failure (HF).

[0012] In any of the embodiments disclosed herein, the SGLT2 inhibitor is dapagliflozin, canagliflozin, empagliflozin, sotagliflozin, ipragliflozin or ertugliflozin, or a pharma- ceutically acceptable salt, solvate, mixed solvate, complex, or prodrug thereof. In at least one embodiment, the SGLT2 inhibitor is dapagliflozin or a pharma- ceutically acceptable salt, solvate, mixed solvate, complex, or prodrug thereof. In at least one embodiment, the dapagliflozin is in the form of a non-crystalline solid. In at least one embodiment, the dapagliflozin is in the form of a crystalline solid. In at least one embodiment, the dapagliflozin has the structure: [ka] It is in the form of an (S)-propylene glycol ((S)-PG) solvate having the formula:

[0013] Further disclosed herein are methods comprising administering an effective amount of an SGLT2 inhibitor, alone or in combination with at least one other therapeutic agent, to a patient in need thereof. In some embodiments, the other therapeutic agent is administered together with the SGLT2 inhibitor in the same or a different pharmaceutical composition. In embodiments where the other therapeutic agent is administered together with the SGLT2 inhibitor in a different pharmaceutical composition, the SGLT2 inhibitor and the other therapeutic agent are administered at the same time or at different times. In some embodiments, the other therapeutic agent is an antidiabetic agent, an antiobesity agent, an antihyperlipidemic agent, an antiatherosclerotic agent, an antihypertensive agent, an antiplatelet agent, an antithrombotic agent, or an anticoagulant agent. In some embodiments, the other therapeutic agent is an angiotensin converting enzyme inhibitor (ACE-I). In some embodiments, the other therapeutic agent is an angiotensin receptor blocker (ARB). In some embodiments, the ACE-I is selected from captopril, enalapril, and lisinopril. In some embodiments, the ARB is selected from valsartan, losartan, and irbesartan.

[0014] In some embodiments, the methods disclosed herein include administering to a patient an SGLT2 inhibitor, such as dapagliflozin or a pharma- ceutically acceptable salt, solvate, mixed solvate, complex, or prodrug thereof, at a dose of 2.5 mg, 5.0 mg, or 10 mg once daily. In at least one embodiment, the dose is 2.5 mg. In at least one embodiment, the dose is 5 mg. In some embodiments, the SGLT2 inhibitor, such as dapagliflozin, is in the form of a tablet.

[0015] In some embodiments of the methods disclosed herein, the patient is administered at least 39 mL / min / 1.73 m 2 More than 67mL / min / 1.73m 2 For example, in some embodiments, patients had an eGFR of 60 mL / min / 1.73 m prior to administration. 2 had an eGFR of ≥ 1.

[0016] In some embodiments, the methods disclosed herein provide a 25% reduction in the relative risk of developing T2D. In some embodiments, the methods disclosed herein provide a 30% reduction in the relative risk of developing T2D. In some embodiments, the methods disclosed herein provide a 3% or greater reduction in the absolute risk of developing T2D over 1.75 years. In at least some embodiments, the methods provide a hazard ratio of 0.65 to 0.8. For example, in some embodiments, the methods disclosed herein provide a hazard ratio of 0.75, 0.72, or 0.69.

[0017] In some embodiments disclosed herein, the patient is diagnosed with the following conditions: (a) The patient is 2 having a body mass index (BMI) of or above; (b) the patient has a first-degree relative with T2D; (c) the patient has a history of hypertension; (d) the patient has a history of dyslipidemia; (e) the patient has had previous gestational diabetes; and / or (f) the patient has polycystic ovary syndrome; Satisfy at least one of the following:

[0018] In some embodiments of the methods disclosed herein, the patient is maintained at a weight of 25 kg / m 2 For example, in some embodiments, the patient has a BMI of 30 kg / m 2 Have a BMI of 100 or above.

[0019] In some embodiments of the methods disclosed herein, the patient is 45 years of age or older and has a blood pressure of 30 kg / m or more if non-Asian. 2 or 27 kg / m for Asians 2 In some embodiments of the methods disclosed herein, the patient has a body mass index greater than or equal to: (g) the patient does not have a fasting plasma glucose of 7 mmol / L or greater; (h) the patient does not have T2D; (i) Patients did not have HF; (j) the patient does not have CKD stages 3 to 5; and / or (k) The patient does not have severe hepatic impairment according to the Child-Pugh classification of 3. Satisfy one or more of the following:

[0020] In some embodiments of the methods disclosed herein, prior to administration, the patient accesses a web page and answers predetermined questions, and the patient is determined to be eligible to purchase an SGLT2 inhibitor based on the answers provided. In some embodiments, administration does not require a prescription.

[0021] In some embodiments, the methods disclosed herein result in a reduced risk of developing microvascular and / or macrovascular complications. For example, in at least one embodiment, the methods disclosed herein result in a 28% reduction in the relative risk of developing microvascular complications. In some embodiments, the methods disclosed herein reduce blood pressure. In some embodiments, the methods disclosed herein reduce body weight.

[0022] In the following description, specific details are set forth to provide a thorough understanding of various embodiments. However, those skilled in the art will understand that the disclosed embodiments may be practiced without these details. These and other embodiments will become apparent upon reference to the following detailed description and the accompanying drawings. [Brief description of the drawings]

[0023] [Figure 1] FIG. 1 shows the changes in insulin resistance, beta cell function, insulin, and glucose levels during the progression from prediabetes to T2D. [Diagram 2]FIG. 2 shows predicted 24-h glucosuria in prediabetic patients in the DAPA-CKD(10 mg) and DAPA-HF(10 mg) studies and in prediabetic patients taking 5 mg dapagliflozin and with various eGFR values. [Diagram 3] Figure 3 shows the time to worsening of blood pressure, analyzing subgroups of the DECLARE study. CI refers to confidence interval; D refers to dapagliflozin 10 mg; FAS refers to the full analysis set; HR refers to hazard ratio; N refers to number of participants; P refers to placebo; UACR refers to urinary albumin-to-creatinine ratio; and N at risk is the number of participants at risk at the start of the period. [Figure 4] FIG. 4 shows the study scheme for the clinical trial described in Example 6. [Diagram 5] Figure 5 shows a web app featuring the technology-assisted self-selection (TASS) tool with software-as-a-medical-device (SaMD) functionality described in Example 7. DFL refers to drug label, AAD refers to ask a doctor, and SaMD refers to programmed medical device. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] The present disclosure relates to a method of reducing the risk of developing type 2 diabetes in a patient in need thereof, the method comprising administering to the patient an effective amount of a sodium glucose cotransporter type 2 (SGLT2) inhibitor, such as dapagliflozin, wherein the patient has an HbA1c of 5.7%-6.4%, and / or a fasting glucose of 100-125 mg / dl.

[0025] The present disclosure also relates to a method of treating prediabetes in a patient in need thereof, the method comprising administering an effective amount of an SGLT2 inhibitor, such as dapagliflozin, to the patient, wherein the patient has an HbA1c of 5.7%-6.4%, and / or a fasting glucose of 100-125 mg / dl.

[0026] In some embodiments, the SGLT2 inhibitor, such as dapagliflozin, or a pharma- ceutically acceptable salt, solvate, mixed solvate, complex, or prodrug thereof, is administered once daily at a dose of 2.5 mg, 5.0 mg, or 10 mg. In at least one embodiment, the dose is 2.5 mg. In at least one embodiment, the dose is 5 mg. In some embodiments, the SGLT2 inhibitor, such as dapagliflozin, is in the form of a tablet.

[0027] In some embodiments, the SGLT2 inhibitor, e.g., dapagliflozin, is administered together with at least one other therapeutic agent (e.g., an antidiabetic agent) in the same or different compositions, at the same time or at different times.

[0028] I. Definition The terms "comprise," "have," "include," and "contain" are to be construed as open-ended terms (i.e., meaning "including, but not limited to"), unless otherwise noted.

[0029] The term "or" is used herein to mean, and is used interchangeably with, the term "and / or," unless the context clearly indicates otherwise. The term "and / or" as used herein in phrases such as "A and / or B" is intended to include the following embodiments: "A and B," "A or B," "A" and "B."

[0030] Similarly, the term "and / or" as used in phrases such as "A, B, and / or C" is intended to include each of the following embodiments: A, B, and C; A, B or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0031] The terms "treating" or "treatment" or "treat" refer to therapeutic measures (e.g., administration of a drug to a subject) that cure, slow, reduce symptoms, and / or halt progression of a diagnosed pathological disease, disorder, or condition, such as prediabetes. Treatment need not result in a complete cure of the condition; partial inhibition or alleviation of the condition being treated is included within the term.

