Methods of treating heart failure with reduced ejection fraction with dapagliflozin

Abstract

To provide methods of treating patients with heart failure with reduced ejection fraction (HFrEF).SOLUTION: The present disclosure is directed to methods of treating patients with heart failure with reduced ejection fraction (HFrEF), with and without T2D, with an SGLT2 inhibitor, such as dapagliflozin. The methods disclosed herein can reduce the risk of a composite outcome of a first episode of worsening heart failure (hospitalization for heart failure or an urgent heart failure visit) or death from cardiovascular causes. Each of the three components of this composite outcome can also be reduced, as well as the total number of heart failure hospitalizations and deaths from cardiovascular causes. SGLT2 inhibitors, such as dapagliflozin, can also reduce a worsening of heart failure symptoms. The methods disclosed herein can also improve heart failure symptoms, health status, and quality of life.SELECTED DRAWING: None

Description

[Background technology]

[0001] Heart failure (HF) is a life-threatening medical condition in which the heart cannot pump enough blood to sustain the body's organs. HF affects 64 million people worldwide, half of whom have reduced ejection fraction (HFrEF), and the prevalence and incidence of HF continues to increase worldwide (Non-Patent Document 1). HF is a chronic and degenerative disease, and half of patients will die within 5 years of diagnosis (Non-Patent Document 2). HF is the leading cause of hospitalization in people over 65 years of age, resulting in a significant clinical and economic burden (Non-Patent Document 3).

[0002] The existing standard treatment paradigm for HF includes the co-administration of one or more of the following classes of drugs: angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), beta-blockers, mineralocorticoid receptor agents such as mineralocorticoid receptor antagonists (MRAs), angiotensin receptor-neprilysin inhibitors (ARNIs), digoxin, diuretics, cardiac pump therapy, selective sinus node inhibitors, vasodilators, and calcium channel blockers (unless the patient suffers from systolic heart failure). Even with the best possible treatments, the 5-year survival rate for HF is lower than most cancers. (Non-Patent Document 4). Morbidity and mortality in HF patients remain high, and patient outcomes require improvement. Alternative methods of treating HF patients, particularly HFrEF patients, are needed to improve patient outcomes by lowering cardiovascular mortality, reducing heart failure events and worsening HF symptoms, and slowing disease progression.

[0003] Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a class of hypoglycemic drugs that improve glycemic control with low risk of hypoglycemia, independent of insulin secretion, and result in reduction of blood pressure, body weight, and uric acid levels (Non-Patent Document 5). SGLT2 inhibitors reduce renal glucose reabsorption, which increases urinary glucose excretion (ibid.). In addition, SGLT2 inhibitors reduce vascular stiffness and improve endothelial function.

[0004] Dapagliflozin is a potent, highly selective, and orally effective inhibitor of human renal SGLT2, which effectively reduces HbAlc with a low risk of inducing hypoglycemia. Dapagliflozin therapy has been shown to reduce body weight, systolic blood pressure, blood uric acid, albuminuria, and improve arterial compliance, all conditions associated with increased CV risk (Non-Patent Document 6). The chemical structure of dapagliflozin is: [ka] It is. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Cannie DEet al.,European Cardiology Review 14(2):89-96(2019) [Non-Patent Document 2] Mamas, MAet al., European Journal of Heart Failure 19:1095-1104(2017) [Non-Patent Document 3] Azad, N. et al., Journal of Geriatric Cardiology 11:329-337(2014) [Non-Patent Document 4] Braunwald, E. et al., Lancet 385:812-824(2015) [Non-Patent Document 5] Inzucchi et al., Diabetes & Vascular Dis Res.12(2):90-100(2015) [Non-Patent Document 6] Shigiyama et al., Cardiovasc Diabetol 16:84(2017) Summary of the Invention [Means for solving the problem]

[0006] Accordingly, the present disclosure relates to methods of treating patients with HFrEF, including those with or without type 2 diabetes (T2D), with an SGLT2 inhibitor, such as dapagliflozin.

[0007] The present disclosure relates to a method of treating heart failure with reduced ejection fraction (HFrEF) in a patient, the method comprising administering to the patient an effective amount of a sodium-glucose cotransporter 2 (SGLT2) inhibitor. For example, in some embodiments, the present disclosure relates to a method of treating HFrEF in a patient without type 2 diabetes (T2D), the method comprising administering to the patient an effective amount of a sodium-glucose cotransporter 2 (SGLT2) inhibitor. In other embodiments, the present disclosure relates to a method of treating HFrEF in a patient with T2D, the method comprising administering to the patient an effective amount of a SGLT2 inhibitor.

[0008] Also disclosed is a method of preventing or delaying a fatal cardiovascular event in a patient with HFrEF with or without T2D, comprising administering to the patient an effective amount of an SGLT2 inhibitor.

[0009] Also disclosed herein is a method of preventing or delaying the onset of diabetes in HFrEF patients without T2D, comprising administering to the patient an effective amount of an SGLT2 inhibitor. In some embodiments, the HFrEF patients without T2D have glycated hemoglobin less than 5.7%. In some embodiments, the HFrEF patients without T2D are pre-diabetic (i.e., have glycated hemoglobin ≧5.7% and <6.5%). In some embodiments, the methods disclosed herein reduce the incidence of T2D compared to placebo. In some embodiments, the methods disclosed herein reduce the incidence of T2D compared to a standard of care for HF. In some embodiments, the reduction in the incidence of T2D is measured by the time to first reported glycated hemoglobin measurement ≧6.5%. In some embodiments, the methods disclosed herein provide a hazard ratio of less than 1 in reducing the incidence of T2D compared to placebo. In some embodiments, the methods disclosed herein provide a hazard ratio of less than 1 in reducing the incidence of T2D compared to standard HF medications.

[0010] Also disclosed are methods of treating HFrEF in patients with or without T2D, comprising administering to the patient an effective amount of an SGLT2 inhibitor, wherein the patient does not experience adverse events associated with renal failure during treatment. In some embodiments, the absence of adverse events associated with renal failure includes no or little reduction in eGFR levels, no end-stage renal disease (ESRD) and / or no deaths from renal causes.

[0011] Disclosed herein is a method for reducing the total number of standard of care medications taken by a patient with HFrEF with or without T2D, comprising administering to the patient an effective amount of an SGLT2 inhibitor.

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

[0013] Further disclosed herein are methods comprising administering an effective amount of an SGLT2 inhibitor, alone or in combination with at least one other therapeutic agent, to a patient in need thereof. In some embodiments, the other therapeutic agent is administered together with the SGLT2 inhibitor in the same or different pharmaceutical composition and at the same or different time. In some embodiments, the other therapeutic agent is an antidiabetic agent, an antiobesity agent, an antihyperlipidemic agent, an antiatherosclerotic agent, an antihypertensive agent, an antiplatelet agent, an antithrombotic agent, or an anticoagulant agent. For example, in at least one embodiment, the other therapeutic agent is an antidiabetic agent, such as a biguanide and / or a DPP4 inhibitor. An exemplary biguanide is metformin or a pharmaceutically acceptable salt thereof. Exemplary DPP4 inhibitors include saxagliptin, linagliptin, sitagliptin, and pharmaceutically acceptable salts thereof.

[0014] In the methods disclosed herein, the patient has a left ventricular ejection fraction (LVEF) of 40% or less, such as 35%, 30%, or 25% or less, and in at least one embodiment, at least 20%. LVEF can be determined, for example, using an echocardiogram, a radionuclide angiogram, angiography, or cardiac MRI.

[0015] In some embodiments, the methods disclosed herein comprise orally administering to a patient once daily an SGLT2 inhibitor, such as dapagliflozin or a pharma- ceutically acceptable salt, solvate, mixed solvate, complex, or prodrug thereof, at a dose of 2.5 mg, 5.0 mg, or 10 mg. In at least one embodiment, the dose is 10 mg.

[0016] In some embodiments, the methods disclosed herein provide for the following outcomes: (i) prolonging the time to first heart failure (HF) event and / or fatal cardiovascular event; and / or (ii) reducing the worsening of heart failure symptoms; and / or (iii) reducing the incidence of heart failure events and / or reducing the incidence of fatal cardiovascular events This results in at least one of the following:

[0017] In some embodiments, the methods disclosed herein reduce the incidence of myocardial infarction. In some embodiments, the myocardial infarction is fatal. In some embodiments, the myocardial infarction is non-fatal. In some embodiments, the patient has a history of myocardial infarction. In some embodiments, the patient does not have a history of myocardial infarction. In some embodiments, the methods disclosed herein reduce the incidence of myocardial infarction compared to a placebo. In some embodiments, the methods disclosed herein reduce the incidence of myocardial infarction compared to a standard of care HF treatment. In some embodiments, the reduction in the incidence of myocardial infarction is measured by the time to first fatal or non-fatal myocardial infarction. In some embodiments, the methods disclosed herein provide a hazard ratio of less than 1 for the reduction in the incidence of myocardial infarction compared to a placebo. In some embodiments, the methods disclosed herein provide a hazard ratio of less than 1 for the reduction in the incidence of myocardial infarction compared to a standard of care treatment.

[0018] In some embodiments, the methods disclosed herein reduce the risk of hospitalization for heart failure and cardiovascular mortality in patients after acute myocardial infarction. In some embodiments, the patient has experienced an acute myocardial infarction within 7 days of starting treatment with an SGLT2 inhibitor. In some embodiments, the patient has experienced a STEMI (ST-segment elevation myocardial infarction). In some embodiments, the patient has experienced an NSTEMI (non-ST-segment elevation myocardial infarction). In some embodiments, the SGLT2 inhibitor is dapagliflozin. In some embodiments, the patient has T2D. In some embodiments, the patient does not have T2D. In some embodiments, the patient has HFrEF. In some embodiments, the patient does not have HFrEF. In some embodiments, the methods disclosed herein reduce the risk of hospitalization for heart failure and cardiovascular mortality in patients after acute myocardial infarction compared to placebo. In some embodiments, the methods disclosed herein reduce the risk of hospitalization for heart failure and cardiovascular mortality in patients after acute myocardial infarction compared to HF standard of care. In the methods disclosed herein, the patient receiving an SGLT2 inhibitor can be receiving one or more standard of care HF medications prior to or during administration of the SGLT2 inhibitor. In some embodiments, the methods disclosed herein are used to evaluate the following outcomes in patients who have experienced an acute myocardial infarction within 7 days: (i) prolonging the time to first heart failure (HF) event and / or fatal cardiovascular event; and / or (ii) reducing the worsening of heart failure symptoms; and / or (iii) reducing the number of heart failure events and / or reducing the incidence of fatal cardiovascular events; and / or (iv) reducing hospitalizations for heart failure and cardiovascular mortality; and / or (v) reducing the risk of fatal or non-fatal myocardial infarction; and / or (vi) reducing the risk of life-threatening adverse cardiac events (a composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke); and / or (vii) reducing the risk of all-cause mortality This results in at least one of the following:

[0019] In some embodiments, the methods described in the above paragraphs result in a hazard ratio of less than 1 for any one of (i)-(vii). In some embodiments, the methods disclosed herein result in a low hazard ratio compared to patients taking HF standard of care medications. In some embodiments, the methods disclosed herein result in a low hazard ratio compared to placebo.

[0020] In some embodiments, the methods disclosed herein reduce the time to first event of cardiovascular death or worsening of heart failure symptoms in acutely decompensated heart failure patients. In some embodiments, the patient is hospitalized for worsening of heart failure symptoms or acutely decompensated heart failure prior to initiation of SGLT2 administration. In some embodiments, the patient has a left ventricular ejection fraction (LVEF) of 40% or less, e.g., 35%, 30% or 25% or less, and in at least one embodiment, at least 20% prior to initiation of SGLT2 administration. In some embodiments, the SGLT2 inhibitor is dapagliflozin. In some embodiments, the patient suffers from T2D prior to initiation of SGLT2 administration. In some embodiments, the patient does not suffer from T2D prior to initiation of SGLT2 administration. In some embodiments, the patient has a LVEF of >30 ml / min / 1.73 m prior to initiation of SGLT2 administration. 2In some embodiments, the patient has an eGFR of 0.001 to 0.001. In some embodiments, the patient has an increased natriuretic peptide before the initiation of SGLT2 administration. In some embodiments, the patient is hospitalized in stable condition for worsening heart failure symptoms or acute heart failure. As used herein, "stable condition" is understood to mean no increase in iv diuretics and no use of iv vasodilators or vasoactive agents at least 24 hours prior to the initiation of SGLT2 administration, such as at least 48 hours, such as at least 72 hours, and in some embodiments at least one week prior to the initiation of SGLT2 administration. In some embodiments, the methods disclosed herein reduce the time to first event of cardiovascular death or worsening heart failure symptoms in patients with acute decompensated heart failure compared to placebo. In some embodiments, the methods disclosed herein reduce the time to first event of cardiovascular death or worsening heart failure symptoms in patients with acute decompensated heart failure compared to HF standard of care. In some embodiments, the patient administered an SGLT2 inhibitor may be receiving one or more HF standard of care medications prior to or during administration of the SGLT2 inhibitor.

[0021] In some embodiments, the methods disclosed herein provide for the prevention of the following outcomes in acutely decompensated heart failure patients: (i) prolonging the time to first fatal cardiovascular event; and / or (ii) prolonging the time to rehospitalization for heart failure; and / or (iii) prolonging time to emergency HF clinic; and / or (iv) Increase survival and total days post-discharge; and / or (v) reducing the worsening of heart failure symptoms; and / or (vi) reducing the risk of all-cause mortality This results in at least one of the following:

[0022] In some embodiments, the methods described in the above paragraphs result in a hazard ratio of less than 1 for any one of (i)-(vi). In some embodiments, the methods disclosed herein result in a low hazard ratio compared to patients taking HF standard of care medications. In some embodiments, the methods disclosed herein result in a low hazard ratio compared to placebo.

[0023] In some embodiments, the methods disclosed herein reduce the incidence of any stroke (ischemic, hemorrhagic, or of unknown etiology). In some embodiments, the stroke is fatal. In some embodiments, the stroke is non-fatal. In some embodiments, the patient has a history of stroke. In some embodiments, the patient does not have a history of stroke. In some embodiments, the methods disclosed herein reduce the incidence of stroke compared to a placebo. In some embodiments, the methods disclosed herein reduce the incidence of stroke compared to a standard of care HF medication. In some embodiments, the reduction in stroke incidence is measured by time to first fatal or non-fatal stroke. In some embodiments, the methods disclosed herein provide a hazard ratio of less than 1 for the reduction in stroke incidence compared to a placebo. In some embodiments, the methods disclosed herein provide a hazard ratio of less than 1 for the reduction in stroke incidence compared to a standard of care HF medication.

[0024] In some embodiments, administration of an SGLT2 inhibitor extends the time to first heart failure (HF) event. In at least one embodiment, the HF event is a hospitalization for HF or an emergency HF outpatient visit. In at least one embodiment, a hospitalization for HF includes a hospitalization lasting at least 24 hours with a primary diagnosis of HF. In some embodiments, administration of an SGLT2 inhibitor reduces the total number of hospitalizations for HF. In at least one embodiment, the total number of hospitalizations for HF includes first and / or re-admissions.

[0025] In some embodiments, hospitalization for HF is determined by meeting the following criteria: (i) new or worsening symptoms of HF experienced by the patient; and / or (ii) objective evidence of new or worsening symptoms of HF; and / or (iii) Initiating or intensifying specialized HF care This is due to one or more of the following:

[0026] In at least one embodiment, the new or worsening symptoms of HF experienced by the patient include dyspnea, decreased exercise tolerance, fatigue, and / or other symptoms of worsening end-organ damage or fluid overload. In at least one embodiment, the objective evidence of new or worsening symptoms of HF includes physical examination findings and / or new or worsening HF laboratory values ​​considered attributable to HF. In at least one embodiment, the physical examination findings include at least two of the following findings: peripheral edema, increasing abdominal distension or ascites, pulmonary rales / crackles / crepitus, increased jugular venous pressure and / or hepatojugular reflux, S3 gallop, and / or clinically significant or rapid weight gain associated with fluid retention. In at least one embodiment, the new or worsening HF laboratory findings include at least one of the following: increased B-type natriuretic peptide (BNP) / N-terminal pro-BNP (NT-proBNP) concentrations consistent with heart failure decompensation; radiological evidence of pulmonary congestion; non-invasive diagnostic evidence of clinically significant elevated left or right ventricular filling pressures or low cardiac output or invasive diagnostic evidence by right heart catheterization. In at least one embodiment, the initiation or intensification of HF specialty therapy includes at least one of the following: increasing oral diuretic therapy, intravenous administration of a diuretic or vasoactive agent, or mechanical or surgical intervention (e.g., mechanical or surgical intervention includes mechanical circulatory support or mechanical fluid removal).

[0027] In some embodiments, an emergency HF visit is an emergency room visit for a primary diagnosis of HF, but does not require hospitalization, such as an emergency walk-in visit to a clinic for a primary diagnosis of HF. In some embodiments where an emergency HF visit is required, the patient is experiencing HF symptoms and / or has physical examination findings and / or new or worsening laboratory findings of HF. In at least one embodiment, the patient experiences one or more symptoms of HF selected from the group consisting of dyspnea, decreased exercise tolerance, fatigue, and / or other symptoms of worsening end-organ damage or fluid overload. In some embodiments where an emergency HF visit is required, the patient undergoes initiation or intensification of HF specialty treatment. In some embodiments where an emergency HF visit is required, the patient requires intravenous therapy.

[0028] In some embodiments, administration of an SGLT2 inhibitor prolongs the time to a fatal cardiovascular event.

[0029] In the aforementioned embodiments, the time to first heart failure event and / or fatal cardiovascular event may be delayed for 8 weeks to 24 months from the first administration of the SGLT2 inhibitor. In at least one embodiment, the time to first heart failure event is delayed for 8 weeks to 24 months from the first administration of the SGLT2 inhibitor. In at least one embodiment, the time to fatal cardiovascular event is delayed for 8 weeks to 24 months from the first administration of the SGLT2 inhibitor.

[0030] In some embodiments, administration of an SGLT2 inhibitor reduces a worsening of HF symptoms in a patient being treated. In at least one embodiment, the reduced alleviation of the patient's heart failure symptoms is over a period of 12 to 36 months. In at least one embodiment, the reduced worsening of heart failure symptoms is characterized by a reduced number of hospitalizations for HF in the patient. In at least one embodiment, the reduced worsening of heart failure symptoms is characterized by a reduced number of emergency HF visits in the patient. In at least one embodiment, the emergency HF visits are emergency room visits or emergency outpatient clinic visits.

[0031] In at least one embodiment, the reduced worsening of heart failure symptoms is characterized by a higher score of the patient based on the Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS) compared to the patient's score prior to administration of the SGLT2 inhibitor. In such an embodiment, the higher score based on the KCCQ-TSS occurs within 16 weeks of initiation of SGLT2 inhibitor administration. In other embodiments, the higher score based on the KCCQ-TSS occurs within 20 weeks of initiation of SGLT2 inhibitor administration. In other embodiments, the higher score based on the KCCQ-TSS occurs within 24 weeks of initiation of SGLT2 inhibitor administration. In other embodiments, the higher score based on the KCCQ-TSS occurs within 28 weeks of initiation of SGLT2 inhibitor administration. In other embodiments, the higher score based on the KCCQ-TSS occurs within 32 weeks or 8 months of initiation of SGLT2 inhibitor administration. In at least one embodiment, the higher score based on the KCCQ-TSS is at least 5 points higher than the score prior to administration of the SGLT2 inhibitor. In at least one embodiment, the higher score based on the KCCQ-TSS is at least 10 points higher than the pre-SGLT2 inhibitor score. In at least one embodiment, the higher score based on the KCCQ-TSS is at least 15 points higher than the pre-SGLT2 inhibitor score.

