Canagliflozin for treatment of diabetic patients with chronic kidney disease

Abstract

To provide a method of treating a diabetic patient with chronic kidney disease.SOLUTION: A method for treating a diabetic patient with chronic kidney disease comprises: (a) determining whether or not the patient has chronic kidney disease; and (b) administering a therapeutically effective amount of canagliflozin to the patient to treat the chronic kidney disease.SELECTED DRAWING: None

Description

Technical Field

[0001] (Cross - Reference to Related Applications) This application claims priority to U.S. Provisional Patent Application No. 62 / 823,719, filed on March 26, 2019 , U.S. Provisional Patent Application No. 62 / 823,722, filed on March 26, 2019, U.S. Provisional Patent Application No. 62 / 823,724, filed on March 26, 2019, and U.S. Provisional Patent Application No. 62 / 835,550, filed on April 18, 2019, the disclosures of which are hereby incorporated by reference in their entireties.

[0002] (Field of the Invention) The present invention relates to a method for treating a subject having chronic kidney disease.

Background Art

[0003] Subjects with type 2 diabetes and chronic kidney disease (CKD) have a high risk of progression to end - stage kidney disease (ESKD) and cardiovascular events, and a short average life expectancy even when using current standard treatments. When patients with diabetic kidney disease develop end - stage kidney disease, their average life expectancy is short , and the 5 - year survival rate of dialysis patients in the United States is 36%, and even lower in developing countries . The high prevalence of old age and a large number of comorbidities over a long period are typical of patient populations with established CKD where unmet medical needs are high.

[0004] The kidneys are bean - shaped organs located near the center of the back. Inside each kidney, about one million small structures called nephrons filter the blood . They remove waste products and excess water, which then become urine. Damage to nephrons represents an important form of kidney disease. This damage The kidneys can be put in a state where they are unable to remove waste products. Some damage, for example, damage related to hyperfiltration, can occur slowly over the years and often initially has no obvious symptoms.

[0005] At the single nephron level, hyperfiltration is an early link in a series of events that leads from glomerular hypertension to albuminuria and subsequently to a reduction in glomerular filtration rate (GFR). Therefore, based on this, hyperfiltration represents the risk for subsequent kidney damage and can be classified as an early manifestation of kidney pathology, often referred to as the hyperfiltration stage. Such kidney hyperfiltration can lead to early glomerular lesions and microalbuminuria, which in itself can lead to overt albuminuria and end-stage kidney disease.

[0006] Creatinine is a breakdown product of creatine phosphate in muscle tissue and is usually produced at a constant rate in the body. Serum creatinine is an important indicator of kidney health because it is an easily measurable byproduct of muscle metabolism that is excreted by the kidneys unchanged. Creatinine is removed from the blood mainly by the kidneys, mainly by glomerular filtration but also by proximal tubule secretion. There is little or no tubular reabsorption of creatinine. When filtration in the kidneys is insufficient, the blood level of creatinine rises. Therefore, blood and urine creatinine levels may be used to calculate creatinine clearance (CrCl), which correlates with glomerular filtration rate (GFR). Blood creatinine levels may also be used alone to estimate GFR (eGFR).

[0007] Albuminuria is the condition in which albumin is present in the urine. Albumin is filtered by the kidneys. The kidneys properly remove large molecules (such as albumin) from the urine. If not properly filtered, albumin is excreted in the urine, typically as a result of kidney damage or excess Albuminuria is also a sign of type I (1) diabetes or type II (2) diabetes. It can occur in patients with long-standing diabetes, either as a result of urinary albuminuria or as a result of urinary urinary albuminuria. , by test strip, or in the total volume of urine collected over a 24-hour period. It can be measured as a direct measure of protein quantity.

[0008] Diabetic nephropathy is one of the microvascular complications of diabetes and is characterized by persistent albuminuria. Diabetic nephropathy is characterized by a progressive decline in kidney function and kidney function. This is an important factor in the progression of the disease.

[0009] The clinical progression of diabetic nephropathy in patients with T1DM (type 1 diabetes) is well characterized. First, hyperfiltration occurs, which is accompanied by an increase in glomerular filtration rate (GFR) and an increase in renal plasma flow. A meta-analysis has shown that the presence of hyperfiltration in patients with T1DM is associated with increased microalbuminuria. It was found to more than double the risk of developing urinary or overt albuminuria. Phase 1 included ≥30 mg / day (or 20 μg / min) and <300 mg / 24 h (or Reduced GFR and microalbuminuria, defined as urinary albumin excretion of less than 200 μg / min Albuminuria continues to progress, which may be accompanied by elevated blood pressure. Later, the GFR continues to decline. Significant progression of the disease, defined as urinary albumin excretion of less than 300 mg / day Proteinuria (i.e., overt albuminuria) follows and is associated with worsening hypertension. Ultimately, ESKD (end-stage kidney disease) progresses, leading to the need for renal replacement therapy.

[0010] In patients with type 2 diabetes mellitus (T2DM), clinical progression varies due to multiple kidney injuries, including not only hyperglycemia but also the vascular pathology that results in ischemic kidney injury. However, other common features that are likely to contribute to kidney injury in T2DM patients include hyperfiltration at a single nephron level, proximal tubular glycotoxicity, and stimulation of tubular cell growth as a result of enhanced transport of sodium-bound glucose into tubular cells.

[0011] The degree of albuminuria is positively correlated with the progression of ESKD and adverse CV outcomes. Use of agents that act by hemodynamic mechanisms (i.e., ACEi and ARB) to reduce albuminuria in patients with T2DM and albuminuria is correlated with a reduction in the progression of diabetic nephropathy and the occurrence of adverse CV outcomes. Thus, agents that act by specific hemodynamic mechanisms to reduce albuminuria more than other antihypertensive or hypoglycemic agents and are additive to agents that interfere with the renin-angiotensin system may exert a kidney-protective effect and may reduce adverse CV outcomes in diabetic nephropathy. SUMMARY OF THE INVENTION PROBLEMS TO BE SOLVED BY THE INVENTION

[0012] Despite current standard treatments, subjects with type II diabetes and chronic kidney disease have a high risk of progression to ESKD and cardiovascular events and a short average life expectancy. What is needed is a method for treating patients at a more advanced stage of chronic kidney disease. MEANS FOR SOLVING THE PROBLEM

[0013] In some aspects, the present disclosure is directed to treating patients having type II diabetes and chronic kidney disease (CKD). In certain embodiments, the patient has stage 2-3 kidney disease. In other embodiments, the patient also has overt albuminuria. The method includes administering a therapeutically effective amount of canagliflozin. In other embodiments, the method further includes administering an angiotensin converting enzyme inhibitor and / or an angiotensin receptor blocker, adjunctive standard of care. The methods described herein have also been shown to be clinically safe and / or clinically effective.

[0014] In other aspects, the present disclosure relates to a method of treating a diabetic patient having chronic kidney disease, the method comprising (a ) determining whether the patient has chronic kidney disease, and (b) administering to the patient a therapeutically effective amount of canagliflozin for treating chronic kidney disease.

[0015] In a further aspect, the present disclosure relates to a method of marketing a formulation comprising canagliflozin, the method comprising marketing a formulation, wherein the formulation label of the reference listed drug for the formulation includes instructions for treating chronic kidney disease.

[0016] In yet another aspect, the present disclosure relates to a pharmaceutical product comprising an amount of canagliflozin that has been shown to be clinically safe and clinically effective. BRIEF DESCRIPTION OF THE DRAWINGS

[0017]

Figure 1

Figure 2

Figure 3

Figure 4

Best Mode for Carrying Out the Invention

[0018] In the present disclosure, unless otherwise specified, the singular forms "a," "an," and "the" include references to the plural forms, and references to specific numerical values include at least that specific value. Thus, for example, a reference to "a material" includes at least one such material, and references to its equivalents known to those skilled in the art, and the like. When a value is expressed as an approximate value by use of the descriptive terms "about" or "substantially," it is understood that that particular value forms another embodiment. Generally, the use of the terms "about" or "substantially" indicates an approximate value that may vary depending on the desired characteristics to be obtained by the disclosed inventive subject matter, and should be interpreted in the particular context in which it is used based on its function. Those skilled in the art can interpret this as an ordinary matter. In some cases, the number of significant figures used for a particular value can be one non-limiting way of determining the degree of the terms "about" or "substantially." In other cases, the gradual changes used in a series of values are

[0019] Another embodiment that may be formed. When a value is expressed as an approximate value by use of the descriptive terms "about" or "substantially," it is understood that that particular value forms another embodiment. Generally, the use of the terms "about" or "substantially" indicates an approximate value that may vary depending on the desired characteristics to be obtained by the disclosed inventive subject matter, and should be interpreted in the particular context in which it is used based on its function. Those skilled in the art can interpret this as an ordinary matter. In some cases, the number of significant figures used for a particular value can be one non-limiting way of determining the degree of the terms "about" or "substantially." In other cases, the gradual changes used in a series of values are Another embodiment that may be formed. When a value is expressed as an approximate value by use of the descriptive terms "about" or "substantially," it is understood that that particular value forms another embodiment. Generally, the use of the terms "about" or "substantially" indicates an approximate value that may vary depending on the desired characteristics to be obtained by the disclosed inventive subject matter, and should be interpreted in the particular context in which it is used based on its function. Those skilled in the art can interpret this as an ordinary matter. In some cases, the number of significant figures used for a particular value can be one non-limiting way of determining the degree of the terms "about" or "substantially." In other cases, the gradual changes used in a series of values may be one non-limiting way of determining the degree of the terms "about" or "substantially." Those skilled in the art can interpret this as an ordinary matter. In some cases, the number of significant figures used for a particular value can be one non-limiting way of determining the degree of the terms "about" or "substantially." In other cases, the gradual changes used in a series of values are Using the variations, determine the intended scope for which the terms "about" or "substantially" are available for each value if possible. If present, all ranges are inclusive and combinable. That is, a reference to a value described in a range includes all values within that range.

[0020] If a list is presented, unless otherwise specified, it should be understood that each individual element of the list and all combinations of the list should be interpreted as separate embodiments. For example, a list of embodiments presented as "A, B, or C" should be interpreted as including the embodiments "A", " B", "C", "A or B", "A or C", "B or C", or "A, B, or C". It should be understood that certain features of the present invention described herein for clarity in the context of separate embodiments may also be provided in combination within a single embodiment

[0021] That is, unless clearly incompatible or excluded, each individual embodiment is considered to be compatible with any other embodiment, and such combinations are considered to be another embodiment. Conversely, different features of the present invention described in the context of a single embodiment for simplicity may also be provided separately or as any partial combination. It should be further noted that the claims may be drafted to exclude any arbitrary element. Therefore, this description is intended to serve as a basis for the use of exclusive terms such as "only", "merely", etc. in relation to the enumeration of elements of the claims, or the use of "negative" limitations. Finally, embodiments may be part of a series of steps or as a portion of a set of steps or as Although it may be described as part of a more general structure, each step may be considered as an embodiment that is independent in itself. It may be considered that way.

[0022] Method The present disclosure provides a method for treating chronic kidney disease (CKD), which includes administering a therapeutically effective amount of canagliflozin to a patient in need of treatment. In some embodiments, the patient is a diabetic patient. In further embodiments, the patient is a diabetic patient having chronic kidney disease. In other embodiments, the patient has been diagnosed with type 2 diabetes. In other embodiments, the patient is further diagnosed with overt albuminuria.

[0023] The methods described herein reflect the effectiveness of canagliflozin in the treatment of a specific subpopulation of patients, namely, patients having type II diabetes (T2DM) and chronic kidney disease (CKD). Since ACE inhibitors (ACEi) and angiotensin receptor blockers (ARB) have been the standard treatment for preventing the progression of diabetic kidney disease for more than 15 years ago, the methods disclosed herein provide a benefit (by any mechanism) to the renal outcomes of these patients. The methods described herein reduce the risk of specific primary endpoints by about 25% in addition to the current standard treatment including ACEi or ARB therapy. The inventors also discovered a significant duration of effect and / or reduction of comorbidities, and that the effects provided by canagliflozin are maintained even after 1 year of treatment. The duration of this effect is consistent across all subgroups of patients tested, thereby suggesting a long-term treatment option for patients suffering therefrom. Importantly, the discovery of the benefits of the primary endpoint was not driven only by laboratory components (i.e., doubling of serum creatinine), but also by the "hard" endpoint of ESKD. ​​​​​​ "Endpoint" (determined by a substantial reduction in eGFR < 15 mL / min / 1.73 m 2 , chronic dialysis, or kidney transplantation).

[0024] As used herein, the term "diabetes" includes type 1 and type 2. In some embodiments , diabetes refers to type 1 diabetes. In other embodiments, diabetes refers to type 2 diabetes. Type 1 and type 2 diabetes are understood by those skilled in the art. In patients with type 1 diabetes, the patient's immune system attacks and destroys the pancreatic beta cells that produce insulin. Thus, a patient with type 1 diabetes does not produce insulin. In patients with type 2 diabetes, the patient's body does not use insulin efficiently. Thus, patients with type 2 diabetes do not respond to insulin produced in the body.

[0025] The terms "Type 2 diabetes" and "Type II diabetes mellitus" are interchangeable and, when measured on at least two separate occasions, define a state in which a patient's fasting ( i.e., without caloric intake for about 8 hours) blood glucose or serum glucose concentration exceeds about 125 mg / dL (about 6.94 mmol / L). Type 2 diabetes is also defined as a state in which, in combination with the classic symptoms of hyperglycemia or hyperglycemic emergencies, during an oral glucose tolerance test (OGTT) the patient's HbA is about 6.5% or more, the 2-hour plasma glucose is about 200 mg / dL (about 11.1 mmol / L) or more, or the random glucose concentration is about 200 mg / dL( 1c (about 11.1 mmol / L) or more. In the absence of obvious hyperglycemia, as with most diagnostic tests, the diagnostic test results for diabetes are repeated to exclude laboratory errors as with most diagnostic tests to exclude laboratory errors​​ It should be repeated.

[0026] HbA 1c The evaluation is certified by the National Glycohemoglobin Standardization Program and is and standardized or traceable to a reference assay for diabetes management and complications testing. When an OGTT is performed, the blood glucose level of a diabetic patient is measured using a fasting method. Approximately 2 hours after ingesting approximately 75g of glucose, approximately 200mg of glucose / d In a glucose tolerance test, approximately 75 g of glucose is taken. Patients in whom the radioactivity is tested after a minimum of about 8 hours, typically about 10 to about 12 hours of fasting. The blood glucose level was measured immediately before glucose intake and approximately 1 and 2 hours after intake. In healthy patients, the blood glucose level before ingesting glucose is approximately 60-80% of the plasma. Approximately 110 mg / dL, and less than 200 mg / dL approximately 1 hour after glucose intake After about 2 hours, the value is between about 140 and about 2 00mg, this is considered impaired glucose tolerance.