[0032] The phrase "reducing the risk of developing" a pathological condition and / or disorder, such as T2D, refers to preventing and / or delaying the onset of a targeted pathological condition and / or disorder, such as T2D. Thus, as used herein, "reducing the risk of developing T2D" includes reducing the incidence of developing T2D compared to patients not treated with the methods disclosed herein.

[0033] The term "about" as used herein refers to within 20%, such as within 10%, and further such as within 5% of a given value or range.

[0034] The term "other therapeutic agent" as used herein refers to a therapeutic agent other than the SLGT2 inhibitors or prodrugs thereof of the present disclosure.

[0035] The term "prodrug" as used herein includes esters and carbonates that can be converted to dapagliflozin, for example, under physiological conditions or by solvolysis. Thus, the term prodrug includes pharma- ceutically acceptable metabolic precursors of dapagliflozin. The term prodrug also includes covalently bonded carriers that release dapagliflozin in vivo when such prodrugs are administered to a patient. Non-limiting examples of prodrugs include esters and carbonates formed by reacting one or more hydroxyls of dapagliflozin with an alkyl, alkoxy, or aryl-substituted acylating agent using procedures known to those skilled in the art to produce acetates, pivalates, methyl carbonates, benzoates, and the like. Various forms of prodrugs are known in the art. For examples of such prodrug derivatives, see: (1) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); (2) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Prodrugs", by H. Bundgaard p. 113-191 (1991); (3) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); (4) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); and (5) N. Kakeya, et al., Chem Pharm See Bull, 32, 692 (1984).

[0036] A "therapeutically effective amount" or "effective amount" refers to an amount of an active pharmaceutical ingredient effective to achieve a desired therapeutic effect (e.g., reducing the risk of developing type 2 diabetes and / or treating pre-diabetes).

[0037] The terms "patient" and "subject" in need of reducing the risk of developing type 2 diabetes (T2D) or treating prediabetes are used interchangeably to refer to an adult individual with an HbA1c value of 5.7% to 6.4% (5.7%≦HbA1c<6.5%) and / or fasting glucose of 100 to 125 mg / dl. (See American Diabetes Association. 2. Classification and diagnosis of diabetes: standards of medical care in diabetes-2021. Diabetes Care. 2021; 44(Suppl 1):S15-33.) In addition, as used herein, "patient" or "subject" in need of reducing the risk of developing T2D includes patients prone to T2D and patients in whom T2D should be prevented.

[0038] As shown in Figure 1, the progression of the disease from prediabetes to T2D begins with insulin resistance. First, the pancreas is able to cope with the increased demand for insulin and produces more insulin to overcome insulin resistance. During this period, blood glucose levels are kept in the normal range. After a period of time, the function of insulin-producing beta cells in the pancreas begins to decline, resulting in an increase in glucose levels. Initially, glucose levels rise to the prediabetic range, but over time, the decline in beta cells progresses and T2D glucose levels are reached. During this process, people may not show noticeable symptoms and may already have developed complications by the time they are diagnosed with T2D. (Honigberg et al.Cardiovascular and kidney outcomes across the glycemic spectrum:insights from the UK biobank.J Amer Coll Cardiol.2021;78(5):453-64;Faghihimani et al.Evaluation of Peripheral Arterial Disease in Prediabetes.Int J Prev Med.2014;5(9):1099-105).

[0039] The terms "administer", "administering", "administration", and the like, as used herein, refer to methods that can be used to enable delivery of an agent, e.g., an SGLT2 inhibitor, as described herein. Administration techniques that can be used with the agents and methods described herein can be found, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current edition, Pergamon; and Remington's, Pharmaceutical Sciences, current edition, Mack Publishing Co., Easton, Pa. In at least one embodiment, the SGLT2 inhibitor is administered orally.

[0040] Administration of an SGLT2 inhibitor "in combination with one or more other therapeutic agents" includes simultaneous (concurrent) or sequential administration in the same or different pharmaceutical compositions (e.g. pills, tablets, capsules), if simultaneous.

[0041] "Other therapeutic agents" include "standard of care heart failure (HF) agents," "standard of care chronic kidney disease (CKD) agents," and any other therapeutic agents described herein.

[0042] "DAPA-HF", "DAPA-CKD", and / or "DECLARE" refer to AstraZeneca's placebo-controlled clinical trial. "DAPA-HF" refers to the DAPA-HF clinical trial, which has ClinicalTrials.gov number NCT03036124. The "DAPA-HF" trial is discussed in U.S. Patent Publication No. 2021 / 0260083, which is incorporated by reference in its entirety (see also Inzucchi SE, et al. Dapagliflozin and the incidence of type 2 diabetes in patients with heart failure and reduced ejection fraction: an exploratory analysis from DAPA-HF. Diabetes Care. 2021;44(2):586-94). "DAPA-CKD" refers to the DAPA-CKD clinical trial, which has ClinicalTrials.gov number NCT03036150. The "DAPA-CKD" trial is discussed in U.S. Patent Application Nos. 17 / 347,230 and 17 / 219,992, which are incorporated by reference in their entireties. (See also Rossing, et al. Dapagliflozin and New-Onset Type 2 Diabetes in Patients with Chronic Kidney Disease or Heart Failure: Pooled Analysis of the DAPA-CKD and DAPA-HF Trials. Lancet Diabetes Endocrinol. 2021; S2213-8587(21)00295-3.) "DECLARE" refers to the DECLARE-TIMI58 clinical trial, which has ClinicalTrials.gov number NCT01730534. (See Stephen et al. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes, N Engl J Med 2019;380:347-357.)

[0043] "eGFR slope" is the change in eGFP over time. "eGFR" stands for estimated glomerular filtration rate. eGFR slope is a measure associated with progressive loss of renal function (microvascular complications) in prediabetic patients and can be used to demonstrate clinical significance due to: 1) the prevalence of microvascular complications such as declining renal function in prediabetic patients prior to T2D diagnosis, 2) the higher risk of CKD in the prediabetic range compared to normoglycemia, and 3) the accelerated decline in renal function (eGFR) in patients approaching the prediabetic state compared to the decline in renal function (eGFR) associated with normal aging.

[0044] II.SGLT2 inhibitors As provided herein, SGLT2 inhibitors are used to reduce the risk of developing type 2 diabetes or to treat pre-diabetes in a patient.

[0045] Sodium-glucose cotransporter 2 (SGLT2) is a sodium-dependent renal protein responsible for the reabsorption of glucose into the blood. SGLT2 inhibitors (also known as "gliflozins") are a class of drugs used to lower blood glucose in type 2 diabetes patients by inhibiting the renal SGLT2 protein. As a result, more sugar is excreted in the urine.

[0046] In some embodiments, the SGLT2 inhibitor is as described in U.S. Pat. No. 6,515,177, WO 2003 / 099836, U.S. 2006 / 0194809, WO 2006 / 0063722A1, WO 2002 / 083066, U.S. 2003 / 0064935, U.S. Pat. No. 6,777,626. No. 4,112, U.S. Patent Application Publication Nos. 2005 / 0209166, 2006 / 0074031, 2006 / 0035841, 2006 / 0009400, 2006 / 0025349, 2006 / 0122126, 2006 / 0019948, 2006 / 0194809, U.S. Patent Patent Nos. 6,908,905, 6,815,428, 6,555,519, 6,683,056, European Patent Application Publication No. 598359A1, JP035988, U.S. Patent No. 5,731,292, European Patent Application Publication No. 0850948A1, U.S. Patent No. 6,048,842, JP-A-09-188625 No. 5,767,094, JP-A-08-027006, EP-A-684254A1, JP-A-10-245391 (Dainippon), U.S. Patent Application Publication No. 2005 / 0233982 (Boehringer Ingelheim Corp.), U.S. Patent Application Publication No. 2005 / 0119192 (Kissei Pharmaceutical Co.), WO 2006 / 035796 (Kissei Pharmaceutical Co.), JP 2006-117651 A (Taisho Pharmaceutical Co.), JP 2004-4359630 A (Yamanouchi Pharmaceutical Co.), WO 2006 / 080421 (Chugai Seiyaku Kabushiki Kaishi), U.S. Patent Application Publication No. 2005 / 0233988 (Tanabe Seiyaku Co.), WO 2005 / 012321 (Tanabe Seiyaku Co.), U.S. Patent No. 7,015,201 (Ajinomoto Co.), WO 2006 / 058597 (Merck Patent GmbH), WO 2006 / 011469 (Chugai Seiyaku Kabushiki Kaisha), U.S. Patent Application Publication No. 2003 / 0195235 (Johnson & Johnson), and WO 2006 / 037537 (Boehringer Ingelheim).

[0047] In some embodiments, the SGLT2 inhibitor is selected from those disclosed in Tsujihara, K. et al., Chem. Pharm. Bull., 44:1174-1180(1996); Hongu, M. et al., Chem. Pharm. Bull., 46:22-33(1998); Hongu, M. et al., Chem. Pharm. Bull., 46:1545-1555(1998); and Oku, A. et al., Diabetes, 48:1794-1800(1999).