[0032] In some embodiments, administration of the SGLT2 inhibitor comprises the following: a) reducing heart failure symptoms; b) reducing physical limitations; c) improving exercise tolerance; and / or d) Reducing the amount of time spent sitting in daily life This results in one or more of the following:

[0033] In at least one embodiment, the reduction in heart failure symptoms is characterized by a higher score for the patient based on the Kansas City Cardiomyopathy Questionnaire Total Symptom Score compared to the patient's score prior to administration of the SGLT2 inhibitor. In such an embodiment, the higher score based on the KCCQ-TSS occurs within 16 weeks (or 4 months) of the start of administration of the SGLT2 inhibitor. In other embodiments, the higher score based on the KCCQ-TSS occurs within 20 weeks of the start of administration of the SGLT2 inhibitor. In other embodiments, the higher score based on the KCCQ-TSS occurs within 24 weeks of the start of administration of the SGLT2 inhibitor. In other embodiments, the higher score based on the KCCQ-TSS occurs within 28 weeks of the start of administration of the SGLT2 inhibitor. In other embodiments, the higher score based on the KCCQ-TSS occurs within 32 weeks or 8 months of the start of administration of the SGLT2 inhibitor. In at least one embodiment, the higher score based on the KCCQ-TSS is at least 5 points higher than the score prior to administration of the SGLT2 inhibitor. In at least one embodiment, the higher score based on the KCCQ-TSS is at least 10 points higher than the score before administration of the SGLT2 inhibitor. In at least one embodiment, the higher score based on the KCCQ-TSS is at least 15 points higher than the score before administration of the SGLT2 inhibitor. In at least one embodiment, the KCCQ-TSS is patient reported, such as patient reported to a clinic. In at least one embodiment, the patient is afflicted with T2D. In some embodiments, the patient is not afflicted with T2D.

[0034] In at least one embodiment, the reduction in physical limitation is characterized by the patient's higher score on the Kansas City Cardiomyopathy Questionnaire-Physical Limitation Score (KCCQ-PLS) compared to the patient's score prior to administration of the SGLT2 inhibitor. In such an embodiment, the higher score on the KCCQ-PLS occurs within 16 weeks (or 4 months) of initiating SGLT2 inhibitor administration. In other embodiments, the higher score on the KCCQ-PLS occurs within 20 weeks of initiating SGLT2 inhibitor administration. In other embodiments, the higher score on the KCCQ-PLS occurs within 24 weeks of initiating SGLT2 inhibitor administration. In other embodiments, the higher score on the KCCQ-PLS occurs within 28 weeks of initiating SGLT2 inhibitor administration. In other embodiments, the higher score on the KCCQ-PLS occurs within 32 weeks or 8 months of initiating SGLT2 inhibitor administration. In at least one embodiment, the higher score on the KCCQ-PLS is at least 1 point higher than the score prior to administration of the SGLT2 inhibitor. In at least one embodiment, the higher score based on the KCCQ-PLS is at least 5 points higher than the score before administration of the SGLT2 inhibitor. In at least one embodiment, the higher score based on the KCCQ-PLS is at least 10 points higher than the score before administration of the SGLT2 inhibitor. In at least one embodiment, the higher score based on the KCCQ-PLS is at least 15 points higher than the score before administration of the SGLT2 inhibitor. In at least one embodiment, the KCCQ-PLS is patient reported, such as patient reported to a clinic. In at least one embodiment, the patient is afflicted with T2D. In some embodiments, the patient is not afflicted with T2D.

[0035] In at least one embodiment, the improvement in exercise tolerance is characterized by a longer 6-minute walk distance (6MWD) of the patient compared to the patient's 6MWD prior to administration of the SGLT2 inhibitor. In such an embodiment, the longer 6MWD distance occurs within 16 weeks of initiation of SGLT2 inhibitor administration. In other embodiments, the longer 6MWD distance occurs within 20 weeks of initiation of SGLT2 inhibitor administration. In other embodiments, the longer 6MWD distance occurs within 24 weeks of initiation of SGLT2 inhibitor administration. In other embodiments, the longer 6MWD distance occurs within 28 weeks of initiation of SGLT2 inhibitor administration. In other embodiments, the longer 6MWD distance occurs within 32 weeks or 8 months of initiation of SGLT2 inhibitor administration. In at least one embodiment, the improvement in 6-minute walk distance (6MWD) is measured by a distance of 30 meters or more. In at least one embodiment, the patient is afflicted with T2D. In some embodiments, the patient is not afflicted with T2D.

[0036] In at least one embodiment, the reduction in sedentary time in daily life is characterized by an increase in the total time the patient spends in vigorous physical activity during the day compared to the time the patient spent in vigorous physical activity during the day before administration of the SGLT2 inhibitor. In such an embodiment, the reduction in sedentary time in daily life is measured within 7 days after 16 weeks of SGLT2 inhibitor administration compared to the time the patient spent in vigorous physical activity during the day before administration of the SGLT2 inhibitor. In another embodiment, the reduction in sedentary time in daily life is measured within 7 days after 20 weeks of SGLT2 inhibitor administration compared to the time the patient spent in vigorous physical activity during the day before administration of the SGLT2 inhibitor. In another embodiment, the reduction in sedentary time in daily life is measured within 7 days after 24 weeks of SGLT2 inhibitor administration compared to the time the patient spent in vigorous physical activity during the day before administration of the SGLT2 inhibitor. In other embodiments, the reduction in the amount of time spent sitting during daily activities is measured within 7 days after 28 weeks of SGLT2i administration, compared to the time the patient spent engaging in vigorous physical activity during the day before administration of the SGLT2i. In other embodiments, the reduction in the amount of time spent sitting during daily activities is measured within 7 days after 32 weeks or 8 months of SGLT2i administration. In such embodiments, the time spent sitting during daily activities is measured by a wearable activity monitor. In at least one embodiment, the patient is afflicted with T2D. In some embodiments, the patient is not afflicted with T2D.

[0037] In some embodiments, administration of an SGLT2 inhibitor reduces the number of HF events and / or reduces the incidence of fatal cardiovascular events. In at least one embodiment, administration of an SGLT2 inhibitor reduces the number of HF events. In at least one embodiment, the HF events are hospitalizations for HF or emergency HF outpatient visits. In at least one embodiment, administration of an SGLT2 inhibitor reduces the number of hospitalizations for HF. In at least one embodiment, administration of an SGLT2 inhibitor reduces the number of emergency HF outpatient visits. In at least one embodiment, the emergency HF outpatient visit is an emergency room visit. In at least one embodiment, the emergency HF outpatient visit requires intravenous therapy.

[0038] In some embodiments, administration of an SGLT2 inhibitor reduces the composite of hospitalization for HF or fatal cardiovascular events.

[0039] In the methods disclosed herein, the patient administered an SGLT2 inhibitor can be receiving one or more standard of care HF treatments prior to or during administration of the SGLT2 inhibitor. In at least one embodiment, the one or more standard of care HF treatments are selected from the group consisting of angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), beta-blockers, mineralocorticoid receptor drugs such as mineralocorticoid receptor antagonists (MRAs), neprilysin inhibitors, antiplatelet agents, aspirin, lipid-lowering drugs (e.g., statins, bile acid sequestrants, niacin, fibrates, omega-3 fatty acids), and diuretics such as loop diuretics.

[0040] In the methods disclosed herein, the patient receiving the SGLT2 inhibitor has a New York Heart Association (NYHA) heart failure class of II to IV. In at least one embodiment, the patient receiving the SGLT2 inhibitor has a NYHA heart failure class of II. In at least one embodiment, the patient receiving the SGLT2 inhibitor has a NYHA heart failure class of III or IV.

[0041] In the methods disclosed herein, the patient receiving an SGLT2 inhibitor may have an eGFR of ≧30 ml / min / 1.73 m2 prior to administration of the SGLT2 inhibitor. In the methods disclosed herein, the patient receiving an SGLT2 inhibitor may have an eGFR of ≧30 ml / min / 1.73 m2 during administration of the SGLT2 inhibitor. 2 have an eGFR of

[0042] In the methods disclosed herein, the patient administered an SGLT2 inhibitor may have a plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) level of at least 400 pg per milliliter, at least 600 pg per milliliter, or at least 900 pg per milliliter prior to administration of the SGLT2 inhibitor.

[0043] In the methods disclosed herein, the patient administered an SGLT2 inhibitor can have been medically diagnosed with symptomatic HFrEF prior to administration of the SGLT2 inhibitor. In at least one embodiment, the patient can have been diagnosed with HFrEF at least two months prior to administration of the SGLT2 inhibitor.

[0044] In the methods disclosed herein, the patient administered the SGLT2 inhibitor may have atrial fibrillation and / or atrial flutter prior to administration of the SGLT2 inhibitor. In at least one embodiment, the patient administered the SGLT2 inhibitor does not have atrial fibrillation or atrial flutter prior to administration of the SGLT2 inhibitor. In at least one embodiment, the methods disclosed herein reduce the incidence of atrial fibrillation in patients with a history of atrial fibrillation or atrial flutter prior to administration of the SGLT2 inhibitor. In at least one embodiment, the methods disclosed herein reduce the incidence of atrial fibrillation in patients without atrial fibrillation or atrial flutter prior to administration of the SGLT2 inhibitor. In some embodiments, the methods disclosed herein reduce the incidence of atrial fibrillation compared to placebo. In some embodiments, the methods disclosed herein reduce the incidence of atrial fibrillation compared to HF standard of care medication. In some embodiments, the reduction in the incidence of atrial fibrillation is measured by the time to first fatal or non-fatal atrial fibrillation. In some embodiments, the methods disclosed herein provide a hazard ratio for reducing the incidence of atrial fibrillation compared to a placebo of less than 1. In some embodiments, the methods disclosed herein provide a hazard ratio for reducing the incidence of atrial fibrillation compared to a HF standard of care drug of less than 1.

[0045] In certain embodiments, the disclosed methods result in a reduction in HbA1c in the patient. In certain embodiments, the disclosed methods result in a reduction in systolic blood pressure in the patient. In certain embodiments, the disclosed methods result in a reduction in weight in the patient. In certain embodiments, the disclosed methods result in a reduction in NT-proBNP levels in the patient. In any of the foregoing embodiments, the reduction can occur within 8 months of initiating SGLT2 inhibitor administration. In certain embodiments, the disclosed methods result in a reduction in ml / min / 1.73m over time in the patient. 2 In such embodiments, the sustained decline can be for 12 months, 18 months, 24 months or more.

[0046] In certain embodiments, the methods disclosed herein result in an improvement in NYHA HF classification.

[0047] In certain embodiments, the methods disclosed herein result in a reduction in re-hospitalizations for HF or a reduction in recurrent HF events. In at least one embodiment, recurrent HF events include hospitalizations for HF or emergency HF outpatient visits.

[0048] In certain embodiments, the methods disclosed herein result in a reduced incidence of mortality from non-cardiovascular causes.

[0049] Further disclosed herein is a method for reducing the rate of a primary composite endpoint of cardiovascular death, HF hospitalization, or emergency HF outpatient visit in HFrEF patients treated with an SGLT2 inhibitor and a standard of care HF treatment, which is reduced relative to patients treated with the standard of care HF treatment alone. Further disclosed herein is a method for reducing the rate of a secondary composite endpoint of cardiovascular death or HF hospitalization in HFrEF patients treated with an SGLT2 inhibitor and a standard of care HF treatment, which is reduced relative to patients treated with the standard of care HF treatment alone. In any of the foregoing embodiments, the SGLT2 inhibitor is, for example, dapagliflozin or a pharma- ceutically acceptable salt, solvate, mixed solvate, complex, or prodrug thereof. In at least one embodiment, the SGLT2 inhibitor is dapagliflozin orally administered to the patient at 10 mg once daily.

[0050] In some embodiments, the methods disclosed herein provide for the following outcomes: (i) prolonging the time to first heart failure (HF) event and / or fatal cardiovascular event; and / or (ii) reducing the worsening of heart failure symptoms; and / or (iii) reducing the number of heart failure events and / or reducing the incidence of fatal cardiovascular events This results in at least one of the following:

[0051] Also provided herein is a method for reducing the risk of hyperkalemia in a HF patient, comprising administering to the patient an effective amount of an SGLT2 inhibitor. In some embodiments, the method disclosed herein reduces the risk of hyperkalemia in a HF patient, comprising administering to the patient a pharmaceutical composition comprising an effective amount of an SGLT2 inhibitor. In some embodiments, an SGLT2 inhibitor for use in reducing the risk of hyperkalemia in a HF patient is disclosed.

[0052] In some embodiments, the disclosure relates to a method of reducing the risk of hyperkalemia associated with MRA use in a HF patient, comprising administering to the patient an effective amount of an SGLT2 inhibitor. In some embodiments, the disclosure relates to a method of reducing the risk of hyperkalemia associated with MRA use in a HF patient, comprising administering to the patient a pharmaceutical composition comprising an effective amount of an SGLT2 inhibitor. In some embodiments, an SGLT2 inhibitor is disclosed for use in reducing the risk of hyperkalemia associated with MRA use in a HF patient.

[0053] In some embodiments, the disclosure relates to a method of treating HF in a patient, comprising administering to the patient an effective amount of an MRA and an effective amount of an SGLT2 inhibitor. In some embodiments, the disclosure relates to a method of treating HF in a patient, comprising administering to the patient a pharmaceutical composition comprising an effective amount of an MRA and an effective amount of an SGLT2 inhibitor. In some embodiments, the disclosure discloses a combination of an SGLT2 inhibitor and an MRA for use in reducing the risk of hyperkalemia in HF patients. In some embodiments, a SGLT2 inhibitor for use in treating a HF patient is disclosed, wherein the treatment comprises separate, sequential or simultaneous administration of an MRA and an SGLT2 inhibitor to the patient.

[0054] In some embodiments, the SGLT2 inhibitor is dapagliflozin. In some embodiments, the MRA is selected from steroidal mineralocorticoid receptor antagonists (MRAs), such as spironolactone (e.g., commercially available as Aldactone®, Aldactazide®) and eplerenone (e.g., commercially available as Inspra®). In some embodiments, the MRA is selected from non-steroidal MRAs, such as finerenone, esaxerenone, KBP-5074, and aparalenone.

[0055] 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, disclosed in WO 2016 / 001631, which has the following structure: [ka]

[0056] In some embodiments, a method of treating HF is disclosed, comprising administering to a patient in need thereof an effective amount of AZD9977 or a pharma- ceutically acceptable salt thereof; and an effective amount of an SGLT2 inhibitor. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharma- ceutically acceptable salt, solvate, mixed solvate, complex, or prodrug thereof.

[0057] In some embodiments, AZD9977 or a pharma- ceutically acceptable salt thereof is disclosed for use in the treatment of HF in a patient, wherein said treatment comprises separate, sequential or simultaneous administration of AZD9977 and an SGLT2 inhibitor to said patient. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharma- ceutically acceptable salt, solvate, mixed solvate, complex or prodrug thereof.

[0058] In some embodiments, an SGLT2 inhibitor is disclosed for use in the treatment of HF in a patient, wherein said treatment comprises separate, sequential or simultaneous administration of an SGLT2 inhibitor and AZD9977 or a pharmaceutically acceptable salt thereof. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt, solvate, mixed solvate, complex or prodrug thereof.

[0059] In some embodiments, a method of reducing the risk of hyperkalemia in a HF patient is disclosed, comprising administering to a patient in need thereof an effective amount of AZD9977, or a pharma- ceutically acceptable salt thereof; and an effective amount of an SGLT2 inhibitor. In some embodiments, the SGLT2 inhibitor is dapagliflozin, or a pharma- ceutically acceptable salt, solvate, mixed solvate, complex, or prodrug thereof.

[0060] In some embodiments, AZD9977 or a pharma- ceutically acceptable salt thereof is disclosed for reducing the risk of hyperkalemia in a HF patient, wherein said treatment comprises separate, sequential or simultaneous administration of AZD9977 and an SGLT2 inhibitor to said patient. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharma- ceutically acceptable salt, solvate, mixed solvate, complex or prodrug thereof.

[0061] In some embodiments, a SGLT2 inhibitor is disclosed for reducing the risk of hyperkalemia in HF patients, wherein said treatment comprises separate, sequential or simultaneous administration of a SGLT2 inhibitor and AZD9977 or a pharmaceutically acceptable salt thereof. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt, solvate, mixed solvate, complex or prodrug thereof.

[0062] In some embodiments, a method of treating HFrEF is disclosed, comprising administering to a patient in need thereof an effective amount of AZD9977, or a pharma- ceutically acceptable salt thereof; and an effective amount of an SGLT2 inhibitor. In some embodiments, the SGLT2 inhibitor is dapagliflozin, or a pharma- ceutically acceptable salt, solvate, mixed solvate, complex, or prodrug thereof.

[0063] In some embodiments, AZD9977 or a pharma- ceutically acceptable salt thereof is disclosed for use in the treatment of HFrEF in a patient, wherein said treatment comprises separate, sequential or simultaneous administration of AZD9977 and an SGLT2 inhibitor to said patient. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharma- ceutically acceptable salt, solvate, mixed solvate, complex or prodrug thereof.

[0064] In some embodiments, an SGLT2 inhibitor is disclosed for use in treating HFrEF in a patient, wherein said treatment comprises separate, sequential or simultaneous administration of an SGLT2 inhibitor and AZD9977 or a pharmaceutically acceptable salt thereof. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt, solvate, mixed solvate, complex or prodrug thereof.

[0065] In some embodiments, a method of treating HFpEF is disclosed, comprising administering to a patient in need thereof an effective amount of AZD9977, or a pharma- ceutically acceptable salt thereof; and an effective amount of an SGLT2 inhibitor. In some embodiments, the SGLT2 inhibitor is dapagliflozin, or a pharma- ceutically acceptable salt, solvate, mixed solvate, complex, or prodrug thereof.

[0066] In some embodiments, AZD9977 or a pharma- ceutically acceptable salt thereof is disclosed for use in treating HFpEF in a patient, wherein said treatment comprises separate, sequential or simultaneous administration of AZD9977 and an SGLT2 inhibitor to said patient. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharma- ceutically acceptable salt, solvate, mixed solvate, complex or prodrug thereof.

[0067] In some embodiments, an SGLT2 inhibitor is disclosed for use in treating HFpEF in a patient, wherein said treatment comprises separate, sequential or simultaneous administration of an SGLT2 inhibitor and AZD9977 or a pharmaceutically acceptable salt thereof. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt, solvate, mixed solvate, complex or prodrug thereof.

[0068] In some embodiments, a method of reducing the risk of cardiovascular mortality and hospitalization for heart failure is disclosed, comprising administering to a patient in need thereof an effective amount of AZD9977 or a pharma- ceutically acceptable salt thereof; and an effective amount of an SGLT2 inhibitor. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharma- ceutically acceptable salt, solvate, mixed solvate, complex, or prodrug thereof.

[0069] In some embodiments, AZD9977 or a pharma- ceutically acceptable salt thereof is disclosed for use in reducing the risk of cardiovascular mortality and hospitalization for heart failure in a patient, wherein said treatment comprises separate, sequential or simultaneous administration of AZD9977 and an SGLT2 inhibitor to said patient. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharma- ceutically acceptable salt, solvate, mixed solvate, complex or prodrug thereof.

[0070] In some embodiments, a SGLT2 inhibitor is disclosed for use in reducing the risk of cardiovascular mortality and hospitalization for heart failure in a patient, wherein said treatment comprises separate, sequential or simultaneous administration of a SGLT2 inhibitor and AZD9977 or a pharmaceutically acceptable salt thereof. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt, solvate, mixed solvate, complex or prodrug thereof.