[0027] In some embodiments, a patient diagnosed with type II diabetes is a patient with type II diabetes, as defined herein. , measured HbA 1c The term "HbA 1c " or "Hemoglobin A 1c "teeth, It refers to the product of non-enzymatic glycation of hemoglobin B chain, the determination of which is well known to those skilled in the art. In monitoring the treatment of urinary diseases, HbA 1c Its production is crucial for blood sugar and red blood cells. Because it essentially depends on the lifespan of the blood glucose level, the HbA 1c is the past Reflects the average blood glucose level over about 4 to about 6 weeks. In certain embodiments, the method described herein results in a patient being in the range of about 7% to about 10.5%, for example, having a measured HbA in the range of 7.0% or more and 10.5 1c % or less. In other embodiments, the patient has a measured HbA of about 7%, about 7.1%, about 7.2%, about 7.3%, about 7.4%, about 7.5%, about 7.6%, about 7.7% , about 7.8%, about 7.9%, about 8%, about 8.1%, about 8.2%, about 8.3%, about 8.4% , about 8.5%, about 8.6%, about 8.7%, about 8.8%, about 8.9%, about 9%, about 9.1% , about 9.2%, about 9.3%, about 9.4%, about 9.5%, about 9.6%, about 9.7%, about 9. 8%, about 9.9%, about 10%, about 10.1%, about 10.2%, about 10.3%, about 10.4 %, or about 10.5% of the measured HbA 1c . In other embodiments, the patient has a measured HbA of about 7% to about 10%, about 7% to about 9.5%, about 7% to about 9%, about 7% to about 8.5%, about % to about 8%, about 7.5% to about 10.5%, about 8% to about 10.5%, about 8.5% to about 10.5% , about 9% to about 10.5%, or about 9.5 to about 10.5% of the measured HbA 1c .

[0028] As disclosed herein, the patient being treated has chronic kidney disease. In some embodiments , the patient has stage 2 chronic kidney disease. In other embodiments, the patient has stage 3 chronic kidney disease. In further embodiments, the patient has stage 2 - 3 chronic kidney disease.

[0029] The method described herein may include a determination that the patient has chronic kidney disease. Typically , that determination is made by the attending physician. The diagnosis or determination of chronic kidney disease is made by those skilled in the art It can be determined using known techniques. In some embodiments, chronic kidney disease is determined by one or more of a blood test, a urine test, a kidney imaging, or a kidney biopsy. Preferably, chronic kidney disease is diagnosed by a blood test. More preferably, the blood test measures the estimated glomerular filtration rate. In some embodiments, a patient having chronic kidney disease has an eGFR of about 30 to less than about 90 mL / min / 1.73m², for example, an eGFR of 30 or more and less than 90 mL / min / 1.73m². In some embodiments, a patient has an eGFR of about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about

[0030] 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, about 73m² 2 In some embodiments, a patient has an eGFR of about 30 to less than about 90 mL / min / 1.73m², for example, an eGFR of 30 or more and less than 90 mL / min / 1.73m². 2 In some embodiments, a patient has an eGFR of about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about 58, about 59, about 60, about 61, about 62, about 63, about 64, about 65, about 66, about 67, about 68, about 69, about 70, about 71, about 72, about 73, about 74, about 75, about 76, about 77, about 78, about 79, about 80, about 81, about 82, about 83, about 84, about 85, about 86, about 87, about 88, or about 89 mL / min / 1.73m². 2 In further embodiments, a patient has an eGFR of about 30 to about 89, about 30 to about 85, about 30 to about 80, about 30 to about 75, about 30 to about 70, about 30 to about 65, about 30 to about 65, about 30 to about 60, about 30 to about 55, about 30 to about 50, about 35 to about 89, about 30 to about 85, about 35 to about 80, about 35 to about 75, about 35 to about 70, about 35 to about 65, about 35 to about 60, about 35 to about 55, about 35 to about 50, about 40 to about 89, about 40 to about 85, about 40 to about 80, about 40 to about 75, about 35 to about 89, about 30 to about 85, about 35 to about 80, about 40 to about 70, about 40 to about 65, about 40 to about 60, about 40 to about 55, about 40 to about 50, about 40 to about 45, about 50 to about 89, about 50 to about 85, about 50 to about 80, about 50 to about 75, about 50 to about 70, about 50 to about 65, about 50 to about 60, about 50 to about 55, about 55 to about 89, about 55 to about 85, about 55 to about 80, about 55 to about 75, about 55 to about 70, about 55 to about 65, about 55 to about 60, about 60 to about 89, about 60 to about 85, about 60 to about 80, about 60 to about 75, about 60 to about 70, about 60 to about 65, about 65 to about 89, about 65 to about 85, about 65 to about 80, about 65 to about 75, about 65 to about 70, about 70 to about 89, about 70 to about 85, about 70 to about 80, about 70 to about 75, about 75 to about 89, about 75 to about 85, about 75 to about 80, about 80 to about 89, or about 85 to about 89 mL / min / 1.73m 2 having an eGFR of 。 In other embodiments, the patient has an eGFR of about 30 to less than about 45 mL / min / 1.73m 2 eGFR, for example, 30 or more and less than about 45 m L / min / 1.73m 2 having an eGFR. In a further embodiment, the patient has an eGFR of about 30 to about 4 0, about 30 to about 35, about 35 to about 45, about 35 to about 40, or about 40 to about 45 mL / min / 1.73m 2 having an eGFR. In yet another embodiment, the patient has an eGFR of about 45 to about 59 mL / min per 1.73m 2 eGFR, for example, 45 or more and less than 60 mL / min / 1.73m 2 of eG FR. In certain embodiments, the eGFR is about 45 to about 59, about 45 to about 55, about 45 to about 50, about 50 to about 59, or about 50 to about 55 mL / min / 1.73m 2 is. Further In other embodiments, the patient has an eGFR of about 60 to about 89 mL / min / 1.73m 2 of eGFR, for example, Have an eGFR of 60 or more and less than 90 mL / min / 1.73m 2 and. In a further embodiment, e GFR is about 60 to about 85, about 60 to about 80, about 60 to about 75, about 60 to about 70, about 65 to about 89, about 65 to about 85, about 65 to about 80, about 65 to about 75, about 70 to about 89, about 70 to about 85, about 70 to about 80, about 75 to about 89, or about 75 to about 85 mL / min / 1.73m 2 Have an eGFR of

[0031] In other embodiments, the patient has stage 2 chronic kidney disease. As used herein , "stage 2 chronic kidney disease" refers to patients having an eGFR of about 60 to about 89 mL / min / 1.73m 2 , for example, 60 or more and less than 90 mL / min / 1.73m 2 Have an eGFR of Patients with stage 2 chronic kidney disease may be asymptomatic. As long as these patients have signs of kidney damage, the signs include, but are not limited to, protein in the urine, physical damage to one or both kidneys, or any combination of these. In certain embodiments, patients with stage 2 chronic kidney disease have existing kidney damage.

[0032] In other embodiments, the patient has stage 3 chronic kidney disease. As used herein , "stage 3 chronic kidney disease" refers to patients having an eGFR of about 30 to about 59 mL / min / 1.73m 2 , for example, 30 or more and less than 60 mL / min / 1.73m 2 Have an eGFR of Patients with stage 3 chronic kidney disease may be asymptomatic. As long as these patients have signs of kidney damage, the signs include, but are not limited to, proteinuria, physical damage to one or both kidneys, hands and / or Swelling of the feet, low back pain, more or less urination than normal, or any combination thereof are included, but not limited to. In certain embodiments, patients with stage 3 chronic kidney disease have moderate kidney damage. In a further embodiment, stage 3 chronic kidney disease is about 45 to about 59 mL / min / 1.73 m 2 and can be stage 3a with an eGFR. In still other embodiments stage 3 chronic kidney disease is stage 3b with an eG 2 FR from about 30 to about 44 mL / min / 1.73 m .

[0033] In a further aspect, the patient has stage 2-3 chronic kidney disease. As used herein in this case, "stage 2-3 chronic kidney disease" means 30 or more and less than 90 mL / min / 1.73 m 2 including and refers to patients having an eGFR of about 30 to about 89 mL / min / 1.73 m 2 . Patients with stage 2 -3 chronic kidney disease may be asymptomatic. As long as these patients have signs of kidney damage , the signs include proteinuria in the urine, physical damage to one or both kidneys, swelling of the hands and / or feet, low back pain, more or less urination than normal, or any combination of these are included, but not limited to. In certain embodiments, patients with stage 2-3 chronic kidney disease have existing kidney damage that can be moderate.

[0034] The term "glomerular filtration rate (GFR)" is defined as the volume of fluid filtered per unit time from the glomerular capillaries of the kidney (renal) into Bowman's capsule. The glomerular filtration rate (GFR) indicates overall kidney function. The glomerular filtration rate (GFR) is determined in the blood It has normal levels and is freely filtered, but is not reabsorbed or secreted by the kidney. It can be calculated by measuring any chemical that is not measured. The rate at which blood is released into the urine is the amount of material derived from a calculable volume of blood. Phosphorus can be determined by injecting inulin into the plasma. Since inulin is not reabsorbed or secreted by the kidneys, its excretion rate is significantly higher than that of water-soluble inulin. The GFR is directly proportional to the rate of filtration through the quality of the glomerular filter. 25mL / min / 1.73m 2 and preferably about 100 to about 125 mL / min / 1.7 3m 2 Other principles that determine GFR are: 51 Cr-EDTA, [ 125 I ] includes measurement of iothalamic acid or iohexyl. GFR is typically measured as the number of blood glucose levels per hour. The volume may be recorded in units, e.g., milliliters / minute, using the following formula: Cut:

[0035]

number

[0036] As used herein, "estimated glomerular filtration rate" or "eGFR" refers to any measurement method known in the art. known in the field, for example, the Chronic Kidney Disease Epidemiology Collaboration formula, the Cockcroft-Gault formula, or Based on the dietary modification formula for kidney disease, screening from serum creatinine level Subjects with normal renal function have an e of approximately 90 mL / min or greater. Defined as having a GFR.

[0037] In addition to having chronic kidney disease and type II diabetes, the patient may have overt albuminuria. As used herein, the term "overt albuminuria" refers to patients with an albumin / creatinine ratio (ACR) exceeding about 300 mg / g. In some embodiments wherein, patients with overt albuminuria have an ACR of about 300 to about 5000 mg / g. In further embodiments, patients with overt albuminuria have an ACR of about 300, about 400, about 500, about 750, about 1000, about 1250, about 1500, about 1750, about 2000, about 2250, about 2500, about 2750, about 3000, about 3250, about 3500, about 3750, about 400 0, about 4250, about 4500, about 4750, or about 5000 mg / g. In other embodiments, patients with overt albuminuria have an ACR of about 300 to about 4000, about 300 to about 3000, about 300 to about 2000, about 300 to about 1000, about 1000 to about 5000, about 1000 to about 4000, about 1000 to about 3000, about 1000 to about 2000, about 2000 to about 5000, about 2000 to about 4000, about 2000 to about 3000, about 3000 to about 50 00, about 3000 to about 4000, or about 4000 to about 5000 mg / g. .

[0038] The method includes administering a therapeutically effective amount of canagliflozin. As used herein the term "therapeutically effective amount" is the amount of an active compound or pharmaceutical agent that elicits a biological or pharmaceutical response in a tissue system, animal, or human, including alleviation of the symptoms of the disease or disorder being treated, as determined by a researcher, veterinarian, physician, or other clinician. In some embodiments wherein, a therapeutically effective amount of canagliflozin is about 50 to about 500 mg. In further embodiments wherein, In this case, the therapeutically effective amount of canagliflozin is about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg , or about 500 mg. In other embodiments, the therapeutically effective amount of canagliflozin is about 5 0 to about 450 mg, about 50 to about 400 mg, about 50 to about 300 mg, about 50 to about 250 m g, about 50 to about 200 mg, about 50 to about 150 mg, about 50 to about 100 mg, about 100 to about 500 mg, about 100 to about 450 mg, about 100 to about 400 mg, about 100 to about 350 mg, about 100 to about 300 mg, about 100 to about 250 mg, about 100 to about 200 mg, about 150 to about 500 mg, about 150 to about 450 mg, about 150 to about 400 mg, about 150 to about 350 mg, about 150 to about 300 mg, about 150 to about 250 mg, about 200 to about 500 mg, about 200 to about 450 mg, about 200 to about 400 mg, about 200 to about 350 mg, about 200 to about 300 mg, about 250 to about 500 mg, about 300 to about 450 mg, about 300 to about 400 mg, about 350 to about 500 mg, about 350 to about 450 mg, or about 400 to about 5 00 mg. In yet another embodiment, the therapeutically effective amount is about 100 to about 300 mg . In yet another embodiment, the therapeutically effective amount is about 100 mg.

[0039] As used herein, unless otherwise specified, the term "canagliflozin" refers to 1,5-anhydro-1-C-(3-{[5-(4-fluorophenyl)thiophen -2-yl]methyl]}-4-methylphenyl)-glucitol of formula ( I).

[0040]

Chemical Formula

[0041] In other embodiments, canagliflozin refers to stereoisomers of canagliflozin such as the enantiomers and diastereomers in pure or substantially pure form. Canagliflozin also refers to its racemic mixture. In certain embodiments, "canagliflozin" refers to 1,5-anhydro-1-C-(3-{[5-(4-fluorophenyl)thiophen-2-yl]methyl})-4-methylphenyl)-D-glucitol. In other embodiments, "canagliflozin" refers to the compound of formula (I):

[0042] {[5-(4-fluorophenyl)thiophen-2-yl]methyl]}-4-methylphenyl)-D-glucitol. In other embodiments, "canagliflozin" refers to the (1S)-1,5-anhydro-1-C-(3-{[5-(4-fluorophenyl) thiophen-2-yl]methyl]}-4-methylphenyl)-D-glucitol of formula (I):

[0043]

Chemical formula

[0044] As used herein, "canagliflozin" also refers to the amorphous or crystalline form of canagliflozin. In some embodiments, canagliflozin is in crystalline form. In other embodiments, canagliflozin is in amorphous form. The degree of crystallinity can be determined by one or more techniques such as single crystal X-ray diffraction, powder X-ray diffraction, differential scanning calorimetry, melting point, etc. by those skilled in the art.

[0045] As used herein, "canagliflozin" includes its anhydride or hydrate. In certain embodiments, canagliflozin is in anhydrous form. In other embodiments, canagliflozin is its hydrate. In further embodiments, the canagliflozin hydrate is its hemihydrate. hydrate.​​​​​​​​​​ It is a hydrate. In other embodiments, canagliflozin is its monohydrate. Thus , canagliflozin, in some embodiments, includes the hemihydrate of the compound of formula (I). In other embodiments, canagliflozin includes the hemihydrate of the compound of formula (II). Further embodiments, canagliflozin refers to the crystalline hemihydrate form of the compound of formula (I). Further in another embodiment, canagliflozin refers to the crystalline hemihydrate form of the compound of formula (II). In certain embodiments, canagliflozin refers to the crystalline hemihydrate form of the compound described in International Patent Publication No. 2008 / 06932 7, the disclosure of which is incorporated herein by reference in its entirety. In other embodiments, canagliflozin includes the monohydrate of the compound of formula (I). In further embodiments, canagliflozin includes the monohydrate of the compound of formula (II).

[0046] As used herein, "canagliflozin" further refers to its solvates. Such solvates include molecules of a solvent that are bonded to one or more positions of the canagliflozin molecule via intermolecular forces or chemical bonds.

[0047] As used herein, "canagliflozin" may also refer to its polymorphs. Such polymorphs of canagliflozin include the crystalline forms of the molecule and have changes in the crystal lattice of each polymorph.

