Methods of treating heart failure with reduced ejection fraction using dapagliflozin

Abstract

To provide a pharmaceutical composition for reducing the rates of hospitalization and cardiovascular death due to heart failure (HF) in a patient after acute myocardial infarction.SOLUTION: A pharmaceutical composition is provided that comprises dapagliflozin, where the patient after acute myocardial infarction does not have type 2 diabetes and where at least one standard HF therapeutic drug is administered to the patient; and the rates of hospitalization and cardiovascular death due to heart failure is reduced compared to an administration regimen receiving only the at least one standard HF therapy.SELECTED DRAWING: None

Description

Background Art

[0001] Heart failure (HF) is a life-threatening medical condition in which the heart is unable to pump sufficient blood to maintain 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 are continuing to increase globally (Non-Patent Document 1). HF is a chronic and degenerative disease, and half of patients can die within 5 years of diagnosis (Non-Patent Document 2). HF is a major cause of hospitalization in people over 65 years old and represents a significant clinical and economic burden (Non-Patent Document 3).

[0002] Existing standard treatment paradigms for HF include the simultaneous administration of one or more drugs from the following classes, such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), β-blockers, mineralocorticoid receptor drugs such as mineralocorticoid receptor antagonists (MRAs), angiotensin receptor-neprilysin inhibitors (ARNI), digoxin, diuretics, heart pump therapy, selective sinus node inhibitors, vasodilators, and calcium channel blockers (unless the patient has non-systolic heart failure). Even with the best treatment available, the 5-year survival rate for HF is lower than that of most cancers (Non-Patent Document 4). The morbidity and mortality rates of HF patients remain high, and there is a need for improvement in patient outcomes. Another method for treating HF patients, particularly HFrEF patients, is sought to improve patient outcomes by reducing cardiovascular mortality, reducing the exacerbation of heart failure events and HF symptoms, and slowing disease progression.

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

[0004] Dapagliflozin is a potent, highly selective, and orally active inhibitor of human renal SGLT2 that effectively reduces HbAlc while having 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 related to increased CV risk) (Non-Patent Document 6). The chemical structure of dapagliflozin is [Chemical formula] as follows. [Prior Art Documents] [Non-Patent Documents]

[0005] [Non-Patent Document 1] Cannie D.E.et al.,European Cardiology Review 14(2):89-96(2019) [Non-Patent Document 2] Mamas,M.A.et 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 Problems]

[0006] Accordingly, 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), using 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 an SGLT2 inhibitor.

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

[0009] Furthermore, the present specification also discloses a method for preventing or delaying the onset of diabetes in patients with HFrEF without T2D, which comprises administering to the patient an effective amount of an SGLT2 inhibitor. In some embodiments, the patient with HFrEF without T2D has a hemoglobin A1c of less than 5.7%. In some embodiments, the patient with HFrEF without T2D is pre-diabetic (i.e., has a hemoglobin A1c ≥ 5.7% and < 6.5%). In some embodiments, the method disclosed herein reduces the incidence of T2D compared to a placebo. In some embodiments, the method disclosed herein reduces the incidence of T2D compared to a standard therapeutic agent for HF. In some embodiments, the reduction in the incidence of T2D is measured by the time to the first reported hemoglobin A1c measurement of ≥ 6.5%. In some embodiments, the method disclosed herein results in a hazard ratio of less than 1 in reducing the incidence of T2D compared to a placebo. In some embodiments, the method disclosed herein results in a hazard ratio of less than 1 in reducing the incidence of T2D compared to a standard HF therapeutic agent.

[0010] Furthermore, a method for treating HFrEF in patients with or without T2D, which comprises administering to the patient an effective amount of an SGLT2 inhibitor, is also disclosed, and the patient does not experience any adverse events related to renal insufficiency during treatment. In some embodiments, the absence of adverse events related to renal insufficiency includes no or only slight reduction in eGFR level, no end-stage renal disease (ESRD), and / or no death due to the kidney.

[0011] The present specification also discloses a method for reducing the total number of standard therapeutic agents for heart failure (HF) taken by patients with HFrEF with or without T2D, which comprises 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, ertugliflozin, or a pharmaceutically acceptable salt, solvate, mixed solvate, complex, or prodrug thereof. In at least one embodiment, the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt, solvate, mixed solvate, complex, or prodrug thereof. In at least one embodiment, dapagliflozin is in the form of an amorphous solid. In at least one embodiment, dapagliflozin is in the form of a crystalline solid. In at least one embodiment, dapagliflozin has the structure:

Chemical formula

[0013] Furthermore, disclosed herein are methods comprising administering to a patient in need thereof an effective amount of an SGLT2 inhibitor, alone or in combination with at least one other therapeutic agent. In some embodiments, the other therapeutic agent is administered with the SGLT2 inhibitor in the same or different pharmaceutical compositions and at the same or different times. In some embodiments, the other therapeutic agent is an anti-diabetic agent, an anti-obesity agent, an anti-hyperlipidemic agent, an anti-atherosclerotic agent, an anti-hypertensive agent, an anti-platelet agent, an anti-thrombotic agent, or an anticoagulant. For example, in at least one embodiment, the other therapeutic agent is an anti-diabetic agent such as a biguanide and / or a DPP4 inhibitor. Exemplary biguanides are metformin or a pharmaceutically acceptable salt thereof. Exemplary DPP4 inhibitors include saxagliptin, linagliptin, sitagliptin, and pharmaceutically acceptable salts thereof.