[0071] In some embodiments, a method of reducing the risk of cardiovascular mortality and hospitalization for heart failure is disclosed, comprising administering to a patient in need thereof, having an LVEF of 55% or less and an eGFR of about 15-45 ml / min / 1.73 m2, an effective amount of AZD9977 or a pharma- ceutical acceptable salt thereof; and an effective amount of an SGLT2 inhibitor. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharma- ceutical acceptable salt, solvate, mixed solvate, complex, or prodrug thereof.

[0072] In some embodiments, AZD9977 or a pharma- ceutically acceptable salt thereof is disclosed for use in reducing the risk of cardiovascular mortality and hospitalization for heart failure in a patient with an LVEF of 55% or less and an eGFR of about 15-45 ml / min / 1.73 m2, wherein said treatment comprises separate, sequential or simultaneous administration of AZD9977 and an SGLT2 inhibitor to said patient. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharma- ceutically acceptable salt, solvate, mixed solvate, complex or prodrug thereof.

[0073] In some embodiments, an SGLT2 inhibitor is disclosed for use in reducing the risk of cardiovascular mortality and hospitalization for heart failure in patients with an LVEF of 55% or less and an eGFR of about 15-45 ml / min / 1.73 m2, wherein said treatment comprises separate, sequential or simultaneous administration of an SGLT2 inhibitor and AZD9977 or a pharma- ceutically acceptable salt thereof. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharma- ceutically acceptable salt, solvate, mixed solvate, complex or prodrug thereof.

[0074] In some embodiments, a method of reducing the rate of a composite endpoint of cardiovascular death, hospitalization for heart failure, or emergency HF outpatient visit is disclosed, comprising administering to a patient in need thereof, having an LVEF of 55% or less and an eGFR of about 15-45 ml / min / 1.73 m2, an effective amount of AZD9977, or a pharma- ceutically acceptable salt thereof; and an effective amount of an SGLT2 inhibitor. In some embodiments, the SGLT2 inhibitor is dapagliflozin, or a pharma- ceutically acceptable salt, solvate, mixed solvate, complex, or prodrug thereof.

[0075] In some embodiments, AZD9977 or a pharma- ceutically acceptable salt thereof is disclosed for use in reducing the rate of a composite endpoint of cardiovascular death, hospitalization for HF, or emergency HF outpatient visit in a patient with an LVEF of 55% or less and an eGFR of about 15-45 ml / min / 1.73 m2, wherein said treatment comprises separate, sequential, or simultaneous administration of AZD9977 and an SGLT2 inhibitor to said patient. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharma- ceutically acceptable salt, solvate, mixed solvate, complex, or prodrug thereof.

[0076] In some embodiments, an SGLT2 inhibitor is disclosed for use in reducing the rate of a composite endpoint of cardiovascular death, hospitalization for heart failure or emergency HF outpatient visit in patients with an LVEF of 55% or less and an eGFR of about 15-45 ml / min / 1.73m2, wherein said treatment comprises separate, sequential or simultaneous administration of an SGLT2 inhibitor and AZD9977 or a pharmaceutically acceptable salt thereof.

[0077] In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharma- ceutically acceptable salt, solvate, mixed solvate, complex, or prodrug thereof. In some embodiments, a method of reducing the rate of any one of all-cause mortality, myocardial infarction, or stroke is disclosed, comprising administering to a patient in need thereof, having an LVEF of 55% or less and an eGFR of about 15-45 ml / min / 1.73 m2, an effective amount of AZD9977 or a pharma- ceutically acceptable salt thereof; and an effective amount of an SGLT2 inhibitor. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharma- ceutically acceptable salt, solvate, mixed solvate, complex, or prodrug thereof.

[0078] In some embodiments, AZD9977 or a pharma- ceutically acceptable salt thereof is disclosed for use in reducing the rate of any one of all-cause mortality, myocardial infarction or stroke in a patient with an LVEF of 55% or less and an eGFR of about 15-45 ml / min / 1.73 m2, wherein said treatment comprises separate, sequential or simultaneous administration of AZD9977 and an SGLT2 inhibitor to said patient. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharma- ceutically acceptable salt, solvate, mixed solvate, complex or prodrug thereof.

[0079] In some embodiments, an SGLT2 inhibitor is disclosed for use in reducing the rate of any one of all-cause mortality, myocardial infarction, or stroke in patients with an LVEF of 55% or less and an eGFR of about 15-45 ml / min / 1.73 m2, wherein said treatment comprises separate, sequential, or simultaneous administration of an SGLT2 inhibitor and AZD9977 or a pharma- ceutically acceptable salt thereof. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharma- ceutically acceptable salt, solvate, mixed solvate, complex, or prodrug thereof.

[0080] In any of the foregoing embodiments, the SGLT2 inhibitor may be, for example, dapagliflozin or a pharma- ceutically acceptable salt, solvate, mixed solvate, complex, or prodrug thereof. In at least one embodiment, the SGLT2 inhibitor is dapagliflozin or a pharma- ceutically acceptable salt, solvate, mixed solvate, complex, or prodrug thereof administered orally at 10 mg once daily. In any of the foregoing embodiments, AZD9977 or a pharma- ceutically acceptable salt thereof is administered orally to the patient in an amount of 100 mg to 150 mg once daily.

[0081] In any of the foregoing embodiments, the patient has a left ventricular ejection fraction (LVEF) of 40% or less, e.g., 35%, 30%, or 25% or less, and in at least one embodiment, at least 20%. In some embodiments, the patient has a left ventricular ejection fraction (LVEF) of 40% or less, e.g., 35%, 30%, or 25% or less, and in at least one embodiment, at least 20%. In some embodiments, the patient has an LVEF of 40% or more, e.g., 45%, 50%, or 55% or more, and in at least one embodiment, at least 55%. In some embodiments, the patient has an eGFR of 45 ml / min / 1.73 m2 or less, e.g., 30 ml / min / 1.73 m2, 25 ml / min / 1.73 m2, 20 ml / min / 1.73 m2, or 15 ml / min / 1.73 m2 or less. In some embodiments, the patient is afflicted with T2D. In some embodiments, the patient is not afflicted with T2D. In some embodiments, hyperkalemia is understood to mean potassium levels above 5.5 mmol / L. In some embodiments, hyperkalemia can be mild (serum potassium levels above 5.5 mmol / L) or moderate / severe (serum potassium levels above 6.0 mmol / L). [Brief description of the drawings]

[0082] [Figure 1]FIG. 1 is a flow chart depicting patient screening, randomization, and follow-up in the Dapagliflozin and Prevention of Adverse Events in Heart Failure (DAPA-HF) multicenter Phase 3 clinical trial, as described in Example 1. All randomized patients were in the intent-to-treat (ITT) population. [Diagram 2] Graphs depicting cardiovascular endpoints from the DAPA-HF Phase 3 clinical trial (see Example 1). Figure 2A depicts the primary endpoint of the trial, a composite of death from cardiovascular causes, hospitalization for heart failure, or emergency heart failure outpatient visits requiring intravenous therapy. The cumulative incidence of the primary endpoint (Figure 2A), heart failure hospitalization (Figure 2B), death from cardiovascular causes (Figure 2C), and all-cause mortality (Figure 2D) was estimated using the Kaplan-Meier method, and hazard ratios and 95% confidence intervals were estimated using Cox regression models, stratified by diabetes status, prior heart failure hospitalization, and treatment with dapagliflozin or placebo as explanatory variables. Analyses were based on all participants who underwent randomization. The display is truncated when less than 10% of patients remain at risk. The insets in each panel show the same data based on an expanded y-axis. [Diagram 3] A summary of the effects of dapagliflozin on worsening heart failure and mortality from the DAPA-HF Phase 3 clinical trial is provided (see Example 1). The figure shows the primary composite endpoint, which was a composite of death from cardiovascular causes, hospitalization for heart failure, or emergency heart failure outpatient visits requiring intravenous therapy, and each of its components. Also shown are the narrower composite of death from cardiovascular causes or hospitalization for heart failure and all-cause mortality, which were secondary endpoints. [Figure 4]

[0033] Figure 1 depicts the primary composite endpoint by pre-specified subgroups from the DAPA-HF Phase 3 clinical trial (see Example 1). Race was reported by the investigator. Body mass index (BMI) is weight in kilograms divided by height in meters squared. NYHA = New York Heart Association; LVEF = left ventricular ejection fraction; NT-proBNP = N-terminal pro-B-type natriuretic peptide; MRA = mineralocorticoid receptor antagonist; and eGFR = estimated glomerular filtration rate. [Diagram 5] Graph depicting baseline KCCQ Total Symptom Score (TSS) divided into three tertiles: (i) ≦65.6, (ii) 65.7-87.5, and (iii) >87.5 points, showing the cumulative percentage change within these tertiles over 24 months from randomization. [Figure 6] Six clinical trial endpoints for patients in the DAPA-HF trial are depicted for dapagliflozin versus placebo, including cardiovascular death, HF hospitalization, or emergency HF outpatient visit; cardiovascular death or HF hospitalization; HF hospitalization or emergency HF outpatient visit; HF hospitalization; cardiovascular death; and all-cause mortality. [Figure 7] 7A-7C are graphs depicting the KCCQ Total Symptom Score (TSS) (FIG. 7A); KCCQ Clinical Symptom Score (CSS) (FIG. 7B); and KCCQ Overall Summary Score (OSS) (FIG. 7C) following treatment with dapagliflozin versus placebo in the DAPA-HF trial. [Figure 8A] 1 is a bar graph comparing KCCQ total symptom scores (TSS) after treatment with dapagliflozin versus placebo in the DAPA-HF trial. [Figure 8B] Odds ratios (OR) corresponding to FIG. 8A. [Figure 8C] 1 is a bar graph comparing KCCQ Clinical Symptom Scores (CSS) after treatment with dapagliflozin versus placebo in the DAPA-HF trial. [Figure 8D] Odds ratios (OR) corresponding to FIG. 8C. [Figure 8E] 8A, 8C, and 8E are bar graphs comparing KCCQ Overall Summary Scores (OSS) after treatment with dapagliflozin versus placebo in the DAPA-HF trial. [Figure 8F] Odds ratios (OR) corresponding to FIG. 8E. [Figure 9A] 1 is a graph depicting the primary composite endpoint of patients from the DAPA-HF trial by baseline diabetes status. [Figure 9B] Here is a graph depicting its components - namely hospitalizations for heart failure. [Figure 9C]FIG. 1 is a graph depicting cardiovascular mortality. [Figure 9D] Graph depicting mortality from all causes. [Figure 10A] The effect of dapagliflozin compared to placebo on the pre-specified primary composite endpoint in patients with and without diabetes and by baseline glycated hemoglobin levels in patients without diabetes (FIG. 10A) and the effect of dapagliflozin compared to placebo on the pre-specified primary and secondary composite endpoints, their components and all-cause mortality by baseline diabetes status (FIG. 10B) are depicted. [Figure 10B] To depict the effect of dapagliflozin compared with placebo by baseline diabetes status on the pre-specified primary and secondary composite endpoints, their components, and all-cause mortality. [Figure 11A] Figure 1 depicts the effect of dapagliflozin compared to placebo by baseline diabetes status (i.e. diabetes or no diabetes) on clinical laboratory measures, body weight, and systolic blood pressure. Changes from baseline in glycated hemoglobin concentration (%) (HbAlc) are shown. Least squares mean changes are shown with 95% confidence intervals (CI). These changes are adjusted for baseline values. *History of diabetes (n=1983) and baseline glycated hemoglobin ≥ 6.5% (n=156). [Figure 11B] Figure 1 depicts the effect of dapagliflozin compared to placebo by baseline diabetes status (i.e. diabetes or no diabetes) on clinical laboratory measures, body weight, and systolic blood pressure. Change from baseline in body weight is shown. Least squares mean changes are shown with 95% confidence intervals (CI). These changes are adjusted for baseline values. *History of diabetes (n=1983) and baseline glycated hemoglobin ≥ 6.5% (n=156). [Figure 11C]Figure 1 depicts the effect of dapagliflozin compared to placebo by baseline diabetes status (i.e. diabetes or no diabetes) on clinical laboratory measures, weight, and systolic blood pressure. Changes from baseline in systolic blood pressure are shown. Least squares mean changes are shown with 95% confidence intervals (CI). These changes are adjusted for baseline values. *History of diabetes (n=1983) and baseline glycated hemoglobin ≥ 6.5% (n=156). [Figure 11D] Figure 1 depicts the effect of dapagliflozin compared to placebo by baseline diabetes status (i.e. diabetes or no diabetes) on clinical laboratory measures, weight, and systolic blood pressure. Change from baseline in hematocrit is shown. Least squares mean changes are shown with 95% confidence intervals (CI). These changes are adjusted for baseline values. *History of diabetes (n=1983) and baseline glycated hemoglobin ≥ 6.5% (n=156). [Figure 11E] Figure 1 depicts the effect of dapagliflozin compared to placebo by baseline diabetes status (i.e. diabetes or no diabetes) on clinical laboratory measures, weight, and systolic blood pressure. Changes from baseline in creatinine are shown. Least squares mean changes are shown with 95% confidence intervals (CI). These changes are adjusted for baseline values. *History of diabetes (n=1983) and baseline glycated hemoglobin ≥ 6.5% (n=156). [Figure 12] Graphs depicting baseline HbAlc outcomes, including the primary composite outcome (FIG. 12A); hospitalization or emergency visit for heart failure (FIG. 12B); death from cardiovascular causes (FIG. 12C); and all-cause mortality (FIG. 12D). [Figure 13] Depict responder analyses showing consistent symptom benefit (e.g., ≥5 points, ≥10 points, ≥15 points) for patients receiving dapagliflozin versus placebo, regardless of threshold KCCQ-TSS score. [Figure 14]We describe a renal composite endpoint by diabetes status (including 82 dapagliflozin and 74 placebo patients with previously undiagnosed diabetes; i.e., HbAlc ≥ 6.5% (≥ 48 mmol / mol) on two occasions), consisting of a sustained decline in eGFR ≥ 50%, end-stage renal disease (defined as sustained eGFR < 15 mL / min / 1.73 m2), or long-term dialysis or kidney transplantation. [Figure 15] 1 shows sustained eGFR decline over time in ml / min / 1.73m2 in dapagliflozin patients compared to placebo patients. [Figure 16] Figure 1. Annualized eGFR per ml / min / 1.73 m2 by baseline diabetes status (including 82 dapagliflozin and 74 placebo patients with previously undiagnosed diabetes; i.e., HbAlc >6.5% (>48 mmol / mol)). [Figure 17] New-onset T2D (HbAlc ≥ 6.5%) or previously undiagnosed diabetes measured at two consecutive study visits after randomization; i.e., it represents the incidence of new-onset T2D as reported by the investigator relative to placebo patients with HbAlc ≥ 6.5%. [Figure 18] Figure 18A depicts the cumulative incidence of moderate hyperkalemia (>5.5 mmol / L) (Figure 18A) and severe hyperkalemia (>6.0 mmol / L) (Figure 18B) in patients treated with mineralocorticoid receptor antagonists in the placebo group (non-dashed line) and the dapagliflozin group (dashed line). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0083] The present disclosure relates to a method of treating patients with heart failure with reduced ejection fraction (HFrEF), including patients with or without type 2 diabetes (T2D), with an SGLT2 inhibitor, such as dapagliflozin. The present disclosure also relates to treating HFrEF patients with an SGLT2 inhibitor, such as dapagliflozin, by prolonging the time to first (or recurrent) HF event, reducing HF symptoms, reducing worsening of HF symptoms, and / or reducing the incidence of death from cardiovascular (CV) events. The present disclosure further relates to a method of reducing the rate of a primary composite endpoint of CV death, HF hospitalization, or emergency HF outpatient visit, or a secondary composite endpoint of CV death and HF hospitalization, in HFrEF patients treated with an SGLT2 inhibitor and a HF standard of care, compared to patients treated with a HF standard of care alone.

[0084] In some embodiments, the SGLT2 inhibitor, such as dapagliflozin, is administered together with a standard of care HF treatment (such as a beta-blocker) in the same or separate composition, either at the same time or at different times.

[0085] In some embodiments, the SGLT2 inhibitor, such as dapagliflozin, is administered together with at least one therapeutic agent (such as an antidiabetic agent) in the same or another composition, either at the same time or at different times.

[0086] I. Definition The terms "comprise," "have," "include," and "contain" are to be construed as open-ended terms (i.e., meaning "including, but not limited to"), unless otherwise noted.

[0087] The term "and / or" as used in phrases such as "A and / or B" is intended to include the following embodiments: "A and B," "A or B" and "B."

[0088] Similarly, the term "and / or" as used in phrases such as "A, B and / or C" is intended to include each of the following embodiments: A, B and C; A, B or C; A or C; A or B; B or C; A and C; A and B; B and C; A (only); B (only); and C (only). Thus, as a practical example, when speaking of one or more emergency HF events (e.g., HF hospitalization and / or ER visits) and / or death from cardiovascular causes, it is intended to encompass the composite item of all specified events together, any combination of composite items of some events together, or each event alone.

[0089] As used herein, the term "prodrug" refers to esters and carbonates that can be converted to SGLT2 inhibitors, for example, under physiological conditions or by solvolysis. Thus, the term prodrug includes pharma- ceutically acceptable metabolic precursors of SGLT2 inhibitors. The term prodrug also includes covalently bonded carriers that release SGLT2 inhibitors in vivo when such prodrugs are administered to a patient. Non-limiting examples of prodrugs include esters and carbonates formed by reacting one or more hydroxyls of an SGLT2 inhibitor with an alkyl, alkoxy, or aryl substituted acylating agent using procedures known in the art to generate acetates, pivalates, methyl carbonates, benzoates, and the like.

[0090] Various forms of prodrugs are known in the art. For examples of such prodrug derivatives, see: (1) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, pp. 309-396, edited by K. Widder et al. (Academic Press, 1985); (2) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Prodrugs," by H. Bundgaard pp. 113-191 (1991); (3) Bundgaard, H., Advanced Drug Delivery Reviews 8:1-38 (1992); (4) Bundgaard, H. et al., Journal of Pharmaceutical Sciences 77:285 (1988); and (5) Kakeya, N. et al., Chem Pharm Bull. 32:692(1984).

[0091] As used herein, the terms "treatment", "treating" and the like refer to a procedure (e.g., administration of a pharmaceutical agent to a subject) that cures, slows, alleviates symptoms, and / or halts the progression of a diagnosed pathological condition or disorder, such as HFrEF. As used herein, patients being treated or in need of treatment with an SGLT2 inhibitor as described herein include patients with a confirmed diagnosis of a disorder, such as HFrEF.

[0092] A "therapeutically effective amount" or "effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic result (eg, treatment of HFrEF).

[0093] Prophylactic treatment refers to measures (e.g., administration of an SGLT2 inhibitor as described herein to a subject) that prevent and / or slow the onset of the targeted pathological condition or disorder. Thus, those in need of prophylactic treatment include those susceptible to the disorder and those in whom the disorder is to be prevented. A "prophylactically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result (e.g., prevention or delay of a fatal cardiovascular event).

[0094] The terms "patient" and "subject" refer to an adult individual who has been diagnosed with HFrEF and has been treated with HF standard of care, as described herein, prior to initiation of SGLT2 therapy. In some embodiments, the patient has been diagnosed with HFrEF for at least two months.

[0095] As used herein, the term "heart failure with reduced ejection fraction," "HFrEF," or "patient with HFrEF" refers to a chronic disease in which the patient's left ventricular ejection fraction (LVEF) is ≦40% and the patient's heart failure symptoms fall into stages II-IV of the New York Heart Association (NYHA) heart failure classification system. See Dolgin M, "Criteria Committee of the New York Heart Association; Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels," 9 th ed., Boston, MA: Little Brown & Co (1994). The NYHA heart failure classification system was used in enrolling patients into the Phase 3 clinical trial described in Example 1. In some embodiments, a "HFrEF patient" falls into stage II of the NYHA HF classification. In some embodiments, a "HFrEF patient" falls into stage III or IV of the NYHA HF classification.