[0048] The term "canagliflozin" may also include its pharmaceutically acceptable salts, which can be readily selected by those skilled in the art. "Pharmaceutically acceptable salts" means salts of canagliflozin that are non-toxic, biologically acceptable, or otherwise biologically suitable for administration to a subject. is intended. For example, Berge, "Pharmaceutical Salts" , J.Pharm.Sci., 1977, 66:1-19, and Handbook of Pharmaceutical Salts, Properties, Selecti on, and Use, Stahl and Wermuth, Eds., Wiley- VCH and VHCA, Zurich, 2002 are referred to, and these are incorporated herein by reference into the specification. Examples of pharmaceutically acceptable salts are salts that are pharmacologically effective and suitable for administration to a patient without undue toxicity, irritation, or allergic reaction. Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, bromides (such as hydrobromide salts), chlorides (such as hydrochloride salts), iodides (such as hydroiodide salts), acetates, propi onates, decanoates, caprylates, acrylate salts, formates, isobutyrates, caproic acid salts, heptanoates, propiolates, oxalates, malonates, succinates, suberates sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne- 1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoic acid salts, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates, methanesulfonates, p ropanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates.

[0049] As will be understood by those skilled in the art, canagliflozin is commercially available. For example, canaglif lozin is available as Invokana®. Canagliflozin exhibits inhibitory activity against sodium-dependent glucose transporters such as, for example, SGLT2, and can be prepared according to the process disclosed in U.S. Patent Application Publication No. 2005 / 0233988, which is incorporated herein by reference.

[0050] As used herein, unless otherwise indicated, the terms “treating” and “treatment” include the management and care of a patient for the purpose of combating a disease, condition or disorder. The terms “treating” and “treatment” also include (a) reducing one or more symptoms or complications of a disease, condition or disorder, (b) preventing the onset of one or more symptoms or complications of a disease, condition or disorder, and / or (c) eliminating one or more symptoms or complications of a disease, condition or disorder, including the administration of a compound or pharmaceutical composition described herein.

[0051] As used herein, unless otherwise indicated, the terms “preventing” and “prevention” include (a) reducing the frequency of one or more symptoms, (b) reducing the severity of one or more symptoms, (c) delaying, slowing or avoiding the progression of further symptoms, and / or (d) slowing or avoiding the progression of a disorder, condition or state to a later or more severe form.

[0052] Those skilled in the art will understand that when the present disclosure relates to a method of prevention, the patients in need thereof include any patient who has experienced or exhibited at least one symptom of a disorder, disease or condition to be prevented. ​​​​​​​​​​​​It is recognized that it includes patients with certain conditions. Furthermore, patients in need thereof, in addition , have not shown symptoms of the disorder, disease, or condition to be prevented, but are considered by a physician, clinician, or other medical professional to be at risk of progression of the disorder, disease, or condition. For example, a patient may be considered at risk of progression of a disorder, disease, or condition (and thus in need of prevention or prophylactic treatment) as a result of the patient's medical history, including, but not limited to, family history, constitution, co-occurring (overlapping) diseases or conditions, genetic testing, etc.

[0053] The terms "subject" and "patient" are used interchangeably herein and refer to an animal, preferably a mammal, most preferably a human, that is the subject of treatment, observation, or experiment. Preferably, a patient has experienced and / or exhibits at least one symptom of a disease or disorder to be treated and / or prevented.

[0054] The methods described herein reduce or prevent the occurrence of one or more kidney events in a patient. Since the patients described herein have chronic kidney disease, they are at high risk of kidney events.

[0055] As used herein, the term "kidney event" refers to a disorder related to and / or affecting kidney function and / or kidney filtration. Kidney disorders include an increase in urinary albumin levels, an increase in serum creatinine, an increase in the serum albumin / creatinine ratio (ACR), kidney filtration injury, diabetic nephropathy (including but not limited to glomerular diabetic nephropathy), kidney filtration, glomerular filtration, kidney allograft filtration, compensatory filtration, filtration chronic kidney disease, filtration Examples include, but are not limited to, transient acute kidney injury, obesity, end-stage kidney disease (ESKD), or kidney death. Not limited to these.

[0056] In some embodiments, one or more kidney events include a doubling of serum creatinine, end-stage kidney disease, or kidney death, or any combination thereof. In other embodiments, one or more kidney events include a doubling of serum creatinine. In other embodiments, one or more kidney events include end-stage kidney disease. In yet other embodiments, one or more kidney events include kidney death.

[0057] The terms "end-stage kidney disease" and "stage 5 kidney disease" are interchangeable and refer to patients with an eGFR of less than about 15 mL / min / 1.7 3m 2 Patients with end-stage kidney disease typically exhibit severe symptoms. Symptoms at this stage can include, but are not limited to, itching, muscle cramps, nausea, vomiting, loss of appetite, swelling (often in the hands and feet), pain such as lower back pain, more or less urine output than normal, shortness of breath, difficulty sleeping, or any combination thereof. In certain embodiments, patients with end-stage chronic kidney disease have kidneys that are near or completely in renal failure. In other embodiments, these patients are either on dialysis, require a kidney transplant, or any combination thereof. The methods described herein also reduce or prevent the occurrence of one or more cardiovascular events in a patient. As used herein, unless otherwise specified, the term "cardiovascular event" refers to cardiovascular death, non-fatal myocardial infarction, non-fatal stroke (ischemic), peripheral artery disease, hypertensive heart disease, ischemia

[0058] or any combination thereof. or prevent.

[0059] As used herein, unless otherwise indicated, the term "cardiovascular event" refers to cardiovascular death, non-fatal myocardial infarction, non-fatal stroke (ischemic), peripheral artery disease, hypertensive heart disease, ischemia Cardiovascular diseases, coronary vascular diseases, peripheral vascular diseases, cerebrovascular diseases, cardiac arrhythmias (other than sinus tachycardia), cardiomyopathy, angina pectoris (including but not limited to unstable angina pectoris), heart failure (requiring hospitalization heart failure, including but not limited to such), and coronary venous valve diseases, but not limited to these. In some embodiments, the cardiovascular event is cardiovascular death, in-hospital heart failure, non-fatal myocardial infarction, non-fatal stroke, or any combination thereof. In other embodiments, the cardiovascular event is cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke In a further embodiment, the cardiovascular or disease is non-fatal myocardial infarction. In a further embodiment the cardiovascular event is non-fatal stroke. In still other embodiments, the cardiovascular event is cardiovascular death. In other embodiments, the cardiovascular event is in-hospital heart failure.

[0060] In other embodiments, the patient may also be diagnosed as having one or more cardiovascular risk factors that can cause a cardiovascular event. Cardiovascular risk factors include fainting, transient ischemic event or stroke (excluding intracranial hemorrhage), cardiovascular surgery such as heart transplantation, implantation of a cardiac device such as a cardiac stimulator (pacemaker) or defibrillator ("ICD"), cerebrovascular or peripheral intervention, pulmonary embolism or deep vein thrombosis, acute pulmonary edema or dyspnea due to heart causes, stable angina pectoris or atypical chest pain, supraventricular rhythm disorders such as atrial fibrillation, fluctuations in arterial pressure (e.g. , hypotension, hypertension, excluding fainting), cardiovascular infections, major bleeding / hemorrhage (requiring two or more blood cell pellets or intracranial hemorrhage), elevated LDL, decreased HDL, elevated triglycerides, etc. cholesterol elevation (hyperlipidemia), obesity, microalbuminuria, peripheral vascular disease, underlying Structural heart disease, atherosclerosis, atrial fibrillation, tachycardia, coronary artery disease, non-rheumatic valvular heart disease, dilated cardiomyopathy of ischemic origin, ablation, supraventricular tachycardia other than atrial fibrillation or flutter, history of cardiac valve surgery, non-ischemic dilated cardiomyopathy, hypertrophic cardiomyopathy, rheumatic valvular disease, sustained ventricular tachycardia, congenital heart disease, ventricular fibrillation, at least one cardiac device (including but not limited to cardiac stimulators, implantable defibrillators, etc.), current or past smoking history, male gender, or any combination thereof, but not limited thereto. For example, see Hohnloser et al., Journal of Cardiovascular electrophysiology, January 200 8, Vol. 19, No. 1, pages 69-73, which is incorporated herein by reference.

[0061] The method also enables the administration of the accompanying standard treatment. The term "standard treatment" typically refers to the treatment prescribed by a physician for the condition in question. In some embodiments, the standard treatment includes, consists of, or consists essentially of administering additional pharmaceuticals that are angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or a combination thereof. In some embodiments, the method includes administering an angiotensin-converting enzyme inhibitor. In other embodiments, the method includes administering an angiotensin receptor blocker. In further embodiments, the method includes administering an angiotensin-converting enzyme inhibitor and an It can be administered to the patient before, after, or simultaneously with the rosin. In some embodiments, the standard treatment is administered before canagliflozin. In other embodiments, the standard treatment is canagliflo zin is administered after. In further embodiments, the standard treatment is administered simultaneously with canagliflozin .

[0062] As used herein, the terms "angiotensin-converting enzyme inhibitor (", "ACE inhibitor agent", or "ACEi" are interchangeable and inhibit angiotensin-converting enzyme, thereby reducing vascular tone and blood volume (i.e., dilating blood vessels), and thus reducing blood pressure . ACE inhibitors, based on their molecular structure, include, but are not limited to, (a) sulfhydryl-containing agents such as alacepril, captopril (CAPOTEN®), and zofenopril , (b) dicarboxylate-containing agents such as enalapril (VASOTEC®), ramipril (ALTACE®, PRILACE®, RAMACE®), quinapril (ACCUPRIL®), perindopril (COVERS YL®, ACEON®), lisinopril (PRINIVIL®, ZESTRIL®), benazepril (LOTENSIN® ), imidapril (TANATRIL®, TANAPRESS®, CARDIPRIL®), zofenopril (ZOFECARD® ), trandolapril (MAVIK®, ODRIK®), moexipril (UNIVASC®), cilazapril, delapril, spirapril, temocapril , and (c) fosinopril . , and (c) fosinopril and not limited to, trandolapril (MAVIK®, ODRIK®), moexipril (UNIVASC®), cilazapril, delapril, spirapril, temocapril , and (c) fosinopril . including, but not limited to, pril (FOSITEN (registered trademark), MONOPRIL (registered trademark)), can be classified into three groups of phosphonate-containing agents. In some embodiments, the ACE inhibitor is benazepril, captopril, enalapril, imidapril, lisinopril, or ramipril. In other embodiments, the ACE inhibitor is enalapril, imidapril, lisinopril, or ramipril. In further embodiments, the ACE inhibitor is benazepril, captopril, enalapril, imidapril, lisinopril, ramipril, or any combination thereof. Those skilled in the art will readily recognize that the recommended dosages and dosing regimens of ACE inhibitors can be determined by referring to appropriate references such as drug package inserts, FDA guidelines, and physician's desk references.

[0063] As used herein, unless otherwise specified, the terms "ARB", "angiotensin receptor blocker", and "angiotensin II receptor antagonist" are interchangeable and refer to pharmaceuticals that modulate the renin-angiotensin-aldosterone system. More specifically, ARB blocks the activation of the angiotensin II AT1 receptor, resulting in, among other effects, vasodilation (dilation of blood vessels), decreased secretion of vasopressin, and decreased production and secretion of aldosterone. The combined effect is to lower blood pressure. Suitable examples of ARBs include losartan (COZAAR (registered trademark)), irbesartan (APROVEL (registered trademark), KARBEA (registered trademark), ​ACAND®), valsartan (DIOVAN®), telmisartan MICARDIS®, azilsartan (EDARBI®) and and eprosartan (TEVETAN®). In some embodiments, the ARB is candesartan, irbesartan, losartan In other embodiments, the ARB is irbesartan or losartan. Those skilled in the art will recognize that recommended dosages and dosing regimens for ARBs are available from drug package inserts, FDA guidelines, and other sources. This can be determined by consulting appropriate references such as guidelines, physician's desk references, etc. You will easily recognize that.

[0064] In yet another embodiment, the occurrence of one or more renal and / or cardiovascular events is assessed by angiocardiography. Standard treatment includes administration of tensin-converting enzyme inhibitors and / or angiotensin receptor blockers. For example, the method may involve treating a patient who is receiving standard of care but has not yet developed a cancer. Patients with the same level of disease progression who are not treated with nagliflozin In comparison, the risk of developing one or more of the renal and / or cardiovascular events described herein and and / or reduce the predicted severity.

[0065] In certain aspects, the methods described herein are useful for determining whether a doubling of serum creatinine, ESKD, or renal death occurs. or cardiovascular (CV) death, or any combination thereof In some embodiments, the method is effective in reducing serum creatinine doubling, ESK In another aspect, the method reduces the relative risk of D, renal death, or CV death. In a further aspect, the method reduces the relative risk for a doubling of creatinine. Reduce the relative risk for. In yet other aspects, the method reduces the relative risk of renal death Reduce. In yet another aspect, the method reduces the relative risk of CV death.

[0066] For example, the methods described herein are those who receive standard treatment such as the labeled maximum daily dose of ACEi and / or ARB but do not receive treatment with canagliflozin, compared to patients with the same level of disease progression The risk of doubling of serum creatinine, ESKD, renal death, or CV Death, or any combination thereof, is reduced by about, or at least about, 10%, 12%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% to be Effective. In certain aspects, the reduction is at least about 25%. In other aspects, the reduction is At least about 30%. Generally, those who receive standard treatment such as the labeled maximum daily dose of ACEi and / or ARB but do not receive treatment with canagliflozin, compared to patients with the same level of disease progression The reduction in the risk of doubling of serum creatinine, ESKD, renal death, or CV death Or any combination thereof, is from about 10% to about 70%, from about 10% to about 60, from about 10% to about 50%, from about 10% to about 40%, from about 10% to about 30%, from about 10% to about 2 0%, from about 20% to about 70%, from about 20% to about 60%, from about 20% to about 50%, from about 20% to about 4 0%, from about 20% to about 30%, from about 30% to about 70%, from about 30% to about 60%, from about 30% to about 5 0%, from about 30% to about 40%, from about 40% to about 70%, from about 40% to about 60%, from about 40% to about 5 0%, from about 50% to about 70%, from about 50% to about 60%, or from about 60% to about 70%. .

[0067] In other embodiments, the method is for patients undergoing standard treatment such as the labeled daily dose of the maximum tolerated amount of an ACEi and / or ARB but not treatment with canagliflozin, and is effective to reduce the risk of doubling of serum creatinine, ESKD, or renal death, or any combination thereof, by about, or at least about, 10%, 12%, 15%, 20% %, 25%, 30%, 35%, 40%, 45%, or 50% compared to patients with the same level of disease progression. In certain embodiments, the reduction is at least about 25%. In other embodiments, the reduction is at least about 30%. Generally, the reduction in the risk of doubling of serum creatinine, ESKD, or renal death, or any combination thereof, compared to patients with the same level of disease progression who are undergoing standard treatment such as the labeled daily dose of the maximum tolerated amount of an ACEi and / or ARB but not treatment with canagliflozin, is in the range of about 10% to about 70%, about 10% to about 60%, about 10% to about 5 0%, about 10% to about 40%, about 10% to about 30%, about 10% to about 20%, about 20% to about 7 0%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 20% to about 3 0%, about 30% to about 70%, about 30% to about 60%, about 30% to about 50%, about 30% to about 4 0%, about 40% to about 70%, about 40% to about 60%, about 40% to about 50%, about 50% to about 7 0%, about 50% to about 60%, or about 60% to about 70%. In other embodiments, the methods described herein are for patients undergoing standard treatment such as the labeled daily dose of the maximum tolerated amount of an ACEi and / or ARB but not treatment with canagliflozin, and are effective to reduce the risk of CV death, hospitalization for heart failure, or any combination thereof, compared to patients with the same level of disease progression.