[0048] In some embodiments, the SGLT2 inhibitor can be dapagliflozin (FARXIGA®), canagliflozin (INVOKANA®), empagliflozin (JARDIANCE®), ertugliflozin (STEGLATRO®), sotagliflozin, ipragliflozin, tofogliflozin, or luseogliflozin, or a pharma- ceutically acceptable salt, solvate, mixed solvate, complex, or prodrug of any of the foregoing.

[0049] In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharma- ceutically acceptable salt, solvate, mixed solvate, complex, or prodrug thereof, such as those described in U.S. Pat. Nos. 6,414,126 and 6,515,117, which are incorporated by reference in their entireties.

[0050] Dapagliflozin (Forxiga™ / Farxiga™) is a highly selective and reversible inhibitor of SGLT2. The mechanism of action of dapagliflozin results in direct and insulin-independent glucose excretion by the kidney, reducing blood glucose levels in patients with type 2 diabetes (T2D). In addition, dapagliflozin has mild diuretic and natriuretic effects. The sustained loss of glucose with associated calories in the urine leads to a consistent and sustained reduction in total body weight, primarily as a result of the reduction in fat mass, including both visceral and subcutaneous adipose tissue. In addition, dapagliflozin has also been shown to reduce BP and albuminuria, two prognostic risk factors for the progression of CKD.

[0051] The chemical structure of dapagliflozin is: [ka]

[0052] In some embodiments, dapagliflozin is in the form of a non-crystalline solid. In some embodiments, dapagliflozin is in the form of a crystalline solid. In some embodiments, dapagliflozin is in the form of an (S)-propylene glycol ((S)-PG) solvate, which has the following structure: [ka]

[0053] Methods for preparing (S)-PG solvates of dapagliflozin, including crystalline S-PG solvates, are provided in U.S. Pat. No. 7,919,598, the contents of which are incorporated by reference.

[0054] In some embodiments, the SGLT2 inhibitor, e.g., dapagliflozin, is administered with at least one other therapeutic agent.

[0055] III. Other Therapeutic Agents Administration of an SGLT2 inhibitor "in combination with one or more other therapeutic agents" includes simultaneous (concurrent) or sequential administration in the same or different pharmaceutical compositions (e.g. pills, tablets, capsules), in the case of simultaneous administration.

[0056] "Other therapeutic agents" include standard of care heart failure (HF) agents, standard of care chronic kidney disease (CKD) agents, and any other therapeutic agents described herein.

[0057] Exemplary standard of care CKD drugs include angiotensin-converting enzyme inhibitors (ACE-I or ACE inhibitors) and angiotensin receptor blockers (ARBs). Standard of care CKD drugs and their dosages are familiar to physicians who examine and treat patients with CKD. Representative examples of ACE inhibitors include captopril, enalapril, and lisinopril. Representative examples of ARBs include valsartan, losartan, and irbesartan.

[0058] Exemplary standard of care HF drugs include, for example, drugs or drug classes other than SGLT2 inhibitors used to treat HF ​​(such as HFrEF). Standard of care HF drugs as described herein may be used prior to and / or during administration of an SGLT2 inhibitor, e.g., dapagliflozin. Standard of care HF drugs and their dosages are well known to cardiologists and other physicians who see and treat patients with HFrEF. Exemplary standard of care HF drugs include: angiotensin-converting enzyme (ACE) inhibitors; angiotensin receptor blockers (ARBs); beta-blockers; mineralocorticoid receptor agents such as mineralocorticoid receptor antagonists (MRAs), and neprilysin inhibitors.

[0059] Other drugs that may be considered "standard of care HF drugs" include diuretics and loop diuretics (e.g., furosemide, bumetanide, and torsemide), digoxin, cardiac pump drugs, selective sinus node inhibitors, ivabradine (a sinoatrial (SA) node modulator), aldosterone antagonists, vasodilators, calcium channel blockers (if the patient does not have systolic heart failure), hydralazine / isosorbide dinitrate, or other HF drugs within clinical practice guidelines. (See Yancy CWet al., "ACC / AHA / HFSA focused update of the 2013 ACCF / AHA guideline for the management of heart failure: A report of the American College of Cardiology / American Heart Association task force on clinical practice guidelines and the Heart Failure Society of America, J Am Coll Cardiol. 70(6):776-803 (2017).)

[0060] Further disclosed herein are methods comprising administering to a patient in need thereof an effective amount of an SGLT2 inhibitor, alone or in combination with at least one other therapeutic agent. In some embodiments, the other therapeutic agent is administered together with the SGLT2 inhibitor in the same or a different pharmaceutical composition, and if in different pharmaceutical compositions, at the same time or at different times.

[0061] In some embodiments, the other therapeutic agent is an antidiabetic agent, an antiobesity agent, an antihyperlipidemic agent, an antiatherosclerotic agent, an antihypertensive agent, an antiplatelet agent, an antithrombotic agent, a mineralocorticoid antagonist, a diuretic agent, and / or an anticoagulant.For example, in at least one embodiment, the other therapeutic agent is an antidiabetic agent, such as a biguanide and / or a DPP4 inhibitor.An exemplary biguanide is metformin or a pharmaceutically acceptable salt thereof.Exemplary DPP4 inhibitors include saxagliptin, linagliptin, sitagliptin, and pharmaceutically acceptable salts thereof.

[0062] In some embodiments, the antidiabetic agent is selected from a biguanide. In some embodiments, the biguanide is metformin or a pharma- ceutically acceptable salt thereof. In some embodiments, the biguanide is metformin HCl. In some embodiments, the biguanide is phenformin.

[0063] In some embodiments, the antidiabetic agent is selected from sulfonylureas and pharma- ceutically acceptable salts thereof. In some embodiments, the sulfonylurea is selected from glyburide, glimepiride, glipizide, gliclazide, and chlorpropamide. In some embodiments, the sulfonylurea is glyburide. In some embodiments, the sulfonylurea is glipizide.

[0064] In some embodiments, the antidiabetic agent is selected from a glucosidase inhibitor and its pharma- ceutically acceptable salts, hi some embodiments, the glucosidase inhibitor is selected from acarbose and miglitol.

[0065] In some embodiments, the antidiabetic agent is selected from a PPARγ agonist. In some embodiments, the PPARγ agonist is selected from a thiazolidinedione. In some embodiments, the thiazolidinedione is troglitazone (e.g., REZULIN® from Warner-Lambert, disclosed in U.S. Pat. No. 4,572,912), rosiglitazone (e.g., manufactured by SKB), pioglitazone (e.g., manufactured by Takeda), MCC-555 from Mitsubishi (disclosed in U.S. Pat. No. 5,594,016), GL-26 from Glaxo-Wellcome, or the like. 2570, englitazone (e.g., CP-68722 manufactured by Pfizer), darglitazone (e.g., CP-86325 manufactured by Pfizer), isaglitazone (e.g., manufactured by MIT / J&J), JTT-501 (JPNT / P&U), L-895645 (Merck), R-119702 (Sankyo / WL), N,N-2344 (Dr. Reddy / NN), or YM-440 (Yamanouchi).

[0066] In some embodiments, the thiazolidinedione is selected from pioglitazone and rosiglitazone. In some embodiments, the thiazolidinedione is pioglitazone. In some embodiments, the thiazolidinedione is rosiglitazone.

[0067] In some embodiments, the antidiabetic agent is selected from PPAR alpha / gamma dual agonists and pharma- ceutically acceptable salts thereof. In some embodiments, the PPAR alpha / gamma dual agonist is selected from AR-HO39242 (Astra / Zeneca), GW-409544 (Glaxo-Wellcome), KRP297 (Kyorin Merck), those disclosed by Murakami et al., "A Novel Insulin Sensitizer Acts As a Coligand for Peroxisome Proliferation-Activated Receptor Alpha (PPAR alpha) and PPAR gamma. Effect on PPAR alpha Activation on Abnormal Lipid Metabolism in Liver of Zucker Fatty Rats," Diabetes, 47:1841-1847 (1998), and those disclosed in U.S. Patent No. 6,414,002.

[0068] In some embodiments, the antidiabetic agent is selected from an aP2 inhibitor and pharma- ceutically acceptable salts thereof, hi some embodiments, the aP2 inhibitor is selected from those disclosed in U.S. Patent No. 6,548,529.

