Methods of treating chronic kidney disease with dapagliflozin

Abstract

The present disclosure relates to methods of treating patients with chronic kidney disease (CKD) and with or without type 2 diabetes mellitus with an SGLT2 inhibitor, such as dapagliflozin.

Description

[0001] This application is a divisional application of the Chinese invention patent application with application number 202180001003.5, application date April 1, 2021, and invention name “Method for treating chronic kidney disease with dapagliflozin”. Summary of the invention

[0002] Chronic kidney disease (CKD) affects about 10% of the adult population worldwide. (Eckardt, KU et al., Lancet 382(9887):158-169, 2013.) The most common causes of CKD are diabetes, hypertension, and chronic glomerulonephritis. Current treatments for CKD include administration of angiotensin converting enzyme inhibitors (ACE-I) and angiotensin II receptor blockers (ARBs), lipid and blood pressure control, and strict glucose control in patients with diabetes.

[0003] Sodium-glucose cotransporter 2 (SGLT2) is a sodium-dependent renal protein that is responsible for reabsorbing glucose back into the blood. SGLT2 inhibitors are a class of glucose lowering agents used to lower blood sugar in patients with type 2 diabetes (T2D) by inhibiting renal GLT2 protein. Therefore, SGLT2 inhibitors can improve glycemic control without relying on insulin secretion, with a low risk of hypoglycemia, thereby providing a reduction in blood pressure, body weight, and uric acid levels. (Inzucchi et al., Diabetes & Vascular Dis Res. [Diabetes and Vascular Disease Research] 12 (2): 90-100, 2015.) SGLT2 inhibitors can reduce the reabsorption of glucose in the kidneys, thereby increasing the excretion of glucose in the urine. (Same).

[0004] The present disclosure relates to compounds, compositions and methods for treating chronic kidney disease (CKD) in patients with and without type 2 diabetes (T2D) using sodium-glucose co-transporter type 2 (SGLT2) inhibitors, such as dapagliflozin.

[0005] In some embodiments, an SGLT2 inhibitor (e.g., dapagliflozin) is administered together with standard CKD care agents (e.g., ACE-I and / or ARBs) in the same or different compositions at the same or different times.

[0006] In some embodiments, the SGLT2 inhibitor (eg, dapagliflozin) is administered together with at least one other therapeutic agent (eg, an antidiabetic agent) in the same or different compositions at the same or different times.

[0007] In the following description, certain details are set forth in order to provide a thorough understanding of various embodiments. However, it will be appreciated by those skilled in the art that the disclosed embodiments may be practiced without these details. These and other embodiments will become apparent by reference to the following detailed description and accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0008] Figure 1 is a schematic diagram outlining the study process, where SED = study end date,

[0009] E = Enrollment, SCV = Study Termination Visit, and R = Randomization.

[0010] Figure 2 This is a summary table of the final overall enrollment details of the dapagliflozin CKD Phase 3 clinical trial.

[0011] Figure 3 This is a summary table of the final enrollment details of the DAPA CKD Phase 3 clinical trial according to demographic groups.

[0012] Figure 4 This is a summary table of final enrollment details for the DAPA CKD Phase 3 clinical trial according to baseline disease status.

[0013] Figure 5 is a summary table of final enrollment details for the DAPA CKD Phase 3 clinical trial according to baseline concomitant medications.

[0014] Figure 6 is a summary of the effects of dapagliflozin on sustained eGFR decline ≥50%, ESRD, and renal or cardiovascular ("CV") death in the DAPA CKD Phase 3 clinical trial. The table shows the primary composite endpoint (which is a composite of sustained eGFR decline ≥50%, ESRD, and renal or CV death) and each of its components (a=adjudicated).

[0015] Figure 7 Figure 2 is a graph depicting the incidence of the primary end points of sustained eGFR decline ≥50%, ESRD, and renal or CV death estimated using the Kaplan-Meier method and the hazard ratios and 95% confidence intervals estimated using the Cox regression model.

[0016] Figure 8 The primary composite outcome according to prespecified subgroups from the DAPA CKD Phase 3 clinical trial (T2DM status, UACR status, eGFR status, systolic blood pressure status) is described.

[0017] Fig. 9The primary composite outcome according to prespecified subgroups (age, sex, race, geographic region) from the DAPA CKD Phase 3 clinical trial is described.

[0018] Fig.10 The primary and secondary endpoints from the DAPA CKD Phase 3 clinical trial were summarized, including secondary endpoints describing the superiority of dapagliflozin in reducing the composite of renal events without CV death, the superiority of dapagliflozin in reducing hospitalizations for HF and CV death, and the superiority of dapagliflozin in reducing overall all-cause mortality (compared with placebo or patients receiving at least one standard CKD care agent alone).

[0019] Fig.11 Secondary endpoints for dapagliflozin were summarized from the DAPA CKD Phase 3 clinical trial, namely, superiority in reducing hospitalization for HF and CV death and each of their components (compared to placebo or patients receiving at least one standard CKD care agent alone).

[0020] Fig.12 Figure 2 is a graph depicting the incidence of the secondary endpoints of the effect of early treatment with dapagliflozin on hospitalization for HF and CV death estimated with the use of the Kaplan–Meier method and the hazard ratios and 95% confidence intervals estimated with the use of the Cox regression model.

[0021] Fig.13 The effects of dapagliflozin on prespecified primary and secondary composite outcomes in patients with and without diabetes were described.

[0022] Fig.14 is a graph depicting the effect of dapagliflozin on all-cause mortality estimated using the Kaplan-Meier method and the hazard ratios and 95% confidence intervals estimated using the Cox regression model.

[0023] Fig.15 is a graph depicting the effect of dapagliflozin on the endpoints of chronic dialysis, kidney transplantation, or renal death estimated using the Kaplan-Meier method and the hazard ratios and 95% confidence intervals estimated using the Cox regression model.

[0024] Fig.16 Summary of exploratory endpoints from the DAPA CKD Phase 3 clinical trial showed that dapagliflozin was superior in reducing the time to first, second, or third hospitalization for HF (compared to placebo or patients receiving at least one standard CKD care agent alone) (*rate used to analyze recurrent events **number of patients with 1, 2, or 3 or more hospitalizations for HF).

[0025] Fig.17The primary endpoint of the DAPA CKD Phase 3 clinical trials (composite of sustained eGFR decline ≥50%, ESKD, or renal or cardiovascular death) was summarized, stratified by underlying cause of kidney disease (diabetic nephropathy, ischemic / hypertensive nephropathy, glomerulonephritis, and unknown etiology) compared with placebo or patients receiving at least one standard CKD care agent alone.

[0026] Fig.18 Secondary renal endpoints (composite of sustained eGFR decline ≥50%, ESKD, or renal death) from the DAPA CKD Phase 3 clinical trials were pooled, stratified by underlying cause of kidney disease (diabetic nephropathy, ischemic / hypertensive nephropathy, glomerulonephritis, and unknown etiology) compared with placebo or patients receiving at least one standard CKD care agent alone.

[0027] Fig.19 Secondary endpoints (cardiovascular death or hospitalization for heart failure) from the DAPA CKD Phase 3 clinical trials were pooled, stratified by underlying cause of kidney disease (diabetic nephropathy, ischemic / hypertensive nephropathy, glomerulonephritis, and unknown etiology) compared with placebo or patients receiving at least one standard CKD care agent alone.

[0028] Fig. 20 Secondary endpoints (all-cause mortality) from the DAPA CKD Phase 3 clinical trials were pooled, stratified by underlying cause of kidney disease (diabetic nephropathy, ischemic / hypertensive nephropathy, glomerulonephritis, and unknown etiology) compared with placebo or patients receiving at least one standard CKD care agent alone.

[0029] Fig.21 The primary endpoint (composite of sustained eGFR decline ≥50%, ESKD, or renal or cardiovascular death) of the DAPA CKD Phase 3 clinical trial was summarized in patients with IgA nephropathy compared with placebo or patients receiving at least one standard CKD care agent alone.

[0030] Fig. 22 The primary endpoint (composite of sustained eGFR decline ≥50%, ESKD, or renal or cardiovascular death) and secondary endpoints (secondary renal endpoint (composite of sustained eGFR decline ≥50%, ESKD, or renal death), secondary endpoint (cardiovascular death or hospitalization for heart failure), and all-cause mortality) of the DAPA CKD Phase 3 clinical trial were summarized, stratified by patients with or without underlying cardiovascular disease (compared to placebo or patients receiving at least one standard CKD care agent alone).

[0031] Fig.23Exploratory results from prespecified and post hoc analyses of the DAPA CKD Phase 3 clinical trial stratified by patients with or without underlying cardiovascular disease compared with placebo or patients receiving at least one standard CKD care agent alone were pooled.

[0032] Fig.24 The primary and secondary endpoints of the DAPA CKD Phase 3 clinical trial in patients with IgA nephropathy were compared with placebo or patients receiving at least one standard CKD care agent alone.

[0033] Fig.25 To describe the incidence of new-onset T2D (HbA1c ≥ 6.5%) measured at 2 consecutive study visits after randomization or new T2D (i.e., HbA1c ≥ 6.5%) reported by the investigator in patients with previously undiagnosed diabetes in the DAPA HF Phase 3 clinical trial relative to placebo. DETAILED DESCRIPTION

[0034] The present disclosure relates to a method for treating a patient with chronic kidney disease by administering an effective amount of an SGLT2 inhibitor (e.g., dapagliflozin) to a patient in need thereof, wherein the patient with chronic kidney disease includes a patient with or without type 2 diabetes (T2D), and / or at least one disease, disorder or condition associated with CKD. The present disclosure also provides a method for treating a patient with CKD associated with ischemia, hypertension, chronic glomerulonephritis or IgA nephropathy.

[0035] In some embodiments, the present disclosure includes a method for treating CKD in a patient who does not suffer from type 2 diabetes (T2D), comprising administering to the patient an effective amount of an SGLT2 inhibitor for treating the patient's CKD. In some embodiments, the method disclosed herein treats the CKD associated with ischemia or hypertension. In some embodiments, the method disclosed herein treats the CKD associated with chronic glomerulonephritis. In some embodiments, the method disclosed herein treats the CKD related to IgA nephropathy (also referred to as Bergey's disease). In other embodiments, the present disclosure includes a method for treating CKD in a patient with T2D, comprising administering to the patient an effective amount of an SGLT2 inhibitor for treating the patient's CKD.

[0036] Also disclosed is a method for preventing or delaying the progress of CKD, cardiovascular (CV) death or renal death in a patient in need, comprising applying an SGLT2 inhibitor of effective dose to the patient.In certain embodiments, this disclosure is included in the method for preventing or delaying the progress of CKD, CV death or renal death in a patient not suffering from T2D, comprising applying an SGLT2 inhibitor of the amount of effectively preventing or delaying the progress of patient's CKD, CV death or renal death to the patient.In certain embodiments, this disclosure is included in the method for preventing or delaying the progress of CKD, CV death or renal death related to ischemia, hypertension, chronic glomerulonephritis or IgA nephropathy in a patient not suffering from T2D, comprising applying an SGLT2 inhibitor of the amount of effectively preventing or delaying the progress of patient's CKD, CV death or renal death to the patient.In other embodiments, this disclosure is included in the method for preventing or delaying the progress of CKD, CV death or renal death in a patient suffering from T2D, comprising applying an SGLT2 inhibitor of the amount of effectively preventing or delaying the progress of patient's CKD, CV death or renal death to the patient.

[0037] Also disclosed is a method for reducing the incidence of the composite endpoint of the patient eGFR of CKD that continues to decline by ≥50%, reaching end-stage renal disease (ESRD), CV death or renal death, including applying an effective amount of SGLT2 inhibitor to the patient. In certain embodiments, this disclosure includes reducing the incidence of the composite endpoint of the patient eGFR of CKD but not T2D that continues to decline by ≥50%, reaching ESRD, CV death or renal death, including applying an effective amount of SGLT2 inhibitor to the patient. In other embodiments, this disclosure includes reducing the incidence of the composite endpoint of the patient eGFR of CKD and T2D that continues to decline by ≥50%, reaching ESRD, CV death or renal death, including applying an effective amount of SGLT2 inhibitor to the patient. In certain embodiments, the method reduces the incidence of the individual endpoint of the eGFR that continues to decline by ≥50% in the patient with CKD. In certain embodiments, the method reduces the incidence of the individual endpoint of the patient with CKD reaching end-stage renal disease (ESRD). In certain embodiments, the method reduces the incidence of the individual endpoint of CV death in the patient with CKD. In certain embodiments, described method reduces the incidence rate of the individual terminal point of kidney death in the patient suffering from CKD.In some embodiments above, relative to placebo, the terminal point incidence rate in treatment group (that is, at least one patient is treated through the SGLT2 inhibitor of effective dose) reduces.In some embodiments above, relative to the application scheme that patient accepts at least one standard CKD nursing agent (that is, without the SGLT2 inhibitor of effective dose) separately, the terminal point incidence rate in treatment group reduces.

[0038] In some embodiments, the disclosure provides a method for reducing the incidence of the composite endpoint of the patient eGFR of CKD that continues to decline by ≥50%, reaches end-stage renal disease (ESRD) or renal death, and the method includes applying an effective amount of SGLT2 inhibitor to the patient. In some embodiments, the disclosure includes reducing the incidence of the composite endpoint of the patient eGFR of CKD but not T2D that continues to decline by ≥50%, reaches ESRD or renal death, and the method includes applying an effective amount of SGLT2 inhibitor to the patient. In other embodiments, the disclosure includes reducing the incidence of the composite endpoint of the composite endpoint of the patient eGFR of CKD and T2D that continues to decline by ≥50%, reaches ESRD or renal death, and the method includes applying an effective amount of SGLT2 inhibitor to the patient. In some of the above-mentioned embodiments, relative to placebo, the incidence of the composite endpoint of the composite endpoint of the patient eGFR of CKD that continues to decline by ≥50% in the treatment group (that is, at least one patient is treated with an effective amount of SGLT2 inhibitor) that reaches end-stage renal disease (ESRD) or renal death is reduced. In some of the above embodiments, the incidence of the composite endpoint of sustained decline in eGFR ≥50%, end-stage renal disease (ESRD), or renal death in patients with CKD in the treatment group is reduced compared to an administration regimen in which the patients receive at least one standard CKD care agent alone (i.e., without treatment with an effective amount of an SGLT2 inhibitor).

[0039] In certain embodiments, this disclosure provides a method for reducing the incidence of the composite endpoint of the CV death of the patient with CKD or hospitalization for heart failure (HF), and the method includes applying an effective amount of SGLT2 inhibitor to the patient. In certain embodiments, this disclosure includes reducing the method for the incidence of the composite endpoint of the CV death of the patient with CKD but not suffering from T2D or hospitalization for heart failure, and the method includes applying an effective amount of SGLT2 inhibitor to the patient. In other embodiments, this disclosure includes reducing the method for the incidence of the composite endpoint of the CV death of the patient with CKD and T2D or hospitalization for heart failure, and the method includes applying an effective amount of SGLT2 inhibitor to the patient. In certain embodiments, the method reduces the incidence of hospitalization for heart failure in the patient with CKD. In some of the above-mentioned embodiments, relative to placebo, the composite endpoint incidence of CV death or hospitalization for heart failure in the treatment group (that is, at least one patient is treated with an effective amount of SGLT2 inhibitor) is reduced. In some of the above-mentioned embodiments, relative to the application scheme of the patient receiving at least one standard CKD nursing agent (i.e., without the SGLT2 inhibitor treatment of an effective amount), the composite endpoint incidence of CV death or hospitalization for heart failure in the treatment group is reduced.

[0040] Disclosed herein is a method for the incidence rate of reducing the death of CKD patients, and the method described includes applying the SGLT2 inhibitor of effective dose to the patient. In certain embodiments, this disclosure includes reducing the method for the incidence rate of the patient's death suffering from CKD but not suffering from T2D, and the method described includes applying the SGLT2 inhibitor of effective dose to the patient. In other embodiments, this disclosure includes reducing the method for the incidence rate of the patient's death suffering from CKD and T2D, and the method described includes applying the SGLT2 inhibitor of effective dose to the patient. In some of the above-mentioned embodiments, relative to placebo, the incidence rate of death in the treatment group (that is, at least one patient is treated through the SGLT2 inhibitor of effective dose) is reduced. In some of the above-mentioned embodiments, relative to the application scheme of the patient receiving at least one standard CKD nursing agent (that is, without the SGLT2 inhibitor of effective dose), the incidence rate of death in the treatment group is reduced.

[0041] In some embodiments, the method reduces the level of glycated hemoglobin (HbA1c) in a CKD patient with T2D compared to baseline.