[0096] In some embodiments, HFrEF patients have a left ventricular ejection fraction (LVEF) of 40% or less, although in some embodiments, the LVEF is 35%, 30%, or 25% or less. In some embodiments, the LVEF is at least 20%. Diagnosis and evaluation of HFrEF patients generally involves cardiac imaging and physical examination, such as assessment of LVEF using an echocardiogram, radionuclide angiogram, angiogram, or cardiac MRI.

[0097] The NYHA HF classification system classifies heart failure according to the patient's subjective symptom assessment into classes I-IV, and based on the patient's ability to function in daily life: Class I: No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitations, or dyspnea; Class II. Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity causes fatigue, palpitations, or dyspnea; Class III. Significant limitation of physical activity. Comfortable at rest. Less than normal physical activity causes fatigue, palpitations, or dyspnea; Class IV. Unable to continue any physical activity without difficulty. Symptoms of heart failure at rest. Difficulty increases when starting any physical activity. Patients with NYHA stage II-IV were enrolled in the Phase III DAPA-HF trial described in Example 1.

[0098] As used herein, "HF standard of care" includes at least one HF standard of care other than SGLT2 inhibitors, e.g., at least two or at least three or more drugs or drug classes, used to treat HF, e.g., HFrEF. The HF standard of care described herein can be used before and / or during administration of an SGLT2 inhibitor, e.g., dapagliflozin. HF standard of care drugs and their dosages are well known to cardiologists and other physicians who see and treat HFrEF patients. Exemplary HF standard of care drugs include: angiotensin-converting enzyme (ACE) inhibitors; angiotensin receptor blockers (ARBs); beta-blockers; mineralocorticoid receptor drugs such as mineralocorticoid receptor antagonists (MRAs) and neprilysin inhibitors.

[0099] Other medications that may be used to treat HFrEF and therefore also be considered "HF standard of care" include diuretics and loop diuretics (e.g., furosemide, bumetanide, and torsemide), digoxin, cardiac pump therapy drugs, selective sinus node depressants, 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 that follow clinical practice guidelines. See Yancy CWet al., "ACC / AHA / HFSA focused update of the 2013 ACCF / AHA guideline for the management of heart failure: A report of the American College of Cardiology / American Heart Association task force on clinical practice guidelines and the Heart Failure Society of America, J Am Coll Cardiol. 70(6):776-803 (2017).

[0100] The terms "administer", "administering", "administration", and the like, as used herein, refer to methods that can be used to enable delivery of an agent, e.g., an SGLT2 inhibitor, as described herein. Administration techniques that can be used for the agents and methods described herein can be found, for example, in: Goodman and Gilman, The Pharmacological Basis of Therapeutics, current edition, Pergamon; and Remington's, Pharmaceutical Sciences, current edition, Mack Publishing Co., Easton, Pa. In at least one embodiment, the SGLT2 inhibitor is administered orally.

[0101] Administration of an SGLT2 inhibitor "in combination with one or more other therapeutic agents" includes simultaneous (concurrent) or sequential administration at the same or different time points, in the same or different pharmaceutical compositions (e.g. pills, tablets, capsules). "Other therapeutic agents" include any of the HF standard therapeutic agents mentioned above or other therapeutic agents listed below, such as antidiabetic agents, antiobesity agents, antihyperlipidemic agents, antiatherosclerotic agents, antihypertensive agents, antiplatelet agents, antithrombotic agents or anticoagulant agents. "Other therapeutic agents" may be in the form of a pharma- ceutically acceptable salt, solvate, mixed solvate, complex or prodrug.

[0102] In some cases, the other therapeutic agent is an antidiabetic agent, such as a biguanide (e.g., metformin) and / or a DPP4 inhibitor (e.g., saxagliptin, linagliptin, or sitagliptin). Representative examples of SGLT2 inhibitor + antidiabetic drug combination preparations include the following: dapagliflozin / metformin extended-release (XIGDUO XR (registered trademark)), dapagliflozin / saxagliptin (QTERN (registered trademark)), dapagliflozin / saxagliptin / metformin (QTERNMET (registered trademark)), canagliflozin / metformin (INVOKAMET (registered trademark)), canagliflozin / metformin extended-release (INVOKAMET XR (registered trademark)), empagliflozin / linagliptin (GLYXAMBI (registered trademark)), empagliflozin / metformin (SYNJARDY (registered trademark)), empagliflozin / metformin extended-release (SYNJARDY (registered trademark)), XR®), ertugliflozin / metformin (STEGLUROMET®), and ertugliflozin / sitagliptin (STEGLUJAN®).

[0103] As used herein, "heart failure event" refers to hospitalization for HF and / or emergency HF outpatient visits.

[0104] As used herein, "hospitalization for HF" or "HF hospitalization" refers to a hospitalization for at least 24 hours with a primary diagnosis of HF. In some embodiments, the hospitalized patient presents with new or worsening symptoms due to HF at the time of admission. In some embodiments, the hospitalized patient has objective evidence of new or worsening HF. In some embodiments, the hospitalized patient undergoes initiation or intensification of HF specialty treatment. In some embodiments, the hospitalized patient has all of the aforementioned criteria.

[0105] As used herein, "HF symptoms" include at least one of dyspnea, decreased exercise tolerance, fatigue, or other symptoms of end-organ damage or fluid overload. In some embodiments, HF symptoms are new or worsening since a previous period, clinic visit, or visit.

[0106] As used herein, "Kansas City Cardiomyopathy Questionnaire (KCCQ)" refers to a questionnaire used by physicians to assess a patient's HF symptoms and / or determine whether a patient's HF symptoms are improving or worsening. The KCCQ uses a scale of 0 to 100, with higher scores indicating fewer HF symptoms, and a change of 5 points or more is considered clinically significant. See Green, CP, "Development and evaluation of the Kansas City Cardiomyopathy Questionnaire: a new health status measure for heart failure," J Am Coll Cardiol. 35:1245-1255 (2000). The KCCQ was administered in the DAPA-HF clinical trial (Example 1) as an index of health-related quality of life (HRQL). The analysis presented in Example 2 reveals that dapagliflozin reduced cardiovascular mortality and HF worsening across a range of baseline KCCQ values, as well as improved symptom burden, physical function, and quality of life in HFrEF patients.

[0107] As used herein, "objective evidence of new or worsening HF" refers to a physician's physical examination finding and / or a laboratory test result of new or worsening HF that is believed to be attributable to HF. In some embodiments, objective evidence of new or worsening HF consists of at least two physical examination findings. In some embodiments, objective evidence of new or worsening HF consists of one physical examination finding and at least one laboratory test result.

[0108] As used herein, "physical examination findings thought to be attributable to HF" (including new or worsening HF) include at least one of the following findings: peripheral edema, increasing abdominal distension or ascites; pulmonary rales / crackles / crepitus; increased jugular venous pressure and / or hepatojugular reflux; S3 gallop; and / or clinically significant or rapid weight gain associated with fluid retention.

[0109] As used herein, "new or worsening HF laboratory findings" refers to at least one of the following findings: increased B-type natriuretic peptide / N-terminal pro-BNP (NT-proBNP) concentrations consistent with decompensation of heart failure (e.g., BNP >500 pg / mL or NT-proBNP >2,000 pg / mL); radiological evidence of pulmonary congestion; pulmonary capillary wedge pressure (pulmonary artery occlusion pressure) ≥18 mmHg, central venous pressure ≥12 mmHg, or cardiac index <2.2 L / min / m 2 Non-invasive diagnostic evidence of clinically significant elevated left or right ventricular filling pressures or low cardiac output, or invasive diagnostic evidence by right heart catheterization, indicating

[0110] As used herein, "initiating or intensifying HF specialty therapy" includes at least one of the following: increasing oral diuretic therapy; intravenous diuretics or vasoactive agents (e.g., inotropic agents, vasopressors or vasodilators); mechanical or surgical intervention (e.g., mechanical circulatory support such as an intra-aortic balloon pump, ventricular assist device, extracorporeal membrane oxygenation, total ventricular artificial heart), and / or mechanical fluid removal (e.g., hyperfiltration, hemofiltration, dialysis).

[0111] As used herein, an "emergency HF visit" refers to an emergency walk-in visit to a clinic or emergency department / emergency room visit for the primary diagnosis of HF, but which does not meet the criteria for HF hospitalization. In some embodiments, patients in an emergency HF visit have HF symptoms and / or physical examination findings and / or new or worsening HF laboratory values, as previously described, and / or undergo initiation or intensification of HF specialty treatment, as previously described.

[0112] As used herein, "cardiovascular (CV) mortality" refers to mortality in patients being treated for HFrEF as described herein due to: acute myocardial infarction (MI), sudden cardiac death, heart failure or cardiogenic shock, stroke (cerebrovascular event), cardiovascular procedures, cardiovascular hemorrhage, other cardiovascular causes (CV mortality not included in the above categories but due to specific known causes (e.g., peripheral arterial obstruction or peripheral arterial disease).

[0113] As used herein, "non-cardiovascular (CV) mortality" refers to any mortality not included in "cardiovascular (CV) mortality."

[0114] As used herein, the term "primary composite outcome" or "primary composite endpoint" refers to the assessment of the following HF events (as previously described) occurring in HFrEF patients receiving an SGLT2 inhibitor (e.g., dapagliflozin) together with a standard of care for HF: ·Cardiovascular (CV) mortality; Hospitalization for HF; or Emergency HF outpatient visits (defined above to include ER and emergency walk-in clinic visits) This refers to the determination of the relative risk reduction in patients taking an SGLT2 inhibitor (e.g., dapagliflozin) compared to patients taking a composite item of HF and a standard of care HF medication alone (see Example 1).

[0115] As used herein, the term "secondary endpoint" refers to a composite of the following HF events: CV death or HF hospitalization (as previously defined) and determination of the relative risk reduction in patients taking an SGLT2 inhibitor (e.g., dapagliflozin) compared to patients taking HF standard of care alone (see Example 1).

[0116] As described herein, the use of comparative phrases such as "reduced," "reduced," "worsened," "decreased," "worsening," "prolonged," "prolonged," etc., in relation to, for example, HF symptoms, HF events, HF hospitalizations, CV mortality, or non-CV mortality, is intended to indicate a comparison of HFrEF patients receiving an SGLT2 inhibitor (e.g., dapagliflozin) with respect to any of the following: A patient (or group of patients) not taking an SGLT2 inhibitor; · A patient (or group of patients) taking only standard HF medications; A patient (or group of patients) receiving a placebo for the same period of time; A patient (or group of patients) taking a placebo and a standard of care HF treatment for the same period of time; -Patients not yet receiving SGLT2 inhibitors; -Average prognostic estimates for a population of patients with HFrEF.

[0117] II.SGLT2 inhibitors As described herein, SGLT2 inhibitors can be used in the methods described herein to treat established HFrEF in patients with and without type 2 diabetes.

[0118] Sodium-glucose cotransporter 2 (SGLT2) is a sodium-dependent renal protein responsible for the reabsorption of sugar into the blood. SGLT2 inhibitors (also known as "gliflozins") are a class of drugs used to lower blood glucose in type 2 diabetes patients by inhibiting the renal SGLT2 protein. As a result, more sugar is excreted in the urine.

[0119] SGLT2 inhibitors that can be used in the disclosed methods of treating HFrEF patients include dapagliflozin (FARXIGA®), canagliflozin (INVOKANA®), empagliflozin (JARDIANCE®), ertugliflozin (STEGLATRO®), sotagliflozin, or ipragliflozin, or a pharma- ceutically acceptable salt, solvate, mixed solvate, complex, or prodrug thereof.

[0120] In at least one embodiment, the SGLT2 inhibitor used in the disclosed methods of treating HFrEF patients is dapagliflozin as described in U.S. Patent Nos. 6,414,126 and 6,515,117, which are incorporated herein by reference in their entireties. FARXIGA® was approved by the USFDA in 2014 as a monotherapy and then in 2017-2019 as part of a combination therapy (XIGDUO®, QTERN®, QTERNMET®) with diet and exercise to improve glycemic control in adults with type 2 diabetes. Dapagliflozin can be administered in doses of 2.5 mg, 5.0 mg, or 10 mg. In at least one embodiment, a 10 mg dose is administered for use in the disclosed methods.

[0121] In some embodiments, "dapagliflozin" may refer to the FDA approved formulation FARXIGA®, or may refer to a pharma- ceutically acceptable salt, solvate, mixed solvate, complex, or prodrug. In some embodiments, dapagliflozin has the structure: [ka] The compound is in the form of an (S)-propylene glycol ((S)-(PG) solvate having the formula:

[0122] In some embodiments, the dapagliflozin is in the form of a crystalline solid or an amorphous solid.

[0123] In some embodiments, "dapagliflozin" is formulated as a fixed dose combination formulation with another therapeutic agent, such as, for example, another antidiabetic agent. Dapagliflozin / metformin extended release (XIGDUO®), dapagliflozin / saxagliptin (QTERN®), and dapagliflozin / saxagliptin / metformin (QTERNMET®) are examples of combination formulations that include dapagliflozin.

[0124] III. Standard treatment for HF As used herein, "HF standard of care" includes at least one, e.g., at least two, at least three or more medications or classes of medications used to treat HF, e.g., HFrEF, other than an SGLT2 inhibitor. The HF standard of care may be used prior to and / or during administration of an SGLT2 inhibitor, e.g., dapagliflozin, as described herein. In some embodiments, the HF standard of care and the SGLT2 inhibitor are administered together at the same time or at different times.

[0125] Exemplary HF standard treatments include angiotensin-converting enzyme (ACE) inhibitors; angiotensin receptor blockers (ARBs); beta-blockers; mineralocorticoid receptor drugs such as mineralocorticoid receptor antagonists (MRAs) and neprilysin inhibitors. HF standard treatments and their dosages are well known to cardiologists and other physicians who see and treat HFrEF patients. A brief description of these HF standard treatments is provided below.

[0126] ACE inhibitors produce vasodilation in both the venous and arterial systems, thereby reducing preload and afterload, increasing blood flow to vital organ systems and improving ejection fraction. These medications also block the enzyme required to convert angiotensin I to angiotensin II, a potent vasoconstrictor that increases blood pressure and releases aldosterone, leading to sodium and water retention. ACE inhibitors block this cascade of actions. Representative examples of ACE inhibitors include captopril, enalapril, and lisinopril.

[0127] ARBS, like ACE inhibitors, block the action of angiotensin II. ARBs block angiotensin II in blood vessels and adrenal glands. In blood vessels, ARBs cause venous and arterial dilation, reducing both preload and afterload. Blocking angiotensin II receptors in the adrenal glands reduces the release of aldosterone, which in turn increases sodium and water excretion. Representative examples of ARBs include valsartan, losartan, and irbesartan.

[0128] Beta-blockers reduce sympathetic nervous system stimulation, lower heart rate and blood pressure, and improve left ventricular function, hemodynamics, and exercise tolerance. Representative examples of beta-blockers include atenolol, propranolol, bisoprolol, carvedilol, and sustained-release metoprolol.

[0129] Mineralocorticoid receptor antagonists (MRAs) or "aldosterone antagonists" are diuretics that antagonize the action of aldosterone at the mineralocorticoid receptor. This class of drugs is often used as adjunctive therapy in combination with other drugs for the management of chronic heart failure. Representative examples of MRAs include spironolactone and eplerenone.

[0130] Mineralocorticoid receptor modulators (MRM) are used to describe compounds that exhibit either tissue- or cell-specific receptor antagonism, full antagonism, or partial antagonism.

[0131] Neprilysin inhibitors break down natriuretic peptides, which are responsible for sodium and water loss when the ventricles are overloaded. By slowing their breakdown, they prolong their effect, allowing more sodium and water to be removed from the body, reducing intravascular volume and blood pressure, thereby reducing preload and afterload. A representative example of a neprilysin inhibitor is sacubitril. Neprilysin inhibitors can be combined with ARBs as a new class of heart failure medications called angiotensin receptor neprilysin inhibitors. The first-in-class drug, sacubitril / valsartan, combines an ARB (valsartan) with a neprilysin enzyme inhibitor (sacubitril).

[0132] Other medications that can be used to treat HFrEF and therefore may be considered "HF standard of care" include diuretics and loop diuretics (e.g., furosemide, bumetanide, and torsemide), digitalis or other cardiac pump therapy drugs, hydralazine / isosorbide dinitrate, ivabradine (a sinoatrial (SA) node modulator), or other HF medications that follow practice guidelines. See Yancy CWet al., "ACC / AHA / HFSA focused update of the 2013 ACCF / AHA guideline for the management of heart failure: A report of the American College of Cardiology / American Heart Association task force on clinical practice guidelines and the Heart Failure Society of America, J Am Coll Cardiol. 70(6):776-803 (2017).

[0133] IV. Other Therapeutic Drugs As described herein, administration of an SGLT2 inhibitor may be in combination with one or more "other therapeutic agents." As used herein, the phrase "other therapeutic agents" typically does not include the HF standard of care agents discussed above, unless the context dictates otherwise.

[0134] Other therapeutic agents that may be administered together with the SGLT2 inhibitors described herein include antidiabetic agents, antiobesity agents, antihyperlipidemic agents, antiatherosclerotic agents, antihypertensive agents, antiplatelet agents, antithrombotic agents or anticoagulant agents. The "other therapeutic agents" may be in the form of a pharma- ceutically acceptable salt, solvate, mixed solvate, complex or prodrug.

[0135] Administration of an SGLT2 inhibitor in combination with one or more "other therapeutic agents" includes simultaneous (concurrent) or sequential administration at the same or different times, and in the same or different pharmaceutical compositions (e.g. pills, tablets, capsules).

[0136] In some cases, the other therapeutic agent is an antidiabetic agent, such as a biguanide (e.g., metformin) and / or a DPP4 inhibitor (e.g., saxagliptin, linagliptin, or sitagliptin). Representative examples of SGLT2 inhibitor + antidiabetic drug combination preparations include the following: dapagliflozin / metformin extended release (XIGDUO®), dapagliflozin / saxagliptin (QTERN®), dapagliflozin / saxagliptin / metformin (QTERNMET®), canagliflozin / metformin (INVOKAMET®), canagliflozin / metformin extended release (INVOKAMET XR®), empagliflozin / linagliptin (GLYXAMBI®), empagliflozin / metformin (SYNJARDY®), empagliflozin / metformin extended release (SYNJARDY XR®), ertugliflozin / metformin (STEGLUROMET®), and ertugliflozin / sitagliptin (STEGLUJAN®).

[0137] V. Methods for Treating HFrEF by Administering SGLT2 Inhibitors The present disclosure provides a method for treating HFrEF in a patient, comprising administering to the patient an effective amount of a sodium-glucose cotransporter 2 (SGLT2) inhibitor as described herein. In some embodiments, the patient also suffers from type 2 diabetes. In some embodiments, the patient does not suffer from type 2 diabetes.

[0138] The present disclosure also provides a method of treating HFrEF in a patient without T2D, comprising administering to the patient an effective amount of an SGLT2 inhibitor, wherein the patient does not experience adverse events associated with renal failure during treatment.

[0139] The disclosure also provides a method of treating HFrEF in a patient with T2D, comprising administering to the patient an effective amount of an SGLT2 inhibitor, wherein the patient does not experience adverse events associated with renal failure during treatment.

[0140] In some embodiments, "absence of adverse events related to renal failure" includes no change or only a slight decrease in the patient's estimated glomerular filtration rate (eGFR) levels while receiving SGLT2 inhibitor therapy, no end-stage renal disease (ESRD) and / or no death from renal causes.