[0068] In other embodiments, the method described herein is for patients undergoing standard treatment such as the labeled daily dose of the maximum tolerated amount of an ACEi and / or ARB but not treatment with canagliflozin, and is effective to reduce the risk of CV death, hospitalization for heart failure, or any combination thereof, compared to patients with the same level of disease progression. Effective to reduce the risk of the combination by about, or at least about, 10%, 12%, 15%, 20%, 25% , 30%, 35%, 40%, 45%, or 50%. In certain embodiments , the reduction is at least about 25%. In other embodiments, the reduction is at least about 30% . Generally, compared to patients with the same level of disease progression who receive standard treatment such as the labeled daily dose at the maximum tolerated dose of ACEi and / or ARB but do not receive treatment with canagliflozin, the reduction in the risk of CV death, hospitalization for heart failure, or a combination thereof is about 10% to about 70%, about 10% to about 60, about 10% to about 50%, about 10% to about 40%, about 10% to about 3 0%, about 10% to about 20%, about 20% to about 70%, about 20% to about 60%, about 20% to about 5 0%, about 20% to about 40%, about 20% to about 30%, about 30% to about 70%, about 30% to about 6 0%, about 30% to about 50%, about 30% to about 40%, about 40% to about 70%, about 40% to about 6 0%, about 40% to about 50%, about 50% to about 70%, about 50% to about 60%, or about 60% to about 70%.

[0069] In other embodiments, the methods described herein are compared to patients with the same level of disease progression who receive standard treatment such as the labeled daily dose at the maximum tolerated dose of ACEi and / or ARB but do not receive treatment with canagliflozin, and are effective to reduce the risk of non-fatal MI, non-fatal stroke, or a combination thereof by about, or at least about, 10%, 12%, 15%, 20%, 25% , 30%, 35%, 40%, 45%, or 50%. In certain embodiments , the reduction is at least about 20%. Generally, compared to patients with the same level of disease progression who receive standard treatment such as the labeled daily dose at the maximum tolerated dose of ACEi and / or ARB but do not receive treatment with canagliflozin ​​​The reduction in the risk of non-fatal MI, non-fatal stroke, or a combination thereof, compared to patients with the same level of disease progression, is from about 10% to about 70%, from about 10% to about 60, from about 10% to about 50%, from about 10% to about 40%, from about 10% to about 30%, from about 10% to about 20%, from about 20% to about 70%, from about 20% to about 60%, from about 20% to about 50%, from about 20% to about 40%, from about 20% to about 30%, from about 30% to about 70%, from about 30% to about 60%, from about 30% to about 50%, from about 30% to about 40%, from about 40% to about 70%, from about 40% to about 60%, from about 40% to about 50%, from about 50% to about 70%, from about 50% to about 60%, or from about 60% to about 70%. In other embodiments, the methods described herein are effective to reduce the risk of in-hospital heart failure by about, or at least about

[0070] 10%, 12%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% compared to patients with the same level of disease progression who receive standard therapy such as the labeled daily dose of the maximum tolerated amount of an ACEi and / or ARB but do not receive treatment with canagliflozin. In certain aspects, the reduction is at least about 35%. Generally, the reduction in the risk of in-hospital heart failure compared to patients with the same level of disease progression who receive standard therapy such as the labeled daily dose of the maximum tolerated amount of an ACEi and / or ARB but do not receive treatment with canagliflozin is from about 10% to about 70%, from about 10% to about 60, from about 10% to about 50%, from about 10% to about 40%, from about 10% to about 30%, from about 10% to about 20%, from about 20% to about 70%, from about 20% to about 60%, from about 20% to about 50%, from about 20% to about 40%, from about 20% to about 30%, from about 30% to about 70%, from about 30% to about 60%, from about 30% to about 50%, from about 30% to about 40%, from about 40% to about 70%, from about 40% to about 60%, from about 40% to about 50%, from about 50% to about 70%, from about 50% to about 60%, or from about 60% to about 70%. ​​​40%, from about 40% to about 70%, from about 40% to about 60%, from about 40% to about 50%, from about 50% to about 70%, from about 50% to about 60%, or from about 60% to about 70%.

[0071] In yet another embodiment, the methods described herein are effective to prevent doubling of serum creatinine, end-stage kidney disease (ESKD), kidney death, or any combination thereof. In some embodiments, the method is effective to prevent doubling of serum creatinine. In further embodiments, the method is effective to prevent ESKD. In other embodiments, the method is effective to prevent kidney death .

[0072] In the methods described herein, a therapeutically effective amount of canagliflozin is safe, effective, or safe and effective. As used herein, unless otherwise indicated, the term "safe" means that there are no unduly harmful side effects (such as toxicity, irritation, or allergic reaction), and is commensurate with a reasonable benefit / risk ratio when used in the context of the present invention. Similarly, unless otherwise indicated, the term "effective" means that when administered at a therapeutically effective dose, it has been shown to be effective in the treatment of patients with chronic kidney disease. In certain embodiments, the methods described herein are safe. In other embodiments, the methods described herein are effective. In further embodiments, the methods described herein are safe and effective. In still further embodiments, a therapeutically effective amount of canagliflozin is safe. In yet further embodiments, a therapeutically effective amount of canagliflozin is effective. In other embodiments, a therapeutically effective amount of canagliflozin is safe and effective.

[0073] ​​​​​​​As used herein, unless otherwise specified, the term "clinically proven" (used alone or to modify the terms "safe" and / or "effective") means that the evidence is demonstrated by Phase III clinical trials sufficient to meet the approval criteria of the US Food and Drug Administration, or similar studies for market approval by the EMEA. Preferably, an appropriately sized randomized double-blind controlled trial is used to clinically demonstrate the effect of canagliflozin compared to a placebo with the patient condition evaluated by the techniques described herein. As used herein, unless otherwise specified, the term "clinically proven" (used alone or to modify the terms "safe" and / or "effective") means that the evidence is demonstrated by Phase III clinical trials sufficient to meet the approval criteria of the US Food and Drug Administration, or similar studies for market approval by the EMEA. Preferably, an appropriately sized randomized double-blind controlled trial is used to clinically demonstrate the effect of canagliflozin compared to a placebo with the patient condition evaluated by the techniques described herein. As used herein, unless otherwise specified, the term "clinically proven" (used alone or to modify the terms "safe" and / or "effective") means that the evidence is demonstrated by Phase III clinical trials sufficient to meet the approval criteria of the US Food and Drug Administration, or similar studies for market approval by the EMEA. Preferably, an appropriately sized randomized double-blind controlled trial is used to clinically demonstrate the effect of canagliflozin compared to a placebo with the patient condition evaluated by the techniques described herein. As used herein, unless otherwise specified, the term "clinically proven" (used alone or to modify the terms "safe" and / or "effective") means that the evidence is demonstrated by Phase III clinical trials sufficient to meet the approval criteria of the US Food and Drug Administration, or similar studies for market approval by the EMEA. Preferably, an appropriately sized randomized double-blind controlled trial is used to clinically demonstrate the effect of canagliflozin compared to a placebo with the patient condition evaluated by the techniques described herein. As used herein, unless otherwise specified, the term "clinically proven" (used alone or to modify the terms "safe" and / or "effective") means that the evidence is demonstrated by Phase III clinical trials sufficient to meet the approval criteria of the US Food and Drug Administration, or similar studies for market approval by the EMEA. Preferably, an appropriately sized randomized double-blind controlled trial is used to clinically demonstrate the effect of canagliflozin compared to a placebo with the patient condition evaluated by the techniques described herein. As used herein, unless otherwise specified, the term "clinically proven" (used alone or to modify the terms "safe" and / or "effective") means that the evidence is demonstrated by Phase III clinical trials sufficient to meet the approval criteria of the US Food and Drug Administration, or similar studies for market approval by the EMEA. Preferably, an appropriately sized randomized double-blind controlled trial is used to clinically demonstrate the effect of canagliflozin compared to a placebo with the patient condition evaluated by the techniques described herein.

[0074] As used herein, unless otherwise specified, the term "clinically proven effective" means that the effectiveness of the treatment is demonstrated to be statistically significant by Phase III clinical trials, i.e., the results of the clinical trials are unlikely to be due to a probability that the alpha level is less than 0.05, or the results of clinical effectiveness are sufficient to meet the approval criteria of the US Food and Drug Administration or similar tests for market approval by the EMEA. For example, canagliflozin, as described herein and specifically described in the examples, has been proven to be clinically effective in the treatment of patients with chronic kidney disease when administered in a therapeutically effective amount to reduce the progression of chronic kidney disease. As used herein, unless otherwise specified, the term "clinically proven effective" means that the effectiveness of the treatment is demonstrated to be statistically significant by Phase III clinical trials, i.e., the results of the clinical trials are unlikely to be due to a probability that the alpha level is less than 0.05, or the results of clinical effectiveness are sufficient to meet the approval criteria of the US Food and Drug Administration or similar tests for market approval by the EMEA. For example, canagliflozin, as described herein and specifically described in the examples, has been proven to be clinically effective in the treatment of patients with chronic kidney disease when administered in a therapeutically effective amount to reduce the progression of chronic kidney disease. As used herein, unless otherwise specified, the term "clinically proven effective" means that the effectiveness of the treatment is demonstrated to be statistically significant by Phase III clinical trials, i.e., the results of the clinical trials are unlikely to be due to a probability that the alpha level is less than 0.05, or the results of clinical effectiveness are sufficient to meet the approval criteria of the US Food and Drug Administration or similar tests for market approval by the EMEA. For example, canagliflozin, as described herein and specifically described in the examples, has been proven to be clinically effective in the treatment of patients with chronic kidney disease when administered in a therapeutically effective amount to reduce the progression of chronic kidney disease. As used herein, unless otherwise specified, the term "clinically proven effective" means that the effectiveness of the treatment is demonstrated to be statistically significant by Phase III clinical trials, i.e., the results of the clinical trials are unlikely to be due to a probability that the alpha level is less than 0.05, or the results of clinical effectiveness are sufficient to meet the approval criteria of the US Food and Drug Administration or similar tests for market approval by the EMEA. For example, canagliflozin, as described herein and specifically described in the examples, has been proven to be clinically effective in the treatment of patients with chronic kidney disease when administered in a therapeutically effective amount to reduce the progression of chronic kidney disease. As used herein, unless otherwise specified, the term "clinically proven effective" means that the effectiveness of the treatment is demonstrated to be statistically significant by Phase III clinical trials, i.e., the results of the clinical trials are unlikely to be due to a probability that the alpha level is less than 0.05, or the results of clinical effectiveness are sufficient to meet the approval criteria of the US Food and Drug Administration or similar tests for market approval by the EMEA. For example, canagliflozin, as described herein and specifically described in the examples, has been proven to be clinically effective in the treatment of patients with chronic kidney disease when administered in a therapeutically effective amount to reduce the progression of chronic kidney disease. As used herein, unless otherwise specified, the term "clinically proven effective" means that the effectiveness of the treatment is demonstrated to be statistically significant by Phase III clinical trials, i.e., the results of the clinical trials are unlikely to be due to a probability that the alpha level is less than 0.05, or the results of clinical effectiveness are sufficient to meet the approval criteria of the US Food and Drug Administration or similar tests for market approval by the EMEA. For example, canagliflozin, as described herein and specifically described in the examples, has been proven to be clinically effective in the treatment of patients with chronic kidney disease when administered in a therapeutically effective amount to reduce the progression of chronic kidney disease. As used herein, unless otherwise specified, the term "clinically proven effective" means that the effectiveness of the treatment is demonstrated to be statistically significant by Phase III clinical trials, i.e., the results of the clinical trials are unlikely to be due to a probability that the alpha level is less than 0.05, or the results of clinical effectiveness are sufficient to meet the approval criteria of the US Food and Drug Administration or similar tests for market approval by the EMEA. For example, canagliflozin, as described herein and specifically described in the examples, has been proven to be clinically effective in the treatment of patients with chronic kidney disease when administered in a therapeutically effective amount to reduce the progression of chronic kidney disease. As used herein, unless otherwise specified, the term "clinically proven effective" means that the effectiveness of the treatment is demonstrated to be statistically significant by Phase III clinical trials, i.e., the results of the clinical trials are unlikely to be due to a probability that the alpha level is less than 0.05, or the results of clinical effectiveness are sufficient to meet the approval criteria of the US Food and Drug Administration or similar tests for market approval by the EMEA. For example, canagliflozin, as described herein and specifically described in the examples, has been proven to be clinically effective in the treatment of patients with chronic kidney disease when administered in a therapeutically effective amount to reduce the progression of chronic kidney disease.

[0075] As used herein, unless otherwise specified, the term "clinically proven safe" means that the safety of the treatment is demonstrated by Phase III clinical trials by analysis of the trial data and results, the treatment has no excessive side effects, and meets the approval criteria of the US Food and Drug Administration or similar tests for market approval by the European Union, Middle East and Africa (EMEA). As used herein, unless otherwise specified, the term "clinically proven safe" means that the safety of the treatment is demonstrated by Phase III clinical trials by analysis of the trial data and results, the treatment has no excessive side effects, and meets the approval criteria of the US Food and Drug Administration or similar tests for market approval by the European Union, Middle East and Africa (EMEA). As used herein, unless otherwise specified, the term "clinically proven safe" means that the safety of the treatment is demonstrated by Phase III clinical trials by analysis of the trial data and results, the treatment has no excessive side effects, and meets the approval criteria of the US Food and Drug Administration or similar tests for market approval by the European Union, Middle East and Africa (EMEA). As used herein, unless otherwise specified, the term "clinically proven safe" means that the safety of the treatment is demonstrated by Phase III clinical trials by analysis of the trial data and results, the treatment has no excessive side effects, and meets the approval criteria of the US Food and Drug Administration or similar tests for market approval by the European Union, Middle East and Africa (EMEA). It means corresponding to a clinically significant clinical benefit (e.g., efficacy) that is statistically significant. For example, Canagliflozin, as described herein and as specifically described in the examples, has been proven to be clinically safe for the treatment of patients with chronic kidney disease when administered in a therapeutically effective amount. has been proven.

[0076] In certain aspects, methods of selling a formulation comprising canagliflozin are also provided. As used herein, the term "sell" or "selling" refers to transferring a formulation, e.g., a pharmaceutical composition or a dosage form, from a seller to a buyer. Thus, the method includes selling a formulation comprising canagliflozin, and the method includes selling the formulation. In some embodiments, the formulation label of the reference listed drug for the formulation includes an indication for treating chronic kidney disease. The method also includes making an offer to sell a formulation comprising canagliflozin. As used herein, the term "making an offer to sell" refers to a proposal by a seller to sell to a buyer for a formulation, e.g., a pharmaceutical composition or dosage form. These methods include selling the formulation.