[0042] In some embodiments, the methods reduce the incidence of newly diagnosed T2D in CKD patients who do not have diabetes.

[0043] In some embodiments, when the patient has an eGFR ≥ 25 and ≤ 75 mL / min / 1.73 m 2 In some embodiments, the patient has CKD and albuminuria. In some embodiments, the patient is identified as having albuminuria when the patient has UACR ≥ 200 and ≤ 5000 mg / g.

[0044] In some embodiments, the method reduces intraglomerular pressure, hypertension, proteinuria and / or fluid / sodium overload in patients with CKD. In some embodiments, the method reduces the systolic BP of the patient compared to baseline. In some embodiments, compared to placebo (or compared to patients receiving at least one standard CKD care agent alone), the method reduces the systolic BP of the patient to a greater extent compared to baseline. In some embodiments, the systolic BP of the patient is measured at the 30th (± 7) day, the 120th (± 7) day, the 240th (± 7) day, the 360th (± 7) day, the 480th (± 14) day and / or the 600th (± 14) day.

[0045] In some embodiments, the methods reduce the number of events of doubling of serum creatinine in patients with CKD compared to placebo (or compared to patients receiving at least one standard CKD care agent alone).

[0046] In some embodiments, the method reduces the incidence of hyperkalemia in patients with CKD, wherein the serum potassium level is >6.0mmol / L. In some embodiments, the method reduces the incidence of hyperkalemia in patients with CKD, wherein the serum potassium level is >5.5mmol / L. In some embodiments, the method reduces the incidence of hypokalemia in patients with CKD, wherein the serum potassium level is <3.5mmol / L. In some embodiments, the method reduces the incidence of hypokalemia in patients with CKD, wherein the serum potassium level is <3.0mmol / L.

[0047] In some embodiments, the method reduces the patient's weight compared to baseline. In some embodiments, compared to placebo (or compared to a patient receiving at least one standard CKD care agent alone), the method reduces the patient's weight to a greater extent compared to baseline. In some embodiments, the patient's weight is measured at the 30th (± 7) day, the 120th (± 7) day, the 240th (± 7) day, the 360th (± 7) day, the 480th (± 14) day and / or the 600th (± 14) day.

[0048] In some embodiments, the method reduces the patient's albuminuria level compared to baseline. In some embodiments, compared to placebo (or compared to a patient receiving at least one standard CKD care agent alone), the method reduces the patient's albuminuria level to a greater extent compared to baseline. In some embodiments, the patient's albuminuria level is measured at the 30th (± 7) day, the 120th (± 7) day, the 240th (± 7) day, the 360th (± 7) day, the 480th (± 14) day and / or the 600th (± 14) day.

[0049] In some embodiments, compared to placebo (or compared to patients receiving at least one standard CKD care agent alone), the method reduces the incidence of sustained reduction in renal function in patients with CKD. In some embodiments, the method does not reduce the patient's eGFR from baseline. In some embodiments, compared to placebo (or compared to patients receiving at least one standard CKD care agent alone), the method reduces eGFR to a lesser extent compared to baseline. In some embodiments, compared to placebo (or compared to patients receiving at least one standard CKD care agent alone), the method reduces the incidence of ≥30% reduction in eGFR in patients with CKD compared to baseline. In some embodiments, compared to placebo (or compared to patients receiving at least one standard CKD care agent alone), the method reduces the incidence of ≥40% reduction in eGFR in patients with CKD compared to baseline. In some embodiments, the patient's eGFR is measured on the 30th (± 7) day, the 120th (± 7) day, the 240th (± 7) day, the 360th (± 7) day, the 480th (± 14) day and / or the 600th (± 14) day.

[0050] In some embodiments, the method reduces the time to first occurrence of CV death in patients compared to placebo (or compared to patients receiving at least one standard CKD care agent alone). In some embodiments, the time to first occurrence of CV death is measured at 30 (± 7) days, 120 (± 7) days, 240 (± 7) days, 360 (± 7) days, 480 (± 14) days, and / or 600 (± 14) days.

[0051] In certain embodiments, compared with placebo (or compared with the patient receiving at least one standard CKD nursing agent alone), the method reduces the time to the first occurrence of renal death in the patient. In certain embodiments, the time to the first occurrence of renal death is measured at the 30th (± 7) day, the 120th (± 7) day, the 240th (± 7) day, the 360th (± 7) day, the 480th (± 14) day and / or the 600th (± 14) day.

[0052] In some embodiments, compared to placebo (or compared to patients receiving at least one standard CKD care agent alone), the method reduces the time to the first occurrence of hospitalization for heart failure in patients. In some embodiments, the time to the first occurrence of hospitalization for heart failure is measured at the 30th (± 7) day, the 120th (± 7) day, the 240th (± 7) day, the 360th (± 7) day, the 480th (± 14) day and / or the 600th (± 14) day.

[0053] In some embodiments, the method reduces the total number of hospitalizations for heart failure and / or CV death in a patient compared to a placebo (or compared to a patient receiving at least one standard CKD care agent alone).

[0054] In some embodiments, the methods reduce the risk of CKD in patients reaching CKD 4 (eGFR <30 mL / min / 1.73 m) compared to placebo (or compared to patients receiving at least one standard CKD care agent alone). 2 ) incidence.

[0055] In some embodiments, compared to placebo (or compared to patients receiving at least one standard CKD care agent alone), the method reduces the incidence of fatal myocardial infarction in patients with CKD. In some embodiments, compared to placebo (or compared to patients receiving at least one standard CKD care agent alone), the method reduces the incidence of non-fatal myocardial infarction in patients with CKD.

[0056] In certain embodiments, compared with placebo (or compared with the patient receiving at least one standard CKD nursing agent separately), the method described reduces the incidence rate of ischemic stroke in patients suffering from CKD. In certain embodiments, compared with placebo (or compared with the patient receiving at least one standard CKD nursing agent separately), the method described reduces the incidence rate of hemorrhagic stroke in patients suffering from CKD. In certain embodiments, compared with placebo (or compared with the patient receiving at least one standard CKD nursing agent separately), the method described reduces the incidence rate of fatal stroke in patients suffering from CKD. In certain embodiments, compared with placebo (or compared with the patient receiving at least one standard CKD nursing agent separately), the method described reduces the incidence rate of non-fatal stroke in patients suffering from CKD.

[0057] In some embodiments, compared to placebo (or compared to a patient receiving at least one standard CKD nursing agent alone), the method reduces the proportion of patients whose NYHA grade worsens compared to baseline. In some embodiments, compared to placebo (or compared to a patient receiving at least one standard CKD nursing agent alone), the method maintains or improves the NYHA grade of the patient compared to baseline. In some embodiments, the NYHA grade of the patient is measured at the 30th (± 7) day, the 120th (± 7) day, the 240th (± 7) day, the 360th (± 7) day, the 480th (± 14) day and / or the 600th (± 14) day.

[0058] In some embodiments, the method improves the patient's health status assessed by the EQ-5D-5L questionnaire compared to placebo (or compared to patients receiving at least one standard CKD care agent alone). In some embodiments, the patient's health status assessed by the EQ-5D-5L questionnaire is measured at day 30 (± 7), day 120 (± 7), day 240 (± 7), day 360 (± 7), day 480 (± 14), and / or day 600 (± 14).

[0059] In some embodiments, the method improves patient health status as assessed by the KDQOL 36 questionnaire compared to placebo (or compared to patients receiving at least one standard CKD care agent alone). In some embodiments, patient health status as assessed by the KDQOL 36 questionnaire is measured on Day 30 (± 7), Day 120 (± 7), Day 240 (± 7), Day 360 (± 7), Day 480 (± 14), and / or Day 600 (± 14).

[0060] Also disclosed herein is a method for preventing or delaying the incidence or onset of T2D in patients with prediabetes (i.e., with glycated hemoglobin ≥5.7% and <6.5%). In some embodiments, the patient is prediabetes with CKD. In other embodiments, the patient is prediabetes with HF. In some embodiments, the patient is prediabetes with HFrEF. In some embodiments, the patient is prediabetes without other comorbidities (e.g., CKD, HF, etc.). In some embodiments, the method disclosed herein reduces the incidence or onset of T2D relative to placebo. In some embodiments, the method disclosed herein reduces the incidence or onset of T2D relative to patients taking standard HF or CKD care agents. In some embodiments, the reduction in the incidence or onset of T2D is measured by the time to the first report of a glycated hemoglobin measurement of ≥6.5%. In some embodiments, the method disclosed herein results in a hazard ratio of less than 1 for reducing the incidence or onset of T2D relative to placebo. In some embodiments, the method disclosed herein results in a hazard ratio of less than 1 for reducing the incidence or onset of T2D relative to standard HF or CKD care agents.

[0061] In some embodiments, the methods disclosed herein result in a hazard ratio of less than 1 for the time to a first composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and CV or renal death relative to a regimen of administration of at least one standard CKD care agent alone. In some methods, the methods result in a hazard ratio of less than 1 for the time to a first composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and CV or renal death relative to a regimen of administration of at least one standard CKD care agent alone. In some embodiments, the methods result in a hazard ratio of about 0.61 for the time to a first composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and CV or renal death relative to a regimen of administration of at least one standard CKD care agent alone. In some methods, the methods result in a 95% confidence interval of about 0.51 to 0.72 for the hazard ratio of about 0.51 to 0.72 for the time to a first composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and CV or renal death relative to a regimen of administration of at least one standard CKD care agent alone. In some embodiments, the method numerically reduces the patient's absolute risk of a composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and CV or renal death, relative to a regimen in which the patient receives at least one standard CKD care agent alone. In some embodiments, the method results in a nominally significant reduction in the risk of a composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and CV or renal death, relative to a regimen in which the patient receives at least one standard CKD care agent alone. In some embodiments, the method results in a numerical reduction in the patient's composite endpoint event of a sustained decrease in eGFR of ≥50%, or ESRD and CV or renal death, relative to a regimen in which the patient receives at least one standard CKD care agent alone.

[0062] In some embodiments, the methods disclosed herein result in a hazard ratio of less than 1 for time to a first composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and CV or renal death in a patient with T2D relative to a patient with T2D receiving an administration regimen of at least one standard CKD care agent alone. In some methods, the methods result in a hazard ratio of less than 1 for time to a first composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and CV or renal death in a patient with T2D relative to a patient with T2D receiving an administration regimen of at least one standard CKD care agent alone. In some embodiments, the methods result in a hazard ratio of about 0.64 for time to a first composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and CV or renal death in a patient with T2D relative to a patient with T2D receiving an administration regimen of at least one standard CKD care agent alone. In some methods, the method results in a 95% confidence interval for the hazard ratio of time to a first composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and CV or renal death in a patient with T2D of about 0.52 to 0.79 relative to a patient with T2D receiving an administration regimen of at least one standard CKD care agent alone. In some embodiments, the method numerically reduces the absolute risk of a composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and CV or renal death in a patient with T2D relative to a patient with T2D receiving an administration regimen of at least one standard CKD care agent alone. In some embodiments, the method results in a nominally significant reduction in the risk of a composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and CV or renal death in a patient with T2D relative to a patient with T2D receiving an administration regimen of at least one standard CKD care agent alone. In some embodiments, the method results in a numerical reduction in a composite endpoint event of a sustained decline in eGFR ≥50%, or ESRD and CV or renal death in a patient with T2D relative to a regimen of administration of at least one standard CKD care agent alone.

[0063] In some embodiments, the methods disclosed herein result in a hazard ratio of less than 1 for time to a first composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and CV or renal death in a patient without T2D relative to a patient without T2D receiving an administration regimen of at least one standard CKD care agent alone. In some methods, the methods result in a hazard ratio of less than 1 for time to a first composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and CV or renal death in a patient without T2D relative to a patient without T2D receiving an administration regimen of at least one standard CKD care agent alone. In some embodiments, the methods result in a hazard ratio of about 0.50 for time to a first composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and CV or renal death in a patient without T2D relative to a patient without T2D receiving an administration regimen of at least one standard CKD care agent alone. In some methods, the method results in a 95% confidence interval for the hazard ratio of time to a first composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and CV or renal death in a patient without T2D of about 0.35 to 0.72 relative to a patient without T2D receiving an administration regimen of at least one standard CKD care agent alone. In some embodiments, the method numerically reduces the absolute risk of a composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and CV or renal death in a patient without T2D relative to a patient without T2D receiving an administration regimen of at least one standard CKD care agent alone. In some embodiments, the method results in a nominally significant reduction in the risk of a composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and CV or renal death in a patient without T2D relative to a patient without T2D receiving an administration regimen of at least one standard CKD care agent alone. In some embodiments, the method results in a numerical reduction in a composite endpoint event of a sustained decline in eGFR ≥50%, or ESRD and CV or renal death in patients without T2D relative to patients without T2D receiving an administration regimen of at least one standard CKD care agent alone.

[0064] In some embodiments, the methods disclosed herein result in a hazard ratio of less than 1 for time to a first composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and CV or renal death for patients with UACR≤1000 mg / g relative to patients with UACR≤1000 mg / g receiving a regimen of administration of at least one standard CKD care agent alone. In some methods, the methods result in a hazard ratio of less than 1 for time to a first composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and CV or renal death for patients with UACR≤1000 mg / g relative to patients with UACR≤1000 mg / g receiving a regimen of administration of at least one standard CKD care agent alone. In some embodiments, the methods result in a hazard ratio of about 0.54 for time to a first composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and CV or renal death for patients with UACR≤1000 mg / g relative to patients with UACR≤1000 mg / g receiving a regimen of administration of at least one standard CKD care agent alone. In some methods, the method results in a 95% confidence interval of a hazard ratio of about 0.37 to 0.77 for the time to a first composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and CV or renal death for patients with UACR≤1000 mg / g relative to a regimen of administration of at least one standard CKD care agent alone. In some embodiments, the method numerically reduces the absolute risk of a composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and CV or renal death for patients with UACR≤1000 mg / g relative to a regimen of administration of at least one standard CKD care agent alone. In some embodiments, the method results in a nominally significant reduction in the risk of a composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and CV or renal death for patients with UACR≤1000 mg / g relative to a regimen of administration of at least one standard CKD care agent alone. In some embodiments, the method results in a numerical reduction in the composite endpoint event of a sustained decline in eGFR of ≥50%, or ESRD and CV or renal death in patients with UACR≤1000 mg / g relative to patients with UACR≤1000 mg / g receiving an administration regimen of at least one standard CKD care agent alone.

[0065] In some embodiments, the methods disclosed herein result in a hazard ratio of less than 1 for time to a first composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and CV or renal death for patients with UACR>1000 mg / g relative to patients with UACR>1000 mg / g receiving an administration regimen of at least one standard CKD care agent alone. In some methods, the methods result in a hazard ratio of less than 1 for time to a first composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and CV or renal death for patients with UACR>1000 mg / g relative to patients with UACR>1000 mg / g receiving an administration regimen of at least one standard CKD care agent alone. In some embodiments, the methods result in a hazard ratio of about 0.62 for time to a first composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and CV or renal death for patients with UACR>1000 mg / g relative to patients with UACR>1000 mg / g receiving an administration regimen of at least one standard CKD care agent alone. In some methods, the method results in a 95% confidence interval of a hazard ratio of about 0.50 to 0.76 for the time to a first composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and CV or renal death for patients with UACR>1000 mg / g relative to a regimen of administration of at least one standard CKD care agent received alone. In some embodiments, the method numerically reduces the absolute risk of a composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and CV or renal death for patients with UACR>1000 mg / g relative to a regimen of administration of at least one standard CKD care agent received alone. In some embodiments, the method results in a nominally significant reduction in the risk of a composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and CV or renal death for patients with UACR>1000 mg / g relative to a regimen of administration of at least one standard CKD care agent received alone. In some embodiments, the method results in a numerical reduction in the composite endpoint event of a sustained decline in eGFR ≥50%, or ESRD and CV or renal death in patients with UACR>1000 mg / g relative to patients with UACR>1000 mg / g receiving an administration regimen of at least one standard CKD care agent alone.