[0014] In the method 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%. The LVEF can be determined, for example, using echocardiogram, radionuclide angiocardiogram, angiography or cardiac MRI.

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

[0016] In some embodiments, the method disclosed herein results in at least one of the following outcomes: (i) extending the time to the 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 recurrence of heart failure events and / or reducing the incidence of fatal cardiovascular events

[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 as compared to a placebo. In some embodiments, the methods disclosed herein reduce the incidence of myocardial infarction as compared to an HF standard therapy. In some embodiments, the reduction in the incidence of myocardial infarction is measured by the time to the first fatal or non-fatal myocardial infarction. In some embodiments, the methods disclosed herein result in a hazard ratio of less than 1 for the reduction in the incidence of myocardial infarction as compared to a placebo. In some embodiments, the methods disclosed herein result in a hazard ratio of less than 1 for the reduction in the incidence of myocardial infarction as compared to a standard therapy.

[0018] In some embodiments, the methods disclosed herein reduce the risk of hospitalization for heart failure and cardiovascular death in patients after acute myocardial infarction. In some embodiments, the patient may have experienced an acute myocardial infarction within 7 days of initiation of treatment with an SGLT2 inhibitor. In some embodiments, the patient may have experienced a STEMI (ST-segment elevation myocardial infarction). In some embodiments, the patient may have 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 death 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 death in patients after acute myocardial infarction compared to HF standard-of-care medications. In the methods disclosed herein, a patient administered an SGLT2 inhibitor can be receiving one or more HF standard-of-care medications before or during administration of the SGLT2 inhibitor. In some embodiments, the methods disclosed herein result in the following outcomes in patients who have experienced an acute myocardial infarction within 7 days: (i) extending the time to the first heart failure (HF) event and / or fatal cardiovascular event; and / or (ii) reducing worsening of HF symptoms; and / or (iii) reducing the number of HF events and / or reducing the incidence of fatal cardiovascular events; and / or (iv) reducing hospitalization for heart failure and cardiovascular death; 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 death result in at least one of

[0019] In some embodiments, the methods described in the paragraphs above 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 lower hazard ratio compared to patients taking an HF standard therapy. In some embodiments, the methods disclosed herein result in a lower hazard ratio compared to a placebo.

[0020] In some embodiments, the methods disclosed herein reduce the time to the first event of cardiovascular death or worsening heart failure symptoms in patients with acute decompensated heart failure. In some embodiments, the patient is hospitalized due to worsening heart failure symptoms or acute decompensated heart failure prior to the initiation of SGLT2 administration. In some embodiments, 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% prior to the initiation of SGLT2 administration. In some embodiments, the SGLT2 inhibitor is dapagliflozin. In some embodiments, the patient has T2D prior to the initiation of SGLT2 administration. In some embodiments, the patient does not have T2D prior to the initiation of SGLT2 administration. In some embodiments, the patient has >30 ml / min / 1.73m prior to the initiation of SGLT2 administration 2has an eGFR. In some embodiments, the patient has increased natriuretic peptide prior to the start of SGLT2 administration. In some embodiments, the patient is hospitalized in a stable condition due to worsening heart failure symptoms or acute heart failure. As used herein, "stable condition" means no increase in i.v. diuretics and no use of i.v. vasodilators or inotropic agents at least 24 hours before the start of SGLT2 administration, e.g., at least 48 hours before the start of SGLT2 administration, e.g., at least 72 hours before and in some embodiments at least 1 week before. In some embodiments, the methods disclosed herein reduce the time to the 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 the first event of cardiovascular death or worsening heart failure symptoms in patients with acute decompensated heart failure compared to HF standard of care agents. In some embodiments, a patient being administered an SGLT2 inhibitor can be receiving one or more HF standard of care agents before or during administration of the SGLT2 inhibitor.

[0021] In some embodiments, the methods disclosed herein result in the following outcomes in patients with acute decompensated heart failure: (i) extending the time to the first fatal cardiovascular event; and / or (ii) extending the time to readmission for heart failure; and / or (iii) extending the time to urgent HF clinic; and / or (iv) extending the total number of days of survival and after discharge; and / or (v) reducing worsening of heart failure symptoms; and / or (vi) reducing the risk of all-cause death resulting in at least one of.

[0022] In some embodiments, the method described in the above paragraph results in a hazard ratio of less than 1 for any one of (i)-(vi). In some embodiments, the methods disclosed herein result in a lower hazard ratio compared to patients taking an HF standard therapy. In some embodiments, the methods disclosed herein result in a lower hazard ratio compared to a placebo.