[0141] In some embodiments, the SGLT2 inhibitor is dapagliflozin, canagliflozin, empagliflozin, sotagliflozin, ipragliflozin, or ertugliflozin, or a pharma- ceutically acceptable salt, solvate, mixed solvate, complex, or prodrug thereof.

[0142] In at least one embodiment, the SGLT2 inhibitor is dapagliflozin or a pharma- ceutically acceptable salt, solvate, mixed solvate, complex, or prodrug thereof. In some embodiments, the dapagliflozin is in the form of a non-crystalline solid. In some embodiments, the dapagliflozin is in the form of a crystalline solid. In some embodiments, the dapagliflozin is in the form of an (S)-propylene glycol ((S)-(PG) solvate, which has the structure: [ka] has.

[0143] In some embodiments, the SGLT2 inhibitor (e.g., dapagliflozin) is orally administered to a patient once daily. In some embodiments, the dapagliflozin is administered to a patient at a dose of 2.5 mg, 5.0 mg, or 10 mg once daily. In at least one embodiment, the dose of dapagliflozin administered is 10 mg.

[0144] In some embodiments, the method of treating HFrEF in a patient further comprises administering to the patient at least one other therapeutic agent, the other therapeutic agent being administered together with the SGLT2 inhibitor at the same or a different time and in the same or a different pharmaceutical composition.

[0145] In some embodiments, the other therapeutic agent is an antidiabetic agent, an antiobesity agent, an antilipidemic agent, an antiatherosclerotic agent, an antihypertensive agent, an antiplatelet agent, an antithrombotic agent, or an anticoagulant agent.

[0146] In some embodiments, the other therapeutic agent is an antidiabetic agent. In some embodiments, the antidiabetic agent is a biguanide and / or a DPP4 inhibitor. In some embodiments, the biguanide is metformin or a pharmaceutically acceptable salt thereof. In some embodiments, the DPP4 inhibitor is saxagliptin, linagliptin, or sitagliptin or a pharmaceutically acceptable salt thereof.

[0147] In some embodiments, the HFrEF patient is receiving one or more HF standard of care medications to treat HF ​​prior to or during administration of an SGLT2 inhibitor, in some embodiments, the HF standard of care medications are selected from the group consisting of angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), beta-blockers, mineralocorticoid receptor drugs such as mineralocorticoid receptor antagonists (MRAs), neprilysin inhibitors, and diuretics.

[0148] In certain embodiments, the at least one HF standard of care is a therapeutically effective amount of an angiotensin-converting enzyme (ACE) inhibitor.

[0149] In certain embodiments, the at least one HF standard of care is a therapeutically effective amount of an angiotensin II receptor blocker (ARB).

[0150] In certain embodiments, at least one standard of care HF treatment is a beta-blocker.

[0151] In certain embodiments, at least one standard of care HF treatment is a mineralocorticoid receptor drug, such as a mineralocorticoid receptor antagonist (MRA).

[0152] In certain embodiments, at least one HF standard of care drug is a neprilysin inhibitor. In some embodiments, the neprilysin inhibitor is combined with an angiotensin II receptor antagonist (e.g., sacubitril / valsartan).

[0153] In certain embodiments, at least one standard of care HF treatment is a loop diuretic.

[0154] In some embodiments, administration of an SGLT2 inhibitor to a patient results in one of the following outcomes: (i) prolonging the time to first heart failure (HF) event and / or fatal cardiovascular (CV) event; and / or (ii) reducing the worsening of heart failure symptoms; and / or (iii) reducing the number of heart failure events and / or reducing the incidence of fatal cardiovascular events This results in at least one of the following:

[0155] In some embodiments, a "HF event" is a hospitalization for HF or an emergency HF outpatient visit.

[0156] In some embodiments, hospitalization for HF includes a hospitalization lasting at least 24 hours with a primary diagnosis of HF.

[0157] In some embodiments, administration of an SGLT2 inhibitor reduces the total number of hospitalizations for HF, including initial and / or re-admissions.

[0158] In some embodiments, hospitalization for HF is due to one or more of the following criteria: (i) new or worsening symptoms of HF experienced by the patient; and / or (ii) objective evidence of new or worsening symptoms of HF; and / or (iii) initiation or intensification of HF specialty treatment. In some embodiments, hospitalization for HF is due to all of the above listed criteria. In some embodiments, new or worsening symptoms of HF experienced by the patient include dyspnea, decreased exercise tolerance, fatigue, and / or other symptoms of worsening end-organ damage or fluid overload. In some embodiments, objective evidence of new or worsening symptoms of HF includes physical examination findings considered attributable to HF and / or new or worsening HF laboratory values. In some embodiments, physical examination findings include at least two of the following findings: peripheral edema, increasing abdominal distension or ascites, pulmonary rales / crackles / crepitus, increased jugular venous pressure and / or hepatojugular reflux, S3 gallop, and / or clinically significant or rapid weight gain associated with fluid retention. In some embodiments, the new or worsening HF laboratory findings include at least one of the following: increased B-type natriuretic peptide (BNP) / N-terminal pro-BNP (NT-proBNP) concentrations consistent with heart failure decompensation; radiological evidence of pulmonary congestion; non-invasive diagnostic evidence of clinically significant elevated left or right ventricular filling pressures or low cardiac output or invasive diagnostic evidence by right heart catheterization. In some embodiments, the initiation or intensification of HF specialty therapy includes at least one of the following: increasing oral diuretic therapy, intravenous administration of diuretics or vasoactive agents, or mechanical or surgical intervention. Mechanical or surgical intervention includes mechanical circulatory support or mechanical fluid removal.

[0159] In some embodiments, an emergency HF visit is an emergency room visit for a primary diagnosis of HF, but does not require hospitalization. In some embodiments, an emergency HF visit is an urgent walk-in visit to a clinic for a primary diagnosis of HF. In some embodiments, the patient is experiencing HF symptoms and / or has physical examination findings and / or new or worsening HF laboratory values. In some embodiments, the patient experiences one or more symptoms of HF selected from the group consisting of dyspnea, decreased exercise tolerance, fatigue, and / or other symptoms of worsening end-organ damage or fluid overload. In some embodiments, the patient undergoes initiation or intensification of HF specialty treatment. In some embodiments, an emergency HF visit requires intravenous therapy.

[0160] In some embodiments, administration of an SGLT2 inhibitor extends the time to a fatal CV event.

[0161] In some embodiments, the time to first heart failure event and / or fatal cardiovascular event may be delayed by 6 to 24 months from the first administration of the SGLT2 inhibitor. In some embodiments, the time to first heart failure event may be delayed by 6 to 24 months from the first administration of the SGLT2 inhibitor. In some embodiments, the time to fatal cardiovascular event may be delayed by 6 to 24 months from the first administration of the SGLT2 inhibitor.

[0162] In some embodiments, administration of an SGLT2 inhibitor reduces the worsening of HF symptoms in a treated patient. In some embodiments, the reduced worsening of the patient's heart failure symptoms is over a period of 12 to 36 months.

[0163] In some embodiments, the reduced worsening of heart failure symptoms is characterized by a reduced number of hospitalizations for HF for the patient. In some embodiments, the reduced worsening of heart failure symptoms is characterized by a reduced number of emergency HF visits for the patient. In some embodiments, emergency HF visits are emergency room visits or emergency outpatient clinic visits.

[0164] In some embodiments, the reduced worsening of heart failure symptoms is characterized by a higher score of the patient based on the Kansas City Cardiomyopathy Questionnaire (KCCQ) compared to the patient's score before administration of the SGLT2 inhibitor. In some embodiments, the higher score based on the KCCQ appears within 8 months of starting administration of the SGLT2 inhibitor. In some embodiments, the higher score based on the KCCQ is at least 5 points higher than the score before administration of the SGLT2 inhibitor. In some embodiments, the higher score based on the KCCQ is at least 10 points higher than the score before administration of the SGLT2 inhibitor. In some embodiments, the higher score based on the KCCQ is at least 15 points higher than the score before administration of the SGLT2 inhibitor.

[0165] In some embodiments, the reduced worsening of heart failure symptoms is characterized by a higher score of the patient based on the Patient Global Impression of Change (PGIC) questionnaire compared to the patient's score before administration of the SGLT2 inhibitor. In some embodiments, the higher score based on the PGIC appears within 8 months of starting administration of the SGLT2 inhibitor. In some embodiments, the higher score based on the PGIC is at least 1 point higher than the score before administration of the SGLT2 inhibitor. In some embodiments, the higher score based on the PGIC is at least 2 points higher than the score before administration of the SGLT2 inhibitor. In some embodiments, the higher score based on the PGIC is at least 3 points higher than the score before administration of the SGLT2 inhibitor.

[0166] In some embodiments, the reduced worsening of heart failure symptoms is characterized by a higher score of the patient based on the Patient Global Impression of Severity (PGIS) questionnaire compared to the patient's score before administration of the SGLT2 inhibitor. In some embodiments, the higher score based on the PGIS appears within 8 months of starting administration of the SGLT2 inhibitor. In some embodiments, the higher score based on the PGIS is at least 1 point higher than the score before administration of the SGLT2 inhibitor. In some embodiments, the higher score based on the PGIS is at least 2 points higher than the score before administration of the SGLT2 inhibitor. In some embodiments, the higher score based on the PGIS is at least 3 points higher than the score before administration of the SGLT2 inhibitor.

[0167] In some embodiments, administration of an SGLT2 inhibitor reduces the number of HF events and / or reduces the incidence of fatal cardiovascular events.

[0168] In some embodiments, administration of an SGLT2 inhibitor reduces the number of HF events. In some embodiments, the HF events are hospitalizations for HF or emergency HF outpatient visits. In some embodiments, administration of an SGLT2 inhibitor reduces the number of HF hospitalizations. In some embodiments, administration of an SGLT2 inhibitor reduces the number of emergency HF outpatient visits. In some embodiments, the emergency HF outpatient visit is an emergency room visit. In some embodiments, the emergency HF outpatient visit requires intravenous therapy.

[0169] In some embodiments, administration of an SGLT2 inhibitor reduces the incidence of fatal cardiovascular events.

[0170] In some embodiments, administration of an SGLT2 inhibitor reduces the composite of hospitalization for HF or fatal cardiovascular events.

[0171] In some embodiments, administration of an SGLT2 inhibitor to adults with HFrEF reduces the risk of cardiovascular death and worsening heart failure, and improves heart failure symptoms.

[0172] In some embodiments, the HFrEF patient has an eGFR of > 30 ml / min / 1.73 m2 prior to administration of the SGLT2 inhibitor. In some embodiments, the HFrEF patient maintains an eGFR of > 30 ml / min / 1.73 m2 during administration of the SGLT2 inhibitor.

[0173] In some embodiments, the HFrEF patient has a plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) level of at least 400 pg per milliliter, at least 600 pg per milliliter, or at least 900 pg per milliliter prior to administration of the SGLT2 inhibitor.

[0174] In some embodiments, the patient has been medically diagnosed with symptomatic HFrEF prior to administration of the SGLT2 inhibitor. In some embodiments, the patient has been diagnosed with HFrEF at least 2 months prior to administration of the SGLT2 inhibitor.

[0175] In some embodiments, the HFrEF patient has atrial fibrillation and / or atrial flutter prior to administration of the SGLT2 inhibitor. In some embodiments, the HFrEF patient does not have atrial fibrillation or atrial flutter prior to administration of the SGLT2 inhibitor. In at least one embodiment, the methods disclosed herein reduce the incidence of atrial fibrillation in HFrEF patients who do not have atrial fibrillation or atrial flutter prior to administration of the SGLT2 inhibitor.

[0176] In some embodiments, administration of an SGLT2 inhibitor reduces HbA1c in a HFrEF patient. In some embodiments, administration of an SGLT2 inhibitor reduces systolic blood pressure in a HFrEF patient. In some embodiments, administration of an SGLT2 inhibitor reduces weight in a HFrEF patient. In certain embodiments, the disclosed methods result in a decrease in NT-proBNP levels in a patient. In some embodiments, this decrease occurs within 8 months of initiating administration of an SGLT2 inhibitor. In certain embodiments, the disclosed methods increase eGFR (ml / min / 1.73m) in a patient. 2 This results in a sustained drop in the

[0177] In some embodiments, administration of an SGLT2 inhibitor results in an improvement in NYHA HF classification.

[0178] In some embodiments, administration of an SGLT2 inhibitor results in a reduction in re-hospitalization for HF or a reduction in recurrent HF events, in some embodiments, a recurrent HF event comprises a hospitalization for HF or an emergency HF outpatient visit.

[0179] In some embodiments, administration of an SGLT2 inhibitor results in a reduced incidence of all-cause mortality, including cardiovascular and non-cardiovascular mortality, in patients with or without T2D. In some embodiments, administration of an SGLT2 inhibitor results in a reduced incidence of non-cardiovascular mortality.

[0180] In another aspect, the disclosure provides a method for reducing the rate of a primary composite endpoint of cardiovascular death, HF hospitalization, or emergency HF outpatient visit in HFrEF patients treated with an SGLT2 inhibitor and a HF standard of care, the rate being reduced relative to patients treated with HF standard of care alone. In another aspect, the disclosure provides a method for reducing the rate of a secondary composite endpoint of cardiovascular death or HF hospitalization in HFrEF patients treated with an SGLT2 inhibitor and a HF standard of care, the rate being reduced relative to patients treated with HF standard of care alone. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharma- ceutically acceptable salt, solvate, mixed solvate, complex, or prodrug thereof. In some embodiments, dapagliflozin is administered at 10 mg once daily.

[0181] In another aspect, the disclosure provides a method of preventing or delaying a fatal CV event in a patient with HFrEF without T2D, comprising administering to the patient an effective amount of an SGLT2 inhibitor as described herein.

[0182] The disclosure also provides a method of preventing or delaying a fatal CV event in a patient with HFrEF and T2D comprising administering to the patient an effective amount of an SGLT2 inhibitor as described herein.

[0183] In some embodiments, the SGLT2 inhibitor is dapagliflozin (FARXIGA®), canagliflozin (INVOKANA®), empagliflozin (JARDIANCE®), ertugliflozin (STEGLATRO®), sotagliflozin, or ipragliflozin, or a pharma- ceutically acceptable salt, solvate, mixed solvate, complex, or prodrug thereof.

[0184] In at least one embodiment, the SGLT2 inhibitor is dapagliflozin, as described herein. In some embodiments, the dapagliflozin is administered in a dose of 2.5 mg, 5 mg, or 10 mg once daily. In at least one embodiment, the dapagliflozin is administered in a dose of 10 mg once daily.

[0185] In another aspect, the disclosure also provides a method of reducing the total number of HF standard of care medications taken by a HFrEF patient without T2D, comprising administering to the patient an effective amount of an SGLT2 inhibitor as described herein.

[0186] The disclosure also provides a method of reducing the total number of HF standard of care medications taken by a HFrEF patient with T2D, comprising administering to the patient an effective amount of an SGLT2 inhibitor.

[0187] In some embodiments, administering an effective amount of an SGLT2 inhibitor to a HFrEF patient as described herein allows the patient to reduce the total number of HF standard of care medications the patient takes. In some embodiments, the total number of HF standard of care medications is reduced to 2, 3, or 4. Reducing the total number of HF standard of care medications a patient must take improves the health-related quality of life for HFrEF patients with and without TD2.

[0188] The following examples further illustrate the present disclosure but, of course, should not be construed as in any way limiting the scope of the disclosure. EXAMPLES

[0189] Example 1 DAPA-HF Phase III Clinical Trial Results Introduction Large clinical trials including participants with type 2 diabetes (T2D) have demonstrated that inhibitors of sodium-glucose cotransporter 2 (SGLT2) reduce the risk of heart failure (HF) hospitalization. 1~4 However, notably, most patients in these trials did not have HF at baseline, so the benefit of SGLT2i treatment was largely due to the prevention of incident HF events. Notably, the reduction in HF hospitalizations was observed early after randomization, raising the possibility of a different mechanism or mode of action than those typically hypothesized to explain the cardiovascular benefits of glucose-lowering therapy. 5~9 In addition to the diuretic and associated hemodynamic effects of SGLT2 inhibitors, effects on myocardial metabolism, ion transporters, fibrosis, adipokines and uric acid have also been demonstrated. 5~9 Most of these effects, as well as the preservation of renal function, would likely benefit patients with established heart failure (including those without diabetes) who have not been studied with SGLT2 inhibitors. 4、10、11

[0190] The DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) clinical trial was designed to evaluate the potential efficacy and safety of SGLT2 inhibitors in chronic heart failure (CHF) in patients with reduced ejection fraction (LVEF ≤ 40%), both with and without T2D. 12、13 In this example, results of a DAPA-HF Phase III clinical trial are provided.

[0191] method Clinical trial design and supervision AstraZeneca sponsored the trial and collected and analyzed the data. 12、13 The clinical trial was conducted and reported in accordance with the protocol and statistical analysis plan. The trial was approved by the ethical committees of each study site. The safety of patients participating in the trial was regularly reviewed by an independent data monitoring committee. The sponsor's analyses were replicated by an independent academic group at the University of Glasgow.

[0192] Study patients Eligibility requirements included age at least 18 years, New York Heart Association (NYHA) class II, III, or IV symptoms, and an ejection fraction of 40% or less. Patients were required to have a plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) level of at least 600 pg per milliliter or NT-proBNP of at least 400 pg per milliliter if the patient had been hospitalized for heart failure within the past 12 months. Patients with atrial fibrillation or atrial flutter on baseline electrocardiogram were required to have an NT-proBNP level of at least 900 pg / mL, regardless of history of hospitalization for heart failure. Patients were required to receive standard medications and device therapy for heart failure, including angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor antagonists (ARBs), or sacubitril / valsartan; beta-blockers unless contraindicated or intolerable, and mineralocorticoid receptor (MR) drugs, if deemed appropriate. Doses were individually optimized according to guideline-recommended targets and were required to be stable for at least 4 weeks (excluding diuretics, which could be flexibly dosed). Investigators were advised that type 2 diabetes patients should continue taking their glucose-lowering medications, but these could be adjusted if necessary. In particular, the protocol stated that, for example, to minimize the risk of hypoglycemia in patients with baseline hemoglobin A1c (HbA1c) levels below 7%, the dose of insulin, sulfonylurea medication, or both could be reduced.

[0193] Exclusion criteria included recent treatment with or intolerance to SGLT2 inhibitors, type 1 diabetes mellitus, symptoms of hypotension or systolic blood pressure less than 95 mm Hg, recent worsening heart failure or other cardiovascular events or surgery (or planned surgery), and a body surface area of ​​1.73 m 2 Estimated glomerular filtration (eGFR) of less than 30 ml per minute (or a rapid decline in renal function) was included.

[0194] Clinical trial procedures After providing all written informed consent, patients entered a 14-day enrollment period during which study inclusion and exclusion criteria were reviewed and baseline information was collected, including findings from clinical and laboratory measurements. After this period, patients were randomly assigned to receive dapagliflozin 10 mg or matching placebo once daily according to a sequestered fixed randomization schedule, with counterbalanced blocks to ensure a near 1:1 ratio of the two treatments. Investigators performed treatment assignments using an automated voice or web response system. Randomization was stratified based on the diagnosis of type 2 diabetes, defined as either a confirmed diagnosis or a central laboratory-confirmed HbAlc value of 6.5% or greater (≥48 mmol / mol) at screening. Patients were evaluated 14 and 60 days after randomization, focusing on evaluation of heart failure and volume status, adverse events, and renal function and potassium tests. Further study visits were performed at 4 months and every 4 months thereafter. The protocol required that any further study drug be discontinued if pregnancy- or diabetic ketoacidosis occurred. In the event of (or to avoid) any sudden unexpected decline in eGFR, volume depletion, or hypotension, dose reduction (to dapagliflozin 5 mg per day or matching placebo) or temporary interruption was permitted, with subsequent dose escalation (or resumption of treatment) encouraged, if possible.