[0066] In some embodiments, relative to eGFR <45 mL / min / 1.73 m 2 The method disclosed herein results in an eGFR <45 mL / min / 1.73 m 2In some methods, patients with an eGFR < 45 mL / min / 1.73 m 2 The method results in the patient receiving a regimen of at least one standard CKD care agent alone, wherein the eGFR is <45 mL / min / 1.73 m 2 The hazard ratio for time to a sustained decline in eGFR of ≥50% or the first composite endpoint of ESRD and CV or renal death is statistically nominally less than 1 in patients with an eGFR of <45 mL / min / 1.73 m 2 The method results in the patient receiving a regimen of at least one standard CKD care agent alone, wherein the eGFR is <45 mL / min / 1.73 m 2 The hazard ratio for time to a sustained decline in eGFR of ≥50% or the first composite endpoint of ESRD and CV or renal death was about 0.63 for patients with eGFR <45 mL / min / 1.73 m 2 The method results in the patient receiving a regimen of at least one standard CKD care agent alone, wherein the eGFR is <45 mL / min / 1.73 m 2 The 95% confidence interval for the hazard ratio for time to a sustained decline in eGFR of ≥50%, or the first composite endpoint of ESRD and CV or renal death, was about 0.51 to 0.78 for patients with eGFR <45 mL / min / 1.73 m 2 Patients receiving a regimen of at least one standard CKD care agent alone, said method numerically lowering said eGFR <45 mL / min / 1.73 m 2 In some embodiments, the absolute risk of a sustained decline in eGFR of ≥50% or a composite endpoint of ESRD and CV or renal death is reduced in patients with eGFR <45 mL / min / 1.73 m 2 The method results in the patient receiving a regimen of at least one standard CKD care agent alone, wherein the eGFR is <45 mL / min / 1.73 m 2 In some embodiments, the risk of sustained decline in eGFR of ≥50% or the composite endpoint of ESRD and CV or renal death is nominally significantly reduced in patients with eGFR <45 mL / min / 1.73 m 2 The method results in the patient receiving a regimen of at least one standard CKD care agent alone, wherein the eGFR is <45 mL / min / 1.73 m 2 A numerical reduction in the number of patients achieving a sustained decline in eGFR ≥50%, or a composite endpoint of ESRD and CV or renal death.

[0067] In some embodiments, relative to eGFR ≥ 45 mL / min / 1.73 m 2 The method disclosed herein results in an eGFR of ≥45 mL / min / 1.73 m 2 In some methods, the hazard ratio for time to a sustained decline in eGFR ≥50% or the first composite endpoint of ESRD and CV or renal death is less than 1 for patients with eGFR ≥45 mL / min / 1.73 m 2 The method results in an eGFR of ≥45 mL / min / 1.73 m 2 The hazard ratio for time to a sustained decline in eGFR of ≥50% or the first composite endpoint of ESRD and CV or renal death is statistically nominally less than 1 in patients with an eGFR of ≥45 mL / min / 1.73 m 2 The method results in an eGFR of ≥45 mL / min / 1.73 m 2 The hazard ratio for time to a sustained decline in eGFR of ≥50% or the first composite endpoint of ESRD and CV or renal death was about 0.49 for patients with eGFR ≥45 mL / min / 1.73 m 2 The method results in an eGFR of ≥45 mL / min / 1.73 m 2 The 95% confidence interval for the hazard ratio for time to a sustained decline in eGFR of ≥50%, or the first composite endpoint of ESRD and CV or renal death, was about 0.34 to 0.69 for patients with eGFR ≥45 mL / min / 1.73 m 2 A regimen of at least one standard CKD care agent alone is administered to patients with the disease, the method numerically reducing the eGFR by ≥ 45 mL / min / 1.73 m 2 In some embodiments, the absolute risk of a sustained decline in eGFR of ≥50% or a composite endpoint of ESRD and CV or renal death is determined for patients with an eGFR of ≥45 mL / min / 1.73 m 2 The method results in an eGFR of ≥45 mL / min / 1.73 m 2In some embodiments, the risk of sustained decline in eGFR ≥ 50% or the composite endpoint of ESRD and CV or renal death is nominally significantly reduced in patients with eGFR ≥ 45 mL / min / 1.73 m 2 The method results in an eGFR of ≥45 mL / min / 1.73 m 2 A numerical reduction in the number of patients achieving a sustained decline in eGFR ≥50%, or a composite endpoint of ESRD and CV or renal death.

[0068] In some embodiments, the methods disclosed herein result in a hazard ratio of less than 1 for the time to a sustained decrease in eGFR of ≥50% for the patient relative to a regimen of administration of at least one standard CKD care agent received alone. In some methods, the method results in a hazard ratio of less than 1 for the time to a sustained decrease in eGFR of ≥50% for the patient relative to a regimen of administration of at least one standard CKD care agent received alone. In some embodiments, the method results in a hazard ratio of about 0.53 for the time to a sustained decrease in eGFR of ≥50% for the patient relative to a regimen of administration of at least one standard CKD care agent received alone. In some methods, the method results in a 95% confidence interval of about 0.42 to 0.67 for the hazard ratio for the time to a sustained decrease in eGFR of ≥50% for the patient relative to a regimen of administration of at least one standard CKD care agent received alone. In some embodiments, the method numerically reduces the absolute risk of a sustained decrease in eGFR of ≥50% for the patient relative to a regimen of administration of at least one standard CKD care agent received alone. In some embodiments, the method results in a nominally significant reduction in the risk of a sustained decrease in eGFR of ≥50% in the patient relative to an administration regimen in which the patient receives at least one standard CKD care agent alone. In some embodiments, the method results in a numerical reduction in a sustained decrease in eGFR of ≥50% in the patient relative to an administration regimen in which the patient receives at least one standard CKD care agent alone.

[0069] In some embodiments, the methods disclosed herein result in a hazard ratio of less than 1 for the time to ESRD of the patient relative to a regimen in which the patient receives at least one standard CKD care agent alone. In some methods, the method results in a hazard ratio of less than 1 for the time to ESRD of the patient relative to a regimen in which the patient receives at least one standard CKD care agent alone. In some embodiments, the method results in a hazard ratio of about 0.64 for the time to ESRD of the patient relative to a regimen in which the patient receives at least one standard CKD care agent alone. In some methods, the method results in a 95% confidence interval of about 0.50 to 0.82 for the hazard ratio of the time to ESRD of the patient relative to a regimen in which the patient receives at least one standard CKD care agent alone. In some embodiments, the method numerically reduces the absolute risk of ESRD of the patient relative to a regimen in which the patient receives at least one standard CKD care agent alone. In some embodiments, the method results in a nominally significant reduction in the risk of ESRD of the patient relative to a regimen in which the patient receives at least one standard CKD care agent alone. In some embodiments, the method results in a numerical reduction in the ESRD of the patient relative to a regimen in which the patient receives at least one standard CKD care agent alone.

[0070] In some embodiments, the methods disclosed herein result in a hazard ratio of less than 1 for the time to CV death of the patient relative to a regimen in which the patient receives at least one standard CKD care agent alone. In some methods, the method results in a hazard ratio of less than 1 for the time to CV death of the patient relative to a regimen in which the patient receives at least one standard CKD care agent alone. In some embodiments, the method results in a hazard ratio of about 0.81 for the time to CV death of the patient relative to a regimen in which the patient receives at least one standard CKD care agent alone. In some methods, the method results in a 95% confidence interval of about 0.58 to 1.12 for the hazard ratio of the time to CV death of the patient relative to a regimen in which the patient receives at least one standard CKD care agent alone. In some embodiments, the method numerically reduces the absolute risk of CV death of the patient relative to a regimen in which the patient receives at least one standard CKD care agent alone. In some embodiments, the method results in a nominally significant reduction in the risk of CV death of the patient relative to a regimen in which the patient receives at least one standard CKD care agent alone. In some embodiments, the method results in a numerical reduction in the CV death of the patient relative to a regimen in which the patient receives at least one standard CKD care agent alone.

[0071] In some embodiments, the methods disclosed herein result in a hazard ratio of less than 1 for the time to a first composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and renal death in the patient relative to a regimen of administration of at least one standard CKD care agent received alone. In some methods, the method results in a hazard ratio of less than 1 for the time to a first composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and renal death in the patient relative to a regimen of administration of at least one standard CKD care agent received alone. In some embodiments, the method results in a hazard ratio of about 0.56 for the time to a first composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and renal death in the patient relative to a regimen of administration of at least one standard CKD care agent received alone. In some methods, the method results in a 95% confidence interval of about 0.45 to 0.68 for the hazard ratio of about 0.45 to 0.68 for the time to a first composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and renal death in the patient relative to a regimen of administration of at least one standard CKD care agent received alone. In some embodiments, the method numerically reduces the absolute risk of the patient's composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and renal death relative to the patient's administration regimen of at least one standard CKD care agent alone. In some embodiments, the method results in a nominally significant reduction in the risk of a composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and renal death relative to the patient's administration regimen of at least one standard CKD care agent alone. In some embodiments, the method results in a numerical reduction in the composite endpoint event of a sustained decrease in eGFR of ≥50%, or ESRD and renal death relative to the patient's administration regimen of at least one standard CKD care agent alone.

[0072] In some embodiments, the methods disclosed herein result in a hazard ratio of less than 1 for time to a first composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and renal death in a patient with T2D relative to a patient with T2D receiving an administration regimen of at least one standard CKD care agent alone. In some methods, the methods result in a hazard ratio of less than 1 for time to a first composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and renal death in a patient with T2D relative to a patient with T2D receiving an administration regimen of at least one standard CKD care agent alone. In some embodiments, the methods result in a hazard ratio of about 0.57 for time to a first composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and renal death in a patient with T2D relative to a patient with T2D receiving an administration regimen of at least one standard CKD care agent alone. In some methods, the method results in a 95% confidence interval of the hazard ratio of the time to the first composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and renal death in the patient with T2D, relative to a regimen of administration of at least one standard CKD care agent alone received by the patient with T2D. . In some embodiments, the method numerically reduces the absolute risk of the composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and renal death in the patient with T2D relative to a regimen of administration of at least one standard CKD care agent alone received by the patient with T2D. In some embodiments, the method results in a nominally significant reduction in the risk of a composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and renal death in the patient with T2D relative to a regimen of administration of at least one standard CKD care agent alone received by the patient with T2D. In some embodiments, the method results in a numerical reduction in the composite endpoint event of a sustained decrease in eGFR of ≥50%, or ESRD and renal death in the patient with T2D relative to a regimen of administration of at least one standard CKD care agent alone received by the patient with T2D.

[0073] In some embodiments, the methods disclosed herein result in a hazard ratio of less than 1 for time to a first composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and renal death in a patient without T2D relative to a patient without T2D receiving an administration regimen of at least one standard CKD care agent alone. In some methods, the methods result in a hazard ratio of less than 1 for time to a first composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and renal death in a patient without T2D relative to a patient without T2D receiving an administration regimen of at least one standard CKD care agent alone. In some embodiments, the methods result in a hazard ratio of about 0.51 for time to a first composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and renal death in a patient without T2D relative to a patient without T2D receiving an administration regimen of at least one standard CKD care agent alone. In some methods, the method results in a 95% confidence interval for the hazard ratio of time to a first composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and renal death in a patient without T2D of about 0.34 to 0.75 relative to a patient without T2D receiving an administration regimen of at least one standard CKD care agent alone. In some embodiments, the method numerically reduces the absolute risk of a composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and renal death in a patient without T2D relative to a patient without T2D receiving an administration regimen of at least one standard CKD care agent alone. In some embodiments, the method results in a nominally significant reduction in the risk of a composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and renal death in a patient without T2D relative to a patient without T2D receiving an administration regimen of at least one standard CKD care agent alone. In some embodiments, the method results in a numerical reduction in a composite endpoint event of a sustained decline in eGFR ≥50%, or ESRD and renal death in patients without T2D relative to patients without T2D receiving an administration regimen of at least one standard CKD care agent alone.

[0074] In some embodiments, the methods disclosed herein result in a hazard ratio of less than 1 for time to a first composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and renal death for patients with eGFR<30, relative to patients with eGFR<30 receiving an administration regimen of at least one standard CKD care agent alone. In some methods, the methods result in a hazard ratio of less than 1 for time to a first composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and renal death for patients with eGFR<30, relative to patients with eGFR<30 receiving an administration regimen of at least one standard CKD care agent alone. In some embodiments, the methods result in a hazard ratio of about 0.73 for time to a first composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and renal death for patients with eGFR<30, relative to patients with eGFR<30 receiving an administration regimen of at least one standard CKD care agent alone. In some methods, the method results in a 95% confidence interval for the hazard ratio of time to a first composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and renal death for patients with eGFR<30 of about 0.53 to 1.02 relative to a regimen of administration of at least one standard CKD care agent alone for patients with eGFR<30. In some embodiments, the method numerically reduces the absolute risk of a composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and renal death for patients with eGFR<30 relative to a regimen of administration of at least one standard CKD care agent alone. In some embodiments, the method results in a nominally significant reduction in the risk of a composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and renal death for patients with eGFR<30 relative to a regimen of administration of at least one standard CKD care agent alone for patients with eGFR<30. In some embodiments, the method results in a numerical reduction in the composite endpoint event of a sustained decline in eGFR ≥50%, or ESRD and renal death in patients with eGFR<30, relative to patients with eGFR<30 receiving an administration regimen of at least one standard CKD care agent alone.

[0075] In some embodiments, the methods disclosed herein result in a hazard ratio of less than 1 for time to a first composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and renal death for patients with eGFR≥30, relative to patients with eGFR≥30 receiving an administration regimen of at least one standard CKD care agent alone. In some methods, the methods result in a hazard ratio of less than 1 for time to a first composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and renal death for patients with eGFR≥30, relative to patients with eGFR≥30 receiving an administration regimen of at least one standard CKD care agent alone. In some embodiments, the methods result in a hazard ratio of about 0.58 for time to a first composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and renal death for patients with eGFR≥30, relative to patients with eGFR≥30 receiving an administration regimen of at least one standard CKD care agent alone. In some methods, the method results in a 95% confidence interval of a hazard ratio of about 0.47 to 0.71 for the time to a first composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and renal death for patients with eGFR≥30, relative to a regimen of administration of at least one standard CKD care agent alone. In some embodiments, the method numerically reduces the absolute risk of a composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and renal death for patients with eGFR≥30, relative to a regimen of administration of at least one standard CKD care agent alone. In some embodiments, the method results in a nominally significant reduction in the risk of a composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and renal death for patients with eGFR≥30, relative to a regimen of administration of at least one standard CKD care agent alone. In some embodiments, the method results in a numerical reduction in the composite endpoint event of a sustained decline in eGFR of ≥50%, or ESRD and renal death in patients with eGFR ≥30, relative to patients with eGFR ≥30 receiving an administration regimen of at least one standard CKD care agent alone.

[0076] In some embodiments, the methods disclosed herein result in a hazard ratio of less than 1 for the time to the first composite endpoint of CV death and hospitalization for heart failure in the patient relative to the administration regimen of at least one standard CKD care agent received alone. In some methods, the method results in a hazard ratio of less than 1 for the time to the first composite endpoint of CV death and hospitalization for heart failure in the patient relative to the administration regimen of at least one standard CKD care agent received alone. In some embodiments, the method results in a hazard ratio of about 0.71 for the time to the first composite endpoint of CV death and hospitalization for heart failure in the patient relative to the administration regimen of at least one standard CKD care agent received alone. In some methods, the method results in a 95% confidence interval of about 0.55 to 0.92 for the hazard ratio of the time to the first composite endpoint of CV death and hospitalization for heart failure in the patient relative to the administration regimen of at least one standard CKD care agent received alone. In some embodiments, the method numerically reduces the absolute risk of the composite endpoint of CV death and hospitalization for heart failure in the patient relative to the administration regimen of at least one standard CKD care agent received alone. In some embodiments, the method results in a nominally significant reduction in the risk of a composite endpoint of CV death and hospitalization for heart failure relative to a regimen in which the patient receives at least one standard CKD care agent alone. In some embodiments, the method results in a numerical reduction in the composite endpoint event of CV death and hospitalization for heart failure relative to a regimen in which the patient receives at least one standard CKD care agent alone.

[0077] In some embodiments, the methods disclosed herein result in a hazard ratio of less than 1 for the time to the first composite endpoint of CV death and hospitalization for heart failure in patients with T2D relative to a regimen of administration of at least one standard CKD care agent alone. In some methods, the method results in a hazard ratio of less than 1 for the time to the first composite endpoint of CV death and hospitalization for heart failure in patients with T2D relative to a regimen of administration of at least one standard CKD care agent alone. In some embodiments, the method results in a hazard ratio of about 0.70 for the time to the first composite endpoint of CV death and hospitalization for heart failure in patients with T2D relative to a regimen of administration of at least one standard CKD care agent alone. In some methods, the method results in a 95% confidence interval of about 0.53 to 0.92 for the hazard ratio of the time to the first composite endpoint of CV death and hospitalization for heart failure in patients with T2D relative to a regimen of administration of at least one standard CKD care agent alone. In some embodiments, the method numerically reduces the absolute risk of the composite endpoint of CV death and hospitalization for heart failure in the patient with T2D relative to the administration regimen of at least one standard CKD care agent alone received by the patient with T2D. In some embodiments, the method results in a nominally significant reduction in the risk of the composite endpoint of CV death and hospitalization for heart failure in the patient with T2D relative to the administration regimen of at least one standard CKD care agent alone received by the patient with T2D. In some embodiments, the method results in a numerical reduction in the composite endpoint event of CV death and hospitalization for heart failure in the patient with T2D relative to the administration regimen of at least one standard CKD care agent alone received by the patient with T2D.