[0077] The term "formulation" is a product containing an active ingredient that has been approved for manufacture and sale by a government agency, e.g., the U.S. Food and Drug Administration or a similar agency in other countries. In some embodiments the formulation includes canagliflozin. In some embodiments, the formulation includes canagliflozin.

[0078] Similarly, "label" or "formulation label" refers to the information provided to the patient that provides relevant information about the formulation. Such information includes a description of the drug, clinical pharmacology, indications (use of the formulation), contraindications (persons who should not take the formulation), warnings, precautions, adverse events (side effects), etc. Drug abuse and dependence, dosage and administration, use during pregnancy, use in nursing mothers, children and use in elderly patients, drug delivery methods, patient safety information, or any combination of these. In certain embodiments, the label or The product label provides instructions for use in patients with type 2 diabetes or overt albuminuria. In other embodiments, the formulation label may include one or more adverse renal or steroid effects compared to standard of care. In a further embodiment, the label or formulation The label will identify canagliflozin as the regulatory approved chemical entity. In embodiments, the label provides instructions for use in patients with chronic kidney disease. In an embodiment, the label provides a definition of chronic kidney disease and indicates if the patient has chronic kidney disease. The patient or physician is instructed to administer nagliflozin.

[0079] As used herein, the term "reference listed drug" or "RLD" refers to a drug that is a biological refers to the drug product to which a newer generic version is compared to demonstrate its clinical equivalence. by the Member States of the European Union or on the basis of a complete dossier, i.e. Directive 2001 / 83 / Quality, preclinical and It is a drug that has been granted marketing authorization by the committee based on the submission of clinical data and Applications for marketing authorization of pharmaceuticals / hybrid drugs are usually supported by the demonstration of bioequivalence. , through the submission of appropriate bioavailability studies, is a reference drug.

[0080] In the United States, companies seeking approval to market generic equivalents must submit their Abbreviated New Drug Application (ANA) In an Abbreviated New Drug Application (ANDA), it is necessary to refer to the RLD. For example, an ANDA applicant relies on the FDA's determination that a previously approved formulation, i.e., the RLD, is safe and effective, and in particular, that the proposed generic formulation is shown in a specified manner to be the same as the RLD. Specifically, with limited exceptions, the formulation submitted in the ANDA must have, among other things, the same active ingredient, conditions of use, route of administration, dosage form, strength, and labeling (with certain tolerances) as the RLD. The RLD is the listed drug for which the ANDA applicant must show that the proposed ANDA formulation is the same with respect to characteristics such as active ingredient, dosage form, route of administration, strength, labeling, conditions of use, etc. The electronic Orange Book has columns for the RLD and for reference standards. In the printed Orange Book, the RLD and reference standards are identified by specific symbols. In Europe, the applicant identifies in the form of the application for the applicant's generic / hybrid medicinal product, which is the same as the ANDA or supplementary NDA (sNDA) formulation, reference medicinal product (product name, strength, dosage form, marketing authorization holder (MAH, first authorization, Member State / Community) and is synonymous with the RLD as follows: 1. A medicinal product authorized or approved in the European Economic Area (EEA) used as a basis for demonstrating that the data protection period provided for in European pharmaceutical law has expired. This reference medicinal product is identified for the purpose of calculating the expiry of the data protection period and may be for a strength, dosage form, route of administration, or presentation different from the generic / hybrid medicinal product.

[0081] In Europe, the applicant identifies in the form of the application for the applicant's generic / hybrid medicinal product, which is the same as the ANDA or supplementary NDA (sNDA) formulation, reference medicinal product (product name, strength, dosage form, marketing authorization holder (MAH, first authorization, Member State / Community) and is synonymous with the RLD as follows: 1. A medicinal product authorized or approved in the European Economic Area (EEA) used as a basis for demonstrating that the data protection period provided for in European pharmaceutical law has expired. This reference medicinal product is identified for the purpose of calculating the expiry of the data protection period and may be for a strength, dosage form, route of administration, or presentation different from the generic / hybrid medicinal product. 1. A medicinal product authorized or approved in the European Economic Area (EEA) used as a basis for demonstrating that the data protection period provided for in European pharmaceutical law has expired. This reference medicinal product is identified for the purpose of calculating the expiry of the data protection period and may be for a strength, dosage form, route of administration, or presentation different from the generic / hybrid medicinal product. 2. A medicinal product authorized or approved in the European Economic Area (EEA) used as a basis for demonstrating that the data protection period provided for in European pharmaceutical law has expired. This reference medicinal product is identified for the purpose of calculating the expiry of the data protection period and may be for a strength, dosage form, route of administration, or presentation different from the generic / hybrid medicinal product. 3. A medicinal product authorized or approved in the European Economic Area (EEA) used as a basis for demonstrating that the data protection period provided for in European pharmaceutical law has expired. This reference 2. A pharmaceutical product in which a single document (product name, strength, pharmaceutical form, MA H, marketing authorization number) is cross-referenced within a generic / hybrid application. This reference pharmaceutical product may be authorized by a separate procedure under a different name, which is identified for the purpose of calculating the expiration of the data protection period and is different from the reference pharmaceutical product. The product information of this reference pharmaceutical product generally functions as the basis for the product information that draws attention to the generic / hybrid pharmaceutical product. 3. A pharmaceutical product (product name, strength, pharmaceutical form, MAH, country of origin of the source) used in a bioequivalence test (if applicable). The different abbreviated approval routes for formulations under the Federal Food, Drug, and Cosmetic (FD&C) Act are the abbreviated approval routes described in Sections 505(j) and 505(b)(2) of the FD&C Act (21 U.S.C. 355(j) and 21 U.S.C. 355(b)(2), respectively).

[0082] According to the FDA ("Determining Whether to Submit an ANDA or a 505(b)(2) Industry Submission," U.S. Department of Health and Human Services, October 2017, pages 1-14, the content of which is incorporated herein by reference), NDAs and ANDAs are classified into the following four categories: (1) A "stand-alone NDA" is an application submitted under Section 505(b)(1) of the FD&C Act and approved under Section 505(c), which contains a complete report of the safety and efficacy investigation conducted by or for the applicant or to which the applicant has the right of reference or use.

[0083] (2) An application under Section 505(b)(2) is submitted under Section 505(b)(1) of the FD&C Act and... and is incorporated herein by reference), NDAs and ANDAs are classified into the following four categories: (1) A "stand-alone NDA" is an application submitted under Section 505(b)(1) of the FD&C Act and approved under Section 505(c), which contains a complete report of the safety and efficacy investigation conducted by or for the applicant or to which the applicant has the right of reference or use. (2) An application under Section 505(b)(2) is submitted under Section 505(b)(1) of the FD&C Act and... (2) An application under Section 505(b)(2) is submitted under Section 505(b)(1) of the FD&C ​​​​An NDA approved under section 505(c) of the C Act, which includes a complete report on the investigation of safety and effectiveness and at least a portion of the information necessary for approval is from research that was not conducted by or for the applicant and for which the applicant has no right of reference or use. (3) An ANDA is an application for a copy of a previously approved drug product submitted and approved under section 505(j) of the FD&C Act. An ANDA relies on the FDA's finding that the previously approved drug product, i.e., the reference listed drug (RLD), is safe and effective. An ANDA must generally contain information demonstrating that the proposed generic product (a) is the same as the RLD with respect to the active ingredient, conditions of use, route of administration, dosage form, strength, and labeling (with certain tolerances), and (b) is bioequivalent to the RLD. If testing is required to establish the safety and effectiveness of the proposed product, the ANDA cannot be submitted. (4) The ANDA applied for is an ANDA for a drug product of a different type with respect to dosage form, route of administration, strength, or active ingredient than the RLD (in a product having two or more active ingredients), and the FDA has determined in response to a submission (a compliance submission) made under section 505(j)(2) of the FD&C Act that the study is not necessary to establish the safety and effectiveness of the proposed drug product.

[0084] The scientific premise underlying the Hatch-Waxman Act is that a drug product approved under an ANDA under section 505(j) of the FD&C Act is presumed to be therapeutically equivalent to its RLD. ​​​​​​​​​​​​​​is to be determined. Products classified as therapeutically equivalent are interchangeable and, when administered to a patient under the conditions specified in the labeling, it is fully expected that the replacement product will provide the same clinical efficacy and safety characteristics as the reference product. In contrast to an ANDA, the section 505(b)(2) application is more flexible with respect to the characteristics of the product being filed. The section 505(b)(2) application does not necessarily have to be rated therapeutically equivalent to the listed drug to which it refers upon approval. and when administered to a patient under the conditions specified in the labeling, it is fully expected that the replacement product will provide the same clinical efficacy and safety characteristics as the reference product. In contrast to an ANDA, the section 505(b)(2) application is more flexible with respect to the characteristics of the product being filed. The section 505(b)(2) application does not necessarily have to be rated therapeutically equivalent to the listed drug to which it refers upon approval. and when administered to a patient under the conditions specified in the labeling, it is fully expected that the replacement product will provide the same clinical efficacy and safety characteristics as the reference product. In contrast to an ANDA, the section 505(b)(2) application is more flexible with respect to the characteristics of the product being filed. The section 505(b)(2) application does not necessarily have to be rated therapeutically equivalent to the listed drug to which it refers upon approval. and when administered to a patient under the conditions specified in the labeling, it is fully expected that the replacement product will provide the same clinical efficacy and safety characteristics as the reference product. In contrast to an ANDA, the section 505(b)(2) application is more flexible with respect to the characteristics of the product being filed. The section 505(b)(2) application does not necessarily have to be rated therapeutically equivalent to the listed drug to which it refers upon approval. and when administered to a patient under the conditions specified in the labeling, it is fully expected that the replacement product will provide the same clinical efficacy and safety characteristics as the reference product. In contrast to an ANDA, the section 505(b)(2) application is more flexible with respect to the characteristics of the product being filed. The section 505(b)(2) application does not necessarily have to be rated therapeutically equivalent to the listed drug to which it refers upon approval. and when administered to a patient under the conditions specified in the labeling, it is fully expected that the replacement product will provide the same clinical efficacy and safety characteristics as the reference product. In contrast to an ANDA, the section 505(b)(2) application is more flexible with respect to the characteristics of the product being filed. The section 505(b)(2) application does not necessarily have to be rated therapeutically equivalent to the listed drug to which it refers upon approval.

[0085] This method may also include, consist of, or essentially consist of bringing canagliflozin into the commercial stream. In certain embodiments, canagliflozin includes a labeling that includes instructions for the safe and effective treatment of chronic kidney disease using canagliflozin. This method may also include, consist of, or essentially consist of bringing canagliflozin into the commercial stream. In certain embodiments, canagliflozin includes a labeling that includes instructions for the safe and effective treatment of chronic kidney disease using canagliflozin. This method may also include, consist of, or essentially consist of bringing canagliflozin into the commercial stream. In certain embodiments, canagliflozin includes a labeling that includes instructions for the safe and effective treatment of chronic kidney disease using canagliflozin. This method may also include, consist of, or essentially consist of bringing canagliflozin into the commercial stream. In certain embodiments, canagliflozin includes a labeling that includes instructions for the safe and effective treatment of chronic kidney disease using canagliflozin.

[0086] In a further aspect, described herein is a method of selling a pharmaceutical composition that includes, consists of, or essentially consists of canagliflozin. In certain embodiments, the pharmaceutical composition includes a labeling that includes instructions for the safe and effective treatment of chronic kidney disease using canagliflozin. In a further aspect, described herein is a method of selling a pharmaceutical composition that includes, consists of, or essentially consists of canagliflozin. In certain embodiments, the pharmaceutical composition includes a labeling that includes instructions for the safe and effective treatment of chronic kidney disease using canagliflozin. In a further aspect, described herein is a method of selling a pharmaceutical composition that includes, consists of, or essentially consists of canagliflozin. In certain embodiments, the pharmaceutical composition includes a labeling that includes instructions for the safe and effective treatment of chronic kidney disease using canagliflozin. In a further aspect, described herein is a method of selling a pharmaceutical composition that includes, consists of, or essentially consists of canagliflozin. In certain embodiments, the pharmaceutical composition includes a labeling that includes instructions for the safe and effective treatment of chronic kidney disease using canagliflozin. In a further aspect, described herein is a method of selling a pharmaceutical composition that includes, consists of, or essentially consists of canagliflozin. In certain embodiments, the pharmaceutical composition includes a labeling that includes instructions for the safe and effective treatment of chronic kidney disease using canagliflozin.

[0087] In yet a further aspect, described herein is a method of offering for sale canagliflozin that includes, consists of, or essentially consists of bringing canagliflozin into the commercial stream. In certain embodiments, canagliflozin includes a labeling that includes instructions for the safe and effective treatment of chronic kidney disease using canagliflozin. In yet a further aspect, described herein is a method of offering for sale canagliflozin that includes, consists of, or essentially consists of bringing canagliflozin into the commercial stream. In certain embodiments, canagliflozin includes a labeling that includes instructions for the safe and effective treatment of chronic kidney disease using canagliflozin. In yet a further aspect, described herein is a method of offering for sale canagliflozin that includes, consists of, or essentially consists of bringing canagliflozin into the commercial stream. In certain embodiments, canagliflozin includes a labeling that includes instructions for the safe and effective treatment of chronic kidney disease using canagliflozin. In yet a further aspect, described herein is a method of offering for sale canagliflozin that includes, consists of, or essentially consists of bringing canagliflozin into the commercial stream. In certain embodiments, canagliflozin includes a labeling that includes instructions for the safe and effective treatment of chronic kidney disease using canagliflozin. Includes attached documentation including the

[0088] Formulation / Composition Pharmaceutical compositions containing canagliflozin as an active ingredient can be formulated according to conventional pharmaceutical compounding techniques. They may be prepared by intimately mixing the compound or compounds with a pharmaceutical carrier. As used herein, the terms "composition" and "formulation" are used interchangeably and are intended to be used interchangeably. Products containing specified amounts of specified ingredients, as well as combinations of specified ingredients in specified amounts The term "pharmaceutical composition" encompasses any product, such as a drug, that is produced directly or indirectly from the See, e.g., Remingo, which is incorporated herein by reference for such disclosure. n:The Science and Practice of Pharmacy,N ineteenth Ed(Easton,Pa.:Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences,Mack Publishing Co.,Easton,Pennsylvania 1975;Liberman,H A. and Lachman, L., Eds., Pharmaceutical Do. sage Forms,Marcel Decker,New York,NY,1 980; and Pharmaceutical Dosage Forms and Dr. ug Delivery Systems,Seventh Ed.(Lippinco This is described in Williams & Wilkins 1999.