[0195] Clinical Trial Evaluation Items The primary outcome was a composite of a first episode of worsening heart failure or death from cardiovascular causes. An episode of worsening heart failure was either an unplanned hospitalization for heart failure or an emergency heart failure outpatient visit requiring intravenous therapy. 14 The first secondary outcome was a composite of heart failure hospitalization or cardiovascular death. Other secondary outcomes were: total number of recurrent heart failure hospitalizations (including rehospitalizations) and cardiovascular death; change from baseline to 8 months in Kansas City Cardiomyopathy Questionnaire (KCCQ) total symptom score using a 0 to 100 scale (higher scores indicate fewer symptoms, and a change of ≥ 5 points is considered clinically important). 15 ≥ 50% sustained decline in eGFR, end-stage renal disease (sustained eGFR < 15 mL / min / 1.73 m 2 the incidence of a composite outcome of worsening renal function, consisting of continued renal function (defined as continued dialysis treatment, or kidney transplant) or renal death; and death from any cause; in all cases, persistent meant lasting at least 28 days. 12

[0196] End points were determined according to prespecified criteria by a clinical endpoint committee blinded to treatment allocation.

[0197] statistical analysis A hazard ratio (HR) of 0.80 for dapagliflozin compared with placebo was estimated for the primary endpoint. Using a two-sided alpha of 5%, we calculated that 844 primary endpoints would provide 90% power for hypothesis testing. With an expected annual event rate of 11% in the placebo treatment group, we estimated that approximately 4500 patients would result in the required number of primary events, based on an expected recruitment period of 18 months and a mean follow-up period of approximately 24 months. Closed testing procedures were used, including prespecified hierarchical testing of the primary and secondary endpoints in the order specified above. Type I error was controlled at a two-sided 0.0499 alpha level for multiplicity across the primary and secondary endpoints, and one intermediate effect analysis was considered.

[0198] Data from all randomized patients were entered into the primary and secondary endpoint analyses according to the intention-to-treat principle. Baseline characteristics were summarized as means and standard deviations, medians and interquartile ranges or percentages. Longitudinal measures, such as glycosylated hemoglobin levels (HbAlc) and weight, were analyzed using mixed models for repeated measures to estimate least-squares mean differences between treatment groups with 95% confidence intervals. Time-to-event data were evaluated using Kaplan-Meier estimates and Cox proportional hazards models, stratifying by diabetes status with history of hospitalization for heart failure and treatment history as fixed-effect factors (for renal endpoints, baseline eGFR was introduced instead of history of hospitalization for heart failure); hazard ratios, 95% confidence intervals and two-sided P values ​​were calculated using Cox models.

[0199] Total events (including recurrences) were analyzed using semiparametric proportional rate models to examine treatment effects and to quantify treatment differences. 16

[0200] KCCQ total symptom scores were analyzed as a composite rank-based endpoint incorporating patient vital status at 8 months, along with the change in score from baseline to 8 months in surviving patients, using the rank analysis of covariance method with the corresponding win ratio used to estimate the magnitude of treatment effect. 17Consistency of treatment effects among the 14 prespecified arms was assessed. Prespecified safety analyses included: serious adverse events; adverse events related to discontinuation of study treatment; "adverse events of interest" i.e. volume depletion, renal events, major hypoglycemic events, fractures, diabetic ketoacidosis, amputation; Fournier's gangrene; and laboratory studies of note. Other adverse events were not routinely collected given the large amount of historically collected data consisting of historical safety data on dapagliflozin. Safety analyses were performed for patients who underwent randomization and received at least one dose of dapagliflozin or placebo. Adverse event rates were compared using Fisher's exact test. Analyses were performed using Stata, version 15 (College Station TX, USA) and R version 3.5.1 (R Foundation for Statistical Computing, Vienna, Austria).

[0201] result Patients Between February 15, 2017 and August 17, 2018, 4744 patients were randomized to receive dapagliflozin 10 mg once daily or matching placebo at 410 sites in 20 countries ( Figure 1 ). Patient characteristics and heart failure treatments were well balanced between study arms at baseline ( Table 1 ).

[0202] [Table 1]

[0203] [Table 2]

[0204] Study Drug Administration and Follow-up Excluding discontinuations due to death, 249 patients (10.5%) receiving dapagliflozin and 258 patients (10.9%) receiving placebo discontinued the study drug (P = .71). At the last evaluation, of the patients taking study drug, 2039 (98.1%) in the dapagliflozin group were maintained on 10 mg daily; 1993 (98.2%) received an equivalent dose of placebo. At the end of the study, there were no patients in the dapagliflozin group and two in the placebo group whose vital status was unknown (Figure 1). The median follow-up was 18.2 months.

[0205] Study Evaluation Items Worsening heart failure events or death from cardiovascular causes (primary end point) occurred in 386 patients (16.3%) in the dapagliflozin group and 502 patients (21.2%) in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.65 to 0.85; P < 0.001 (Figure 2A and Table 2). Event rates for all three components of the composite end point favored dapagliflozin; the most common worsening heart failure event was hospitalization (Figure 2 and Table 2). Of patients receiving dapagliflozin, 231 (9.7%) were hospitalized for heart failure, compared with 1.6% in the placebo group. and 318 (13.4%) patients receiving placebo (hazard ratio, 0.70; 95% CI, 0.59 to 0.83; P < 0.001) (Fig. 2B and Table 2). Death from cardiovascular causes occurred in 227 patients (9.6%) in the dapagliflozin group and in 273 patients (11.5%) in the placebo group (hazard ratio, 0.82; 95% CI, 0.69 to 0.98; P < 0.03) (Fig. 2C and Table 2). Over the course of the trial, the number of patients who would have needed to be treated with dapagliflozin to prevent one major event was 21.

[0206] The secondary outcome of heart failure hospitalization or death from cardiovascular causes was reduced with dapagliflozin (hazard ratio, 0.75; 95% CI, 0.65 to 0.85; P<0.001) (Figure 2). There were a total of 567 first and recurrent events in the dapagliflozin arm (340 heart failure hospitalizations and 227 cardiovascular deaths in 382 patients) and 742 events in the placebo arm (469 heart failure hospitalizations and 273 cardiovascular deaths in 495 patients), yielding a ratio of 0.75 (95% CI, 0.65, 0.88; P<0.001) (Table 2).

[0207] The KCCQ total symptom score increased from baseline to 8 months by a median of 6.1 ± 18.6 points in the dapagliflozin group and 3.3 ± 19.2 points in the placebo group (between-group difference, 2.8 points; 95% CI, 1.6 to 4.0 (Winn ratio, 1.18; 95% CI, 1.11, 1.26; P < .001) (Table 2). Compared with placebo, more patients in the dapagliflozin group had a score improvement of 5 or more points (58% vs. 51%; OR 1.15, 95% CI, 1.08, 1.23; P < .001) and fewer had a worsening (25% vs. 33%; OR 0.84, 95% CI, 0.78, 0.90; P < .001).

[0208] The prespecified renal composite end point occurred in 28 patients (1.2%) receiving dapagliflozin and in 39 patients (1.6%) receiving placebo (hazard ratio, 0.71; 95% CI, 0.44 to 1.16; P = 0.17) ( Table 2 ).

[0209] In total, 276 patients (11.6%) in the dapagliflozin group and 329 patients (13.9%) in the placebo group died from any cause (hazard ratio, 0.83; 95% CI, 0.71 to 0.97) (Figure 2D and Table 2). The effect of dapagliflozin on heart failure worsening and death is summarized in Figure 3.

[0210] The effect of dapagliflozin on the primary outcome was generally consistent across prespecified subgroups, including patients without diabetes at baseline, but the benefit was less in patients with NYHA functional class III and IV compared with class II (Figure 4). In a post hoc subgroup analysis of patients taking sacubitril-valsartan at baseline, the dapagliflozin-versus-placebo hazard ratio for the primary outcome was 0.75 (95% CI, 0.50, 1.13) compared with 0.74 (0.65, 0.86) in patients not taking sacubitril-valsartan.

[0211] [Table 3]

[0212] [Table 4]

[0213] Other evaluation items Changes from baseline to 8 months in glycosylated hemoglobin, hematocrit, plasma potassium, systolic blood pressure, and body weight are shown in Table 3. Mean creatinine concentrations increased from baseline to 2 weeks in the dapagliflozin group by 0.08 ± 0.19 mg per deciliter and in the placebo group by 0.01 ± 0.17 mg per deciliter (between-group difference, 0.07 mg per deciliter; 95% CI, 0.05 to 0.08; P < 0.001); the corresponding changes at 8 months were 0.07 ± 0.24 and 0.04 ± 0.25 mg per deciliter, respectively (difference, 0.02 mg per deciliter; 95% CI, 0.01 to 0.04; P = 0.04). The mean creatinine concentration increased from baseline to 2 weeks in the dapagliflozin group by 0.08 ± 0.19 mg per deciliter and in the placebo group by 0.01 ± 0.17 mg per deciliter (between-group difference, 0.07 mg per deciliter; 95% CI, 0.05 to 0.08; P < 0.001); the corresponding changes at 8 months were 0.07 ± 0.24 and 0.04 ± 0.25 mg per deciliter, respectively (difference, 0.02 mg per deciliter; 95% CI, 0.01 to 0.04; P = 0.04). The mean mean creatinine concentration increased from baseline to 2 weeks in the dapagliflozin group by 0.08 ± 0.19 mg per deciliter and in the placebo group by 0.01 ± 0.17 mg per deciliter (between-group difference, 0.07 mg per deciliter; 9 2 The change in eGFR per day was also measured and is shown in Figures 15 and 16.

[0214] [Table 5]

[0215] safety Prespecified safety outcomes of particular interest are shown in Table 2. Five patients assigned to dapagliflozin and three assigned to placebo did not receive study drug and were therefore excluded from the safety analysis. In the dapagliflozin group, 178 patients (7.5%) had adverse events related to volume depletion compared with 162 patients (6.8%) assigned to placebo (P = .40). Serious adverse events related to volume depletion occurred in 29 dapagliflozin-treated patients (1.2%) and 40 patients (1.7%) in the placebo group (P = .23).

[0216] Adverse events related to renal insufficiency occurred in 153 patients (6.5%) in the dapagliflozin group versus 170 patients (7.2%) in the placebo group (P = .36) (Table 2). Serious renal adverse events occurred in 38 dapagliflozin-treated patients (1.6%) and 65 patients (2.7%) in the placebo group (P = .009).

[0217] Adverse events requiring discontinuation of treatment were rare (Table 2). Lower limb amputations and fractures occurred only rarely, and the incidence of each was similar in the two treatment groups (Table 2). Life-threatening hypoglycemia (4 patients in the dapagliflozin group and 4 in the placebo group) and diabetic ketoacidosis (3 vs. 0) were also rare (Table 2). There were no cases of Fournier's gangrene reported in the dapagliflozin group compared with 1 in the placebo group. There was no significant excess of any serious adverse events (SAEs) in the dapagliflozin group.

[0218] Essay In this multicenter, randomized, placebo-controlled trial of patients with chronic heart failure with reduced ejection fraction, dapagliflozin reduced the risk of the primary composite endpoint of a first episode of worsening heart failure (hospitalization for heart failure or emergency heart failure outpatient visit requiring intravenous therapy) or death from cardiovascular causes. Each of the three components of this endpoint was reduced, as were the combined numbers of heart failure hospitalizations and death from cardiovascular causes. Dapagliflozin also improved heart failure symptoms, as measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ) total symptom score. The observed benefits, which were substantial and clinically important, occurred early after randomization and were obtained in participants receiving recommended background therapy for heart failure, including renin-angiotensin system blockers, beta-blockers, and mineralocorticoid receptor antagonists in a high proportion of patients.

[0219] Notably, dapagliflozin was effective in 55 percent of patients without type 2 diabetes, as well as in participants with diabetes. This first demonstration of the cardiovascular benefits of an SGLT2 inhibitor in patients without diabetes lends support to previous suggestions that this type of treatment may have beneficial effects beyond lowering blood glucose. 4~11 Thus, insights gained from DAPA-HF may potentially extend the therapeutic role of dapagliflozin beyond diabetes.

[0220] Reductions in the primary endpoint were generally consistent across the remaining prespecified subgroups, although one subgroup showed smaller benefits in patients with NYHA functional classes III and IV compared with class II, suggesting that the treatment effect may be heterogeneous. However, other subgroups that also exhibited more advanced disease, such as lower ejection fraction, worsening renal function, and higher NT-proBNP, were not consistent with the NYHA class findings.

[0221] The population studied in the DAPA-HF trial differed considerably from previous SGLT2 inhibitor trials in that DAPA-HF patients were at much higher risk for heart failure hospitalization and cardiovascular death. Because most patients were already treated with loop diuretics and mineralocorticoid receptor antagonists, it was unclear whether dapagliflozin would cause the expected initial natriuresis and diuresis observed in other patient groups. These effects could lead to volume depletion and worsening renal function, especially since many of the present patients had chronic kidney disease. Neither of these two adverse effects was common (occurring in less than 8 percent of patients in each treatment group, respectively), and serious renal adverse events were generally rare and significantly less frequent in the dapagliflozin group. Overall, very few patients discontinued study treatment due to either adverse event (less than 5 percent in either treatment group). Life-threatening hypoglycemia was rare, as was diabetic ketoacidosis, and all cases of both adverse events occurred in patients with coexisting diabetes.

[0222] Baseline use of sacubitril-valsartan, which is more effective than renin-angiotensin system blockade alone in reducing heart failure hospitalizations and death from cardiovascular causes, was low. 18 However, the hypothesized mechanisms of action of SGLT2 inhibition and neprilysin inhibition are different, and in post hoc subgroup analyses, the benefit of dapagliflozin was similar in patients treated with and without sacubitril-valsartan. 19、20

[0223] In conclusion, the SGLT2 inhibitor dapagliflozin reduced the risk of worsening heart failure and cardiovascular mortality and improved symptoms in patients with heart failure and low ejection fraction, including those without type 2 diabetes.

[0224] References : 1Zinman B.et al.,“Empagliflozin,Cardiovascular Outcomes,and Mortality in Type 2 Diabetes,”N Engl J Med.373(22):2117-2128(2015). 2 Neal B.et al.,“Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes,”N Engl J Med.377(7):644-657(2017). 3 Wiviott S.D.et al.,“Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes,N Engl J Med.380:347-357(2019). 4 Perkovic V.et al.,Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy,N Engl J Med.380:2295-2306(2019). 5 Packer M.et al.,“Effects of Sodium-Glucose Cotransporter 2 Inhibitors for the Treatment of Patients With Heart Failure:Proposal of a Novel Mechanism of Action,”JAMA Cardiol.2(9):1025-1029(2017). 6 Verma S.and McMurray J.J.V.,“SGLT2 inhibitors and mechanisms of cardiovascular benefit:a state-of-the-art review,”Diabetologia 61(10):2108-2117(2018). 7Inzucchi S.E.et al.,“Improvement in Cardiovascular Outcomes With Empagliflozin Is Independent of Glycemic Control,”Circulation 138(17):1904-1907(2018). 8 Lytvyn Y.et al.,“Sodium Glucose Cotransporter-2 Inhibition in Heart Failure:Potential Mechanisms,Clinical Applications,and Summary of Clinical Trials,”Circulation 136(17):1643-1658(2017). 9 Bonnet F.and Scheen A.J.,“Effects of SGLT2 inhibitors on systemic and tissue low-grade inflammation:The potential contribution to diabetes complications and cardiovascular disease,”Diabetes Metab.44:457-464(2018). 10 Wanner C.et al.,“Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes,”N Engl J Med.375:323-334(2016). 11 Zelniker T.A.et al.,“SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes:a systematic review and meta-analysis of cardiovascular outcome trials,”Lancet 393:31-39(2019). 12 McMurray J.J.V.et al.,“DAPA-HF design paper - A trial to evaluate the effect of the sodium glucose co-transporter 2 inhibitor dapagliflozin on morbidity and mortality in patients with heart failure and reduced left ventricular ejection fraction(DAPA-HF),Eur J Heart Fail.21:665-675(2019). 13 McMurray J.J.V.et al.,“The Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure(DAPA-HF) trial:baseline characteristics,”Eur J Heart Fail.,doi:10.1002 / ejhf.1548.[Epub ahead of print](2019 Jul 15). 14 Hicks K.A.et al.,“Standardized Data Collection for Cardiovascular Trials Initiative(SCTI)2017 Cardiovascular and Stroke Endpoint Definitions for Clinical Trials,”Circulation 137:961-972(2018). 15 Green C.P.,“Development and evaluation of the Kansas City Cardiomyopathy Questionnaire:a new health status measure for heart failure,”J Am Coll Cardiol.35:1245-1255(2000). 16Lin DYet al., “Semiparametric regression for the mean and rate functions of recurrent events,” JR Stat Soc Series B Stat Methodol 62:711-730(2000). 17 Wang D. and Pocock S., “A win ratio approach to comparing continuous non-normal outcomes in clinical trials.” Pharm Stat.15:238-245(2016). 18 McMurray JJet al., “Angiotensin-neprilysin inhibition versus enalapril in heart failure,” N Engl J Med.371:993-1004 (2014). 19 McMurray JJ, “Neprilysin inhibition to treat heart failure: a tale of science, serendipity, and second chances,” Eur J Heart Fail.17:242-247 (2015). 20 Packer M.,”Reconceptualization of the Molecular Mechanism by Which Sodium-Glucose Cotransporter 2 Inhibitors Reduce the Risk of Heart Failure Events,”Circulation 140:443-445(2019).

[0225] Example 2 DAPA-HF Phase III Clinical Trial Results - Effect of Dapagliflozin on HF Symptoms, Health Status, and Quality of Life Introduction Patients with HF and HFrEF are at high risk for disease progression leading to clinical deterioration, repeated hospitalizations, and death. Bui, AL et al., Nat Rev Cardiol 8:30-41 (2011). Importantly, these patients also experience a high burden of debilitating symptoms that impact their daily functioning and quality of life. Indeed, some therapeutic agents for HFrEF that have favorable effects on mortality and hospitalizations do not improve health status (Reddy, P. and Dunn, AB, Pharmacotherapy 20:679-689 (2000)), highlighting the high unmet need for alternative effective therapies that not only improve clinical events but also reduce symptom burden and physical limitations, as well as improve quality of life. Indeed, improving patient health status is a major goal of heart failure management and is increasingly recognized by clinical practice guidelines (Tsevat, J. et al., J Gen Intern Med. 9:576-582 (1994); Lewis, EF et al., J Heart Lung Transplant 20:1016-1024 (2001)) and is recognized as an important endpoint by regulatory agencies. US FDA, “Treatment for Heart Failure: Endpoints for Drug Development Guidance for Industry,”https: / / wwwfdagov / regulatory-information / search-fda-guidance-documents / treatment-heart-failure-endpoints-drug-development-guidance-industry(2019).

[0226] In the DAPA-HF trial described in Example 1, the SGLT2 inhibitor dapagliflozin added to other guideline-recommended therapies reduced the risk of mortality and HF hospitalization and improved symptoms in 4,744 patients with HFrEF. See also McMurray, JJV et al., N Engl J Med, doi:10.1056 / NEJMoa1911303 [Epub ahead of print] (2019 Sep 19); McMurray, JJV et al., Eur J Heart Fail 21:665-675 (2019); McMurray JJV et al., Eur J Heart Fail., doi:10.1002 / ejhf.1548. [Epub ahead of print] (2019 Jul 15) (incorporated by reference in their entireties). To better understand the effects of dapagliflozin on a broad range of health outcome measures, we examined its effects on different domains of the KCCQ, a validated self-administered instrument that quantifies heart failure-related symptoms, function, and quality of life.