[0078] In some embodiments, the methods disclosed herein result in a hazard ratio of less than 1 for the time to the first composite endpoint of CV death and hospitalization for heart failure in patients without T2D relative to a regimen of administration of at least one standard CKD care agent alone in patients without T2D. In some methods, the method results in a hazard ratio of less than 1 for the time to the first composite endpoint of CV death and hospitalization for heart failure in patients without T2D relative to a regimen of administration of at least one standard CKD care agent alone in patients without T2D. In some embodiments, the method results in a hazard ratio of about 0.79 for the time to the first composite endpoint of CV death and hospitalization for heart failure in patients without T2D relative to a regimen of administration of at least one standard CKD care agent alone in patients without T2D. In some methods, the method results in a 95% confidence interval of about 0.40 to 1.55 for the hazard ratio of the time to the first composite endpoint of CV death and hospitalization for heart failure in patients without T2D relative to a regimen of administration of at least one standard CKD care agent alone in patients without T2D. In some embodiments, the method numerically reduces the absolute risk of the composite endpoint of CV death and hospitalization for heart failure in patients without T2D relative to the administration regimen of at least one standard CKD care agent alone received by patients without T2D. In some embodiments, the method results in a nominally significant reduction in the risk of the composite endpoint of CV death and hospitalization for heart failure in patients without T2D relative to the administration regimen of at least one standard CKD care agent alone received by patients without T2D. In some embodiments, the method results in a numerical reduction in the composite endpoint event of CV death and hospitalization for heart failure in patients without T2D relative to the administration regimen of at least one standard CKD care agent alone received by patients without T2D.

[0079] In some embodiments, the methods disclosed herein result in a hazard ratio of less than 1 for the time to all-cause death of the patient relative to the administration regimen of at least one standard CKD care agent received by the patient alone. In some methods, the method results in a hazard ratio of less than 1 for the time to all-cause death of the patient relative to the administration regimen of at least one standard CKD care agent received by the patient alone. In some embodiments, the method results in a hazard ratio of about 0.69 for the time to all-cause death of the patient relative to the administration regimen of at least one standard CKD care agent received by the patient alone. In some methods, the method results in a 95% confidence interval of about 0.53 to 0.88 for the hazard ratio of the time to all-cause death of the patient relative to the administration regimen of at least one standard CKD care agent received by the patient alone. In some embodiments, the method numerically reduces the absolute risk of all-cause death of the patient relative to the administration regimen of at least one standard CKD care agent received by the patient alone. In some embodiments, the method results in a nominally significant reduction in the risk of all-cause death of the patient relative to the administration regimen of at least one standard CKD care agent received by the patient alone. In some embodiments, the method results in a numerical reduction in all-cause mortality in the patient relative to a patient receiving an administration regimen of at least one standard CKD care agent alone.

[0080] In some embodiments, the methods disclosed herein result in a hazard ratio of less than 1 for the time to all-cause death for a patient with T2D relative to a regimen of administration of at least one standard CKD care agent alone for a patient with T2D. In some methods, the method results in a hazard ratio of less than 1 for the time to all-cause death for a patient with T2D relative to a regimen of administration of at least one standard CKD care agent alone for a patient with T2D. In some embodiments, the method results in a hazard ratio of about 0.74 for the time to all-cause death for a patient with T2D relative to a regimen of administration of at least one standard CKD care agent alone for a patient with T2D. In some methods, the method results in a 95% confidence interval of about 0.56 to 0.98 for the hazard ratio of the time to all-cause death for a patient with T2D relative to a regimen of administration of at least one standard CKD care agent alone for a patient with T2D. In some embodiments, the method numerically reduces the absolute risk of all-cause death for a patient with T2D relative to a regimen of administration of at least one standard CKD care agent alone for a patient with T2D. In some embodiments, the method results in a nominally significant reduction in the risk of all-cause mortality in patients with T2D relative to a regimen of administration of at least one standard CKD care agent alone in patients with T2D. In some embodiments, the method results in a numerical reduction in all-cause mortality in patients with T2D relative to a regimen of administration of at least one standard CKD care agent alone in patients with T2D.

[0081] In some embodiments, the methods disclosed herein result in a hazard ratio of less than 1 for the time to all-cause death in patients without T2D relative to a regimen of administration of at least one standard CKD care agent alone in patients without T2D. In some methods, the method results in a hazard ratio of less than 1 for the time to all-cause death in patients without T2D relative to a regimen of administration of at least one standard CKD care agent alone in patients without T2D. In some embodiments, the method results in a hazard ratio of about 0.52 for the time to all-cause death in patients without T2D relative to a regimen of administration of at least one standard CKD care agent alone in patients without T2D. In some methods, the method results in a 95% confidence interval of about 0.29 to 0.93 for the hazard ratio of the time to all-cause death in patients without T2D relative to a regimen of administration of at least one standard CKD care agent alone in patients without T2D. In some embodiments, the method numerically reduces the absolute risk of all-cause death in patients without T2D relative to a regimen of administration of at least one standard CKD care agent alone in patients without T2D. In some embodiments, the method results in a nominally significant reduction in the risk of all-cause mortality in patients without T2D relative to a regimen of administration of at least one standard CKD care agent alone in patients without T2D. In some embodiments, the method results in a numerical reduction in all-cause mortality in patients without T2D relative to a regimen of administration of at least one standard CKD care agent alone in patients without T2D.

[0082] In some embodiments, the methods disclosed herein result in a hazard ratio of less than 1 for the time to the first composite endpoint of chronic dialysis, kidney transplantation, or renal death in the patient relative to the administration regimen of at least one standard CKD care agent received alone. In some methods, the method results in a hazard ratio of less than 1 for the time to the first composite endpoint of chronic dialysis, kidney transplantation, or renal death in the patient relative to the administration regimen of at least one standard CKD care agent received alone. In some embodiments, the method results in a hazard ratio of about 0.66 for the time to the first composite endpoint of chronic dialysis, kidney transplantation, or renal death in the patient relative to the administration regimen of at least one standard CKD care agent received alone. In some methods, the method results in a 95% confidence interval of about 0.49 to 0.90 for the hazard ratio of the time to the first composite endpoint of chronic dialysis, kidney transplantation, or renal death in the patient relative to the administration regimen of at least one standard CKD care agent received alone. In some embodiments, the method numerically reduces the absolute risk of the composite endpoint of chronic dialysis, kidney transplantation, or renal death in the patient relative to the administration regimen of at least one standard CKD care agent received alone. In some embodiments, relative to the application regimen in which the patient receives at least one standard CKD care agent alone, the method results in a nominally significant reduction in the risk of the composite endpoint of chronic dialysis, kidney transplantation, or renal death for the patient. In some embodiments, relative to the application regimen in which the patient receives at least one standard CKD care agent alone, the method results in a numerical reduction in the composite endpoint event of chronic dialysis, kidney transplantation, or renal death for the patient.

[0083] In some embodiments, the methods disclosed herein result in a hazard ratio of less than 1 for the time to first hospitalization for HF in the patient relative to a regimen of administration of at least one standard CKD care agent received by the patient alone. In some methods, the method results in a hazard ratio of less than 1 for the time to first hospitalization for HF in the patient relative to a regimen of administration of at least one standard CKD care agent received by the patient alone. In some embodiments, the method results in a hazard ratio of about 0.51 for the time to first hospitalization for HF in the patient relative to a regimen of administration of at least one standard CKD care agent received by the patient alone. In some methods, the method results in a 95% confidence interval of about 0.34 to 0.76 for the hazard ratio for the time to first hospitalization for HF in the patient relative to a regimen of administration of at least one standard CKD care agent received by the patient alone. In some embodiments, the method numerically reduces the risk of the time to first hospitalization for HF in the patient relative to a regimen of administration of at least one standard CKD care agent received by the patient alone. In some embodiments, the method results in a nominally significant reduction in the risk of first hospitalization for HF in the patient relative to a regimen of administration of at least one standard CKD care agent received by the patient alone. In some embodiments, the method results in a numerical reduction in the patient's risk of time to first hospitalization for HF relative to a patient receiving an administration regimen of at least one standard CKD care agent alone.

[0084] In some embodiments, the methods disclosed herein result in a hazard ratio of less than 1 for time to a first composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and CV or renal death in a patient with IgA nephropathy relative to a patient with IgA nephropathy receiving an administration regimen of at least one standard CKD care agent alone. In some methods, the methods result in a hazard ratio of less than 1 for time to a first composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and CV or renal death in a patient with IgA nephropathy relative to a patient with IgA nephropathy receiving an administration regimen of at least one standard CKD care agent alone. In some embodiments, the methods result in a hazard ratio of about 0.29 for time to a first composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and CV or renal death in a patient with IgA nephropathy relative to a patient with IgA nephropathy receiving an administration regimen of at least one standard CKD care agent alone. In some methods, the method results in a 95% confidence interval for the hazard ratio of about 0.12 to 0.73 for the time to a first composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and CV or renal death in a patient with IgA nephropathy relative to a regimen of administration of at least one standard CKD care agent alone. In some embodiments, the method numerically reduces the risk of the time to a first composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and CV or renal death in a patient with IgA nephropathy relative to a regimen of administration of at least one standard CKD care agent alone. In some embodiments, the method results in a nominally significant reduction in the risk of the time to a first composite endpoint of a sustained decrease in eGFR of ≥50%, or ESRD and CV or renal death in a patient with IgA nephropathy relative to a regimen of administration of at least one standard CKD care agent alone. In some embodiments, the method results in a numerical reduction in the risk of time to a first composite endpoint of a sustained decline in eGFR ≥50%, or ESRD and CV or renal death in a patient with IgA nephropathy relative to a patient with IgA nephropathy receiving an administration regimen of at least one standard CKD care agent alone.

[0085] Also disclosed herein is AZD9977, 2-{(3S)-7-fluoro-4-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl]-3,4-dihydro-2H-1,4-benzoxazin-3-yl}-N-methylacetamide, which is disclosed in WO 2016 / 001631 and has the following structure:

[0086]

[0087] In some embodiments, a method for treating CKD is disclosed, comprising administering an effective amount of AZD9977 or a pharmaceutically acceptable salt thereof to a patient in need thereof; and an effective amount of an SGLT2 inhibitor. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt, solvate, mixed solvate, complex or prodrug thereof.

[0088] In some embodiments, AZD9977 or a pharmaceutically acceptable salt thereof for treating CKD in a patient is disclosed, wherein the treatment comprises administering AZD9977 and an SGLT2 inhibitor to the patient separately, sequentially or simultaneously. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt, solvate, mixed solvate, complex or prodrug thereof.

[0089] In some embodiments, an SGLT2 inhibitor for treating CKD in a patient is disclosed, wherein the treatment comprises administering the SGLT2 inhibitor and AZD9977 or a pharmaceutically acceptable salt thereof separately, sequentially or simultaneously. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt, solvate, mixed solvate, complex or prodrug thereof.

[0090] In some embodiments, a method of reducing the rate of progression of renal failure and / or renal death and / or CV death in a patient with CKD is disclosed, comprising administering an effective amount of AZD9977 or a pharmaceutically acceptable salt thereof to a patient in need thereof; and an effective amount of an SGLT2 inhibitor. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt, solvate, mixed solvate, complex or prodrug thereof. In at least one embodiment, renal failure can be defined as, for example, a decrease in eGFR or ESRD of ≥40%. In some embodiments, a patient with CKD may, for example, have a 15-89 ml / min / 1.73 m 2 In other embodiments, a patient with CKD may, for example, have an eGFR of 15-59 ml / min / 1.73 m 2 In some embodiments, patients with CKD may, for example, be at high risk for hyperkalemia (i.e., patients with T2D and / or with an eGFR of 15-59 ml / min / 1.73 m 2 eGFR).

[0091] In some embodiments, AZD9977 or a pharmaceutically acceptable salt thereof for reducing the progression rate of renal failure and / or renal death and / or CV death in patients with CKD is disclosed, wherein the treatment comprises administering AZD9977 and an SGLT2 inhibitor to the patient separately, sequentially or simultaneously. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt, solvate, mixed solvate, complex or prodrug thereof. In at least one embodiment, renal failure can be defined as, for example, a decrease in eGFR or ESRD of ≥40%. In some embodiments, a patient with CKD may, for example, have a 15-89 ml / min / 1.73 m 2 In other embodiments, a patient with CKD may, for example, have an eGFR of 15-59 ml / min / 1.73 m 2 In some embodiments, patients with CKD may, for example, be at high risk for hyperkalemia (i.e., patients with T2D and / or with an eGFR of 15-59 ml / min / 1.73 m 2 eGFR).

[0092] In some embodiments, SGLT2 inhibitors for reducing the progression rate of renal failure and / or renal death and / or CV death in patients with CKD are disclosed, wherein the treatment includes administering SGLT2 inhibitors and AZD9977 or a pharmaceutically acceptable salt thereof separately, sequentially or simultaneously. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt thereof, solvate, mixed solvate, complex or prodrug. In at least one embodiment, renal failure can be defined as, for example, a decrease of ≥40% in eGFR or ESRD. In some embodiments, patients with CKD may, for example, have a 15-89 ml / min / 1.73 m 2 In other embodiments, a patient with CKD may, for example, have an eGFR of 15-59 ml / min / 1.73 m 2 In some embodiments, patients with CKD may, for example, be at high risk for hyperkalemia (i.e., patients with T2D and / or with an eGFR of 15-59 ml / min / 1.73 m 2 eGFR).

[0093] In some embodiments, a method for reducing the risk of hyperkalemia in CKD patients is disclosed, comprising administering an effective amount of AZD9977 or a pharmaceutically acceptable salt thereof to a patient in need thereof; and an effective amount of an SGLT2 inhibitor. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt, solvate, mixed solvate, complex or prodrug thereof.

[0094] In some embodiments, AZD9977 or a pharmaceutically acceptable salt thereof for reducing the risk of hyperkalemia in a CKD patient in a patient is disclosed, wherein the treatment comprises administering AZD9977 and an SGLT inhibitor to the patient separately, sequentially or simultaneously. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt, solvate, mixed solvate, complex or prodrug thereof.

[0095] In some embodiments, an SGLT2 inhibitor for reducing the risk of hyperkalemia in a CKD patient is disclosed, wherein the treatment comprises administering the SGLT2 inhibitor and AZD9977 or a pharmaceutically acceptable salt thereof separately, sequentially or simultaneously. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt, solvate, mixed solvate, complex or prodrug thereof.

[0096] In some embodiments, a method for treating HFrEF and CKD is disclosed, comprising administering to a patient in need thereof an effective amount of AZD9977 or a pharmaceutically acceptable salt thereof; and an effective amount of an SGLT2 inhibitor. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt, solvate, mixed solvate, complex or prodrug thereof.

[0097] In some embodiments, AZD9977 or a pharmaceutically acceptable salt thereof for treating HFrEF and CKD in a patient is disclosed, wherein the treatment comprises administering AZD9977 and an SGLT inhibitor to the patient separately, sequentially or simultaneously. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt, solvate, mixed solvate, complex or prodrug thereof.

[0098] In some embodiments, a SGLT2 inhibitor for treating HFrEF and CKD in a patient is disclosed, wherein the treatment comprises administering the SGLT2 inhibitor and AZD9977 or a pharmaceutically acceptable salt thereof separately, sequentially or simultaneously. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt, solvate, mixed solvate, complex or prodrug thereof.

[0099] In some embodiments, a method for treating HFpEF and CKD is disclosed, comprising administering to a patient in need thereof an effective amount of AZD9977 or a pharmaceutically acceptable salt thereof; and an effective amount of an SGLT2 inhibitor. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt, solvate, mixed solvate, complex or prodrug thereof.

[0100] In some embodiments, AZD9977 or a pharmaceutically acceptable salt thereof for treating HFpEF and CKD in a patient is disclosed, wherein the treatment comprises administering AZD9977 and an SGLT inhibitor to the patient separately, sequentially or simultaneously. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt, solvate, mixed solvate, complex or prodrug thereof.