[0069] In some embodiments, the antidiabetic agent is selected from DPP4 inhibitors and pharma- ceutically acceptable salts thereof. In some embodiments, the DPP4 inhibitor is one disclosed in U.S. Pat. No. 6,395,767, WO 99 / 38501, WO 99 / 46272, WO 99 / 67279 (PROBIODRUG), WO 99 / 67278 (PROBIODRUG), WO 99 / 61431 (PROBIODRUG), NVP-DPP728A (1-[[[2-[(5-cyanopyridin-2-yl)amino]ethyl]amino]acetyl]-2-cyano-(S)-pyrrolidine) (Novartis), one disclosed in Hughes et al., Biochemistry, 38(36):11597-11603 (1999), TSL-225 (tryptophyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Yamada et al. al., Bioorg. & Med. Chem. Lett., 8:1537-1540 (1998)), 2-cyanopyrrolidides and 4-cyanopyrrolidides (disclosed in Ashworth et al, Bioorg. & Med. Chem. Lett., 6(22):1163-1166 and 2745-2748 (1996)).

[0070] In some embodiments, the DPP4 inhibitor is selected from saxagliptin, vildagliptin, linagliptin, alogliptin, and sitagliptin. In some embodiments, the DPP4 inhibitor is selected from saxagliptin and pharma- ceutically acceptable salts thereof. In some embodiments, the DPP4 inhibitor is saxagliptin. In some embodiments, the DPP4 inhibitor is saxagliptin HCl.

[0071] In some cases, the other therapeutic agent is an antidiabetic agent, such as a biguanide (e.g., metformin) and / or a DPP4 inhibitor (e.g., saxagliptin, linagliptin, or sitagliptin). Representative examples of SGLT2 inhibitor + antidiabetic agent combination formulations include the following: dapagliflozin / metformin extended release (XIGDUO®), dapagliflozin / saxagliptin (QTERN®), dapagliflozin / saxagliptin / metformin (QTERNMET®), canagliflozin / metformin (INVOKAMET®), canagliflozin / metformin extended release (INVOKAMET XR®), empagliflozin / linagliptin (GLYXAMBI®), empagliflozin / metformin (SYNJARDY®), empagliflozin / metformin extended release (SYNJARDY XR®), ertugliflozin / metformin (STEGLUROMET®), and ertugliflozin / sitagliptin (STEGLUJAN®).

[0072] In some embodiments, the antidiabetic agent is selected from a meglitinide and a pharma- ceutically acceptable salt thereof. In some embodiments, the meglitinide is selected from repaglinide, nateglinide (Novartis), and KAD1229 (PF / Kissei). In some embodiments, the meglitinide is repaglinide.

[0073] In some embodiments, the antidiabetic agent is selected from a glucokinase activator, a DGAT-1 inhibitor, and pharma- ceutically acceptable salts thereof. In some embodiments, the glucokinase activator is selected from those disclosed in WO 2008 / 005964. In some embodiments, the DGAT-1 inhibitor is selected from those disclosed in U.S. Patent Application Publication No. 2008 / 0090876A1.

[0074] In some embodiments, the antidiabetic agent is selected from insulin, a GLP-1 receptor agonist, and pharma- ceutically acceptable salts thereof, hi some embodiments, the antidiabetic agent is insulin.

[0075] In some embodiments, the at least one other therapeutic agent is selected from an anti-obesity agent and its pharma- ceutically acceptable salts. In some embodiments, the anti-obesity agent is selected from a beta 3 adrenergic agonist, a lipase inhibitor, a serotonin (and dopamine) reuptake inhibitor, a thyroid receptor beta modulator, an MCH-1 receptor antagonist, an agonist of the 5-HT2c receptor, an appetite suppressant, a neuropeptide Y (NPY) antagonist, a leptin analog, an MC4 receptor agonist, and an antagonist of the cannabinoid receptor.

[0076] In some embodiments, the beta 3 adrenergic agonist is selected from AJ9677 (Takeda / Dainippon), SB-418790, L750355 (Merck), CP331648 (Pfizer), other known beta 3 agonists such as those disclosed in U.S. Patent Nos. 5,541,204, 5,770,615, 5,491,134, 5,776,983, and 5,488,064. In some embodiments, the beta 3 adrenergic agonist is selected from AJ9677, L750355, and CP331648.

[0077] In some embodiments, the at least one other therapeutic agent is selected from an antihyperlipidemic agent and its pharma- ceutically acceptable salt. In some embodiments, the hyperlipidemic agent is selected from an HMG CoA reductase inhibitor. In some embodiments, the HMG-CoA reductase inhibitor is selected from mevastatin and related compounds disclosed in U.S. Pat. No. 3,983,140, ​​lovastatin (mevinolin) and related compounds disclosed in U.S. Pat. No. 4,231,938, pravastatin and related compounds such as those disclosed in U.S. Pat. No. 4,346,227, simvastatin and related compounds disclosed in U.S. Pat. Nos. 4,448,784 and 4,450,171, and rosuvastatin and related statin compounds disclosed in U.S. Pat. No. 5,753,675.

[0078] In some embodiments, the at least one other therapeutic agent is selected from an antihypertensive agent and its pharma- ceutically acceptable salts. In some embodiments, the antihypertensive agent is selected from a beta-adrenergic blocker, a calcium channel blocker (L-type and / or T-type), a diuretic, a renin inhibitor, an ACE inhibitor, an AT-1 receptor antagonist, an ET receptor antagonist as disclosed in U.S. Pat. Nos. 5,612,359 and 6,043,265, a dual ET / AII antagonist as disclosed in WO 00 / 01389, a neutral endopeptidase (NEP) inhibitor, a vasopeptidase inhibitor, and a nitrate.

[0079] In some embodiments, the antihypertensive agent is bisoprolol, carvedilol, metaprolol succinate, diltiazem, verapamil, nifedipine, amlodipine, mibefradil, chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, tricrynafen ethacrynate, chlorthalidone, furosemide, musolimine, bumetanide, triamtrenene, amiloride, spironolact In some embodiments, the active ingredient is selected from among benzodiazepine, torsemide, indapamide, metolazone, triamterene, eplerenone, captopril, zofenopril, fosinopril, enalapril, ceranopril, cirazopril, delapril, pentopril, quinapril, ramipril, lisinopril, perindopril, trandolapril, losartan, irbesartan, valsartan, candesartan, sitaxsentan, atrsentan, omapatrilat, gemopatrilat, hydralazine, isosorbide dinitrate, nitroglycerin, and nitroprusside.

[0080] In some embodiments, the at least one other therapeutic agent is selected from an antiplatelet agent and a pharma- ceutically acceptable salt thereof, hi some embodiments, the antiplatelet agent is selected from clopidogrel, ticlopidine, prasugrel, and aspirin.

[0081] In some embodiments, the at least one other therapeutic agent is selected from antithrombotic agents, anticoagulants, and pharma- ceutically acceptable salts thereof. In some embodiments, the antithrombotic and / or anticoagulant agents are selected from thrombin inhibitors, platelet aggregation inhibitors, PAI-1 inhibitors, inhibitors of alpha-2-antiplasmin, thromboxane receptor antagonists, prostacyclin mimetics, and phosphodiesterase (PDE) inhibitors.

[0082] In some embodiments, the antithrombotic and / or anticoagulant agent is selected from clopidogrel, ticlopidine, prasugrel (Eli Lilly), XR-330, T-686, anti-alpha-2-antiplasmin antibody, ifetroban, dipyridamole, cilostazol, aspirin, ifetroban, picotamide, and ketanserin.

[0083] In some embodiments, the SGLT2 inhibitor, e.g., dapagliflozin, is administered with at least one other therapeutic agent, either in the same or different compositions, and if in different compositions, at the same time or at different times. In some embodiments, the at least one other therapeutic agent is administered before, after, or simultaneously with the SGLT2 inhibitor, e.g., dapagliflozin.

[0084] IV. Methods of Reducing the Risk of Developing Type 2 Diabetes or Treating Prediabetes The present disclosure relates to a method of reducing the risk of developing type 2 diabetes in a patient in need thereof, the method comprising administering to the patient an effective amount of a sodium glucose cotransporter type 2 (SGLT2) inhibitor, such as dapagliflozin, wherein the patient has an HbA1c of 5.7%-6.4%, and / or a fasting glucose of 100-125 mg / dl.

[0085] The present disclosure also relates to a method of treating prediabetes in a patient in need thereof, the method comprising administering an effective amount of an SGLT2 inhibitor, such as dapagliflozin, to the patient, wherein the patient has an HbA1c of 5.7%-6.4%, and / or a fasting glucose of 100-125 mg / dl.

[0086] In some embodiments, the patient does not have type 1 diabetes (T1D) or type 2 diabetes (T2D). In some embodiments, the patient has not been previously administered prescription medication for diabetes. In some embodiments, the patient does not have chronic kidney disease (CKD) and / or heart failure (HF).