[0227] method The design, baseline characteristics and primary outcomes of the DAPA-HF trial were as described in Example 1 and McMurray, JJV et al., N Engl J Med, doi:10.1056 / NEJMoa1911303[Epub ahead of print](2019 Sep 19); McMurray, JJV et al., Eur J Heart Fail 21:665-675(2019); and McMurray JJV et al., Eur J Heart Fail., doi:10.1002 / ejhf.1548.[Epub ahead of print](2019 Jul 15). The primary endpoint of the DAPA-HF trial was a composite of episodes of worsening heart failure (HF hospitalization or emergency HF outpatient visit) or cardiovascular (CV) death (whichever occurred first). Additional clinical endpoints evaluated were the occurrence of HF hospitalization or CV death; HF worsening events (HF hospitalization or emergency HF outpatient visit), hospitalization for HF, cardiovascular death, and all-cause mortality.

[0228] Kansas City Cardiomyopathy Questionnaire The KCCQ was completed electronically by patients (as verified) without assistance from local study staff and was assessed at randomization, 4 months and 8 months. The KCCQ is a 23-item, self-administered disease-specific instrument that quantifies symptoms (frequency, severity and recent changes) over the past 2 weeks, physical functioning, quality of life and social functioning. In the KCCQ, the Total Symptom Score (TSS) quantifies symptom frequency and severity, the KCCQ Clinical Summary Score (KCCQ-CSS) includes the physical functioning and symptom domains and the KCCQ Overall Summary Score (OSS) is derived from the following domains (total symptom score, physical functioning, quality of life and social functioning). For each domain, validity, reproducibility, responsiveness and interpretability have been established independently. Scores are converted to a range of 0 to 100, where higher scores represent better health status.

[0229] statistical analysis In this study, patients were divided into three subgroups based on baseline KCCQ-TSS (which was a prespecified KCCQ domain as a secondary endpoint) tertiles: (i) ≤65.6, (ii) 65.7–87.5, and (iii) >87.5 points. Baseline characteristics were summarized as means and standard deviations, medians and interquartile ranges or percentages. Rates of CV mortality and HF worsening (independent of treatment allocation) across KCCQ-TSS tertiles were calculated and compared using Kaplan-Meier estimates.

[0230] To compare the effects of dapagliflozin versus placebo on clinical endpoints across KCCQ-TSS tertiles, we evaluated time-to-event data using Kaplan-Meier estimates and calculated hazard ratios, 95% confidence intervals, and two-sided P values ​​using Cox proportional hazards models, stratified by diabetes status with history of HF hospitalization and treatment group allocation as fixed-effect factors.

[0231] Mixed models for repeated measures were used to analyze the differences between treatment groups in mean KCCQ-TSS, CSS and OSS at 4 and 8 months in surviving patients, estimating least squares mean differences between treatment groups adjusted for baseline values. Responder analyses were performed looking at the proportion of patients with worsening and clinically important improvement in the KCCQ at 8 months. For all responder analyses across this KCCQ domain, the established clinically important thresholds for the KCCQ (≥ 5 points (at least small), ≥ 10 points (moderate) and ≥ 15 points (large) change) were used. To account for missing KCCQ values, multiple imputation was used to compare the proportion of responders between patients treated with dapagliflozin versus placebo (see below).

[0232] Odds ratios and their corresponding 95% confidence intervals and two-sided P values ​​for estimating differences between treatment groups were estimated from logistic regression models including treatment group, stratification variable (T2D at randomization) and baseline KCCQ value; these models used imputed data to account for missing KCCQ values ​​and fitted estimates using Rubin's rule. Missing data were imputed using random missing assumptions and predictive mean matching multiple imputation models and the method of fully conditional specification implemented in SAS Procedure MI (FCS statement). Imputation models included categorical variables representing treatment group, type 2 diabetes randomization strata, baseline, 4-month and 8-month KCCQ scores and number of investigator-reported HF events (0, 1, ≥2 events) in the intervals from randomization to 4 months and 4-8 months. Death was handled by assigning the lowest value. Patients with baseline KCCQ scores that were too high for them to experience improvement according to a particular threshold (e.g., baseline score ≥ 95 points for a 5-point threshold) were defined as improved if their scores remained high (i.e., ≥ 95 points) at 8 months. Similarly, patients with baseline KCCQ scores that were too low for them to experience deterioration were defined as worsened if their scores remained low at 8 months. All analyses were performed using STATA version 15.1 (College Station, TX, USA) and SAS version 9.4 (SAS Institute, Cary, NC, USA). A P value of 0.05 was considered statistically significant.

[0233] result Overall, 4744 patients were randomized. Baseline KCCQ TSS was available for 4443 (93.7%) patients. Median KCCQ TSS was 77.1 (IQR 58.3-91.7). Numbers and percentages of patients in KCCQ TSS tertiles are shown in Table 4.

[0234] [Table 6]

[0235] [Table 7]

[0236] Patient characteristics Compared with participants with higher baseline KCCQ-TSS scores, participants with lower scores were younger, more frequently female, white, and enrolled in Europe and the Americas. These participants also had higher body mass index and natriuretic peptide values; and lower eGFR (Table 4); and were more likely to be in NYHA functional class III / IV and to have type 2 diabetes and atrial fibrillation than class II. With regard to basal HF therapy, patients with low baseline KCCQ-TSS were more frequently treated with mineralocorticoid receptor antagonists (MRAs) and diuretics. Baseline use of angiotensin receptor neprilysin inhibitors (ARNIs) was generally low but similar across age groups. The proportion of patients treated with implantable cardiac devices was generally comparable across KCCQ-TSS subgroups.

[0237] Clinical endpoints Patients with lower baseline KCCQ-TSS experienced higher rates of CV mortality or HF deterioration (25.0%, 17.3%, and 13.6% for patients across KCCQ-TSS tertiles of ≦65.6, 65.7-87.5, and >87.5, respectively; p<0.001). In Cox proportional hazards models, patients with lower baseline KCCQ-TSS had a higher risk of CV mortality or HF deterioration (tertile >87.5: referent; tertile 65.7-87.5: HR 1.30 (95% CI: 1.08-1.56), p=0.006; tertile ≦65.6: HR 1.93 (95% 1.62-2.30), p<0.001; Figure 5).

[0238] The effect of dapagliflozin on the range of clinical endpoints is summarized in Figure 6. Dapagliflozin reduced the primary endpoint of CV death or worsening HF across the entire range of KKCQ-TSS scores, and there was no evidence of treatment effect heterogeneity (HR (95% CI) from lowest to highest tertile: 0.70 (0.57-0.86), 0.77 (0.61-0.98), and 0.62 (0.46-0.83), respectively; P for heterogeneity = 0.52). Similar results were observed for CV death or hospitalization for HF; worsening HF events; HF hospitalization; CV death; and all-cause mortality (Figure 6; all P values ​​for heterogeneity non-significant).

[0239] Health status evaluation items The mean changes in KCCQ-TSS, CSS, and OSS over time are shown in Figures 7A, 7B, and 7C, respectively. Patients treated with dapagliflozin had modest but significant improvements in mean KCCQ-TSS, CSS, and OSS at 4 months (1.9, 1.8, and 1.7 points higher than placebo, respectively; P<0.0001 for all). These beneficial effects amplified over time, with the corresponding mean differences at 8 months being 2.8, 2.5, and 2.3 points higher for dapagliflozin versus placebo (P<0.0001 for all).

[0240] The results of the responder analysis are shown in Figures 8A-8F. Fewer patients treated with dapagliflozin had a clinically beneficial worsening (≥ 5-point drop in KCCQ-TSS (25.3% vs. 32.9%; OR 0.84, 95% CI 0.01–0.25; P = .01). 0.78-0.90; p<0.0001); more patients treated with dapagliflozin had at least small (58.3% vs. 50.9%), moderate (54.5% vs. 47.6%) and large (54.0% vs. 48.2%) improvements (corresponding odds ratios (OR), 95% CI: 1.15, (1.08-1.23); 1.15 (1.08-1.22); 1.14 (1.07-1.22); number needed to treat (NNT) = 14 (10-23), 15 (11-25) and 18 (12-35), respectively; P<0.0001 for all; Figures 8A-8B). These findings were similar for the KCCQ-CSS and OSS (Figures 8C-8F).

[0241] Essay In this prospective study evaluating prespecified health status outcomes using the KCCQ in the DAPA-HF trial, treatment with dapagliflozin reduced the risk of all major clinical events, including the primary composite endpoint of CV death or HF worsening and its components, to a similar extent across the baseline KCCQ range, indicating that the beneficial effects of dapagliflozin on HF outcomes are independent of baseline impaired health status. Furthermore, dapagliflozin significantly improved KCCQ-TSS, CSS, and OSS (a composite of disability, physical function, quality of life, and social function), and these effects were amplified over time. Finally, significantly fewer patients treated with dapagliflozin experienced clinically important deterioration, and significantly more experienced at least small, moderate, and large clinically important improvements in health status. These effects were substantial, with the number needing treatment ranging from 12 to 18 after only 8 months of treatment.

[0242] These results have several important implications. First, analysis of clinical endpoints across baseline KCCQ-TSS subgroups shows no evidence of heterogeneity in the benefit of dapagliflozin by grade of baseline symptomatic impairment. A previously reported prespecified subgroup analysis of the primary endpoint (CV death or worsening HF) suggested that the benefit of dapagliflozin may be more pronounced in patients with NYHA functional class II compared with class III-IV. However, NYHA class, although prognostically important, represents a more subjective, arbitrary, and non-patient-centered assessment of symptom burden; given this report, the observations from the previous NYHA class subgroup analysis were likely opportunistic.

[0243] Second, the findings substantially elaborate the previously reported effects of dapagliflozin on health status, as measured by the KCCQ, in patients with HFrEF. In the Dapagliflozin Effects on Biomarkers, Symptoms, and Functional Status in Patients with Heart Failure with Reduced Ejection Fraction (DEFINE-HF) trial, a modestly sized randomized, placebo-controlled trial conducted at 26 centers in the United States, dapagliflozin also demonstrated favorable effects on several domains of the KCCQ, with mean differences for dapagliflozin versus placebo being somewhat larger than those observed in the DAPA-HF trial, although responder analyses and numbers needed to treat were comparable after only 12 weeks of treatment. Nassif, ME et al., Circulation 140:1463-1476 (Sept. 2019). These findings confirm the above-mentioned beneficial effects on symptoms, function, and quality of life in a much larger global trial with a longer follow-up period. Overall, findings from both the DEFINE-HF and DAPA-HF trials indicate that dapagliflozin significantly improves heart failure-related health outcomes as measured by the KCCQ, and that these benefits are both early and sustained over the long term.

[0244] Third, the magnitude of improvement in the KCCQ observed with dapagliflozin versus placebo in the DAPA-HF trial compares favorably with other effective therapies for HFrEF. As an example, in the Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trial (SHIFT), ivabradine demonstrated a mean improvement in the KCCQ-OSS of 2.4 points and a mean improvement in the KCCQ-CSS of 1.8 points after 12 months of treatment. Ekman, I. et al., Eur Heart J 32:2395-2404(2011). In the PARADIGM-HF trial, Lewis,EF et al.Circ Heart Fail.10:doi:10.1161 / CIRCHEARTFAILURE.116.003430(2017), sacubitril-valsartan demonstrated 1.3 and 0.9 point improvements in KCCQ-OS and KCCQ-CS, respectively, versus enalapril after 8 months of treatment.In HF-ACTION, Flynn,KE et al.,JAMA 301:1451-1459(2009), exercise therapy for HFrEF resulted in a 1.9 point improvement in KCCQ-OSS. In the MADIT-CRT trial of cardiac resynchronization therapy (CRT) in patients with HFrEF and QRS widening, Veazie, PJ et al., J Am Coll Cardiol. 60:1940-1944 (2012), treatment with CRT resulted in improvements of 2.0, 2.0 and 2.4 points in KCCQ-TSS, CSS and OSS, respectively, in patients with left bundle branch block (LBBB), and no significant improvement in KCCQ in patients without LBBB. Although responder analyses have only been performed to date, the magnitude of benefit observed with dapagliflozin (e.g. number of procedures required) in the responder analysis of DAPA-HF also compares very favorably with previously observed results. Ekman, I. et al., Eur Heart J 32:2395-2404 (2011). The time needed to treat for clinically important improvement on the KCCQ is based on a comparison of dapagliflozin- and placebo-treated patients (who also experienced improvements in health status consistent with a sizable "placebo effect" observed in both our trial and in the DEFINE-HF trial).Thus, the magnitude of dapagliflozin effects on health outcomes in clinical practice (obviously without the use of placebo) may be greater than observed. Given the reduction in symptom burden and physical limitations and improved quality of life (major goals of HF management endorsed by clinical guidelines and regulatory agencies), our findings provide further support for dapagliflozin as a new treatment option for patients with HFrEF.

[0245] conclusion In the DAPA-HF trial, treatment with dapagliflozin reduced death and heart failure hospitalization across a range of baseline KCCQ values ​​while improving symptom burden, functional status, and quality of life in patients with HFrEF. Furthermore, dapagliflozin significantly increased the proportion of patients experiencing small, moderate, and large improvements in health status; these effects were sustained and clinically important.

[0246] Example 3 DAPA-HF Phase III Clinical Trial Results: Effects of Dapagliflozin on Clinical, Metabolic, Hemodynamic and Renal Endpoints in Patients with and without Diabetes Mellitus Introduction As described in Example 1, in the DAPA-HF trial, SGLT2 inhibition resulted in similar reductions in the primary endpoint of worsening HF events or death from cardiovascular causes in HF patients with and without diabetes. See also McMurray, JJV et al., Eur J Heart Fail 21:665-675 (2019); McMurray, JJV et al., N Engl J Med doi:10.1056 / NEJMoa1911303 [Epub ahead of print] (2019 Sep 19), which is incorporated by reference in its entirety. In the prespecified analyses described in this example, the efficacy and safety of dapagliflozin, along with metabolic and hemodynamic changes, are described in HF patients across a range of baseline glycated hemoglobin (also known as hemoglobin A1c or HbA1c) in DAPA-HF.

[0247] method Eligibility requirements, baseline characteristics and exclusion criteria for DAPA-HF study patients were as described in Example 1 and McMurray, JJV et al., Eur J Heart Fail 21:665-675 (2019); McMurray, JJV et al., N Engl J Med doi:10.1056 / NEJMoa1911303 [Epub ahead of print] (2019 Sep 19). Study procedures, study endpoints and statistical analyses were also as described in Example 1 and McMurray, JJV et al., Eur J Heart Fail 21:665-675 (2019); McMurray, JJV et al., N Engl J Med doi:10.1056 / NEJMoa1911303 [Epub ahead of print] (2019 Sep 19)).

[0248] Baseline classification of diabetes status Investigators recorded whether patients had a history of diabetes at the enrollment visit (Visit 1). Patients also had central laboratory measurements of glycated hemoglobin (HbAlc) levels at Visit 1 and again 14 (± 7) days later at Visit 2 (randomization visit). For this prespecified subgroup analysis, patients were classified as having diabetes if they had a history of diabetes or had glycated hemoglobin of at least 6.5% (≧48 mmol / mol) at both Visits 1 and 2. Patients with glycated hemoglobin levels <5.7% (<39 mmol / mol) at both Visits 1 and 2 were considered to have normal glycated hemoglobin. For the purposes of this study, patients with glycated hemoglobin levels ≧5.7% and <6.5% were considered to have prediabetes. Ibid.

[0249] result patient Baseline glycemic status Of the 4,744 patients enrolled, 2605 (55%) did not have diabetes. Of the remaining, 1983 (41.8%) had a history of diabetes at screening, and an additional 156 (3.3%) were found to have previously undiagnosed diabetes, i.e., glycated hemoglobin ≥ 6.5% at Visit 1 (enrollment) and Visit 2 (randomization). Of the 2605 patients without diabetes, 1748 (67.1%) had glycated hemoglobin values ​​≥ 5.7% at either Visit 1 or 2, and 839 patients (32.2%) had glycated hemoglobin values ​​< 5.7% at both Visits 1 and 2. In addition, 12 patients had only a single glycated hemoglobin measurement < 5.7%, and 6 patients were missing both baseline glycated hemoglobin measurements (these 18 were included in the normal hemoglobin group).

[0250] Patient characteristics by baseline glycemic status Baseline characteristics of patients with and without diabetes are shown in Table 5 and were well balanced within each patient group between patients assigned to dapagliflozin or placebo (Table 6). Patients without diabetes were less likely to be black and to have an ischemic etiology than patients with diabetes (Table 5). Mean body mass index, heart rate, systolic blood pressure, and NT-proBNP levels were lower in participants without diabetes compared with those with diabetes. Mean eGFR was higher in participants without diabetes compared with those with diabetes. Mean glycated hemoglobin level in patients without diabetes was 5.8% compared with 7.4% in patients with diabetes. Mean duration of diabetes was 7.41 years (IQR 2.75, 13.5).

[0251] At baseline, both NYHA functional class and KCCQ-TSS were superior in patients without diabetes compared with patients with diabetes.

[0252] [Table 8]

[0253] [Table 9]

[0254] [Table 10]

[0255] [Table 11]

[0256] [Table 12]

[0257] [Table 13]

[0258] [Table 14]

[0259] Evaluation items Baseline glycemic status endpoints Patients without diabetes had lower prespecified mortality and worsening HF rates (Table 7, Figures 9A-9D, and Figure 10A). Among patients without diabetes, endpoint rates were highest in those in the upper third of baseline glycated hemoglobin (≥6.0%), i.e., individuals with prediabetes (Figure 10A). The risk of the renal composite endpoint was also lower in participants without diabetes (Figure 14). In contrast, the overall change from baseline in KCCQ-TSS did not differ between patients with or without diabetes.

[0260] [Table 15]

[0261] [Table 16]

[0262] Effect of dapagliflozin versus placebo by baseline glycemic status The effects of dapagliflozin on the primary composite outcome and on the individual mortality and hospitalization outcomes, as well as emergency department visits due to worsening heart failure requiring intravenous therapy, are shown in Table 7 and Figure 10B. The effect of dapagliflozin on each outcome was similar in patients with and without diabetes, as was the effect of the study drug on the renal composite outcome.

[0263] Among patients without diabetes at baseline, when divided into three equal groups, the effect of dapagliflozin on the primary outcome was consistent across the range of glycated hemoglobin (Figure 10A). Notably, for patients in the bottom third (glycated hemoglobin values ​​≤ 5.6%), the dapagliflozin vs placebo hazard ratio was 0.74 (95% CI 0.53, 1.04), compared with 0.71 (0.48, 1.04) for those in the middle third (> 5.6 to < 6.0%) and 0.72 (0.52, 1.00) for those in the top third (≥ 6.0%); P interaction = 0.837. A separate analysis using glycated hemoglobin as a continuous variable demonstrated the benefit of dapagliflozin across the range included (Figures 12A-12D).

[0264] From baseline to 8 months, KCCQ-TSS increased by 2.2 (95% CI 0.7 to 3.7) points with dapagliflozin compared with placebo in patients without diabetes and by 3.5 (95% CI 1.6 to 5.4) points in patients with diabetes; P interaction = 0.176 (Table 7).