[0101] In some embodiments, an SGLT2 inhibitor for treating HFpEF and CKD in a patient is disclosed, wherein the treatment comprises administering the SGLT2 inhibitor and AZD9977 or a pharmaceutically acceptable salt thereof separately, sequentially or simultaneously. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt, solvate, mixed solvate, complex or prodrug thereof.

[0102] In some embodiments, a method for treating HF and CKD is disclosed, comprising administering an effective amount of AZD9977 or a pharmaceutically acceptable salt thereof to a patient in need thereof with a LVEF of less than 55% and an eGFR of about 30-60 ml / min / 1.73 m2; and an effective amount of an SGLT2 inhibitor. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt, solvate, mixed solvate, complex or prodrug thereof.

[0103] In some embodiments, AZD9977 or a pharmaceutically acceptable salt thereof for treating HF and CKD in patients with LVEF less than 55% and eGFR of about 30-60 ml / min / 1.73 m2 is disclosed, wherein the treatment comprises administering AZD9977 and an SGLT inhibitor to the patient separately, sequentially or simultaneously. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt, solvate, mixed solvate, complex or prodrug thereof.

[0104] In some embodiments, an SGLT2 inhibitor for treating HF and CKD in patients with LVEF less than 55% and eGFR of about 30-60 ml / min / 1.73 m2 is disclosed, wherein the treatment comprises administering the SGLT2 inhibitor and AZD9977 or a pharmaceutically acceptable salt thereof separately, sequentially or simultaneously. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt, solvate, mixed solvate, complex or prodrug thereof.

[0105] In any of the above embodiments, the SGLT2 inhibitor can be, for example, dapagliflozin or a pharmaceutically acceptable salt, solvate, mixed solvate, complex or prodrug thereof. In at least one embodiment, the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt, solvate, mixed solvate, complex or prodrug thereof, 10 mg orally administered once a day. In any of the above embodiments, AZD9977 or a pharmaceutically acceptable salt thereof can be orally administered to a patient once a day in an amount in the range of 15-150 mg, for example, 100 mg-150 mg orally once a day. In any of the above embodiments, AZD9977 or a pharmaceutically acceptable salt thereof can be orally administered to a patient twice a day in an amount in the range of 15-150 mg, for example, 60 mg twice a day. In any of the above embodiments, AZD9977 or a pharmaceutically acceptable salt thereof can be orally administered to a patient once a week in an amount in the range of 15-150 mg.

[0106] In any of the above embodiments, the patient's left ventricular ejection fraction (LVEF) is less than or equal to 40%, such as less than or equal to 35%, 30% or 25%, and in at least one embodiment, at least 20%. In some embodiments, the patient's LVEF is greater than or equal to 40%, such as greater than or equal to 45%, 50% or 55%, and in at least one embodiment, less than 55%. In some embodiments, the patient's eGFR before administration is less than or equal to 60 ml / min / 1.73m2, such as less than or equal to 50 ml / min / 1.73m2, 45 ml / min / 1.73m2, 40 ml / min / 1.73m2, or 35 ml / min / 1.73m2. In some embodiments, the patient's eGFR before administration is greater than or equal to 30 ml / min / 1.73m2, such as greater than or equal to 35 ml / min / 1.73m2, 40 ml / min / 1.73m2, 45 ml / min / 1.73m2, or 50 ml / min / 1.73m2. In some embodiments, the patient has T2D. In some embodiments, the patient does not have T2D. In some embodiments, hyperkalemia is understood to refer to a potassium level greater than 5.5 mmol / L. In some embodiments, hyperkalemia can be mild (serum potassium level greater than 5.5 mmol / L) or moderate / severe (serum potassium level greater than 6.0 mmol / L).

[0107] In some embodiments, the SGLT2 inhibitor is selected from U.S. Pat. No. 6,515,177, WO / 2003 / 099836, U.S. PG Publication No. 2006 / 0194809, U.S. PG Publication No. 2006 / 0063722A1, WO / 2002 / 083066, U.S. PG Publication No. 2003 / 0064935, U.S. Pat. No. 6,774,112, U.S. PG Publication No. 2005 / 0209166, U.S. PG Publication No. 2006 / 0074031, U.S. PG Publication No. 2006 / 0035841, U.S. PG Publication No. 2006 / 0009400, U.S. PG Publication No. 2006 / 0025349, U.S. PG Publication No. 2006 / 0122126, U.S. PG Publication No. 2006 / 0019948, U.S. PG Publication No. 2006 / 0194809, U.S. Patent No. 6,908,905, U.S. Patent No. 6,815,428, U.S. Patent No. 6,555,519, U.S. Patent No. 6,683,056, EP 598359A1, JP 035988, U.S. Patent No. 5,731,292, EP 0850948 A1, U.S. Patent No. 6,048,842, JP 09188625A, JP 09124685 A, JP 09124684, EP 773226A1, U.S. Patent No. 5,767,094, JP 08027006 A, EP 684254A1, JP 10245391 (Dainippon), U.S. PG Publication No. 2005 / 0233982 (Boehringer Ingelheim Group), U.S. PG Publication No. 2005 / 0119192 (Orange Pharmaceuticals), WO / 2006 / 035796 (Orange Pharmaceuticals), JP 2006 / 117651 (Taisho Pharmaceuticals), JP 2004 / 4359630 (Yamanochi Pharmaceutical Co.), WO / 2006 / 080421 (Chugai Pharmaceutical Co.), U.S. PG Publication No. 2005 / 0233988 (Tanabe Seiyaku Co.), WO / 2005 / 012321 (Tanabe Seiyaku Co.), U.S. Pat. No. 7,015,201 (Ajinomoto Co.), WO 2006 / 058597 (Merck Patent GmbH), WO 2006 / 011469 (Chugai Seiyaku Kabushiki Kaisha), U.S. PG Publication No. 2003 / 0195235 (Johnson & Johnson), and WO 2006 / 037537 (Boehringer Ingelheim Group).

[0108] In some embodiments, the SGLT2 inhibitor is selected from those disclosed in Tsujihara, K. et al., Chem. Pharm. Bull., 44: 1174-1180 (1996); Hongu, M. et al., Chem. Pharm. Bull., 46: 22-33 (1998); Hongu, M. et al., Chem. Pharm. Bull., 46: 1545-1555 (1998); and Oku, A. et al., Diabetes, 48: 1794-1800 (1999).

[0109] In some embodiments, the SGLT2 inhibitor can be dapagliflozin ( )、Canagliflozin( ), empagliflozin ( )、Erugliflozin( ), sogliflozin, ipragliflozin, togliflozin or rupagliflozin, or a pharmaceutically acceptable salt, solvate, mixed solvate, complex or prodrug of any of the foregoing.

[0110] In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt, solvate, mixed solvate, complex or prodrug thereof, such as described in US Pat. Nos. 6,414,126 and 6,515,117, which are incorporated by reference in their entireties.

[0111] Dapagliflozin (Forxiga TM / Farxiga TM ) is a highly selective and reversible inhibitor of SGLT2. The mechanism of action of dapagliflozin results in direct and insulin-independent elimination of glucose by the kidneys, resulting in lower blood glucose levels in patients with type 2 diabetes (T2D). In addition, dapagliflozin has a mild diuretic and natriuretic effect. The continued loss of glucose and the associated calories in the urine results in a sustained and maintained reduction in total body weight, primarily as a result of a reduction in fat mass, including visceral and subcutaneous adipose tissue. In addition, dapagliflozin has been shown to reduce BP and albuminuria, two prognostic risk factors for CKD progression.

[0112] The chemical structure of dapagliflozin is:

[0113]

[0114] In some embodiments, dapagliflozin is in the form of a non-crystalline solid. In some embodiments, dapagliflozin is in the form of a crystalline solid. In some embodiments, dapagliflozin is in the form of a (S)-propylene glycol ((S)-PG) solvate having the following structure:

[0115]

[0116] A method for preparing (S)-PG solvate of dapagliflozin (including crystalline S-PG solvate) is provided in US Pat. No. 7,919,598.

[0117] In certain embodiments, SGLT2 inhibitors (e.g., dapagliflozin) are used together with standard care therapy. In certain embodiments, standard care therapy includes the treatment of controlling comorbidities and / or the treatment for reducing CV death and heart failure event complexity. In certain embodiments, standard care therapy includes one or more drugs or drug classes other than SGLT2 inhibitors, which are used to treat CKD.

[0118] Standard CKD care agents as described herein may be used before and / or during administration of an SGLT2 inhibitor, such as dapagliflozin. In some embodiments, standard CKD care agents and SGLT2 inhibitors are administered together at the same or different times.

[0119] Exemplary standard CKD care agents include angiotensin converting enzyme inhibitors (ACE-I or ACE inhibitors) and angiotensin receptor blockers (ARBs). Standard CKD care agents and dosages thereof are well known to medical practitioners who examine and treat CKD patients. Representative examples of ACE inhibitors include captopril, enalapril and lisinopril. Representative examples of ARBs include valsartan, losartan and irbesartan.

[0120] Exemplary "standard HF care agents" include at least one standard HF care agent, for example, at least two or at least three or more drugs or drug classes other than SGLT2 inhibitors, which are used to treat HF, such as HFrEF. Standard HF care agents as described herein may be used before and / or during administration of SGLT2 inhibitors such as dapagliflozin. Standard HF care drugs and their dosages are well known to cardiologists and other medical practitioners who examine and treat HFrEF patients. Exemplary standard HF care agents include: angiotensin converting enzyme (ACE) inhibitors; angiotensin receptor blockers (ARBs); beta blockers; mineralocorticoid receptor agents such as mineralocorticoid receptor antagonists (MRAs), and enkephalinase inhibitors.

[0121] Other agents that may be considered “standard HF care agents” include diuretics and loop diuretics (e.g., furosemide, bumetanide, and torsemide), digoxin, heart pump medications, selective sinus node inhibitors, ivabradine (a sinoatrial (SA) node modulator), aldosterone antagonists, vasodilators, calcium channel blockers (unless the patient has systolic heart failure), hydralazine / isosorbide dinitrate, or other HF medications in the practice guidelines. See Yancy CW et al., “ACC / AHA / HFSA focused update of the 2013 ACCF / AHA guideline for the management of heart failure: A report of the American College of Cardiology / American Heart Association task force on clinical practice guidelines and the Heart Failure Society of America,” J Am Coll Cardiol 70(6):776-803 (2017).

[0122] Further disclosed herein are methods comprising administering an effective amount of an SGLT2 inhibitor to a patient in need thereof, either alone or in combination with at least one other therapeutic agent. In certain embodiments, the other therapeutic agent and the SGLT2 inhibitor are administered in the same or different pharmaceutical compositions and at the same or different times.

[0123] In some embodiments, the other therapeutic agents are antidiabetic agents, antiobesity agents, antihyperlipidemic agents, antiatherosclerotic agents, antihypertensive agents, antiplatelet agents, antithrombotic agents, mineralocorticoid antagonists, diuretics, and / or anticoagulant agents. For example, in at least one embodiment, the other therapeutic agents are antidiabetic agents, such as biguanides and / or DPP4 inhibitors. Exemplary biguanides are metformin or a pharmaceutically acceptable salt thereof. Exemplary DPP4 inhibitors include saxagliptin, linagliptin, sitagliptin and a pharmaceutically acceptable salt thereof.

[0124] In some embodiments, the antidiabetic agent is selected from biguanides.

[0125] The biguanide is metformin or a pharmaceutically acceptable salt thereof. In some embodiments, the biguanide is metformin hydrochloride. In some embodiments, the biguanide is phenformin.

[0126] In some embodiments, the antidiabetic agent is selected from sulfonylurea and pharmaceutically acceptable salts thereof. In some embodiments, the sulfonylurea is selected from glyburide, glimepiride, glipizide, gliclazide and chlorpropamide. In some embodiments, the sulfonylurea is glyburide. In some embodiments, the sulfonylurea is glipizide.

[0127] In some embodiments, the antidiabetic agent is selected from a glucosidase inhibitor and a pharmaceutically acceptable salt thereof. In some embodiments, the glucosidase inhibitor is selected from acarbose and miglitol.

[0128] In some embodiments, the antidiabetic agent is selected from a PPARγ agonist. In some embodiments, the PPARγ agonist is selected from a thiazolidinedione. In some embodiments, the thiazolidinedione is selected from troglitazone (e.g., troglitazone from Warner-Lambert). No. 4,572,912), rosiglitazone (e.g., manufactured by SKB), pioglitazone (e.g., manufactured by Takeda), MCC-555 of Mitsubishi (disclosed in U.S. Pat. No. 5,594,016), GL-262570 of Glaxo-Wellcome, englitazone (e.g., CP-68722, manufactured by Pfizer), izer), darglitazone (e.g., CP-86325, manufactured by Pfizer), isaglitazone (e.g., as manufactured by MIT / J&J), JTT-501 (JPNT / P&U), L-895645 (Merck), R-119702 (Sankyo / WL), N,N-2344 (Dr. Reddy / NN) or YM-440 (Yamanouchi).

[0129] In some embodiments, the thiazolidinedione is selected from pioglitazone and rosiglitazone. In some embodiments, the thiazolidinedione is pioglitazone. In some embodiments, the thiazolidinedione is rosiglitazone.

[0130] In some embodiments, the antidiabetic agent is selected from PPARα / γ dual agonists and pharmaceutically acceptable salts thereof. In some embodiments, the PPARα / γ dual agonist is selected from AR-HO39242 (Astra / Zeneca), GW-409544 (Glaxo-Wellcome), KRP297 (Kyorin Merck), Murakami et al., "A Novel Insulin Sensitizer Acts As a Coligand for Peroxisome Proliferation-Activated Receptor Alpha (PPAR alpha) and PPAR gamma. Effect on PPAR alpha Activation on Abnormal Lipid Metabolism in Liver of Zucker Fatty Rats" [Novel insulin sensitizer acts as a ligand for peroxisome proliferation-activated receptor alpha (PPARα) and PPARγ. Effect of PPARα activation on abnormal lipid metabolism in the liver of Zucker obese rats], Diabetes, 47:1841-1847 (1998) and those disclosed in U.S. Pat. No. 6,414,002.

[0131] In some embodiments, the antidiabetic agent is selected from aP2 inhibitors and pharmaceutically acceptable salts thereof. In some embodiments, the aP2 inhibitor is selected from those disclosed in US Pat. No. 6,548,529.

[0132] In some embodiments, the antidiabetic agent is selected from DPP4 inhibitors and pharmaceutically acceptable salts thereof. In some embodiments, the DPP4 inhibitor is selected from those disclosed in U.S. Pat. No. 6,395,767, WO 99 / 38501, WO 99 / 46272, WO 99 / 67279 (PROBIODRUG), WO 99 / 67278 (PROBIODRUG), WO 99 / 61431 (PROBIODRUG), NVP-DPP728A (1-[[[2-[(5-cyanopyridin-2-yl)amino]ethyl]amino]acetyl]-2-cyano-(S)-pyrrolidine) (Novartis), Hughes et al., Biochemistry, 38(36):11597-11603 (1999), TSL-225 (tryptophanyl-1,2,3,4-tetracycline) disclosed in Hydroisoquinoline-3-carboxylic acid (disclosed by Yamada et al., Bioorg. & Med. Chem. Lett., 8:1537-1540 (1998)), 2-cyanopyrrolidine and 4-cyanopyrrolidine (disclosed by Ashworth et al., Bioorg. & Med. Chem. Lett., 6(22):1163-1166 and 2745-2748 (1996)).

[0133] In some embodiments, the DPP4 inhibitor is selected from saxagliptin, vildagliptin, linagliptin, alogliptin and sitagliptin. In some embodiments, the DPP4 inhibitor is selected from saxagliptin and pharmaceutically acceptable salts thereof. In some embodiments, the DPP4 inhibitor is saxagliptin. In some embodiments, the DPP4 inhibitor is saxagliptin hydrochloride.

[0134] In some embodiments, the antidiabetic agent is selected from meglitinide and pharmaceutically acceptable salts thereof. In some embodiments, the meglitinide is selected from repaglinide, nateglinide (Novartis) and KAD1229 (PF / Orange). In some embodiments, the meglitinide is repaglinide.

[0135] In some embodiments, the antidiabetic agent is selected from glucokinase activators, DGAT-1 inhibitors and pharmaceutically acceptable salts thereof. In some embodiments, the glucokinase activators are selected from those disclosed in WO 2008 / 005964. In some embodiments, the DGAT-1 inhibitors are selected from those disclosed in U.S. PG Publication No. 2008 / 0090876A1.