[0087] In at least one embodiment, the SGLT2 inhibitor is dapagliflozin or a pharma- ceutically acceptable salt, solvate, mixed solvate, complex, or prodrug thereof. In some embodiments, the dapagliflozin is in the form of a non-crystalline solid. In some embodiments, the dapagliflozin is in the form of a crystalline solid. In some embodiments, the dapagliflozin is in the form of a (S)-propylene glycol ((S)-PG) solvate, which has the following structure: [ka]

[0088] An effective amount or a therapeutically effective amount refers to an amount of at least one compound or pharmaceutical composition of the present disclosure, comprising at least one such compound of the present disclosure, that is effective to produce at least one therapeutic effect when administered to a patient as a single dose or as part of a series of doses. The dose may depend on the patient's body mass, weight, and / or blood volume. The patient may generally be monitored for therapeutic effectiveness using an assay appropriate for the disease, disorder, and / or condition being treated or prevented. The level of the compound administered to the patient may be monitored by determining the level of the compound (or a metabolite of the compound) in a biological fluid, such as blood, a blood fraction (e.g., serum), urine, and / or other biological sample from the patient. To measure the level of the compound over the course of a treatment regimen, any method practiced in the art for detecting a compound or its metabolite may be used.

[0089] The dose of the compounds described herein may depend on the patient's condition, i.e., the stage of the disease, the severity of the symptoms caused by the disease, general health, as well as age, sex, and weight, and other factors apparent to one skilled in the art.

[0090] In some embodiments, at least one compound selected from SGLT2 inhibitors, such as dapagliflozin and prodrugs thereof, is administered at a dose equivalent to about 1 to about 500 mg / day of dapagliflozin. In some embodiments, at least one compound selected from SGLT2 inhibitors, such as dapagliflozin and prodrugs thereof, is administered at a dose equivalent to about 2 to about 400 mg / day of dapagliflozin. In some embodiments, at least one compound selected from SGLT2 inhibitors, such as dapagliflozin and prodrugs thereof, is administered at a dose equivalent to about 0.5 to about 200 mg / day of dapagliflozin. In some embodiments, at least one compound selected from SGLT2 inhibitors, such as dapagliflozin and prodrugs thereof, is administered at a dose equivalent to about 1 to about 100 mg / day of dapagliflozin. In some embodiments, at least one compound selected from SGLT2 inhibitors, such as dapagliflozin and prodrugs thereof, is administered at a dose equivalent to about 1 to about 50 mg / day of dapagliflozin. In some embodiments, at least one compound selected from SGLT2 inhibitors, such as dapagliflozin and prodrugs thereof, is administered at a dose equivalent to about 1 to about 20 mg / day of dapagliflozin. In some embodiments, at least one compound selected from SGLT2 inhibitors, such as dapagliflozin and prodrugs thereof, is administered at a dose equivalent to about 2.5 to about 20 mg / day of dapagliflozin. In some embodiments, at least one compound selected from SGLT2 inhibitors, such as dapagliflozin and prodrugs thereof, is administered at a dose equivalent to about 2.5 to about 10 mg / day of dapagliflozin. In some embodiments, at least one compound selected from SGLT2 inhibitors, such as dapagliflozin and prodrugs thereof, is administered at a dose equivalent to about 10 mg / day of dapagliflozin. In some embodiments, at least one compound selected from SGLT2 inhibitors, such as dapagliflozin and prodrugs thereof, is administered at a dose equivalent to about 5 mg / day of dapagliflozin.In some embodiments, at least one compound selected from SGLT2 inhibitors, e.g., dapagliflozin, a prodrug thereof, is administered at a dose equivalent to about 2.5 mg / day of dapagliflozin.

[0091] In some embodiments, the SGLT2 inhibitor (e.g., dapagliflozin) is orally administered to a patient once daily. In some embodiments, the dapagliflozin is orally administered to a patient once daily at a dose of 2.5 mg, 5.0 mg, or 10 mg. In at least one embodiment, the oral dose of dapagliflozin administered is 2.5 mg. In at least one embodiment, the oral dose of dapagliflozin administered is 5.0 mg.

[0092] In some embodiments, the method further comprises administering at least one other therapeutic agent to the patient. In some embodiments, the other therapeutic agent is administered in the same composition with the SGLT2 inhibitor. In some embodiments, the other therapeutic agent is administered in a different pharmaceutical composition and at the same or different time points with the SGLT2 inhibitor. In some embodiments, the weight ratio of the combination of at least one compound selected from SGLT2 inhibitors, e.g., dapagliflozin, and prodrugs thereof, and at least one other therapeutic agent is in the range of about 0.01:1 to about 300:1. In some embodiments, the weight ratio of the combination of at least one compound selected from SGLT2 inhibitors, e.g., dapagliflozin, and prodrugs thereof, and at least one other therapeutic agent is in the range of about 0.1:1 to about 200:1. In some embodiments, the weight ratio of the combination of at least one compound selected from SGLT2 inhibitors, e.g., dapagliflozin, and prodrugs thereof, and at least one other therapeutic agent is in the range of about 0.2:1 to about 100:1.

[0093] In some embodiments, the other therapeutic agent is an antidiabetic agent, an antiobesity agent, an antihyperlipidemic agent, an antiatherosclerotic agent, an antihypertensive agent, an antiplatelet agent, an antithrombotic agent, or an anticoagulant agent. In some embodiments, the other therapeutic agent is an antidiabetic agent. In some embodiments, the antidiabetic agent is a biguanide and / or a DPP4 inhibitor. In some embodiments, the biguanide is metformin or a pharmaceutically acceptable salt thereof. In some embodiments, the DPP4 inhibitor is saxagliptin, linagliptin, or sitagliptin, or a pharmaceutically acceptable salt thereof.

[0094] In some embodiments, the at least one other therapeutic agent is an angiotensin-converting enzyme inhibitor (ACE inhibitor), such as captopril, enalapril, and lisinopril. In some embodiments, the at least one other therapeutic agent is an angiotensin receptor blocker (ARB), such as valsartan, losartan, and irbesartan.

[0095] In some embodiments, prior to administration, the patient is maintained at 45 mL / min / 1.73 m 2 Above 90mL / min / 1.73m 2 In some embodiments, prior to administration, the patient had an eGFR of 60 mL / min / 1.73 m 2 Above 90mL / min / 1.73m 2 In some embodiments, prior to administration, the patient had an eGFR of 39 mL / min / 1.73 m 2 More than 67mL / min / 1.73m 2 For example, in some embodiments, prior to administration, the patient had an eGFR of 60 mL / min / 1.73 m 2 In some embodiments, prior to administration, the patient had an eGFR of 60 mL / min / 1.73 m 2 Above 65mL / min / 1.73m 2 For example, prior to dosing, patients had an eGFR of 61, 62, 63, 64, 65, and / or 66 mL / min / 1.73 m 2 The patients had an eGFR of .

[0096] In some embodiments, the method reduces the risk of developing T2D in the patient. In some embodiments, the method reduces the risk of developing T2D compared to patients not treated with an effective amount of an SGLT2 inhibitor. In some embodiments, the reduction in risk of developing T2D is assessed by measuring the incidence of T2D compared to patients not treated with an effective amount of an SGLT2 inhibitor. In some embodiments, the risk of developing T2D is measured compared to a baseline value measured for the patient before being treated with an effective amount of an SGLT2 inhibitor. In some embodiments, the risk of developing T2D is measured compared to one or more patients not treated with an effective amount of an SGLT2 inhibitor.

[0097] In some embodiments, the method provides a 25% or greater reduction in the relative risk of developing T2D in the patient. For example, in some embodiments, the method provides a 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, and / or 40% reduction in the relative risk. In some embodiments, the method provides a 30% reduction in the relative risk of developing T2D. In some embodiments, the method provides a 25%-35%, 25%-30%, 28%-32%, and / or 29%-31% reduction in the relative risk of developing T2D. In some embodiments, the reduction in the relative risk of developing T2D is measured relative to a baseline value measured for the patient prior to treatment with an effective amount of an SGLT2 inhibitor. In some embodiments described herein, the reduction in the relative risk of developing T2D is measured compared to one or more patients not treated with an effective amount of an SGLT2 inhibitor.

[0098] In some embodiments, the method provides a reduction in the absolute risk of developing T2D of 3% or more over 1.75 years. For example, in at least one embodiment, the method provides a reduction in the absolute risk of developing T2D of 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, and / or 10.0% or more over 1.75 years. In some embodiments, the reduction in the absolute risk of developing T2D is measured relative to a baseline value measured for the patient before being treated with an effective amount of an SGLT2 inhibitor. In some embodiments, the reduction in the absolute risk of developing T2D is measured relative to one or more patients not treated with an effective amount of an SGLT2 inhibitor.

[0099] In some embodiments, the method provides a hazard ratio of 0.65 to 0.8. For example, in some embodiments, the method provides a hazard ratio of 0.65, 0.66, 0.67, 0.68, 0.69, 0.70, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, and / or 0.80. For example, in some embodiments, the hazard ratio is 0.69. In some embodiments, the hazard ratio is 0.72. In some embodiments, the hazard ratio is 0.75.