[0089] The pharmaceutical composition or formulation can be administered by several routes as determined by one skilled in the art. Therefore, it can be administered. Preferably, the pharmaceutical composition or formulation is administered by a route suitable for canagliflozin. In some embodiments, the pharmaceutical composition or formulation is administered orally, parenterally, or any combination thereof. In other embodiments, the pharmaceutical composition or formulation is administered orally. In further embodiments, the pharmaceutical composition or formulation is administered parenterally. The pharmaceutical composition or formulation can be administered in a form suitable for the selected route of administration. Thus, the pharmaceutical composition or formulation can be administered as a suspension, elixir, solution, powder, pill, for example, capsules, tablets, or caplets, troches, granules, syrups, thin films, medicinal candies, sprays, pastes, or injection solutions. In some embodiments, the pharmaceutical composition or formulation is administered by injection such as intradermal injection, subcutaneous injection, intramuscular injection, intraosseous injection, intraperitoneal injection, or intravenous injection. In other embodiments, the pharmaceutical composition or formulation is administered as a suspension, elixir, solution, powder, pill, for example, capsules (hard or soft), tablets, or caplets, troches, granules, syrups, thin films, medicinal candies,

[0090] sprays, or pastes. Pills can be formulated for swallowing, chewable, sublingual use, or buccal use, or can be effervescent for dissolving or dispersing in water before administration. In some embodiments, the pharmaceutical product includes pills, tablets, powders, sterile parenteral solutions, or liquid sprays. The carrier can take a wide variety of forms depending on the desired route of administration (e.g., oral, parenteral). Therefore, in the case of oral liquid formulations such as suspensions, elixirs, and solutions, In some embodiments, the pharmaceutical composition or formulation is administered by injection such as intradermal injection, subcutaneous injection, intramuscular injection, intraosseous injection, intraperitoneal injection, or intravenous injection. In other embodiments, the pharmaceutical composition or formulation is administered as a suspension, elixir, solution, powder, pill, for example, capsules (hard or soft), tablets, or caplets, troches, granules, syrups, thin films, medicinal candies, sprays, or pastes. Pills can be formulated for swallowing, chewable, sublingual use, or buccal use, or can be effervescent for dissolving or dispersing in water before administration. In some embodiments, the pharmaceutical product includes pills, tablets, powders, sterile parenteral solutions, or liquid sprays. The carrier can take a wide variety of forms depending on the desired route of administration (e.g., oral, parenteral). Therefore, in the case of oral liquid formulations such as suspensions, elixirs, and solutions, In some embodiments, the pharmaceutical composition or formulation is administered by injection such as intradermal injection, subcutaneous injection, intramuscular injection, intraosseous injection, intraperitoneal injection, or intravenous injection. In other embodiments, the pharmaceutical composition or formulation is administered as a suspension, elixir, solution, powder, pill, for example, capsules (hard or soft), tablets, or caplets, troches, granules, syrups, thin films, medicinal candies, sprays, or pastes. Pills can be formulated for swallowing, chewable, sublingual use, or buccal use, or can be effervescent for dissolving or dispersing in water before administration. In some embodiments, the pharmaceutical product includes pills, tablets, powders, sterile parenteral solutions, or liquid sprays. The carrier can take a wide variety of forms depending on the desired route of administration (e.g., oral, parenteral). Therefore, in the case of oral liquid formulations such as suspensions, elixirs, and solutions, In some embodiments, the pharmaceutical composition or formulation is administered by injection such as intradermal injection, subcutaneous injection, intramuscular injection, intraosseous injection, intraperitoneal injection, or intravenous injection. In other embodiments, the pharmaceutical composition or formulation is administered as a suspension, elixir, solution, powder, pill, for example, capsules (hard or soft), tablets, or caplets, troches, granules, syrups, thin films, medicinal candies, sprays, or pastes. Pills can be formulated for swallowing, chewable, sublingual use, or buccal use, or can be effervescent for dissolving or dispersing in water before administration. In some embodiments, the pharmaceutical product includes pills, tablets, powders, sterile parenteral solutions, or liquid sprays. In some embodiments, the pharmaceutical composition or formulation is administered by injection such as intradermal injection, subcutaneous injection, intramuscular injection, intraosseous injection, intraperitoneal injection, or intravenous injection. In other embodiments, the pharmaceutical composition or formulation is administered as a suspension, elixir, solution, powder, pill, for example, capsules (hard or soft), tablets, or caplets, troches, granules, syrups, thin films, medicinal candies, sprays, or pastes. Pills can be formulated for swallowing, chewable, sublingual use, or buccal use, or can be effervescent for dissolving or dispersing in water before administration. In some embodiments, the pharmaceutical product includes pills, tablets, powders, sterile parenteral solutions, or liquid sprays. In some embodiments, the pharmaceutical composition or formulation is administered by injection such as intradermal injection, subcutaneous injection, intramuscular injection, intraosseous injection, intraperitoneal injection, or intravenous injection. In other embodiments, the pharmaceutical composition or formulation is administered as a suspension, elixir, solution, powder, pill, for example, capsules (hard or soft), tablets, or caplets, troches, granules, syrups, thin films, medicinal candies, sprays, or pastes. Pills can be formulated for swallowing, chewable, sublingual use, or buccal use, or can be effervescent for dissolving or dispersing in water before administration. In some embodiments, the pharmaceutical product includes pills, tablets, powders, sterile parenteral solutions, or liquid sprays. In some embodiments, the pharmaceutical composition or formulation is administered by injection such as intradermal injection, subcutaneous injection, intramuscular injection, intraosseous injection, intraperitoneal injection, or intravenous injection. In other embodiments, the pharmaceutical composition or formulation is administered as a suspension, elixir, solution, powder, pill, for example, capsules (hard or soft), tablets, or caplets, troches, granules, syrups, thin films, medicinal candies, sprays, or pastes. Pills can be formulated for swallowing, chewable, sublingual use, or buccal use, or can be effervescent for dissolving or dispersing in water before administration. In some embodiments, the pharmaceutical product includes pills, tablets, powders, sterile parenteral solutions, or liquid sprays. In some embodiments, the pharmaceutical composition or formulation is administered by injection such as intradermal injection, subcutaneous injection, intramuscular injection, intraosseous injection, intraperitoneal injection, or intravenous injection. In other embodiments, the pharmaceutical composition or formulation is administered as a suspension, elixir, solution, powder, pill, for example, capsules (hard or soft), tablets, or caplets, troches, granules, syrups, thin films, medicinal candies, sprays, or pastes. Pills can be formulated for swallowing, chewable, sublingual use, or buccal use, or can be effervescent for dissolving or dispersing in water before administration. In some embodiments, the pharmaceutical product includes pills, tablets, powders, sterile parenteral solutions, or liquid sprays.

[0091] The carrier can take a wide variety of forms depending on the desired route of administration (e.g., oral, parenteral). Therefore, in the case of oral liquid formulations such as suspensions, elixirs, and solutions, In some embodiments, the pharmaceutical composition or formulation is administered by injection such as intradermal injection, subcutaneous injection, intramuscular injection, intraosseous injection, intraperitoneal injection, or intravenous injection. In other embodiments, the pharmaceutical composition or formulation is administered as a suspension, elixir, solution, powder, pill, for example, capsules (hard or soft), tablets, or caplets, troches, granules, syrups, thin films, medicinal candies, sprays, or pastes. Pills can be formulated for swallowing, chewable, sublingual use, or buccal use, or can be effervescent for dissolving or dispersing in water before administration. In some embodiments, the pharmaceutical product includes pills, tablets, powders, sterile parenteral solutions, or liquid sprays. Suitable carriers and additives include water, glycol, oil, alcohol, flavoring agents, preservatives, stabilizers, coloring agents, etc. In the case of oral solid preparations such as powders, capsules, and tablets, suitable carriers and additives include starch, saccharides, diluents, granulating agents, lubricants, binders, disintegrants, etc. Oral solid preparations may also be coated with substances such as sugar to regulate the main absorption site, or may be enteric-coated. For parenteral administration, the carrier usually consists of sterile water, and other components may be added for increased solubility or preservation. Therefore, in the case of parenteral administration, the pharmaceutical composition or drug is a sterile parenteral solution. Injectable suspensions or solutions may also be prepared using an aqueous carrier with appropriate additives. To prepare such a pharmaceutical composition, canagliflozin as the active ingredient is intimately mixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, and the carrier can take a variety of forms depending on the form of the preparation desired for administration, such as oral or parenteral forms like intramuscular. When preparing the composition in an oral dosage form, any ordinary pharmaceutical medium can be used. Therefore, for example, in the case of oral liquid preparations such as suspensions, elixirs, and solutions, suitable carriers and additives include water, glycol, oil, alcohol, flavoring agents, preservatives, coloring agents, etc. In the case of oral solid preparations such as powders, capsules, caplets, gel caps, and tablets, suitable carriers and additives include starch, saccharides, diluents, granulating agents, lubricants, binders, disintegrants, etc. Tablets and capsules are the most advantageous oral dosage unit forms because administration is easy, and it is obvious that a solid pharmaceutical carrier is used in this case.

[0092] Yes. If desired, the tablets may be sugar-coated or enteric-coated by standard techniques. For parenteral administration, the carrier will generally be sterile water, but may contain other ingredients, for example, for the purpose of solubility enhancement or for preservation. Injectable suspensions may be prepared, in which case appropriate liquid carriers, suspending agents and the like may be used. The pharmaceutical compositions herein are provided in dosage units, for example, each tablet, capsule, powder, injection, teaspoonful, etc. contains the quantity of the active ingredient necessary to deliver the abovementioned effective amount. The pharmaceutical compositions herein are provided in unit dosage forms, for example, each tablet, capsule, powder, injection, suppository, teaspoonful, etc. contains from about 25 mg to about 500 mg of canagliflozin or any amount or range therein (preferably about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, or about 300 mg of canagliflozin). However, the dosage will vary according to the requirements of the patient, the severity of the condition being treated and the compound being used. Either continuous or intermittent administration may be employed. Preferably, the pharmaceutical composition is in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosols or liquid sprays, drops, ampoules, autoinjectors or suppositories, for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. To prepare solid compositions such as tablets, the primary active ingredient (e.g., canagliflozin) is admixed with a pharmaceutical carrier, such as conventional tableting ingredients, for example, corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, for example, as disclosed herein. For parenteral administration, the carrier will generally be sterile water, but may contain other ingredients, for example, for the purpose of solubility enhancement or for preservation. Injectable suspensions may be prepared, in which case appropriate liquid carriers, suspending agents and the like may be used. The pharmaceutical compositions herein are provided in dosage units, for example, each tablet, capsule, powder, injection, teaspoonful, etc. contains the quantity of the active ingredient necessary to deliver the abovementioned effective amount. Yes. If desired, the tablets may be sugar-coated or enteric-coated by standard techniques. The pharmaceutical compositions herein are provided in unit dosage forms, for example, each tablet, capsule, powder, injection, suppository, teaspoonful, etc. contains from about 25 mg to about 500 mg of canagliflozin or any amount or range therein (preferably about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, or about 300 mg of canagliflozin). However, the dosage will vary according to the requirements of the patient, the severity of the condition being treated and the compound being used. Either continuous or intermittent administration may be employed. Preferably, the pharmaceutical composition is in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosols or liquid sprays, drops, ampoules, autoinjectors or suppositories, for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. To prepare solid compositions such as tablets, the primary active ingredient (e.g., canagliflozin) is admixed with a pharmaceutical carrier, such as conventional tableting ingredients, for example, corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, for example, as disclosed herein. Yes. If desired, the tablets may be sugar-coated or enteric-coated by standard techniques. For parenteral administration, the carrier will generally be sterile water, but may contain other ingredients, for example, for the purpose of solubility enhancement or for preservation. Injectable suspensions may be prepared, in which case appropriate liquid carriers, suspending agents and the like may be used. The pharmaceutical compositions herein are provided in dosage units, for example, each tablet, capsule, powder, injection, teaspoonful, etc. contains the quantity of the active ingredient necessary to deliver the abovementioned effective amount. Yes. If desired, the tablets may be sugar-coated or enteric-coated by standard techniques.

[0093] Preferably, the pharmaceutical composition is in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosols or liquid sprays, drops, ampoules, autoinjectors or suppositories, for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. To prepare solid compositions such as tablets, the primary active ingredient (e.g., canagliflozin) is admixed with a pharmaceutical carrier, such as conventional tableting ingredients, for example, corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, for example, as disclosed herein. For parenteral administration, the carrier will generally be sterile water, but may contain other ingredients, for example, for the purpose of solubility enhancement or for preservation. Injectable suspensions may be prepared, in which case appropriate liquid carriers, suspending agents and the like may be used. The pharmaceutical compositions herein are provided in dosage units, for example, each tablet, capsule, powder, injection, teaspoonful, etc. contains the quantity of the active ingredient necessary to deliver the abovementioned effective amount. Yes. If desired, the tablets may be sugar-coated or enteric-coated by standard techniques. For parenteral administration, the carrier will generally be sterile water, but may contain other ingredients, for example, for the purpose of solubility enhancement or for preservation. Injectable suspensions may be prepared, in which case appropriate liquid carriers, suspending agents and the like may be used. The pharmaceutical compositions herein are provided in dosage units, for example, each tablet, capsule, powder, injection, teaspoonful, etc. contains the quantity of the active ingredient necessary to deliver the abovementioned effective amount. Form a solid preliminary formulation composition comprising a compound of or a pharmaceutically acceptable salt thereof or a homogeneous mixture thereof and mix it with water. In certain embodiments, the two active ingredients are formulated together, for example, in a bilayer tablet formulation. When these preliminary formulation compositions are referred to as homogeneous, the active ingredients are uniformly dispersed throughout the composition so that the composition can be readily subdivided into dosage forms as effective as tablets, pills and capsules. This solid preliminary formulation composition is then subdivided into unit dosage forms of the above-described type containing about 25 to about 500 mg or any amount or range within that range of canagliflozin. Tablets or pills of the composition can be coated or otherwise formulated to provide a dosage form that confers the advantage of sustained action. For example, tablets or pills can contain an internal administration component and an external administration component, the latter being in a form that encloses the former. Liquid forms in which the compositions of the present disclosure can be incorporated for oral or injectable administration include aqueous solutions, preferably flavored syrups, aqueous or oily suspensions, and emulsions flavored with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, and elixirs and similar pharmaceutical excipients. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginates, dextran, carboxymethylcellulose sodium,

[0094] methylcellulose, polyvinylpyrrolidone or gelatin.

[0095] The methods described herein may also be practiced using a pharmaceutical composition comprising canagliflozin and a pharmaceutically acceptable carrier. The carrier can be a binder, suspending agent, lubricant, flavoring agent, etc. Examples include, but are not limited to, agents, sweeteners, preservatives, dyes, and coatings, and necessarily include necessary and inert pharmaceutical excipients. Suitable compositions for oral administration include solid forms, such as tablets, pills, caplets, capsules (each including immediate release, timed release, and sustained release formulations), granules, and powders, as well as liquid forms, such as solutions, syrups, elixirs, emulsions, and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions, and suspensions. Advantageously, canagliflozin may be administered once daily as a single dose, or the total daily dose may be

[0096] divided and administered 2, 3, or 4 times daily. For example, in the case of oral administration in the form of tablets or capsules, the active drug ingredient (e.g.,

[0097] canagliflozin) can be combined with an inert carrier that is non-toxic and pharmaceutically acceptable for oral use, such as ethanol, glycerol, or water. Further, if desired or necessary, suitable binders, lubricants, disintegrants, and colorants can also be incorporated into the mixture. Suitable binders include natural sugars such as starch, gelatin, glucose, or β-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc., but are not limited thereto. Disintegrants include starch, methylcellulose, agar, bentonite, xanthan gum, etc., but are not limited thereto.

[0098] Liquid forms include synthetic and natural gums such as tragacanth, acacia, and methylcellulose. For parenteral administration, the formulation may take the form of a suitably flavored suspending or dispersing agent such as cereals containing gluten. Bacterial suspensions and solutions are preferred. If intravenous administration is desired, suitable preservatives will generally be included. An isotonic preparation is used.