[0136] In some embodiments, the antidiabetic agent is selected from insulin, a GLP-1 receptor agonist, and pharmaceutically acceptable salts thereof. In some embodiments, the antidiabetic agent is insulin.

[0137] In some embodiments, the at least one other therapeutic agent is selected from anti-obesity agents and pharmaceutically acceptable salts thereof. In some embodiments, the anti-obesity agent is selected from β3 adrenergic agonists, lipase inhibitors, serotonin (and dopamine) reuptake inhibitors, thyroid receptor β modulators, MCH-1 receptor antagonists, 5-HT2c receptor agonists, anorexigenic agents, neuropeptide Y (NPY) antagonists, leptin analogs, MC4 receptor agonists, and cannabinoid receptor antagonists.

[0138] In some embodiments, the β3 adrenergic agonist is selected from AJ9677 (Takeda / Dainippon), SB-418790, L750355 (Merck), CP331648 (Pfizer) and other known β3 agonists as disclosed in U.S. Pat. Nos. 5,541,204, 5,770,615, 5,491,134, 5,776,983 and 5,488,064. In some embodiments, the β3 adrenergic agonist is selected from AJ9677, L750355 and CP331648.

[0139] In some embodiments, the at least one other therapeutic agent is selected from antihyperlipidemic agents and pharmaceutically acceptable salts thereof. In some embodiments, the antihyperlipidemic agent is selected from HMG CoA reductase inhibitors. In some embodiments, HMG-CoA reductase inhibitors are selected from mevastatin and related compounds disclosed in U.S. Patent No. 3,983,140, ​​lovastatin (lovastatin) (mevinolin) and related compounds disclosed in U.S. Patent No. 4,231,938, pravastatin and related compounds disclosed in U.S. Patent No. 4,346,227, simvastatin and related compounds disclosed in U.S. Patent Nos. 4,448,784 and 4,450,171, and rosuvastatin and related inhibitor compounds disclosed in U.S. Patent No. 5,753,675.

[0140] In some embodiments, the at least one other therapeutic agent is selected from antihypertensive agents and pharmaceutically acceptable salts thereof. In some embodiments, the antihypertensive agent is selected from beta adrenergic blockers, calcium channel blockers (L-type and / or T-type), diuretics, renin inhibitors, ACE inhibitors, AT-1 receptor antagonists, ET receptor antagonists (such as those disclosed in U.S. Pat. Nos. 5,612,359 and 6,043,265), dual ET / AII antagonists (such as those disclosed in WO 00 / 01389), neutral endopeptidase (NEP) inhibitors, vasopeptidase inhibitors, and nitrates.

[0141] In some embodiments, the antihypertensive agent is selected from bisoprolol, carvedilol, metaprolol succinate, diltiazem, verapamil, nifedipine, amlodipine, mibefradil, chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid,tricrynafen, chlorthalidone, furosemide, musolimine, bumetanide, triamtrenene, amiloride, spironolactone, torsemide, indapamide, metolazone, triamterene, eplerenone, captopril, zofenopril, fosinopril, enalapril, ceranopril , cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril, perindopril, trandolapril, losartan, irbesartan, valsartan, candesartan, sitaxsentan, atrsentan, omapatrilat, gemopatrilat, hydralazine, isosorbide dinitrate, nitroglycerin, and nitroprusside.

[0142] In some embodiments, the at least one other therapeutic agent is selected from antiplatelet agents and pharmaceutically acceptable salts thereof. In some embodiments, the antiplatelet agent is selected from clopidogrel, ticlopidine, prasugrel and aspirin.

[0143] In some embodiments, the at least one other therapeutic agent is selected from antithrombotic agents, anticoagulant agents and pharmaceutically acceptable salts thereof. In some embodiments, the antithrombotic agents and / or anticoagulant agents are selected from thrombin inhibitors, platelet aggregation inhibitors, PAI-1 inhibitors, alpha-2-antiplasmin inhibitors, thromboxane receptor antagonists, prostacyclin mimetics and phosphodiesterase (PDE) inhibitors.

[0144] In some embodiments, the antithrombotic and / or anticoagulant agent is selected from clopidogrel, ticlopidine, prasugrel (Eli Lilly), XR-330, T-686, anti-alpha-2-antiplasmin antibody, ifetroban, dipyridamole, cilostazol, aspirin, ifetroban, picotamide, and ketanserin.

[0145] In certain embodiments, SGLT2 inhibitor (e.g., dapagliflozin) is administered together with at least one other therapeutic agent in the same or different compositions at the same or different times. In certain embodiments, the at least one other therapeutic agent is administered before or after the SGLT2 inhibitor (e.g., dapagliflozin) or simultaneously with the SGLT2 inhibitor (e.g., dapagliflozin).

[0146] In some embodiments, dapagliflozin is formulated with another therapeutic agent, such as another antidiabetic agent, as a fixed-dose combination pharmaceutical composition. ) and dapagliflozin / saxagliptin ( ) and dapagliflozin / saxagliptin / metformin ( ) is an example of a combination pharmaceutical composition comprising dapagliflozin.

[0147] In some embodiments, the weight ratio of the combination of the at least one compound selected from SGLT2 inhibitors (e.g., dapagliflozin) and prodrugs thereof to the at least one other therapeutic agent is in the range of about 0.01:1 to about 300:1. In some embodiments, the weight ratio of the combination of the at least one compound selected from SGLT2 inhibitors (e.g., dapagliflozin) and prodrugs thereof to the at least one other therapeutic agent is in the range of about 0.1:1 to about 200:1. In some embodiments, the weight ratio of the combination of the at least one compound selected from SGLT2 inhibitors (e.g., dapagliflozin) and prodrugs thereof to the at least one other therapeutic agent is in the range of about 0.2:1 to about 100:1.

[0148] In some embodiments, the patient being treated meets at least one of the following conditions:

[0149] (a) the patient does not suffer from autosomal dominant or autosomal recessive polycystic kidney disease, lupus nephritis or ANCA-associated vasculitis;

[0150] (b) the patient had not received cytotoxic therapy, immunosuppressive therapy or other immunotherapy for primary or secondary renal disease within 6 months prior to treatment with SGLT2 inhibitors;

[0151] (c) the patient has no history of organ transplantation;

[0152] (d) the patient has no intolerance to SGLT2 inhibitors;

[0153] (e) the patient does not suffer from type 1 diabetes (T1D);

[0154] (f) the patient does not suffer from New York Heart Association (NYHA) Class IV congestive heart failure at the time of treatment;

[0155] (g) the patient has not had myocardial infarction (MI), unstable angina, stroke or transient ischemic attack (TIA) within 12 weeks prior to treatment with SGLT2 inhibitor;

[0156] (h) The patient has not undergone coronary revascularization (percutaneous coronary intervention [PCI] or coronary artery bypass grafting [CABG]) or valve repair / replacement within 12 weeks prior to treatment and is not planning to undergo any such surgery;

[0157] (i) The patient has no medical conditions outside the area of ​​renal and CV disease and has a limited life expectancy of less than 2 years;

[0158] (j) the patient does not have an active malignancy requiring treatment at the time of treatment;

[0159] (k) the patient has no liver damage (aspartate aminotransferase [AST]>3 times the upper limit of normal [ULN], alanine aminotransferase [ALT]>3 times the upper limit of normal [ULN], or total bilirubin>2 times ULN) during treatment;

[0160] (l) the patient does not have a known blood-borne disease selected from Ebola virus, Lassa fever virus, hepatitis A, B, C, D or E virus, and HIV type 1 or 2; and / or

[0161] (m) The patient is not (1) a woman of childbearing potential who has not undergone chemical or surgical sterilization or is unwilling to use a medically accepted method of contraception, (2) has a positive pregnancy test, or (3) is breastfeeding.

[0162] In some embodiments, the patient is selected when the patient satisfies one or more of the conditions (a) to (m) listed above. In some embodiments, the patient is selected when the patient satisfies each of the conditions (a) to (m) listed above.

[0163] In some embodiments, the patient's HbA1c is in the range of about 6.0% to about 6.9%. In some embodiments, the patient's HbA1c is in the range of about 5.7% to about 6.5%.

[0164] A person of ordinary skill in the relevant field can easily determine the effectiveness of the compounds of the present disclosure in treating and / or preventing CKD and / or diseases, disorders and / or conditions associated therewith. A person of ordinary skill in the relevant field can also easily determine and adjust an appropriate dosing regimen (e.g., adjusting the amount of the compound per dose and / or the number and frequency of dose of the dose). One or any combination of diagnostic methods, including physical examination, evaluation and monitoring of clinical symptoms, and the execution of analytical tests and methods described herein, can be used to monitor the health status of patients.

[0165] An effective amount or therapeutically effective amount refers to at least one compound of the disclosure or a pharmaceutical composition comprising at least one such compound of the disclosure, when administered to a patient as a single dose or as part of a series of doses, effectively producing at least one amount of therapeutic effect. The dosage may depend on the patient's body mass, body weight and / or blood volume. Usually, an assay suitable for the disease, disorder and / or condition to be treated or prevented can be used to monitor the therapeutic effectiveness of the patient. The level of the compound administered to the patient can be monitored by measuring the level of the compound (or metabolite of the compound) in biological fluids such as blood, blood fractions (e.g., serum) and / or urine and / or other biological samples from the patient. In the course of the treatment regimen, the level of the compound can be measured using any method practiced in the art for detecting a compound or its metabolite.

[0166] The dosage of the compounds described herein may depend on the patient's condition, i.e., the stage of the disease, the severity of symptoms caused by the disease, the general health, as well as the age, sex, and weight, and other factors apparent to one of ordinary skill in the medical arts.

[0167] In some embodiments, the at least one compound selected from SGLT2 inhibitors (e.g., dapagliflozin) and prodrugs thereof is administered at a dapagliflozin dose equivalent of about 1 to about 500 mg / day. In some embodiments, the at least one compound selected from SGLT2 inhibitors (e.g., dapagliflozin) and prodrugs thereof is administered at a dapagliflozin dose equivalent of about 2 to about 400 mg / day. In some embodiments, the at least one compound selected from SGLT2 inhibitors (e.g., dapagliflozin) and prodrugs thereof is administered at a dapagliflozin dose equivalent of about 0.5 to about 200 mg / day. In some embodiments, the at least one compound selected from SGLT2 inhibitors (e.g., dapagliflozin) and prodrugs thereof is administered at a dapagliflozin dose equivalent of about 1 to about 100 mg / day. In some embodiments, the at least one compound selected from SGLT2 inhibitors (e.g., dapagliflozin) and prodrugs thereof is administered at a dapagliflozin dose equivalent of about 1 to about 50 mg / day. In some embodiments, the at least one compound selected from SGLT2 inhibitors (e.g., dapagliflozin) and prodrugs thereof is administered at a dapagliflozin dose equivalent of about 1 to about 20 mg / day. In some embodiments, the at least one compound selected from SGLT2 inhibitors (e.g., dapagliflozin) and prodrugs thereof is administered at a dapagliflozin dose equivalent of about 2.5 to about 20 mg / day. In some embodiments, the at least one compound selected from SGLT2 inhibitors (e.g., dapagliflozin) and prodrugs thereof is administered at a dapagliflozin dose equivalent of about 2.5 to about 10 mg / day. In some embodiments, the at least one compound selected from SGLT2 inhibitors (e.g., dapagliflozin) and prodrugs thereof is administered at a dapagliflozin dose equivalent of about 10 mg / day. In some embodiments, the at least one compound selected from SGLT2 inhibitors (e.g., dapagliflozin) and prodrugs thereof is administered at a dapagliflozin dose equivalent of about 5 mg / day. In some embodiments, the at least one compound selected from SGLT2 inhibitors (e.g., dapagliflozin) and prodrugs thereof is administered at a dapagliflozin dose equivalent of about 2.5 mg / day.

[0168] In some embodiments, the methods disclosed herein include orally administering to a patient an SGLT2 inhibitor, such as dapagliflozin or a pharmaceutically acceptable salt, solvate, mixed solvate, complex or prodrug thereof, at a dose of 2.5 mg / day, 5.0 mg / day, or 10 mg / day. In at least one embodiment, the dose of dapagliflozin is 10 mg.

[0169] The term "treating" or "treatment" or "to treat" refers to therapeutic measures to cure, slow down, alleviate the symptoms of, and / or halt the progression of a diagnosed pathological disease, disorder, or condition. Treatment need not result in a complete cure of the condition; the term encompasses partial inhibition or alleviation of the condition being treated.

[0170] As used herein, the term "about" means within 20%, such as within 10%, and further such as within 5%, of a given value or a given range.

[0171] The term "or" is used herein to mean, and is used interchangeably with, the term "and / or," unless the context clearly indicates otherwise.

[0172] As used herein, the term "other therapeutic agent" refers to a therapeutic agent other than the SLGT2 inhibitor of the present disclosure or a prodrug thereof.

[0173] As used herein, the term "prodrug" includes esters and carbonates that can be converted to dapagliflozin, for example, under physiological conditions or by solvolysis. Therefore, the term prodrug includes a metabolic precursor of pharmaceutically acceptable dapagliflozin. The term prodrug also includes a covalently bound carrier that releases dapagliflozin in vivo when such a prodrug is administered to a patient. Non-limiting examples of prodrugs include esters and carbonates formed by reacting one or more hydroxyl groups of dapagliflozin with an acylating agent substituted with an alkyl, alkoxy or aryl group using methods known to those skilled in the art to produce acetates, pivalates, methyl carbonates, benzoates and the like. Various forms of prodrugs are known in the art. For examples of such prodrug derivatives, see: (1) Design of Prodrugs, H. Bundgaard, ed., (Elsevier, 1985) and Methods in Enzymology, Vol. 42, pp. 309-396, K. Widder et al., eds. (Academic Press, 1985); (2) A Textbook of Drug Design and Development, Krogsgaard-Larsen and H. Bundgaard, eds., Chapter 5, "Design and Application of Prodrugs," H. Bundgaard, pp. 113-191 (1991); (3) H. Bundgaard, Advanced Drug Delivery Reviews 8: 1-38 (1992); (4) H. Bundgaard et al., Journal of Pharmaceutical Design and Development, vol. 42, pp. 309-396. Sciences [Journal of Pharmaceutical Sciences] 77: 285 (1988); and (5) N. Kakeya et al., Chem Pharm Bull [Chemistry and Pharmaceutical Bulletin], 32, 692 (1984).

[0174] As used herein, the term "reaching end-stage renal disease (ESRD)" refers to (i) having an eGFR persistently <15 mL / min / 1.73 m 2 , (ii) receiving chronic dialysis treatment, or (iii) receiving a kidney transplant. ESRD may also be referred to as "end-stage renal disease" (ESKD) and are used interchangeably herein.

[0175] The following examples provide illustrative embodiments of the present disclosure. One of ordinary skill in the art will recognize that various modifications and variations can be made without changing the spirit or scope of the present disclosure. Such modifications and variations are within the scope of the present disclosure. The examples provided are in no way limiting of the present disclosure.

[0176] Examples

[0177] Example 1: Study to Evaluate the Effect of Dapagliflozin on Renal Outcomes and Cardiovascular Mortality in Patients with Chronic Kidney Disease (DAPA CKD)

[0178] Study Design

[0179] This was an international, multicenter, event-driven, randomized, double-blind, parallel-group, placebo-controlled study evaluating the effect of dapagliflozin 10 mg versus placebo, given once daily in addition to standard of care, for the prevention of progression of chronic kidney disease (CKD) or cardiovascular (CV) death / renal death. Figure 1 Design shown.

[0180] Table 1 below shows the schedule of study visits and assessments.

[0181]

[0182] a Optional local laboratory evaluation to assess eGFR and / or albuminuria may be performed to assess eligibility (according to local practice).

[0183] b Central laboratory evaluations included alkaline phosphatase (ALP), ALT, AST, bilirubin, blood urea nitrogen (BUN), creatinine (including eGFR assessment), hematocrit, hemoglobin (Hb), HbA1c, phosphate, potassium, and sodium.

[0184] c Blood and urine samples for future biomarker and / or genetic studies are optional. Biomarker samples were collected at Visits 2 and 7, and genetic samples were collected at Visit 2. PK samples were collected at Visit 7.

[0185] d SAEs were collected throughout the study from the time of informed consent up to and including the patient's last visit. Study endpoints, DAEs, AEs leading to dose reductions and temporary interruptions, and other AEs of interest were collected throughout the study from randomization up to and including the patient's last visit.

[0186] ePRO questionnaires were completed as specified until Visit 7, and every 12 months thereafter, and at the PTDV and Study End Visit (SCV).