[0100] In some embodiments, the administration reduces the risk of developing a microvascular and / or macrovascular complication in the patient. For example, in some embodiments, the administration results in a 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, and / or 35% reduction in the relative risk of developing a microvascular complication. In some embodiments, the administration reduces the risk of developing a microvascular and / or macrovascular complication compared to a patient not treated with an effective amount of an SGLT2 inhibitor. In some embodiments, the risk of developing a microvascular and / or macrovascular complication is measured compared to a baseline value measured for the patient before being treated with an effective amount of an SGLT2 inhibitor. In some embodiments, the risk of developing a microvascular and / or macrovascular complication is measured compared to one or more patients not treated with an effective amount of an SGLT2 inhibitor.

[0101] In some embodiments, the administration reduces blood pressure in the patient, in some embodiments, the administration reduces blood pressure compared to a patient not treated with an effective amount of an SGLT2 inhibitor.

[0102] In some embodiments, the administration reduces body weight, in some embodiments, the administration reduces body weight compared to a patient not treated with an effective amount of an SGLT2 inhibitor.

[0103] In some embodiments, the patient being treated has one of the following conditions: (a) The patient is 2 having a BMI of ≥ ; (b) the patient has a first-degree relative with T2D; (c) the patient has a history of hypertension; (d) the patient has a history of dyslipidemia; (e) the patient has had previous gestational diabetes; and / or (f) the patient has polycystic ovary syndrome; Satisfy one or more of the following:

[0104] In some embodiments, the patient meets one or more of conditions (a)-(f) above. In some embodiments, the patient meets each of conditions (a)-(f) above.

[0105] In some embodiments of the methods disclosed herein, the patient is maintained at a weight of 25 kg / m 2 For example, in some embodiments, the patient has a BMI of 30 kg / m 2 Have a BMI of 100 or above.

[0106] In some embodiments, the patient is 45 years of age or older and 30 kg / m 2 or 27 kg / m for Asians 2 have a body mass index of >.

[0107] In some embodiments, the patient being treated has one of the following conditions: (a) the patient does not have a fasting plasma glucose of 7 mmol / L or greater; (b) the patient does not have T2D; (c) patients do not have HF; (d) the patient does not have CKD stages 3 to 5; and / or (e) The patient does not have severe hepatic impairment according to the Child-Pugh classification of 3. Satisfy one or more of the following:

[0108] In some embodiments, the patient meets one or more of conditions (a)-(e) above. In some embodiments, the patient meets each of conditions (a)-(e) above.

[0109] In some embodiments, prior to administration, the patient accesses a web page and answers predetermined questions, and the patient is deemed eligible to purchase the SGLT2 inhibitor based on the answers provided. In some embodiments, the patient receives a prescription after being deemed eligible to purchase the SGLT2 inhibitor. In some embodiments, administration does not require a prescription.

[0110] The following examples provide exemplary embodiments of the present disclosure. Those skilled in the art will recognize numerous modifications and variations that can be made without changing the spirit or scope of the present disclosure. Such modifications and variations are encompassed within the scope of the present disclosure. The examples provided do not limit the present disclosure in any way. EXAMPLES

[0111] Example 1: Analysis of DAPA-HF, DAPA-CKD, and DECLARE Subpopulations DAPA-HF primarily tested dapagliflozin to reduce the risk of composite CV death and HF in a broad patient population with HFrEF, regardless of T2D status. A total of 2605 of 4744 patients did not have T2D at baseline. DAPA-CKD primarily tested dapagliflozin to reduce the risk of major adverse renal and CV events and all-cause mortality in patients with CKD, regardless of T2D status. A total of 1398 of 4304 patients did not have T2D at baseline.

[0112] Exploratory analyses of the DAPA-HF and DAPA-CKD studies demonstrated that treatment with dapagliflozin reduced the incidence of T2D in nondiabetic patients with HF and CKD, respectively, as shown in Table 1. Furthermore, meta-analyses of the DAPA-HF and DAPA-CKD populations also demonstrated that treatment with dapagliflozin reduced the incidence of T2D.

[0113] [Table 1]

[0114] The DECLARE study enrolled a broad population of T2D patients. The DECLARE population was divided into four subgroups by using parameters to select a relatively healthy population that approximated the prediabetic population. The four DECLARE subgroups were: 2with an eGFR of 0.001, no history of HF at baseline, and: 1. HbA1c < 7%, SBP < 140mmHg, and UACR ≤ 300mg / g, or 2. HbA1c < 7%, SBP < 140mmHg, and UACR ≤ 30mg / g, or 3. T2D < 5 years and UACR < 300mg / g, or 4.T2D < 5 years and UACR ≦ 30mg / g.

[0115] In DECLARE, as shown in Table 2, the placebo eGFR slope in the subgroup close to prediabetes was gentler than the eGFR slope in the entire DECLARE population (-1.51 to -2.36 ml / min / 1.73 m 2 / year vs. -2.17~-2.55ml / min / 1.73m 2 / year), but the decline in eGFR was 1.00 ml / min / 1.73 m 2 / year decline is even faster than the average population decline. (See Baba et al. Longitudinal Study of the Decline in Renal Function in Healthy Subjects. PLoS One. 2015;10(6).) A steeper slope was also seen in people with IGT (mean baseline HbA1c of about 5.8%), which is consistent with the DECLARE subgroup. (See Currie et al. Effect of valsartan on kidney outcomes in people with impaired glucose tolerance. Diabetes Obes Metab. 2017;19(6):791-99.) Furthermore, the decline in GFR of 60 ml / min / 1.73 m 2The higher event rate in prediabetic patients compared with normoglycemia, which reaches less than 10% of the normal range, supports the accelerated decline in eGFR. (Chen et al. Association between Prediabetes and Renal Dysfunction from a Community-based Prospective Study. Int J Med Sci. 2020; 17(11): 1515-21; Li et al. Risk of chronic kidney disease defined by decreased estimated glomerular filtration rate in individuals with different prediabetic phenotypes. BMJ Open Diabetes Res Care. 2020; 8(1).) In summary, the DECLARE prediabetic subpopulation may be a good reference for indicating prediabetic patients.

[0116] The treatment effect of dapagliflozin on chronic slope in the DECLARE subpopulation closest to prediabetes and the DAFA-HF and DAPA-CKD prediabetes populations is summarized in Table 2. As shown in Table 2, the treatment effect is greater in patients with a faster decline in eGFR. In the DECLARE population closest to prediabetes, the decline in eGFR is of a magnitude that is considered clinically relevant, as it is associated with a HR of subsequent end-stage kidney disease (ESKD) of approximately 0.7. (See Inker et al., GFR Slope as a Surrogate End Point for Kidney Disease Progression in Clinical Trials: A Meta-Analysis of Treatment Effects of Randomized Controlled Trials. J Am Soc Nephrol. 2019;30(9):1735-45; Levey et al., GFR decline as an end point for clinical trials in CKD. Am J Kidney Dis. 2014;64(6):821-35.)

[0117] In the subpopulation with diabetes duration <5 years and UACR <30 mg / g, dapagliflozin reduced the rate of decline in eGFR by 1.03 ml / min / 1.73 m in the second and third years, respectively. 2 / year and 0.96ml / min / 1.73m 2 In the subpopulation with HbA1c <7%, SBP <140mmHg, and UACR <30mg / g, dapagliflozin slowed the rate of decline in eGFR by 1.25ml / min / 1.73m in the second and third years, respectively. 2 / year and 1.17ml / min / 1.73m 2 Delayed.

[0118] In summary, the eGFR slope is a measure associated with progressive loss of renal function (microvascular complications) in prediabetic patients and demonstrates clinical relevance due to: 1) the prevalence of microvascular complications such as declining renal function in prediabetic patients before T2D diagnosis, 2) the higher risk of CKD in the prediabetic range compared to normoglycemia, and 3) the accelerated decline in renal function (eGFR) in patients approaching the prediabetic state compared to the normal age-related decline in renal function (eGFR). The risk of CKD and the accelerated decline in eGFR are associated with an eGFR < 60 ml / min / 1.73 m 2 These findings may contribute to the development of CKD, defined as chronic kidney disease (ESKD), which increases the risk of ESKD by 5-20-fold. (See Gansevoort et al., Lower estimated GFR and higher albuminuria are associated with adverse kidney outcomes. A collaborative meta-analysis of general and high-risk population cohorts. Kidney Int. 2011;80(1):93-104.)