[0099] To prepare the pharmaceutical composition of the present disclosure, canagliflozin as the active ingredient is used in the conventional It may be intimately mixed with a pharmaceutical carrier according to pharmaceutical compounding techniques, which carrier may be used in combination with the desired dosage form for administration. These can take a wide variety of forms depending on the form of preparation being taken (eg, oral or parenteral). Suitable pharmaceutically acceptable carriers are well known in the art. Some descriptions of acceptable carriers are published by the American Pharmaceutical Association and the British Pharmaceutical Association. and "Handbook of Pharmaceutical Excipients," the disclosure of which is incorporated herein by reference. To be incorporated.

[0100] Methods for formulating pharmaceutical compositions are disclosed in the US Pat. No. 6,499,499, published by Marcel Dekker, Inc. Pharmaceutical Dosage Forms: Tablets, S econd Edition,Revised and Expanded,Volum es 1-3, edited by Lieberman et al, Pharmac. eutical Dosage Forms: Parental Medicati ons, Volumes 1-2, edited by Avis et al, and P harmaceutical dosage forms:Disperse Syst ems, Volumes 1-2, edited by Lieberman et a described in l, the disclosures of which are incorporated herein by reference.

[0101] The present disclosure also provides a pharmaceutical product containing an amount of canagliflozin that has been proven to be clinically safe and proven to be clinically effective. Typically, the pharmaceutical product is in a package or packaged.

[0102] In some embodiments, the package includes a label. In certain embodiments, the label identifies canagliflozin as an approved chemical component by a regulatory agency. In other embodiments the label provides instructions for use in patients with chronic kidney disease. In further embodiments, the label provides a definition of chronic kidney disease and instructs the patient or physician to administer canagliflozin if the patient has chronic kidney disease. In still other embodiments, the label further includes instructions for use in patients having type II diabetes or overt albuminuria, or both. In yet another embodiment, the label includes data indicating a reduction in one or more adverse renal or cardiovascular events compared to standard therapy.

[0103] The following examples are provided to illustrate some of the concepts described within the present disclosure. The examples are considered to provide one embodiment, but should not be considered to limit the more general embodiments described herein .

[0104] In the following examples, efforts have been made to ensure accuracy with respect to the numerical values used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be taken into account.

Example

[0105] I. Study Design This is a randomized, double-blind, event-driven, placebo-controlled, parallel-group, two-arm, multi-center joint study to evaluate the effect of canagliflozin compared with placebo on the doubling of serum creatinine, progression to end-stage kidney disease (ESKD), kidney or cardiovascular (CV) death in patients with type 2 diabetes (T2DM), stage 2 or 3 chronic kidney disease (CKD), and overt albuminuria. Patients received standard treatment, including the labeled daily dose at the maximum tolerated dose of an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin receptor blocker (ARB). The primary objective was to demonstrate the superiority of canagliflozin compared with placebo in reducing the primary composite endpoint. The safety objective was to evaluate the overall safety and tolerability of canagliflozin. Randomization included a 1:1 ratio of canagliflozin 100 mg or matching placebo, stratified by screening estimated glomerular filtration rate (eGFR) [30 or more and less than 45, 45 or more and less than 60, 60 or more and less than 90 mL / min / 1.73m . The primary efficacy composite endpoint was the time until the doubling of serum creatinine, ESKD, and the first occurrence of kidney death or CV death. The main secondary efficacy endpoints (in the following hierarchical order of testing) included the following:

[0106] ○ Composite of CV death and hospitalized heart failure ○ Composite of CV death, non-fatal MI, and non-fatal stroke (i.e., 3-point "MACE")[[]]END]] ○ Hospitalized heart failure 2 ○ Composite of doubling of serum creatinine, ESKD, and kidney death ○ CV death ○ All-cause death ​​​​​​○CV death, non-fatal MI, non-fatal stroke, heart failure during hospitalization, unstable angina during hospitalization Composite

[0107] A planned interim analysis was performed on 413 primary endpoints, and the IDMC subsequently recommended early termination of the study for efficacy based on pre-specified stopping criteria .

[0108] II. Statistical Methods The primary analysis was performed using a stratified Cox proportional hazards model that included treatment as an explanatory variable in the intention-to-treat (ITT) analysis set (i.e., all randomized subjects until the end of the study), stratified by screening eGFR. Secondary endpoints were analyzed similarly .

[0109] Hypothesis testing for the primary and major secondary efficacy endpoints was performed in a pre-specified hierarchical order and proceeded conditionally based on the significance of previous tests until the endpoints no longer showed significance. As a result of the stop in the interim analysis, the primary endpoint was tested at a two-sided significance level of 0.022 based on the alpha spending function while the secondary endpoints were tested at 0.038 .

[0110] Safety analyses and summaries attributable to treatment were presented using the on-treatment analysis set (i.e., all treated subjects up to 30 days after the last dose), while analyses of amputations, fractures, and malignancies were performed using the on-study analysis set (i.e., all treated subjects until the end of the study) .

[0111] III. Results 1. Subject and Treatment Information 1.1. Trial Completion / Withdrawal Information ​​​​A total of 4,401 randomized subjects were included in the ITT analysis set, and only 4 subjects were not administered, so a total of 4,397 subjects were included in both the on-study and during-treatment analysis sets for safety evaluation. Both the known final vital status and study completion were very high. Regarding Table 1, when subjects were followed up until the time point between the Global Trial End Date notification (GTED) and GTED, or until the time of death of subjects who died before GTED, subjects were considered to have completed the trial regardless of whether they took the investigational drug or not. A higher percentage of subjects were discontinued in the placebo group compared to the canagliflozin group, and adverse

[0112]

Table 1

[0113] 1.2. Demographic and Baseline Characteristics Both the final vital status (99.9%) and study completion (99.1%) were very high. The main reason for early discontinuation of the investigational drug was adverse events (12% in the canagliflozin group and 13% in the placebo group). There were no significant differences in baseline demographics, anthropometrics, and diabetes characteristics between the two treatment groups. Overall, the mean age was 63 years, 66 .1% of the subjects were male, and the majority were white (66.6%). The mean duration of diabetes was 16 years, the mean baseline HbA 1c was 8.27%, and 53.2% of the subjects had baseline Hb A 1c ≧8% (mean HbA 1c was 8.27%), and the baseline median urinary albumin The inulin / creatinine was 927 mg / g. The most frequent blood glucose-lowering drugs (AHA) used at baseline were insulin (65.5%), biguanide (57.8%), and sulfonylurea drugs (28.8%). Almost all subjects (99.9%) were using ACEi or ARB at randomization, and 95% were using ACEi or ARB 2 years after randomization. Approximately 92% of the subjects received cardiovascular therapy (excluding ACEi / ARB) at baseline, approximately 60% took antithrombotic agents (including aspirin), and 69% took statins / hypotensive drugs. The most frequent blood glucose-lowering drugs (AHA) used at baseline were insulin (65.5%), biguanide (57.8%), and sulfonylurea drugs (28.8%). Almost all subjects (99.9%) were using ACEi or ARB at randomization, and 95% were using ACEi or ARB 2 years after randomization. Approximately 92% of the subjects received cardiovascular therapy (excluding ACEi / ARB) at baseline, approximately 60% took antithrombotic agents (including aspirin), and 69% took statins / hypotensive drugs. Approximately 92% of the subjects received cardiovascular therapy (excluding ACEi / ARB) at baseline, approximately 60% took antithrombotic agents (including aspirin), and 69% took statins / hypotensive drugs. Approximately 92% of the subjects received cardiovascular therapy (excluding ACEi / ARB) at baseline, approximately 60% took antithrombotic agents (including aspirin), and 69% took statins / hypotensive drugs. Approximately 92% of the subjects received cardiovascular therapy (excluding ACEi / ARB) at baseline, approximately 60% took antithrombotic agents (including aspirin), and 69% took statins / hypotensive drugs.

[0114] The mean baseline eGFR was 56.2 mL / min / 1.73 m², and the baseline eGFR of approximately 60% of the population was less than 60 mL / min / 1.73 m². The mean duration of diabetes in the subjects was approximately 16 years. The proportion of subjects with a previous history of CV disease was 50.4%, 14.8% had a history of heart failure, and 5.3% had a history of amputation. The entire study population had nephropathy at baseline, but approximately 64% of the population had at least two microvascular complications (i.e., diabetic nephropathy and another microvascular complication). No clinically relevant differences were observed between the treatment groups in these baseline characteristics. 2 The mean baseline eGFR was 56.2 mL / min / 1.73 m², and the baseline eGFR of approximately 60% of the population was less than 60 mL / min / 1.73 m². The mean baseline eGFR was 56.2 mL / min / 1.73 m², and the baseline eGFR of approximately 60% of the population was less than 60 mL / min / 1.73 m². 2 The mean baseline eGFR was 56.2 mL / min / 1.73 m², and the baseline eGFR of approximately 60% of the population was less than 60 mL / min / 1.73 m². The mean duration of diabetes in the subjects was approximately 16 years. The proportion of subjects with a previous history of CV disease was 50.4%, 14.8% had a history of heart failure, and 5.3% had a history of amputation. The mean duration of diabetes in the subjects was approximately 16 years. The proportion of subjects with a previous history of CV disease was 50.4%, 14.8% had a history of heart failure, and 5.3% had a history of amputation. The entire study population had nephropathy at baseline, but approximately 64% of the population had at least two microvascular complications (i.e., diabetic nephropathy and another microvascular complication). The entire study population had nephropathy at baseline, but approximately 64% of the population had at least two microvascular complications (i.e., diabetic nephropathy and another microvascular complication). No clinically relevant differences were observed between the treatment groups in these baseline characteristics.

[0115] The proportion of subjects with a history of amputation was similar between groups (5.4% in the canagliflozin group and 5.2% in the placebo group). The proportion of subjects with a history of amputation was similar between groups (5.4% in the canagliflozin group and 5.2% in the placebo group).

[0116] 1.3. Exposure and Follow-up Scope The mean exposure to the investigational drug was equivalent between the treatment groups (115 weeks in total) as well as over the follow-up period (for a total of 136 weeks). The mean exposure to the investigational drug was equivalent between the treatment groups (115 weeks in total) as well as over the follow-up period (for a total of 136 weeks).

[0117] 2. Primary endpoint analysis Canagliflozin significantly reduced the risk of the primary composite endpoint by 30% compared with placebo [HR: 0.70, 95% CI: 0.59, 0.82, p-value < 0.0001 (Table 2A), thereby successfully achieving the main objective of the study. Furthermore, each individual component was consistent with the overall results of the primary composite endpoint (Table 2A), and furthermore, the supportive analysis using the on-treatment analysis set [HR: 0.64, 95% CI: 0.53, 0.78] was consistent with the primary efficacy analysis of the ITT analysis set.

[0118] [Table 2]

[0119] Figure 1 shows the Kaplan-Meier plot of the time until the primary composite endpoint first occurred, which occurred at week 52 and showed an initial separation maintained throughout the study. As shown in Tables 2B and 2C, the robustness of the primary composite endpoint was demonstrated across all 15 subgroups. In the evaluation of the proportional hazards assumption underlying the above analysis, no evidence of lack of proportionality (p = 0.3116) was obtained.

[0120] [Table 3]

[0121] [Table 4]

[0122] 3. Major secondary endpoints Canagliflozin significantly reduced the risk of the following secondary endpoints (Table 3B) Shown by the p-value of the character "Tai": ● The composite of CV death and in-hospital heart failure was 31% [HR: 0.69, p = 0.0001, 95% CI: 0.57, 0.83], and ● MACE was 20% [HR: 0.80, p = 0.0121, 95% CI: 0.67, 0.95], and ● Hospitalization due to heart failure was 39% [HR: 0.61, p = 0.0003, 95% CI: 0 .47, 0.80], and ● The composite of doubling of serum creatinine, ESKD, and renal death was 34% [HR: 0.66, p < 0.0001 95% CI: 0.53, 0.81].

[0123] The remaining secondary endpoints, due to the hierarchical trial sequence, trended in favor of canagliflozin but were not statistically significant. Furthermore, since canagliflozin reduced the risk of the exploratory hard composite of ESKD, renal death and CV death [HR: 0.73, 95% CI: 0.61, 0.87], the treatment effect was consistent regardless of whether the doubling component of serum creatinine was included. For Tables 3A and 3B, HHF = heart failure during hospitalization, DoSC = doubling of serum creatinine, NFMI = non-fatal MI, NF Stroke = non-fatal stroke, HU SA = unstable angina during hospitalization.

[0124]

Table 5

[0125]

Table 6

[0126] 4. Other efficacy analyses At the end of treatment, a statistically significant reduction from baseline minus placebo (kanagliflozin minus placebo) was observed for HbA [least squares mean difference: -0. 1c 13%], body weight [least squares mean difference: -1.72%], and systolic blood pressure [least squares mean difference: -2.81 mmHg] in subjects treated with kanagliflozin. Considering that the subjects already had a fairly well-controlled mean baseline systolic blood pressure of 140 mmHg, the difference in systolic blood pressure observed between treatment groups was unlikely to have had a significant impact on the primary efficacy findings (Home, Impact of the UKPDS: an overview, Diabet. Med., 2008, 25:2 - 8, Kazama, Chronic kidney disease and fragility fra cture, Clin. Exp. Nephrol., 2017, 21(Suppl 1) :S46 - S52, Zoungas, Combined effects of rou tine blood pressure lowering and intensi ve glucose control on macrovascular and microvascular outcomes in patients with type 2 diabetes: New results from the ADV ANCE trial, 2009, Diabetes Care 32:2068 - 20 74).

[0127] 5. Safety The safety analysis was performed on the on-treatment analysis set (study subjects treated from the last dose up to 30 days) or during the study ​​​​It was carried out using any of the analysis sets (treatment subjects until the end of the study). As described in this specification the incidence of amputations [HR 1.11, 95% CI: 0.79 to 1.56] and adjudicated fractures [HR 0.98, 95% CI: 0.70 to 1.37] were lower in this study compared to other studies in this technical field. In the canagliflozin group, compared to placebo the incidences of overall adverse events and serious adverse events were numerically lower.

[0128] In summary, in the canagliflozin group, compared to placebo, the incidences of overall adverse events, serious adverse events, and adverse events leading to discontinuation were numerically lower. There was no increase in the incidence of adverse events of hyperkalemia and no numerical increase in the incidence of adverse events related to volume depletion.

[0129] 5.1. Summary of all adverse events In the canagliflozin group, compared to placebo, the incidences of overall adverse events, serious adverse events, and adverse events leading to discontinuation were numerically lower (Table 4).

[0130]

Table 7

[0131] 5.2. Selected adverse events of interest 5.2.1. Lower limb amputation Despite the relatively high historical incidence of non-traumatic lower limb amputations in this population [HR: 1.11, 95 % CI: 0.79, 1.56], considering that the 95% confidence interval of the hazard ratio comparing canagliflozin and placebo includes "1.00", there was no difference in non-external There was no statistical difference in the risk of traumatic lower limb amputation [HR: 1.11, 95% CI: 0.79 , 1.56] (Table 5).