[0187] Patient-reported outcomes (PRO): PRO is an umbrella term for all outcomes and symptoms directly reported by patients. The following PROs were used in the study: KDQOL TM -36 and EQ-5D-5L (see Appendix B and Appendix C). Patients were asked to complete the EQ-5D-5L and KDQOL as shown in Table 1 during the visit. TM -36.

[0188] Kidney Disease Quality of Life-36 (KDQOL TM -36): KDQOL TM The -36 is the abbreviated form of KDQOL, which is a self-report questionnaire combining generic and disease-specific components to assess the health-related quality of life in patients with CKD (see Appendix B).

[0189] EuroQol Five Dimensions Five Levels (EQ-5D-5L): The EQ-5D-5L is a self-report questionnaire that derives a standardized measure of health status, also known as a utility score. The EQ-5D-5L utility score is widely accepted by reimbursement authorities and will be used to support health economic evaluations (see Appendix C).

[0190] Patient population:

[0191] The study population selected for this study includes a broad population of patients with impaired renal function. The target population has CKD (defined as eGFR ≥ 25 and ≤ 75 mL / min / 1.73 m 2 ) with albuminuria (defined as urine albumin-to-creatinine ratio [UACR] ≥200 and ≤5000 mg / g), with or without type 2 diabetes (T2D). However, patients with known polycystic kidney disease, with onset glomerulonephritis (lupus or antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis), or ongoing active renal inflammation were excluded.

[0192] Patients with T2D who were randomized in this study continued their T2D treatment. Patients were eligible for adjustment of their antidiabetic therapy at the discretion of their diabetes healthcare provider.

[0193] Combination therapy with open-label SGLT2 inhibitors (e.g., dapagliflozin, empagliflozin, canagliflozin, erpagliflozin, tolagliflozin, and rupagliflozin), as well as fixed-dose combinations containing these drugs (i.e., combination therapy with an investigational product (“IP”)) is prohibited.

[0194] The final patient enrollment date for the Phase 3 clinical trial of dapagliflozin for CKD was Figure 2-5 Described in .

[0195] Patients included in the study met the following criteria:

[0196] ●Females or males aged ≥18 years at the time of consent.

[0197] eGFR ≥25 and ≤75 mL / min / 1.73 m at first visit 2 (CKD-EPI formula).

[0198] ●Increased albuminuria three months or more before the first visit and UACR ≥200 and ≤5000 mg / g at the first visit.

[0199] ●If there are no medical contraindications, stable treatment with an ACE-I or ARB at the patient's maximally tolerated labeled daily dose for at least 4 weeks prior to visit 1.

[0200] Patients were excluded from the study if any of the following exclusion criteria were met:

[0201] ●Autosomal dominant or autosomal recessive polycystic kidney disease, lupus nephritis, or ANCA-associated vasculitis.

[0202] ●Receipt of cytotoxic therapy, immunosuppressive therapy, or other immunotherapy for primary or secondary renal disease within 6 months prior to enrollment.

[0203] ●History of organ transplantation.

[0204] ●Received SGLT2 inhibitor treatment within 8 weeks prior to enrollment or was previously intolerant to SGLT2 inhibitors.

[0205] Type 1 diabetes (T1D).

[0206] ● Had New York Heart Association (NYHA) class IV congestive heart failure at the time of enrollment (see Appendix A).

[0207] ●MI, unstable angina, or transient ischemic attack (TIA) within 12 weeks prior to enrollment.

[0208] ●Coronary revascularization (percutaneous coronary intervention [PCI] or coronary artery bypass graft [CABG]) or valve repair / replacement within 12 weeks before enrollment, or any such procedure planned after randomization.

[0209] Any disease outside the area of ​​renal and CV disease, such as but not limited to malignancy, and with limited life expectancy of less than 2 years.

[0210] ●Active malignancy requiring treatment at visit 1 (except successfully treated basal cell carcinoma or treated squamous cell carcinoma).

[0211] ●Hepatic impairment (aspartate aminotransferase [AST] > 3 times the upper limit of normal [ULN], alanine aminotransferase [ALT] > 3 times the upper limit of normal [ULN], or total bilirubin > 2 times the ULN at enrollment). An isolated increase in bilirubin in a patient with known Gilbert's syndrome is not a reason to exclude.

[0212] ● Known blood-borne diseases such as Ebola virus, Lassa fever virus, hepatitis A, B, C, D or E virus, and / or type 1 or 2 / HIV.

[0213] ●Women of childbearing potential (i.e., women who have not undergone chemical or surgical sterilization or are not postmenopausal) who are unwilling to use a medically accepted method of contraception throughout the study period from the time of informed consent and for 4 weeks thereafter or who have a positive pregnancy test at enrollment or randomization or who are breastfeeding.

[0214] ●Participated in the planning and / or implementation of the research.

[0215] ●Previously randomized in this study.

[0216] ● Participated in another clinical study of an investigational product within the last month prior to enrollment.

[0217] ● In the opinion of the investigator, the patient is unable to understand and / or comply with the study product, procedure, and / or follow-up, or any condition that in the opinion of the investigator may prevent the patient from completing the study. Patients who are unable to complete the patient-reported outcome (PRO) assessments may still participate in the study.

[0218] Main outcome measures and rationale:

[0219] The primary outcome measure of the study was to determine the efficacy of adding dapagliflozin to patients with an eGFR ≥ 25 and ≤ 75 mL / min / 1.73 m 2 Whether dapagliflozin is superior to placebo in reducing the incidence of a sustained decline in eGFR ≥50%, reaching the primary composite endpoint of ESRD, CV death, or renal death, when used in combination with current background therapy in patients with idiopathic leukoencephalitis and albuminuria (UACR ≥200 and ≤5000 mg / g).

[0220] Endpoints related to eGFR decline: Baseline eGFR was defined as the mean central laboratory value at visit 1 and visit 2.

[0221] The primary outcome measure was based on the requirements outlined in the European Medicines Agency (EMA) draft guidance, which states that a composite endpoint of sustained decline in eGFR ≥50%, end-stage renal disease (ESRD), and renal death (death due to ESRD without dialysis) is an acceptable outcome measure (EMA 2016). This endpoint has also been used in multiple prior outcome studies.

[0222] Because CV mortality was high in the study population and the risk of CV death was associated with the risk of developing ESRD, CV mortality was added as a component of the composite end point.

[0223] For the purpose of efficacy analysis, death was subdivided into CV-primary and non-CV-primary causes and renal-primary causes (death due to ESRD when dialysis was not given).

[0224] Secondary outcome measures and rationale:

[0225] Secondary outcome measures included (1) determining whether dapagliflozin (compared with placebo) resulted in a reduction in the incidence of the composite endpoint of worsening renal function; (2) determining whether dapagliflozin (compared with placebo) resulted in a reduction in the incidence of the composite endpoint of CV death or hospitalization for heart failure; and (3) determining whether dapagliflozin (compared with placebo) resulted in a reduction in the incidence of all-cause mortality (i.e., death due to any / all causes).

[0226] Heart failure was assessed as a secondary endpoint because it is particularly common in patients with CKD. All-cause mortality was assessed as a secondary endpoint to evaluate the effect of dapagliflozin on non-CV (including infection (e.g., sepsis) and malignancy), as well as CV, mortality, and total mortality.

[0227] Further outcomes include determining whether dapagliflozin (compared with placebo) leads to a reduction in the incidence of the composite endpoint of chronic dialysis, kidney transplantation, or renal death.

[0228] Duration of treatment:

[0229] The study was event driven and lasted for 40 months. The study was terminated early due to overwhelming efficacy (60% of planned events).

[0230] Investigational Product (IP), Dosage and Mode of Administration:

[0231] Patients were randomized 1:1 to receive either dapagliflozin 10 mg or placebo. If clinically indicated, the dapagliflozin 5 mg dose was also used in the study in addition to the 10 mg dose. However, if the investigator determined that the patient's condition was stable, the dose should be increased back to dapagliflozin 10 mg or matching placebo as soon as possible if the dose had been reduced to 5 mg.

[0232] Statistical methods:

[0233] The primary objective of the study was to determine the superiority of dapagliflozin versus placebo in reducing the incidence of the primary composite endpoint (i.e., compared with patients receiving at least one standard CKD care agent alone).

[0234] All patients randomized to study treatment were included in the full analysis set (FAS), regardless of protocol adherence and continued participation in the study. The primary variable was the time to the first event included in the primary composite endpoint. The primary analysis was based on the intention-to-treat (ITT) principle using the FAS. In the analysis of the primary composite endpoint, dapagliflozin will be compared with placebo using a Cox proportional hazards model stratified by randomization stratification factors (T2D, UACR) and with treatment groups adjusted for eGFR.

[0235] An interim analysis was performed when 75% of the prespecified number of responses to the primary endpoint were confirmed using the Haybittle-Peto rule. The interim analysis assessed the superiority of dapagliflozin compared with placebo.

[0236] A closed-label testing procedure was used that included a prespecified stratified order for the primary and secondary end points. No multiple controls were set for exploratory end points.

[0237] Safety Assessment

[0238] Definition of Serious Adverse Event (SAE): A SAE was defined as an AE occurring during any phase of the study (i.e., run-in, treatment, screening, and follow-up) that met one or more of the following criteria:

[0239] ● Lead to death

[0240] ●Immediately life-threatening

[0241] ● Requirement of hospitalization or prolonged hospitalization

[0242] ● Resulting in persistent or significant disability / incapacity or a serious disruption of the ability to carry out normal life functions

[0243] ●Congenital malformation or birth defect

[0244] ●A significant medical event that could endanger the patient or might require medical intervention to prevent one of the above outcomes

[0245] Study Results

[0246] The final results of the primary endpoint measure are shown in Figure 6-10 and Fig.13The primary objective was achieved, with treatment with dapagliflozin resulting in a clinically meaningful and statistically significant reduction in the composite of sustained eGFR decline ≥50%, ESRD, and renal or CV death. All components contributed to the observed treatment effect. The treatment benefit was consistent across all patient subgroups, including: diabetes status, UACR, and eGFR( Figure 8 The treatment benefit was consistent across all patient subgroups, including age, sex, race, and geographic region ( Fig. 9 ).

[0247] The final results of the secondary endpoints were shown in Figure 10-13 Significant treatment effects on renal-only secondary endpoints (composite of sustained decline in eGFR ≥50%, ESRD, and renal death) confirmed the positive renal treatment effect ( Fig.10 ). The secondary endpoint of the composite of CV death and hospitalization for HF was statistically significantly reduced, as Figure 11-12 Both components contribute to the therapeutic effect. Dapagliflozin is superior to placebo in reducing all-cause mortality ( Figure 13-14 ).

[0248] A sustained decline in eGFR of ≥50%, ESRD, CV disease, or renal death (the primary end point) occurred in 197 patients (9.2%) in the dapagliflozin group and in 312 (14.5%) in the placebo group (hazard ratio, 0.61; 95% confidence interval [CI], 0.51 to 0.72; P < 0.0001 ( Figure 6 ). Additional specific data points for each of the primary and secondary endpoints are provided in Figure 6-13 In the description.

[0249] The composite endpoint of chronic dialysis, kidney transplantation, or renal death was statistically significantly reduced. Fig.15 shown.

[0250] The primary and secondary endpoints were also stratified by underlying cause of renal disease (diabetic nephropathy, ischemic / hypertensive nephropathy, glomerulonephritis, and unknown etiology) ( Figure 17-20 ) or stratified by patients with underlying cardiovascular disease ( Fig. 22 ). Further prespecified and post hoc exploratory results were stratified by patients with underlying cardiovascular disease ( Fig.23 The primary endpoint was also assessed in patients with underlying IgA nephropathy ( Fig.21 ) and secondary endpoints ( Fig.24 ).

[0251] Safety results are illustrated in Table 2 below (AE = adverse event). There were fewer deaths, SAEs (serious adverse events), and DAEs (discontinuations due to adverse events) in the dapagliflozin group. Adverse events leading to dose interruptions were balanced between treatment groups. AEs leading to dose reductions were rare but more common in the dapagliflozin group. Overall, fewer patients reported SAEs in the dapagliflozin group. The number of patients experiencing SAEs was generally balanced between treatment groups across SOCs.

[0252] Table 2 Safety results

[0253]

[0254]

[0255] *AEs of fracture and amputation are listed for patients during treatment and while off treatment. All other safety variables during treatment are listed

[0256] The overall safety profile of patients with T2DM and those without diabetes was generally consistent (Table 3 below). Patients without diabetes did not report diabetic ketoacidosis or severe hypoglycemia. Overall, regardless of treatment, patients with T2DM reported more AEs in all categories than patients without diabetes.

[0257] Table 3 Safety results in patients with and without T2DM

[0258]

[0259] *AEs or SAEs with outcomes of death, fracture, and amputation are listed for patients during treatment and while off treatment. All other safety variables during treatment are listed

[0260] Prevalence of T2D in patients with prediabetes

[0261] A subgroup of 1,398 patients enrolled in the DAPA-CKD trial with CKD and prediabetes (HbA1c ≥5.7% and <6.5% at baseline) and no prior history of diabetes were randomized to dapagliflozin 10 mg once daily or placebo. The onset of newly diagnosed T2D (confirmed HbA1c ≥6.5%) was determined by regular HbA1c testing and comparisons between treatment groups were assessed by Cox proportional hazards models.

[0262] After a median follow-up of 2.4 years, T2D occurred in 33 / 701 patients (4.7%) in the placebo group and 21 / 697 patients (3.0%) in the dapagliflozin group, corresponding to event rates of 2.4 and 1.5 per 100 patient-years, respectively. Dapagliflozin resulted in a 38% reduction in T2D incidence (hazard ratio [HR] [95% CI] 0.62 [0.36, 1.08]). The effect of dapagliflozin on T2D prevention was not heterogeneous according to most key prespecified subgroups, including age, glycemic status, blood pressure, estimated glomerular filtration rate, albuminuria, race, and region, but the effect was more pronounced in women (p interaction 0.03). More than 90% of participants who developed T2D had prediabetes at baseline (HbA1c ≥ 5.7%-6.4%).

[0263] In the DAPA-HF trial (heart failure with reduced ejection fraction), of the 2605 patients enrolled at baseline without T2D (approximately 55% of the total patients), 157 developed T2D during the trial, of whom 150 (95.5%) had prediabetes (HbA1c ≥ 5.7%-6.4%) (compared with 136 [86.6%] using the more restrictive 6.0%-6.4% criteria). Patients who developed T2D had higher mean baseline A1c (6.2±0.3 vs. 5.7±0.4%; p<0.001), greater BMI (28.5±5.9 vs. 27.1±5.7 kg / m2) and a higher BMI (28.5±5.9 vs. 27.1±5.7 kg / m2) compared with those who remained free of diabetes. 2 ; p = 0.003), and lower eGFR (61.5 ± 17.4 vs. 68.2 ± 19.3 ml / min / 1.73 m 2 ; p<0.001). Dapa reduced new-onset diabetes by 32%: placebo 93 / 1307 (7.1%) vs. dapa 64 / 1298 (4.9%); HR 0.68 (95% CI, 0.50-0.94; p=0.019) (Cox.)( Fig.25 )

[0264] Meta-analysis of DAPA-CKD and DAPA-HF showed that dapagliflozin could reduce new-onset diabetes (HR 0.67 [0.51-0.87]; p = 0.003), with no heterogeneity among studies (p interaction 0.78).

[0265] Appendix A

[0266] New York Heart Association (NYHA) functional classification

[0267] NYHA functional class

[0268]

[0269] Appendix B

[0270] Patient-reported outcome (PRO) questionnaire: Kidney Disease Quality of Life-36 (KDQOL TM -36)

[0271]

[0272]

[0273]

[0274]

[0275] Appendix C

[0276] Patient-reported outcome (PRO) questionnaire: Euroqol five-dimensional five-level questionnaire (Eq-5d-5l

[0277]

[0278]

[0279] Embodiments of the present invention include the following.

[0280] 1. A method for treating chronic kidney disease (CKD) and / or at least one disease, disorder or condition associated therewith in a patient, the method comprising administering to a patient in need thereof an effective amount of a sodium-glucose co-transporter 2 (SGLT2) inhibitor.

[0281] 2. The method according to technical solution 1, wherein the patient has an eGFR ≥ 25 and ≤ 75 mL / min / 1.73 m 2 .

[0282] 3. A method according to technical solution 1 or 2, wherein the patient suffers from type 2 diabetes.

[0283] 4. The method according to technical solution 1 or 2, wherein the patient does not suffer from type 2 diabetes.

[0284] 5. A method according to any one of technical solutions 1 to 4, wherein the method treats CKD.