[0119] The results of the exploratory analysis of dapagliflozin in Table 2 support the benefit of dapagliflozin in reducing the decline in eGFR in prediabetic patients. Thus, it is useful to be able to measure the progression of renal function decline or progression to CKD, and the clinical benefit is in normalizing the rate of eGFR decline in these patients. Furthermore, early detection and treatment are more effective than later intervention in preventing adverse renal outcomes. (See Schievink et al., Early renin-angiotensin system intervention is more beneficial than late intervention in delaying end-stage renal disease in patients with type 2 diabetes. Diabetes Obes Metab. 2016;18(1):64-71.) Dapagliflozin treatment in the prediabetic state may significantly affect the course of renal function decline in these at-risk patients. Thus, the reduction in eGFR slope is a suitable way to demonstrate the reduction in microvascular complications as a relevant clinical outcome in prediabetic patients.

[0120] [Table 2]

[0121] Example 2: Micro- and Macrovascular Clinical Benefits of Dapagliflozin in Prediabetic Patients Dapagliflozin reduced the risk of renal events in patients with T2D, HF, and CKD, independent of glycemic status. In DAPA-CKD, dapagliflozin reduced the risk of the primary composite outcome of worsening renal function or death in patients with diabetes (HR: 0.64; 95% CI 0.52 to 0.79) and patients without diabetes (HR: 0.50; 95% CI 0.35 to 0.72) (p-value for interaction = 0.24). Patients without diabetes (i.e., T2D) included patients with prediabetes. Dapagliflozin treatment slowed the decline in eGFR slope in patients with and without T2D, including those with prediabetes. From baseline to end of treatment, the placebo-adjusted difference in patients with T2D was 1.18 ml / min / 1.73 m 2 / year (95% CI 0.79 to 1.56, p < 0.0001), with a placebo-adjusted difference of 0.46 ml / min / 1.73 m in patients without T2D. 2 / year (95% CI -0.10 to 1.03; p = 0.11). The placebo-corrected difference in slope from 2 weeks to the end of treatment in patients with T2D was 2.26 ml / min / 1.73 m 2 / year (95% CI 1.88 to 2.64), and the placebo-adjusted difference in patients without T2D was 1.29 ml / min / 1.73 m 2 / year (95% CI 0.73-1.85).

[0122] Furthermore, dapagliflozin reduced the rate of decline in kidney function, even in patients without CKD. (See Jhund et al., Efficacy of Dapagliflozin on Renal Function and Outcomes in Patients With Heart Failure With Reduced Ejection Fraction: Results of DAPA-HF. Circulation. 2021;143(4):298-309; Mosenzon et al. Effects of dapagliflozin on development and progression of kidney disease in patients with type 2 diabetes. Lancet Diabetes Endocrinol. 2019;7(8):606-617; Wheeler et al. Effects of dapagliflozin on major adverse kidney and cardiovascular events in patients with diabetic and non-diabetic chronic kidney disease. Lancet Diabetes Endocrinol. 2021;9(1):22-31.) These findings suggest that treatment with dapagliflozin may also be useful for early prevention of CKD. In fact, the DECLARE data shows that eGFR is between 60 and 90 ml / min / 1.73 m 2 and 90 ml / min / 1.73 m 2 We demonstrated that these T2D patients experienced renal benefit in terms of reduced eGFR and albuminuria following dapagliflozin treatment.

[0123] Predefined subgroup analyses of the primary and secondary endpoints in DAPA-HF and DAPA-CKD demonstrated that dapagliflozin was effective in reducing CV morbidity and mortality, and the risk of major renal adverse events, independent of diabetes status. In DAPA-HF, dapagliflozin reduced the risk of the primary composite outcome (CV death, hospitalization for heart failure, or emergency visit for heart failure) in patients with diabetes (HR: 0.75; 95% CI: 0.63 to 0.90) and without diabetes (HR: 0.73; 95% CI: 0.60 to 0.88) (p-value for interaction = 0.80). Collectively, these results support the benefit of dapagliflozin in reducing the risk of CV and major renal adverse events in people without diabetes, including those with prediabetes.

[0124] Example 3: Dapagliflozin reduces blood pressure Exploratory subgroup analyses were conducted to determine the effect of dapagliflozin using available data from the DECLARE subgroup closer to prediabetes patients. As shown in Figure 3, treatment with dapagliflozin reduced the risk of blood pressure worsening compared with placebo (time to worsening in blood pressure categories).

[0125] Figure 3 shows the analysis of participants according to the following criteria: HbA1c < 7% at baseline, eGFR ≥ 60 ml / min / 1.73 m at baseline. 2 , no history of HF at baseline, and UACR≦300 mg / g. For the purposes of analysis, one month equals 30 days. Figure 3 analyzes the time from randomization to the first occurrence of an event or censoring, and two-sided p-values ​​are displayed. HR, CI, and p-values ​​are from the Cox proportional hazards model. Blood pressure categories included: normal (SBP<120mmHg and DBP<80mmHg); elevated blood pressure (SBP 120-129mmHg and DBP<80mmHg); stage 1 hypertension (SBP 130-139mmHg or DBP 80-89mmHg); stage 2 hypertension (SBP>140mmHg or DBP>90mmHg); hypertensive emergency (SBP>180mmHg and / or DBP>120mmHg).

[0126] These results indicate that dapagliflozin may reduce the risk of macrovascular complications, such as atherosclerotic cardiovascular disease (ASCVD), in prediabetic patients through its blood pressure lowering effect.

[0127] Example 4: Dosing rationale for dapagliflozin 5 mg A 5 mg dapagliflozin dose is evaluated in the clinical study described in Example 6. This dose was selected, in part, based on the following rationale.

[0128] Pharmacokinetic / pharmacodynamic and maximum drug-induced effect models were previously developed to investigate glucose-insulin kinetics in T2D patients participating in Phase I-III clinical trials of dapagliflozin. Although the relationship is not linear, dapagliflozin treatment in T2D patients leads to increased glycosuria that correlates with a decline in HbA1c over time, and this correlation is expected to extend across the HbA1c continuum in people with prediabetes.

[0129] A modeling approach was applied to determine glycosuria in prediabetic patients. Both DAPA-HF and DAPA-CKD included a prediabetic population randomized to dapagliflozin 10 mg. A modeling approach was used to predict the extent of 24-hour glycosuria in the prediabetic populations of DAPA-HF and DAPA-CKD with dapagliflozin 10 mg. This was then used to estimate the efficacy / glycemic control of dapagliflozin 5 mg in prediabetic patients. The following approach was adopted: (1) To predict mean diabetes in DAPA-CKD and DAPA-HF prediabetic populations taking dapagliflozin 10 mg using their HbA1c and eGFR values. (2) Mean diabetes in people with prediabetes taking dapagliflozin 5 mg was assessed by a range of eGFR > 45 ml / min / 1.73 m 2 Predict with. (3) Glycosuria in DAPA-HF and DAPA-CKD prediabetic patients (10 mg dose) (from (1)) was diagnosed by eGFR > 45 ml / min / 1.73 m 2 The results are compared with those of prediabetic patients (5 mg dose) (from (2)).

[0130] In particular, eGFR > 45 ml / min / 1.73 m 2 was selected as the diabetes prediction standard for prediabetes patients because it is the current lower limit of eGFR for T2D in the dapagliflozin US Prescribing Information (USPI). The results of simulated diabetes in prediabetes patients at various eGFR values ​​in DAPA-CKD (10 mg), DAPA-HF (10 mg), and prediabetes patients taking dapagliflozin 5 mg are shown in Figure 2. Based on diabetes modeling, the results of simulated diabetes in prediabetes patients with eGFR of 60 ml / min / 1.73 m 2 It was predicted that administering 5 mg of dapagliflozin once daily to these prediabetic patients would result in improvements in diabetes and blood glucose levels that were similar to or slightly better than those seen in the DAPA-CKD trial (dapagliflozin 10 mg once daily).

[0131] Example 5: Safety of Dapagliflozin 5 mg in Patients with Prediabetes DAPA-HF and DAPA-CKD included patients without diabetes, including those considered prediabetic. Results from this subgroup for adverse events ("AEs") of all categories were generally consistent with the overall safety results. Patients without T2D at baseline generally reported fewer AEs than patients with T2D, which can be explained by the older age and generally higher morbidity of T2D patients. No events of definite or probable diabetic ketoacidosis ("DKA") and major hypoglycemic AEs were observed in nondiabetic and prediabetic patients.

[0132] All DAPA-HF and DAPA-CKD patients were treated with dapagliflozin 10 mg once daily or placebo. The safety profile in nondiabetic and prediabetic patients was consistent with that established in T2D patients, except for the absence of DKA or hypoglycemic events. The safety profile of dapagliflozin in diabetic and prediabetic patients has been well characterized based on a substantial safety database consisting of results from the pivotal diabetes trials DECLARE, DAPA-HF, and DAPA-CKD.