[0132]

Table 8

[0133] 5.2.2. Fracture The incidence rates were 12.09 and 1 1.80 per 1000 subject - years in the placebo and canagliflozin groups, respectively. There was no statistical difference in the risk of adjudicated fracture between the treatment groups, and the estimated hazard ratio was close to 1.00 [HR: 0.98, 95% CI: 0.70, 1.37] (Table 6).

[0134]

Table 9

[0135] 5.2.3. Selected Malignant Tumors The overall incidence of tumors was low and balanced between the treatment groups.

[0136] 5.2.3.1. Renal Cell Carcinoma The incidence of adjudicated renal cell carcinoma (RCC) was numerically higher in the placebo group [5 subjects (0.2%)] compared to the canagliflozin group [1 subject (<0.1%)]. Specifically, the proportion of subjects who experienced confirmed RCC was low, and in subjects treated with canagliflozin , the incidence of adjudicated RCC was numerically reduced compared to placebo (the incidence rates per 1000 patient - years in the placebo and can agliflozin groups were 0.87 and 0.17 respectively).

[0137] 5.2.3.2. Other Malignant Tumors The incidence of bladder cancer per 1000 subject - years was similar in both treatment groups [incidence difference (I RD): 0.16, 95% CI: -1.41, 1.73], while the incidence of breast cancer in women was , which was numerically higher in the canagliflozin group compared with placebo (placebo and canagliflozin incidence rates per 1000 patient-years in the Rosin group were 1.59 and 4.08, respectively), However, the 95% confidence interval for IRD was "0" [IRD: 2.49, 95% CI: -1.25 There were no reports of pheochromocytoma or testicular cell carcinoma reported in this study. Regarding Table 7, the proportions were calculated using the number of subjects in each group as the denominator, and the incidence rates were calculated using the number of events. Based on the number of subjects experiencing at least one adverse event, rather than the number of , based on the normal approximation of the incidence rate difference (IRD), the denominator is restricted to women with breast cancer.

[0138] [Table 10]

[0139] 5.2.4. Kidney-related adverse events The incidence of kidney-related adverse events was lower in the canagliflozin group compared with placebo. (57.12 vs. 79.12 per 1,000 subject-years, respectively). The preferred term frequently reported was "increased blood creatinine." This finding This provides reassurance in this population, which is at particularly high risk for adverse renal events, and Further strengthening the role of canagliflozin in reducing the risk of renal outcomes in patients with refractory glaucoma. The proportions were calculated using the number of subjects in each group as the denominator, and the incidence rates were calculated using the number of events, not the number of events. Both are based on the number of subjects experiencing one adverse event.

[0140] [Table 11]

[0141] 5.2.5. Other selected adverse events The incidence of adverse events of hyperkalemia was significantly lower in the canagliflozin group compared with placebo. were lower (29.74 vs. 36.91 per 1,000 subject-years, respectively), whereas fluid volume The incidence of adverse events was higher in the canagliflozin group compared with placebo (1 28.36 vs. 23.45 per 1,000 subject-years, respectively, in the canagliflozin group. The incidence of diabetic ketoacidosis (DKA) per 1,000 subject-years was The 95% confidence interval of IRD was "0" [IRD: 1.73, 95% CI: 0.32, 3.14] are excluded.

[0142] 6. Other Effects In subjects treated with canagliflozin, HbA 1c , weight, and systolic blood pressure A statistically significant placebo-subtracted reduction from baseline was observed in The effect on blood glucose is smaller as the eGFR is lower. bA 1c The LS mean placebo-subtracted difference for change from baseline in 0.03 (95% CI: -0.128, 0.180) in the GFR stratum and -0 in the 45-60 stratum. 18 (-0.328, -0.030), and in the eGFR stratum of 60 to less than 90, -0.21 ( 95%CI: -0.33, -0.08). 1c Nobe See Figures 2-4, which show the LS mean change from baseline. A similar trend was observed.

[0143] The primary efficacy analysis was HbA1c and the measured values after the baseline of systolic blood pressure were adjusted Analyses were performed to evaluate the effect on... HbA1 after baseline was used as a time-varying covariate c A series of proportional hazards regression models including HbA and systolic blood pressure measurements were fitted 1c change Since changes in HbA have a delayed effect on cardiovascular risk, several models were constructed. In each model, HbA 1c was first evaluated using a single concordant value and a single lag value, and then as a running average value. A single simultaneous systolic blood pressure measurement was used in all analyses

[0144] As shown in Table 9, the treatment effect of canagliflozin on the primary composite endpoint remained robust regardless of the approach used to adjust for time-varying HbA 1c and systolic blood pressure measurements. Simultaneous HbA showed no significant effect, but both the lag value and the running average HbA 1c showed a moderate but significant effect on the primary efficacy endpoint, similar to simultaneous systolic blood pressure 1c The higher both HbA and systolic blood pressure were after baseline, the higher the risk of experiencing the primary composite endpoint after adjusting for treatment effect

Table 12

[0145]

Table 12

[0146] These results show that treatment with canagliflozin achieved favorable effects on renal function, ESKD, and CV or renal death with only minor treatment-related differences in glycemic control treatment-related differences, and achieved favorable effects on renal function, ESKD, and CV or renal death In general, treatment with canagliflozin was associated with the achieved glycemic, blood pressure Or, without significant difference in lipid control, patients who receive standard treatment for diabetes and prevention of CV and renal events (which includes the maximum labeled dose or tolerance of an ARB or ACE inhibitor) showed improvement in renal outcomes.

[0147] 7. Summary of Results In conclusion, this example demonstrates important progress in the management of subjects with established CKD and T2DM. Despite current standard treatment established over 15 years ago, subjects with T2 DM and CKD are at high risk of progression to ESKD and CV events and have a short mean life expectancy. Canagliflozin has an acceptable safety profile and has been shown to significantly reduce the risk of clinically important renal and CV events in these subjects.

[0148] Although the present invention has been described in conjunction with its preferred specific embodiments, it should be understood that the foregoing description and the subsequent examples are intended to illustrate and not to limit the scope of the invention. It should be understood that various changes may be made without departing from the scope of the invention, that equivalents may be substituted, and further, that other aspects, advantages, and modifications will be apparent to those skilled in the art to which the invention pertains. In addition to the embodiments described herein, the present invention contemplates inventions obtained from combinations of the features of the invention enumerated herein, and inventions of the cited prior art references that complement the features of the present invention, and claims are made. Similarly, any described substance, feature, or article may be used in combination with any other substance, feature, or article, and such combinations are considered to be within the scope of the present invention.

[0149] The disclosures of each patent, patent application, and publication cited or described in this specification are hereby incorporated by reference in their entireties for all purposes. ​

Claims

1. A method for treating a diabetic patient having chronic kidney disease, comprising: (a) determining whether the patient has chronic kidney disease; and (b) administering to the patient a therapeutically effective amount of canagliflozin for treating the chronic kidney disease. A method comprising the above.

2. The method according to claim 1, wherein the patient is a human.

3. The method according to claim 1 or 2, wherein the diabetes is type II diabetes.

4. The method according to any one of claims 1 to 3, wherein the chronic kidney disease is determined by blood test, urine test, renal imaging, or renal biopsy.

5. The method according to any one of claims 1 to 4, wherein the chronic kidney disease is determined by estimated glomerular filtration rate.

6. The patient has a measured HbA in the range of 7.0% or more and 10.5% or less １ｃ having, claim The method according to any one of claims 1 to 5.

7. The method according to any one of claims 1 to 6, wherein the chronic kidney disease is stage 2 and / or stage 3 chronic kidney disease.

8. wherein the patient has an estimated glomerular filtration rate (eGFR) of 30 or more and less than 90 mL / min / 1.73 m ２ 2 The method according to any one of claims 1 to 7, having

9. wherein the patient has an eGFR of 30 or more and less than 45 mL / min / 1.73 m ２ as claimed in claim 4 The method according to

10. wherein the patient has an eGFR of 45 or more and less than 60 mL / min / 1.73 m ２ as claimed in claim 4 The method according to

11. wherein the patient has an eGFR of 60 or more and less than 90 mL / min / 1.73 m ２ as claimed in claim 4 The method according to

12. The method according to any one of claims 1 to 11, wherein the patient has overt albuminuria.

13. The method according to any one of claims 1 to 12, wherein the method prevents doubling of serum creatinine, end-stage kidney disease (ESKD), kidney death, or any combination thereof.

14. The method according to any one of claims 1 to 13, wherein the method prevents cardiovascular death, heart failure during hospitalization, non-fatal myocardial infarction, non-fatal stroke, or any combination thereof.

15. The method according to any one of claims 1 to 14, further comprising an accompanying standard treatment.

16. The method according to claim 15, wherein the standard treatment comprises administering an angiotensin-converting enzyme inhibitor and / or an angiotensin receptor antagonist.

17. The risk of doubling of serum creatinine, ESKD, kidney death, or cardiovascular death is reduced by at least about 25% compared to patients with the same level of disease progression receiving standard treatment, and the standard treatment comprises administering an angiotensin-converting enzyme inhibitor and / or an angiotensin receptor antagonist, but does not include treatment with canagliflozin. The method according to any one of claims 1 to 16.

18. The risk of cardiovascular death or hospitalization for heart failure is at least about 25% lower compared to patients with the same level of disease progression receiving standard treatment, where the standard treatment includes administration of an angiotensin-converting enzyme inhibitor and / or an angiotensin receptor antagonist, but does not include treatment with canagliflozin, the method according to any one of claims 1 to 17. The risk of non-fatal MI or non-fatal stroke is at least about 20% lower compared to patients with the same level of disease progression receiving standard treatment, where the standard treatment includes administration of an angiotensin-converting enzyme inhibitor and / or an angiotensin receptor antagonist, but does not include treatment with canagliflozin, the method according to any one of claims 1 to 18. The risk of hospitalization for heart failure is at least about 35% lower compared to patients with the same level of disease progression receiving standard treatment, where the standard treatment includes administration of an angiotensin-converting enzyme inhibitor and / or an angiotensin receptor antagonist, but does not include treatment with canagliflozin, the method according to any one of claims 1 to 19. The method according to any one of claims 1 to 20, wherein the therapeutically effective amount of canagliflozin is about 50 to about 500 mg. Claim 19 The method according to claim 21, wherein the therapeutically effective amount of canagliflozin is about 100 to about 300 mg. The method according to claim 22, wherein the therapeutically effective amount of canagliflozin is about 100 mg. A method for treating chronic kidney disease, comprising administering a therapeutically effective amount of canagliflozin to a patient in need thereof, wherein the patient is diagnosed with type II diabetes. The method according to claim 24. The method according to claim 24 or 25, wherein the chronic kidney disease is stage 2 and / or stage 3 chronic kidney disease. The method according to claim 24 or 26, wherein the patient further has overt albuminuria. The method according to any one of claims 24 to 30, wherein the occurrence of one or more kidney events is reduced or prevented. Claim 25 Claim 26 Claim 27 Claim 28 Claim 29 Claim 30 Claim 31 Claim 32 Claim 33 Claim 34 。 Claim 35 Claim 36 Claim 37 Claim 38 The patient has a measured HbA in the range of 7.0% or more and 10.5% or less １ｃ having, claim Claim 39 Claim 40 Claim 41 Claim 42 Claim 43 wherein the patient has an estimated glomerular filtration rate (eGFR) of 30 or more and less than 90 mL / min / 1.73 m ２ 2 Claim 44 ​ wherein the patient has an eGFR of 30 or more and less than 45 mL / min / 1.73 m ２ as claimed in claim 2 ​ ​ wherein the patient has an eGFR of 45 or more and less than 60 mL / min / 1.73 m ２ as claimed in claim 2 ​ ​ wherein the patient has an eGFR of 60 or more and less than 90 mL / min / 1.73 m ２ as claimed in claim 2 ​ ​ ​ ​ ​ ​ ​ ​ The method according to claim 32, wherein the one or more kidney events include a doubling of serum creatinine, end-stage kidney disease (ESKD), kidney death, or any combination thereof. **Claim 34** The method according to any one of claims 24 to 33, wherein the occurrence of one or more cardiovascular events is reduced or prevented. **Claim 35** The method according to claim 34, wherein the one or more cardiovascular events include cardiovascular death, heart failure during hospitalization, non-fatal myocardial infarction, non- fatal stroke, or any combination thereof. **Claim 36** The method according to claim 35, wherein the one or more cardiovascular events include cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke **Claim 37** The method according to any one of claims 24 to 36, further comprising an accompanying standard treatment including the administration of an angiotensin-converting enzyme inhibitor and / or an angiotensin receptor blocker. **Claim 38** The method according to any one of claims 32 to 37, wherein the occurrence of the one or more kidney and / or cardiovascular events is reduced or prevented as compared to a standard treatment, the standard treatment including the administration of an angiotensin-converting enzyme inhibitor and / or an angiotensin receptor blocker but not including treatment with canagliflozin. **Claim 39** The method according to any one of claims 34 to 38, wherein the therapeutically effective amount of canagliflozin is about 50 to about 500 mg. **Claim 40** The method according to claim 39, wherein the therapeutically effective amount of canagliflozin is about 100 to about 300 mg. **Claim 41** The method according to claim 39, wherein the therapeutically effective amount of canagliflozin is about 100 mg. 。 **Claim 42** A method of selling a formulation comprising canagliflozin, the method comprising selling the formulation, and the formulation label of the reference listed drug for the formulation includes instructions for treating chronic kidney disease. **Claim 43** A method of submitting an offer to sell a formulation comprising canagliflozin, the method comprising submitting an offer to sell such a formulation, and the formulation label of the reference listed drug for such a formulation includes instructions for treating chronic kidney disease. **Claim 44** The method according to claim 42 or 43, wherein the formulation is an ANDA formulation, a supplemental application formulation, or a 505(b)(2) formulation. **Claim 45** The label includes instructions for use in patients having type II diabetes or overt albuminuria. The method according to any one of claims 42 to 44, which provides a display. **Claim 46** The method according to any one of claims 42 to 45, wherein the formulation label includes data on reducing one or more harmful renal or cardiovascular events as compared to standard treatment. **Claim 47** The method according to claim 46, wherein the standard treatment includes administering an angiotensin-converting enzyme inhibitor and / or an angiotensin receptor blocker, but does not include treatment by administering canagliflozin. **Claim 48** The method according to claim 46 or 47, wherein the one or more renal events include doubling of serum creatinine, end-stage renal disease (ESKD), renal death, or any combination thereof. **Claim 49** The method according to claim 46 or 47, wherein the one or more cardiovascular events include cardiovascular death, heart failure during hospitalization, non-fatal myocardial infarction, non-fatal stroke, or any combination thereof. **Claim 50** Canagliflozin for use in the method defined by any one of claims 1 to 49. **Claim 51** Canagliflozin, an angiotensin-converting enzyme inhibitor, and / or an angiotensin receptor blocker for use in the method defined by any one of claims 16 to 23 or 37 to 41. **Claim 52** 。 The canagliflozin, the angiotensin-converting enzyme inhibitor, and / or the angiotensin receptor blocker according to claim 51 for use in the method defined by claim 51, wherein the canagliflozin, the angiotensin-converting enzyme inhibitor, and / or the angiotensin receptor blocker are administered simultaneously, separately, or sequentially. **Claim 53** A formulation containing canagliflozin for use in the method defined by any one of claims 42 to 49. ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​

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