[0265] In individuals without diabetes, more patients in the dapagliflozin group than in the placebo group self-reported an increase of at least 5 points on the KCCQ-TSS (57.7% vs. 51.7%; odds ratio 1.12 (95% CI 1.03, 1.22), and fewer patients reported a significant worsening (26.0% vs. 31.3%; odds ratio 0.88 (0.81, 0.97); P<0.01 for both comparisons. Corresponding rates in individuals with diabetes were: ≥5-point improvement-58.9% vs. 49.9% odds ratio 1.20 (1.09, 1.31); and worsening 24.5% vs. 34.8% odds ratio, 0.78 (0.71, 0.87); P<0.001 for both comparisons (P=0.294 for exchange effect for improvement and P=0.075 for exchange effect for worsening).

[0266] Among individuals without diabetes, 157 developed T2D during the study, of whom 150 (95.5%) had prediabetes (Alc 5.7-6.4%) (136 [86.6%] using the more restrictive 6.0-6.4% criterion). Patients who developed T2D had higher baseline Alc (6.2±0.3 vs. 5.7±0.4%; p<0.001) and higher BMI (28.5±5.9 vs. 27.1±5.7 kg / m2) than those who remained diabetes-free. 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). Dapagliflozin reduced new-onset diabetes by 32%: placebo 93 / 1307 (7.1%) vs. dapagliflozin 64 / 1298 (4.9%); HR 0.68 (95% CI, 0.50-0.94; p=0.019) (Cox.) (Figure 17).

[0267] Clinical laboratory measurements, weight and blood pressure Figures 11A-11E show the changes in laboratory measurements, weight, and blood pressure, adjusted for baseline values. Glycated hemoglobin remained largely unchanged in patients without diabetes, but there was a slight decrease by 60 days in patients with diabetes (P exchange effect < 0.0001) (Figure 11A). Weight and systolic blood pressure decreased in both patient groups (Figures 11B and 11C, respectively). Hematocrit increased with dapagliflozin in both patient groups, reaching a plateau after approximately 4 months; this increase was lower in patients without diabetes than in patients with diabetes (P exchange effect = 0.0002) (Figure 11D). There was a small initial increase in creatinine with dapagliflozin in both groups, although the difference between treatments attenuated by 6 months; this increase was lower in patients without diabetes than in patients with diabetes (P exchange effect = 0.0005) (Figure 11E).

[0268] N-terminal pro-B-type natriuretic peptide In patients without diabetes, NT-proBNP decreased by 144 ± 2286 pg / ml from baseline to 8 months in the dapagliflozin group and increased by 84 ± 2993 pg / ml in the placebo group; treatment difference -278 (-485 to -71) pg / ml; p = 0.009. The corresponding changes in participants with diabetes were a decrease of 257 ± 2502 pg / ml in the dapagliflozin group and an increase of 121 ± 2884 pg / ml in the placebo group; treatment difference -333 (-562 to -104) pg / ml; p = 0.004 (P exchange effect = 0.728).

[0269] Tolerability and safety Among patients without diabetes, 144 patients (11.1%) in the dapagliflozin group and 141 patients (10.8%) in the placebo group discontinued the study drug. Among patients with diabetes, these numbers were 105 (9.8%) and 117 (11.0%), respectively.

[0270] The most common adverse events of note were volume depletion and nephropathy, which were less common in patients without diabetes than in those with diabetes (Table 8). The incidence of these adverse events did not differ between dapagliflozin and placebo in either patient group.

[0271] [Table 17]

[0272] [Table 18]

[0273] A doubling of serum creatinine occurred in 22 patients (1.7%) without diabetes assigned to dapagliflozin and in 36 patients (2.8%) assigned to placebo, p=0.08; the corresponding numbers in patients with diabetes were 21 (2.0%) and 41 (3.9%), p=0.01.

[0274] Three patients (0.06%) experienced definite or probable diabetic ketoacidosis during the study, all of whom had diabetes randomized to dapagliflozin. Eight patients (0.17%) experienced life-threatening hypoglycemia during the study, all of whom had diabetes: four randomized to dapagliflozin and four randomized to placebo. Overall, 25 patients (0.53%) underwent amputation; among individuals without diabetes, one was in the dapagliflozin group and three were in the placebo group; among individuals with diabetes, 12 patients were in the dapagliflozin group and nine were in the placebo group.

[0275] Essay A key finding from this analysis of patients with HF and low ejection fraction was that the SGLT2 inhibitor dapagliflozin improved all prespecified mortality and hospitalization outcomes to a similar extent in people with and without diabetes. Furthermore, among individuals without diabetes, reductions in the primary outcome with dapagliflozin were consistent across the range of baseline glycated hemoglobin values, whether assessed as a categorical or continuous measure. Indeed, by coincidence, in the tertile analysis of participants without diabetes, quartiles were selected that reflected the US (≥5.6%) and European (≥6.0%) definitions of prediabetes based on glycated hemoglobin criteria. (American Diabetes Association. 2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2019, Diabetes Care 42(Suppl 1):S13-S28(2019); Chatterton, H. et al., BMJ 345:e4624(2012)). The benefit of dapagliflozin was similar in individuals with prediabetes diagnosed using either definition as well as in those with normal glycated hemoglobin. The data provide convincing evidence that the benefit of SGLT2 inhibition is not limited to people with diabetes or prediabetes, but is also applicable to patients with heart failure and low ejection fraction, independent of glycemic status. Furthermore, the observed benefit is also obtained in participants already receiving recommended therapies for HF, including renin-angiotensin system blockers, beta-blockers and mineralocorticoid receptor antagonists.

[0276] The present analysis also demonstrates the effects of dapagliflozin on metabolic, hemodynamic and anthropometric measures in people with and without diabetes. As expected, dapagliflozin reduced glycated hemoglobin in patients with type 2 diabetes, but had no effect on this measure in people without diabetes. However, the effects of dapagliflozin on weight, blood pressure, hematocrit, creatinine and NT-proBNP were directionally similar in people with and without diabetes, although somewhat more pronounced in the former group.

[0277] From the findings of this study, it can be assumed that the benefit of dapagliflozin was independent of the reduction in plasma glucose. Other mechanisms of action of SGLT2 inhibitors have been proposed, including diuretic effect. (Hallow, KMet al., Diabetes Obes Metab 20 479-487(2018); McMurray, J., J Diabetes Complications 30:3-4(2016)). Although this mechanism was not directly measured in this study, the early reductions in systolic blood pressure and weight, as well as the increase in creatinine, were consistent with a diuretic effect. However, little is known about the effect of SGLT2 inhibitors on urinary sodium and water excretion, especially when added to conventional diuretic therapy in patients with HF, especially in those without diabetes. (Hallow,KM et al., supra; Devineni,D.et al.,Clin Ther 36:698-710(2014); Nassif,ME et al.,Circulation(2019 Sep); Kosiborod,M.et al.,J Diabetes Complications 31:1215-1221(2017)). There are other possible explanations for the increase in creatinine and hematocrit. SGLT2 inhibitors are thought to induce tubuloglomerular feedback independent of diuresis, which promotes constriction of the afferent arteriole and a decrease in glomerular filtration rate. (Heerspink, HK et al., Circulation 134:752-72(2016); Kidokoro, K. et al., Circulation 140:303-315(2019). Similarly, the increase in hematocrit may be due to increased renal erythropoietin secretion due to SGLT2 inhibitor-mediated improvement in renal function. (Yanai, H. et al., J Clin Med Res 9:178-179(2017)). The time courses of creatinine and hematocrit we observed were quite different, with an initial increase in creatinine that reversed after 14 days, whereas hematocrit increased gradually for the first 4 months and then plateaued. Diuretic volume contraction is unlikely to explain these diverse changes.

[0278] Other diuretic-independent effects, such as effects on ion transporters, fibrosis, adipokines, sympathetic nervous system activity and vascular function, have been proposed but supportive clinical evidence is scarce. (Thomas,MC et al.,Diabetologia 61:2098-2107(2018);Garg,V.et al.Prog Cardiovasc Dis pii:S0033-0620(19)30102-1(2019);Wojcik,C.et al.,Curr Cardiol Rep 21:130(2019);Verma S.et al.,Diabetologia 61:2108-2117(2018).Some data suggest that SGLT2 inhibitors may reduce left ventricular volumes, and an effect on cardiac remodeling may explain the observed reduction in NT-proBNP by dapagliflozin.(Verma,S.et al.,Circulation(2019 Aug.22)). Recent experimental studies have further demonstrated the benefits of SGLT2 inhibitors on cardiac structure and function in non-diabetic animals. (Thomas,MC et al.,Diabetologia 61:2098-2107(2018);Yurista,SR et al.,Eur J Heart Fail 21:862-873(2019);Garg,V.et al.,Prog Cardiovasc Dis pii:S0033-0620(19)30102-1(2019)). Prevention of renal function decline may also be beneficial in heart failure.

[0279] The overall rates of other important adverse events of note, related to heart failure and volume depletion, were low and similar in participants with and without diabetes. This finding is also consistent with the notion that diuresis may not be the primary mechanism underlying the beneficial effects of dapagliflozin. Other prespecified safety endpoints were rare in both patient groups, and study drug discontinuations were rare in both groups. Neither life-threatening hypoglycemia nor diabetic ketoacidosis occurred in patients without diabetes. No significant effects on our prespecified renal endpoints were identified, which did not occur in most patients. However, doubling of serum creatinine was found to be significantly less in patients receiving dapagliflozin, both in patients with and without diabetes. Serious renal adverse events were also less frequent in patients assigned to dapagliflozin compared to placebo.

[0280] In conclusion, in patients with HF and low ejection fraction, the SGLT2 inhibitor dapagliflozin reduced the risk of worsening heart failure and cardiovascular mortality and improved symptoms independent of baseline diabetes and glycated hemoglobin levels. These benefits were observed superior to superior standard of care in both people with and without diabetes. Taken together, these data support the use of dapagliflozin as a treatment for heart failure with low ejection fraction in people with and without diabetes, independent of glycemic status.

[0281] All references cited in this specification, including publications, patent applications, and patents, are herein incorporated by reference to the same extent as if each reference was individually and specifically indicated to be incorporated by reference and was set forth in its entirety.

[0282] Unless otherwise indicated, the description of ranges of values ​​herein is merely intended to serve as a shorthand method of individually referring to each individual value falling within the range, and each individual value is incorporated herein as if it were individually described herein. All methods described herein can be performed in any suitable order, unless otherwise indicated herein or otherwise clearly contradicted by context. Any examples or illustrative phrases provided herein (e.g., "etc.") are intended merely to more clearly illustrate the disclosure, and do not pose limitations on the scope of the disclosure unless otherwise claimed. No phraseology in this specification should be construed as indicating any non-claimed element as essential to the practice of the disclosure.

[0283] Various embodiments of the present disclosure are described herein, including the best mode known to the inventors for carrying out the disclosure. Variations of these embodiments will be apparent to those skilled in the art upon reading the above description. The inventors anticipate that those skilled in the art will use such variations as appropriate, and the inventors intend for the present disclosure to be carried out in ways other than as expressly described herein. Accordingly, the present disclosure includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, the present disclosure encompasses any combination of the above-described elements in all possible variations thereof, unless otherwise indicated herein or otherwise clearly contradicted by context.

[0284] Example 4 DAPA-HF Phase III Clinical Trial Results-Effect of Dapagliflozin on Reducing Hyperkalemia in Patients with HF Introduction Hyperkalemia often limits the use of mineralocorticoid receptor antagonists (MRAs) in patients with heart failure and low ejection fraction (HFrEF), preventing the use of life-saving therapy in these patients. In the prespecified analysis presented in this example, the sodium-glucose cotransporter 2 (SGLT-2) inhibitor dapagliflozin was evaluated to determine whether treatment with dapagliflozin reduces the risk of hyperkalemia associated with MRA use in patients with HFrEF.

[0285] method In the Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure trial (DAPA-HF), we investigated the risk of developing mild hyperkalemia (potassium >5.5 mmol / L) and moderate / severe hyperkalemia (>6.0 mmol / L) according to baseline MRA use and randomized treatment allocation using Cox regression analysis.

[0286] result Overall, 3370 (70.1%) patients in DAPA-HF were treated with MRA. Mild and moderate / severe hyperkalemia occurred in 180 (11%) and 21 (1.2%) patients treated with dapagliflozin, compared with 204 (12.6%) and 40 (2.4%) patients receiving placebo (Table 8 and Figures 18A-18B). This resulted in a hazard ratio (HR) of 0.86 (0.70-1.05) for mild hyperkalemia and 0.50 (0.29, 0.85) for moderate / severe hyperkalemia comparing dapagliflozin with placebo. Treatment with dapagliflozin halved the incidence of moderate / severe hyperkalemia associated with MRA in HFrEF patients.

[0287] [Table 19]

Claims

1. A pharmaceutical composition for reducing the risk of cardiovascular mortality and worsening heart failure in patients with heart failure with reduced ejection fraction (HFrEF), comprising dapagliflozin, wherein the patient does not have type II diabetes and has a glycated hemoglobin level (HbA1c) of <5.7%.

2. 2. The pharmaceutical composition of claim 1, wherein the worsening heart failure comprises unplanned hospitalization for heart failure (HF) and / or emergency heart failure outpatient visits.

3. Unplanned hospitalization for heart failure: (a) new or worsening symptoms of HF experienced by the patient; and / or (b) objective evidence of new or worsening symptoms of HF; and / or (c) Initiating or intensifying specialized HF care The pharmaceutical composition of claim 2, wherein the composition is one or more of the following:

4. 4. The pharmaceutical composition of claim 3, wherein the unplanned hospitalization due to heart failure includes initial and / or re-hospitalization for HF.

5. Emergency HF outpatient clinic: (a) Emergency room visits for the primary diagnosis of HF not requiring hospitalization; (b) emergency room visits for the primary diagnosis of HF requiring treatment other than simply increasing oral diuretics but not requiring hospitalization; (c) emergency walk-in visits to clinics for the primary diagnosis of HF; (d) Urgent walk-in visits to clinics requiring treatment other than simply increasing oral diuretics; (e) initiation or intensification of HF-specific treatment; and / or (f) Initiation of intravenous therapy The pharmaceutical composition of claim 2 comprising one or more of:

6. The pharmaceutical composition of any one of claims 1 to 5, wherein the amount of dapagliflozin administered is 10 mg per day.

7. The pharmaceutical composition according to any one of claims 1 to 6, which further improves symptoms of heart failure.

8. 8. The pharmaceutical composition of claim 7, wherein the improvement in heart failure symptoms is measured by a higher score on the KCCQ TSS of the patient compared to the patient's score before initiation of treatment with a pharmaceutical composition comprising a therapeutically effective amount of dapagliflozin.

9. 9. The pharmaceutical composition of claim 8, wherein the higher score on the KCCQ TSS is at least 5 points higher than the score prior to administration of the pharmaceutical composition.

10. 9. The pharmaceutical composition of claim 8, wherein the higher score on the KCCQ TSS is at least 10 points higher than the score prior to administration of the pharmaceutical composition.

11. 9. The pharmaceutical composition of claim 8, wherein the higher score on the KCCQ TSS is at least 15 points higher than the score prior to administration of the pharmaceutical composition.

12. 8. The pharmaceutical composition of claim 7, wherein the improvement in heart failure symptoms is measured by the patient's KCCQ TSS score.

13. The pharmaceutical composition satisfies the following conditions: a) numerically reduce the absolute risk of the composite endpoint of hospitalization for HF, cardiovascular death, or emergency HF outpatient visit in patients; b) results in a nominally significant reduction in the risk of a composite endpoint of hospitalization for HF, cardiovascular mortality, or emergency HF outpatient visits in patients; c) resulting in a numerical reduction in the composite endpoint event of hospitalization for HF, cardiovascular death, or emergency HF visit in patients; d) resulting in a numerical reduction in the risk of a composite endpoint event of hospitalization for HF, cardiovascular death, or emergency HF visit in patients; e) resulting in a reduction in the mean change in NT-proBNP levels in patients within 8 months of starting treatment; and / or f) resulting in a reduction in the mean change in NT-proBNP levels of -278 pg / ml in patients within 8 months of starting treatment The pharmaceutical composition according to any one of claims 1 to 12, which satisfies at least one of the above.

14. The pharmaceutical composition satisfies the following conditions: a) numerically reduce the absolute risk of the composite endpoint of hospitalization for HF or cardiovascular death in patients; b) results in a nominally significant reduction in the risk of a composite endpoint of hospitalization for HF or cardiovascular death in patients; c) resulting in a numerical reduction in a composite endpoint of hospitalization for HF or cardiovascular mortality in patients; and / or d) result in a numerical reduction in the risk of a composite endpoint of hospitalization for HF or cardiovascular death in patients The pharmaceutical composition according to any one of claims 1 to 13, which satisfies at least one of the above.

15. The pharmaceutical composition satisfies the following conditions: a) Numerical reduction in absolute risk of all-cause mortality; b) results in a nominally significant reduction in the risk of all-cause mortality in patients; c) resulting in a numerical reduction in all-cause mortality; and / or d) result in a numerical reduction in the risk of all-cause mortality in patients The pharmaceutical composition according to any one of claims 1 to 14, which satisfies at least one of the above.

16. The pharmaceutical composition satisfies the following conditions: a) numerically reduce the total number of hospitalizations (initial and re-admissions) for HF events and the absolute risk of CV mortality in patients; b) result in a nominally significant reduction in the total number of hospitalizations (initial and re-admissions) and the rate of CV mortality for HF events in patients; c) resulting in a numerical reduction in the total number of hospitalizations (initial and re-admissions) and CV mortality due to HF events in patients; and / or d) result in a numerical reduction in the total number of hospitalizations (initial and re-admissions) for HF events and in the risk of CV mortality in patients The pharmaceutical composition according to any one of claims 1 to 15, which satisfies at least one of the above.

17. A pharmaceutical composition for reducing the risk of hospitalization for heart failure and cardiovascular mortality in patients after acute myocardial infarction comprising dapagliflozin, wherein the patient does not have type II diabetes and has a glycated hemoglobin level (HbA1c) of <5.7%.

18. 18. The pharmaceutical composition of claim 17, wherein the patient experiences an acute myocardial infarction within 7 days of starting treatment with the pharmaceutical composition.

19. 19. The pharmaceutical composition of claim 18, wherein the acute myocardial infarction is ST-segment elevation myocardial infarction (STEMI) or non-ST-segment elevation myocardial infarction.

20. Hospitalization for heart failure was: (i) new or worsening symptoms of HF experienced by the patient; (ii) objective evidence of new or worsening symptoms of HF; and / or (iii) Initiation or intensification of specialized HF treatment 18. The pharmaceutical composition of claim 17, wherein said composition is one or more of the following:

21. 21. The pharmaceutical composition of claim 20, wherein the hospitalization for heart failure includes initial and / or re-hospitalization for HF.

22. A pharmaceutical composition for reducing the risk of cardiovascular mortality or worsening of heart failure symptoms in a patient with acute decompensated heart failure comprising dapagliflozin, wherein the patient does not have type II diabetes and has a glycated hemoglobin level (HbA1c) of <5.7%.

23. 23. The pharmaceutical composition of claim 22, wherein the patient is admitted in stable condition with worsening heart failure symptoms or acute decompensated heart failure.

24. 23. The pharmaceutical composition of claim 22, wherein the patient has a left ventricular ejection fraction (LVEF) of 40% or less.

25. 23. The pharmaceutical composition of claim 22, wherein the reduction in the rate of worsening of heart failure symptoms is met by a reduction in hospitalizations for heart failure or a reduction in emergency HF outpatient visits.

26. Hospitalization for heart failure includes initial and / or rehospitalization for HF, including the following: (i) new or worsening symptoms of HF experienced by the patient; (ii) objective evidence of new or worsening symptoms of HF; and / or (iii) Initiation or intensification of specialized HF treatment 26. The pharmaceutical composition of claim 25, wherein the composition is one or more of:

27. 26. The pharmaceutical composition of claim 25, wherein the emergency HF outpatient visit requires treatment for worsening heart failure other than simply increasing oral diuretics.

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