[0133] Results of the subgroup analysis by baseline T2D status showed that the safety profile of dapagliflozin was similar to the overall results, regardless of baseline T2D status. DKA and major hypoglycemic events were observed only in patients with T2D. As DKA is a condition associated with severe insulin deficiency, DKA events were not expected in the population without T2D (55% of the study population), including prediabetic patients, and this was confirmed by the results. (See Umpierrez G, Korytkowski M. Diabetic emergencies-ketoacidosis, hyperglycaemic hyperosmolar state and hypoglycaemia. Nat Rev Endocrinol. 2016;12(4):222-32.) The safety profile of dapagliflozin 5 mg is expected to be consistent with that of 10 mg, as the known side effects are not dose-related.

[0134] Example 6: Study Design Overview The study is designed as an event-driven, randomized, double-blind, placebo-controlled, parallel-group, international, multicenter study in participants with prediabetes to evaluate the effect of once-daily oral dapagliflozin 5 mg versus placebo in reducing the risk of developing T2D.

[0135] The study population will include male and female participants (age 45 and older) with prediabetes at risk for developing T2D and without HF or KD. Approximately 4800 participants will be randomized to study treatments. Randomization may cap the proportion of prediabetic participants with HbA1c in the range of 5.7% ≤ HbA1c < 6.0%. Laboratory parameters (e.g. HbA1c, creatinine / eGFR, UACR), vital signs, and AEs will be collected at randomization and then every 3 months until study completion. Safety and tolerability will be assessed in terms of serious adverse events (SAEs) and adverse events (AEs) leading to discontinuation of study drug.

[0136] The primary efficacy endpoint will be the time from randomization to new onset of T2D based on two HbA1c values ​​above the cut-off level for diabetes (HbA1c ≥ 6.5%). Participants with HbA1c ≥ 6.5% will be required to provide a follow-up blood sample, and a second HbA1c rise will confirm the diagnosis of T2D. The diagnosis of T2D may also be based on patients achieving a diagnosis and / or treatment with oral antidiabetic drugs outside the study. Participants who develop T2D during the treatment period will be able to receive rescue therapy according to local standard of care (excluding SGLT2 inhibitors). Participants receiving rescue therapy will remain in the study.

[0137] One of the secondary efficacy endpoints is the percentage change in eGFR over time from 3 months after randomization to the end of the study (i.e., eGFR chronic slope). Participants without pre-existing known kidney disease will be enrolled. The sponsor, investigators, and participants will be blinded to the eGFR and UACR, and investigators will administer standard of care to participants as needed. The study design is further shown in Figure 4 and Table 3.

[0138] [Table 3]

[0139] Study population Study subjects included overweight adult men and women with prediabetes and at least one additional established T2D risk factor. Major inclusion and exclusion criteria are shown in Table 4.

[0140] [Table 4]

[0141] Objectives and Endpoints Table 5 provides an overview of the study objectives and endpoints.

[0142] [Table 5]

[0143] Primary Objective The primary objective of the study is to determine the superiority of dapagliflozin over placebo in reducing the risk of T2D. Assuming a true hazard ratio between dapagliflozin and placebo of 0.75, using a one-sided alpha of 2.5%, 508 primary endpoint events would provide 90% statistical power for the test of the primary endpoint. This is based on an overall 1:1 allocation between dapagliflozin and placebo. Based on an expected recruitment period of 1.5 years with an overall dropout rate of 10% and a maximum follow-up period of approximately 3 years, with an annualized event rate of 6.0% in the placebo arm, it is estimated that 4788 participants (i.e., 2394 per arm) would provide the required number of primary endpoint events.

[0144] Secondary Objectives The secondary objective of eGFR chronic slope is to compare the treatment effect of dapagliflozin vs placebo on eGFR slope from 3 months to the end of the study and to evaluate microvascular benefits. The planned 4788 participants in the study (i.e., 2394 per arm) will have a common standard deviation of 6 ml / min / 1.73 m 2 Assuming that the slope of eGFR between dapagliflozin and placebo is 0.5 ml / min / 1.73 m2 This provides more than 80% power to detect a difference of 6 ml / min / 1.73 m at a significance level of 0.025 (one-sided). 2 The common standard deviation assumed is based on estimates from the DECLARE eGFR slope analysis in subgroups that approximate the planned prediabetic population (T2D < 5 years or HbA1c < 7% and other factors). 2 Group differences in eGFR are considered clinically meaningful in the early stages of CKD, where the expected decline in eGFR in the prediabetic stage is the same as that in early CKD. (See Levey et al., Change in Albuminuria and GFR as End Points for Clinical Trials in Early Stages of CKD. Am J Kidney Dis. 2020;75(1):84-104.)

[0145] The secondary efficacy endpoint analysis of eGFR chronic slope will compare dapagliflozin 5 mg to placebo based on the between-treatment group difference in eGFR chronic slope using a mixed-effects model in the full analysis set (FAS). The model includes fixed effects of treatment group, baseline HbA1c range stratification status, baseline eGFR, time, and treatment-by-treatment interaction. Random effects include intercept and slope (3 months to end of study). The end of study is the date when the predefined target number of events for the primary endpoint occurred.

[0146] Other secondary objectives are to compare the treatment effects of dapagliflozin versus placebo on blood pressure and body weight as a way to assess macrovascular benefits. The sample size also provides sufficient power to evaluate the treatment effects of dapagliflozin versus placebo on the secondary efficacy endpoints of blood pressure and body weight.

[0147] Example 7: Development of a Web application program Develop a product paired with a medical device in the form of a web app. The program restricts consumer access to online purchases after the consumer qualifies (and requalifies for subsequent purchases) via the web app by answering predefined questions that correspond to elements of the drug description label (DFL). Use of the web app must be combined with online access that requires a consumer self-selected assessment prior to each purchase.

[0148] The web app features a Technology Assisted Self-Participant (TASS) tool with programmable medical device (SaMD) capabilities. Specifically, the diagnostic and treatment decisions provided by the TASS qualify the web app as a SaMD. The TASS provides a decision on whether the product is appropriate for the consumer. Figure 5 outlines the inputs, processes, and outputs of the SaMD that lead to one of three treatment decisions (i.e., do not use, may use, or consult a physician before use).

[0149] The Technology Assisted Self-Participant (TASS) serves as a digitized, interactive version of the DFL, where consumers can answer a dynamic, personalized set of health-related questions instead of browsing / searching the DFL for information relevant to them. This ensures that only consumers who will benefit from the drug can receive it. If the consumer is eligible based on their use of the web app, the consumer purchases the product online through the website. The product is only available to consumers who determine that they are "good to use" and decide to purchase via the website. The product is then shipped to consumers with a valid U.S. address. Before repurchasing the product, the consumer must answer a few additional questions regarding changes in their health status before they are eligible to repurchase.

Claims

1. 1. A pharmaceutical for use in a method for treating prediabetes in a patient in need thereof, said method comprising administering an effective amount of dapagliflozin to said patient, said patient having an HbA1c of 5.7% to 6.4% and / or a fasting glucose of 100 to 125 mg / dl, said patient not previously taking prescription medication for diabetes, wherein said method results in a reduction in the relative risk of developing T2D of 25% or more. Medicine.

2. The pharmaceutical of claim 1, wherein the patient does not have chronic kidney disease (CKD) and / or heart failure (HF).

3. 2. The pharmaceutical composition of claim 1, wherein the dapagliflozin is in the form of a pharmaceutically acceptable solvate, mixed solvate, or complex.

4. The pharmaceutical composition according to claim 1, wherein the dapagliflozin is in the form of an (S)-propylene glycol ((S)-PG) solvate.

5. Prior to the administration, the patient had a blood flow of 39 mL / min / 1.73 m ２ More than 67 mL / min / 1.73 m ２ The pharmaceutical of claim 1, having the following eGFR:

6. Prior to the administration, the patient was receiving a blood glucose monitor at a rate of 60 mL / min / 1.73 m ２ The pharmaceutical according to claim 1, having the above eGFR.

7. The method of claim 1, wherein the method results in a 30% reduction in the relative risk of developing T2D.

8. 2. The method of claim 1, wherein the method results in a reduction in the absolute risk of developing T2D of 3% or more over 1.75 years.

9. The patient has one of the following conditions: (f) the patient does not have a fasting plasma glucose of 7 mmol / L or greater; (g) the patient does not have T2D; (h) the patient does not have HF; (i) the patient does not have CKD stages 3 to 5; and / or (j) the patient does not have severe liver impairment according to Child-Pugh classification 3. The pharmaceutical composition of claim 1, which satisfies one or more of the following conditions:

10. The pharmaceutical composition of claim 1, wherein, prior to said administration, said patient accesses a web page and answers predetermined questions; and said patient is determined to be eligible to purchase an SGLT2 inhibitor based on said provided answers.

11. The method of claim 1, wherein said administration does not require a prescription.

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