[0285] 6. A method according to any one of technical solutions 1 to 5, wherein the SGLT2 inhibitor is selected from dapagliflozin, canagliflozin, empagliflozin, sogliaflozin, ipagliaflozin, erpagliflozin, togliflozin, and rupagliflozin, or a pharmaceutically acceptable salt, solvate, mixed solvate, complex or prodrug of any of the foregoing.

[0286] 7. The method according to any one of technical solutions 1 to 6, wherein the SGLT2 inhibitor is dapagliflozin, which has the following structure

[0287]

[0288] 8. The method according to technical solution 7, wherein the dapagliflozin is in the form of a pharmaceutically acceptable solvate, mixed solvate or complex.

[0289] 9. The method according to technical solution 7 or 8, wherein the dapagliflozin is in the form of a non-crystalline solid.

[0290] 10. The method according to technical solution 7 or 8, wherein the dapagliflozin is in the form of a crystalline solid.

[0291] 11. A method according to any one of technical solutions 7 to 10, wherein the dapagliflozin is in the form of a (S)-propylene glycol ((S)-PG) solvate having the following structure

[0292]

[0293] 12. The method according to any one of technical solutions 7 to 11, wherein the dapagliflozin is in a form suitable for oral administration.

[0294] 13. The method according to technical solution 12, wherein the dapagliflozin is in the form of a tablet.

[0295] 14. The method according to any one of technical solutions 7 to 13, wherein the dapagliflozin is administered at a dose of about 2.5 mg / day, 5 mg / day or 10 mg / day.

[0296] 15. The method according to any one of technical solutions 7 to 14, wherein the dapagliflozin is administered at a dose of about 10 mg / day.

[0297] 16. The method according to any one of technical solutions 7 to 15, wherein the dapagliflozin is administered once a day.

[0298] 17. The method according to any one of technical solutions 7 to 16, wherein the dapagliflozin is administered in combination with at least one other therapeutic agent.

[0299] 18. A method according to technical solution 17, wherein the at least one other therapeutic agent is selected from anti-diabetic agents, anti-obesity agents, anti-hyperlipidemic agents, anti-atherosclerotic agents, anti-hypertensive agents, anti-platelet agents, anti-thrombotic agents, mineralocorticoid antagonists, diuretics, and anticoagulant agents.

[0300] 19. A method according to technical solution 17, wherein the at least one other therapeutic agent is an angiotensin-converting enzyme inhibitor (ACE inhibitor).

[0301] 20. The method according to technical solution 19, wherein the ACE inhibitor is selected from captopril, enalapril and lisinopril.

[0302] 21. A method according to technical solution 17, wherein at least one other therapeutic agent is an angiotensin receptor blocker (ARB).

[0303] 22. The method according to technical solution 21, wherein the ARB is selected from valsartan, losartan and irbesartan.

[0304] 23. A method according to any one of technical solutions 17 to 22, wherein the at least one other therapeutic agent is administered before, after, or simultaneously with dapagliflozin.

[0305] 24. The method according to any one of technical solutions 1 to 23, wherein the patient satisfies at least one of the following conditions:

[0306] (a) the patient does not suffer from autosomal dominant or autosomal recessive polycystic kidney disease, lupus nephritis or ANCA-associated vasculitis;

[0307] (b) the patient has not received cytotoxic therapy, immunosuppressive therapy or other immunotherapy for primary or secondary renal disease within 6 months prior to treatment;

[0308] (c) the patient has no history of organ transplantation;

[0309] (d) the patient has no intolerance to SGLT2 inhibitors;

[0310] (e) the patient does not suffer from type 1 diabetes (T1D);

[0311] (f) the patient does not suffer from New York Heart Association (NYHA) Class IV congestive heart failure at the time of treatment;

[0312] (g) the patient has not had myocardial infarction (MI), unstable angina, stroke or transient ischemic attack (TIA) within 12 weeks prior to treatment;

[0313] (h) The patient has not undergone coronary revascularization (percutaneous coronary intervention [PCI] or coronary artery bypass grafting [CABG]) or valve repair / replacement within 12 weeks prior to treatment and is not planning to undergo any such surgery;

[0314] (i) the patient has no medical conditions outside the areas of renal and cardiovascular (CV) disease and has a limited life expectancy of less than 2 years;

[0315] (j) the patient does not have an active malignancy requiring treatment at the time of treatment;

[0316] (k) the patient has no liver damage (aspartate aminotransferase [AST]>3 times the upper limit of normal [ULN], alanine aminotransferase [ALT]>3 times the upper limit of normal [ULN], or total bilirubin>2 times ULN) during treatment;

[0317] (l) the patient does not have a blood-borne disease selected from Ebola virus, Lassa fever virus, hepatitis A, B, C, D or E virus, and HIV type 1 or 2; and / or

[0318] (m) The patient is not (1) a woman of childbearing potential who has not undergone chemical or surgical sterilization or is unwilling to use a medically accepted method of contraception, (2) has a positive pregnancy test, or (3) is breastfeeding.

[0319] 25. A method according to technical solution 24, wherein the patient satisfies each of conditions (a) to (o) according to technical solution 23.

[0320] 26. A method according to any one of technical solutions 1 to 25, wherein the patient suffers from CKD with albuminuria.

[0321] 27. A method according to technical solution 26, wherein the patient has a urine albumin-to-creatinine ratio [UACR] ≥ 200 and ≤ 5000 mg / g.

[0322] 28. A method according to any one of technical solutions 1 to 27, wherein the method reduces the incidence of a composite endpoint of sustained decline in eGFR ≥50%, end-stage renal disease (ESRD), CV death, or renal death in patients with CKD.

[0323] 29. A method according to technical solution 28, wherein when the method is added to the current background therapy of patients with CKD and albuminuria, the method reduces the incidence of the primary composite endpoint of a sustained decline in eGFR ≥50%, ESRD, CV death or renal death.

[0324] 30. A method according to any one of technical solutions 1 to 29, wherein the method reduces the patient's intraglomerular pressure, hypertension, proteinuria and / or fluid / sodium overload.

[0325] 31. A method according to any one of technical solutions 1 to 30, wherein the method reduces the patient's systolic blood pressure (BP) compared to baseline.

[0326] 32. A method according to any one of technical solutions 1 to 31, wherein the method further reduces the patient's systolic BP compared to baseline compared to placebo.

[0327] 33. A method according to technical solution 31 or 32, wherein the patient's systolic BP is measured on the 30th (±7) day, the 120th (±7) day, the 240th (±7) day, the 360th (±7) day, the 480th (±14) day and / or the 600th (±14) day.

[0328] 34. A method according to any one of technical solutions 1 to 33, wherein the method reduces the patient's weight compared to baseline.

[0329] 35. A method according to any one of technical solutions 1 to 34, wherein compared with placebo, the method further reduces the patient's weight compared to baseline.

[0330] 36. A method according to technical solution 34 or 35, wherein the patient's weight is measured on the 30th (±7) day, the 120th (±7) day, the 240th (±7) day, the 360th (±7) day, the 480th (±14) day and / or the 600th (±14) day.

[0331] 37. A method according to any one of technical solutions 1 to 36, wherein the method reduces the patient's albuminuria level compared to baseline.

[0332] 38. A method according to any one of technical solutions 1 to 37, wherein the method further reduces the patient's albuminuria level compared to baseline compared to placebo.

[0333] 39. A method according to technical solution 37 or 38, wherein the patient's albuminuria level is measured on day 30 (±7), day 120 (±7), day 240 (±7), day 360 (±7), day 480 (±14) and / or day 600 (±14).

[0334] 40. A method according to any one of technical solutions 1 to 39, wherein the method does not cause the patient's eGFR to decrease compared to baseline.

[0335] 41. A method according to any one of technical solutions 1 to 40, wherein the method reduces the patient's eGFR to a lesser extent compared to baseline compared to placebo.

[0336] 42. A method according to technical solution 40 or 41, wherein the patient's eGFR is measured on the 30th (±7) day, the 120th (±7) day, the 240th (±7) day, the 360th (±7) day, the 480th (±14) day and / or the 600th (±14) day.

[0337] 43. A method according to any one of technical solutions 1 to 42, wherein the patient's HbA1c is in the range of about 6.0% to about 6.9%.

[0338] 44. A method according to technical solution 43, wherein the patient's HbA1c is in the range of about 5.7% to about 6.5%.

[0339] 45. A method according to any one of technical solutions 1 to 44, wherein the method reduces the patient's time to first occurrence of CV death compared to placebo.

[0340] 46. ​​A method according to technical solution 45, wherein the time to the first occurrence of CV death is measured on the 30th (±7) day, the 120th (±7) day, the 240th (±7) day, the 360th (±7) day, the 480th (±14) day and / or the 600th (±14) day.

[0341] 47. A method according to any one of technical solutions 1 to 44, wherein the method reduces the patient's time to first occurrence of renal death compared to placebo.

[0342] 48. A method according to technical solution 47, wherein the time to the first occurrence of renal death is measured on the 30th (±7) day, the 120th (±7) day, the 240th (±7) day, the 360th (±7) day, the 480th (±14) day and / or the 600th (±14) day.

[0343] 49. A method according to any one of technical solutions 1 to 48, wherein the method reduces the patient's time to first hospitalization for heart failure compared to placebo.

[0344] 50. A method according to technical solution 49, wherein the time to the first hospitalization due to heart failure is measured on the 30th (±7) day, the 120th (±7) day, the 240th (±7) day, the 360th (±7) day, the 480th (±14) day and / or the 600th (±14) day.

[0345] 51. A method according to any one of technical solutions 1 to 50, wherein the method reduces the total number of patients hospitalized for heart failure and / or CV death compared to placebo.

[0346] 52. A method according to any one of technical solutions 1 to 51, wherein the method maintains or improves the patient's NYHA class compared to baseline compared to placebo.

[0347] 53. A method according to technical solution 52, wherein the patient's NYHA class is measured on the 30th (±7) day, the 120th (±7) day, the 240th (±7) day, the 360th (±7) day, the 480th (±14) day and / or the 600th (±14) day.

[0348] 54. A method according to any one of technical solutions 1 to 53, wherein the method improves the health status of the patient assessed by the EQ-5D-5L questionnaire compared to placebo.

[0349] 55. A method according to technical solution 54, wherein the health status of the patient assessed by the EQ-5D-5L questionnaire is measured on the 30th (±7) day, the 120th (±7) day, the 240th (±7) day, the 360th (±7) day, the 480th (±14) day and / or the 600th (±14) day.

[0350] 56. A method according to any one of technical solutions 1 to 53, wherein the method improves the health status of the patient assessed by the KDQOL 36 questionnaire compared to placebo.

[0351] 57. A method according to technical solution 56, wherein the health status of the patient assessed by the KDQOL 36 questionnaire is measured on the 30th (±7) day, the 120th (±7) day, the 240th (±7) day, the 360th (±7) day, the 480th (±14) day and / or the 600th (±14) day.

[0352] 58. A method according to any one of technical solutions 1 to 57, wherein the method further comprises administering the SGLT2 inhibitor in addition to standard of care therapy.

[0353] 59. A method according to technical solution 58, wherein the standard of care therapy includes treatment to control comorbidities and / or treatment to reduce the combined incidence of CV death and heart failure events.

Claims

1. A pharmaceutical composition comprising a therapeutically effective amount of dapagliflozin for use in preventing or delaying the progression of chronic kidney disease in a patient with chronic kidney disease; wherein the patient does not suffer from type II diabetes.

2. A pharmaceutical composition comprising a therapeutically effective amount of dapagliflozin for use in reducing the risk of sustained decline in estimated glomerular filtration rate (eGFR), end-stage kidney disease (ESKD), CV and renal death in patients with chronic kidney disease; wherein the patient does not have type 2 diabetes.

3. A pharmaceutical composition comprising a therapeutically effective amount of dapagliflozin for use in reducing the risk of sustained decline in estimated glomerular filtration rate (eGFR), end-stage kidney disease (ESKD), CV and renal death, hospitalization for heart failure, and all-cause mortality in patients with chronic kidney disease; wherein the patient does not have type 2 diabetes.

4. The pharmaceutical composition according to claims 1-3, wherein the estimated glomerular filtration rate (eGFR) is continuously decreased by ≥ 50%.

5. The pharmaceutical composition according to claims 1-3, wherein end-stage renal disease includes eGFR persistently <15 mL / min / 1.73 m2, initiation of chronic dialysis treatment and / or renal transplantation.

6. The pharmaceutical composition according to claims 1-3, wherein the patient's eGFR is ≥25 and ≤75 mL / min / 1.73 m2.

7. The pharmaceutical composition according to claims 1-3, wherein the patient's urine albumin-to-creatinine ratio (UACR) is ≥200 and ≤5000 mg / g.

8. The pharmaceutical composition according to claims 1-3, wherein at least one standard CKD care agent is also administered to the patient.

9. The pharmaceutical composition according to claim 8, wherein the at least one standard of care agent is selected from angiotensin converting enzyme inhibitors (ACE-I or ACE inhibitors) and angiotensin receptor blockers (ARBs).

10. The pharmaceutical composition according to claim 9, wherein the angiotensin converting enzyme inhibitor is selected from the group consisting of captopril, enalapril and lisinopril.

11. The pharmaceutical composition according to claim 9, wherein the angiotensin receptor blocker is selected from valsartan, losartan and irbesartan.

12. A pharmaceutical composition comprising a therapeutically effective amount of dapagliflozin for use in reducing the risk of sustained decline in estimated glomerular filtration rate (eGFR), end-stage kidney disease (ESKD), CV and renal death in patients with chronic kidney disease; wherein the patient does not suffer from type II diabetes; wherein at least one standard CKD care agent is also administered to the patient; and wherein the risk of sustained decline in estimated glomerular filtration rate (eGFR), end-stage kidney disease (ESKD), CV and renal death is reduced relative to a regimen in which patients receive at least one standard CKD care agent alone.

13. The pharmaceutical composition according to claim 12, wherein the composition satisfies at least one of the following conditions: a) the composition results in a hazard ratio of less than 1 for time to a first composite endpoint of sustained decline in eGFR of ≥50%, or ESRD and CV or renal death, relative to an administration regimen in which the patient receives at least one standard CKD care agent alone; b) the composition results in a hazard ratio of time to a first composite endpoint of a sustained decline in eGFR of ≥50%, or ESRD and CV or renal death that is statistically nominally less than 1 in the patient relative to an administration regimen in which the patient receives at least one standard CKD care agent alone; c) the composition results in a hazard ratio of about 0.61 for time to a first composite endpoint of a sustained decline in eGFR of ≥50%, or ESRD and CV or renal death, relative to an administration regimen in which the patient receives at least one standard CKD care agent alone; d) the composition results in a 95% confidence interval for a hazard ratio of about 0.51 to 0.72 for time to a first composite endpoint of a sustained decline in eGFR of ≥50%, or ESRD and CV or renal death, relative to an administration regimen in which the patient receives at least one standard CKD care agent alone; e) the composition numerically reduces the absolute risk of a sustained decline in eGFR of ≥50%, or a composite endpoint of ESRD and CV or renal death in the patient relative to an administration regimen in which the patient receives at least one standard CKD care agent alone; f) the composition results in a nominally significant reduction in the risk of a sustained decline in eGFR of ≥50%, or a composite endpoint of ESRD and CV or renal death in the patient relative to an administration regimen in which the patient receives at least one standard CKD care agent alone; and / or g) the composition results in a numerical reduction in a sustained decline in eGFR of ≥50%, or a composite endpoint of ESRD and CV or renal death in the patient relative to an administration regimen in which the patient receives at least one standard CKD care agent alone.

14. A pharmaceutical composition comprising a therapeutically effective amount of dapagliflozin for use in preventing or delaying the incidence or onset of T2D in patients with prediabetes (glycosylated hemoglobin ≥5.7% and <6.5%).

15. The pharmaceutical composition according to claim 14, wherein the patient is prediabetic with CKD and / or HF.

16. A pharmaceutical composition comprising a therapeutically effective amount of dapagliflozin and AZD9977 or a pharmaceutically acceptable salt thereof for use in treating chronic kidney disease in a patient suffering from chronic kidney disease.

17. The pharmaceutical composition of claim 16, wherein the reduction in chronic kidney disease progression comprises a sustained decline in estimated glomerular filtration rate (eGFR), end-stage kidney disease (ESKD), CV and / or renal death.

18. The pharmaceutical composition of claim 16 or claim 17, wherein the patient also has heart failure.

19. The pharmaceutical composition according to claim 18, wherein the patient's ejection fraction is <55%.

20. A pharmaceutical composition according to claim 16, wherein the amount of AZD9977 or a pharmaceutically acceptable salt thereof administered is 15-150 mg per day.

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