[0023] In some embodiments, the methods disclosed herein reduce the incidence of any seizure (ischemic, hemorrhagic, or of unknown cause). In some embodiments, the seizure is fatal. In some embodiments, the seizure is non-fatal. In some embodiments, the patient has a history of seizures. In some embodiments, the patient has no history of seizures. In some embodiments, the methods disclosed herein reduce the incidence of seizures compared to a placebo. In some embodiments, the methods disclosed herein reduce the incidence of seizures compared to an HF standard therapy. In some embodiments, the reduction in the incidence of seizures is measured by the time to the first fatal or non-fatal seizure. In some embodiments, the methods disclosed herein result in a hazard ratio of less than 1 for the reduction in the incidence of seizures compared to a placebo. In some embodiments, the methods disclosed herein result in a hazard ratio of less than 1 for the reduction in the incidence of seizures compared to an HF standard therapy.

[0024] In some embodiments, administration of an SGLT2 inhibitor prolongs the time to the first heart failure (HF) event. In at least one embodiment, the HF event is hospitalization for HF or an urgent HF clinic visit. In at least one embodiment, hospitalization for HF includes a hospitalization that lasts at least 24 hours with a primary diagnosis of HF. In some embodiments, administration of an SGLT2 inhibitor decreases the total number of hospitalizations for HF. In at least one embodiment, the total number of hospitalizations for HF includes initial and / or readmissions.

[0025] In some embodiments, hospitalization for HF is based on 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-specific treatment is due to one or more of the above.

[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 clinical test values of new or worsening HF that are considered to be due 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 / crepitations, increased jugular venous pressure and / or hepatojugular reflux, S3 gallop, and / or a clinically significant or rapid weight gain associated with fluid retention. In at least one embodiment, the clinical test values of new or worsening HF include at least one of the following findings: increased B-type natriuretic peptide (BNP) / N-terminal pro-BNP (NT-proBNP) concentration consistent with decompensated heart failure; radiographic evidence of pulmonary congestion; non-invasive diagnostic evidence of clinically significantly elevated left or right ventricular filling pressure or low cardiac output, or invasive diagnostic evidence by right heart catheterization. In at least one embodiment, the initiation or intensification of HF-specific treatment includes at least one of the following: an increase in oral diuretic therapy, intravenous administration of a diuretic or vasoactive agent, or a mechanical or surgical intervention (e.g., the mechanical or surgical intervention includes mechanical circulatory support or mechanical fluid removal).

[0027] In some embodiments, the acute HF outpatient visit is an outpatient visit outside the emergency department for primary diagnosis of HF, but does not require hospitalization, such as an outpatient visit without an emergency appointment to a clinic for primary diagnosis of HF. In some embodiments where an acute HF outpatient visit is needed, the patient has experienced HF symptoms and / or has physical examination findings and / or new or worsening clinical 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 acute HF outpatient visit is needed, the patient receives initiation or intensification of HF specialized treatment. In some embodiments where an acute HF outpatient visit is needed, 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 embodiments described above, the time to the first heart failure event and / or a fatal cardiovascular event can be delayed from 8 weeks to 24 months from the first administration of the SGLT2 inhibitor. In at least one embodiment, the time to the first heart failure event is delayed from 8 weeks to 24 months from the first administration of the SGLT2 inhibitor. In at least one embodiment, the time to a fatal cardiovascular event is delayed from 8 weeks to 24 months from the first administration of the SGLT2 inhibitor.

[0030] In some embodiments, administration of an SGLT2 inhibitor reduces the worsening of HF symptoms in the treated patient. In at least one embodiment, the reduced alleviation of the patient's heart failure symptoms occurs 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 the patient's HF. In at least one embodiment, the reduced worsening of heart failure symptoms is characterized by a reduced number of acute HF outpatient visits for the patient. In at least one embodiment, the acute HF outpatient visit is an outpatient visit outside the emergency department or an outpatient clinic visit for an emergency department patient.

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

[0032] In some embodiments, the administration of the SGLT2 inhibitor results in any one or more of 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

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

[0034] In at least one embodiment, the reduction in physical limitations is characterized by a higher score for the patient based on the Kansas City Cardiomyopathy Questionnaire Physical Limitations Score (KCCQ-PLS) compared to the patient's score prior to SGLT2 inhibitor administration. In such embodiments, the higher score based on the KCCQ-PLS appears within 16 weeks (or 4 months) from the start of SGLT2 inhibitor administration. In other embodiments, the higher score based on the KCCQ-PLS appears within 20 weeks from the start of SGLT2 inhibitor administration. In other embodiments, the higher score based on the KCCQ-PLS appears within 24 weeks from the start of SGLT2 inhibitor administration. In other embodiments, the higher score based on the KCCQ-PLS appears within 28 weeks from the start of SGLT2 inhibitor administration. In other embodiments, the higher score based on the KCCQ-PLS appears within 32 weeks or 8 months from the start of SGLT2 inhibitor administration. In at least one embodiment, the higher score based on the KCCQ-PLS is at least 1 point higher than the score prior to SGLT2 inhibitor administration. In at least one embodiment, the higher score based on the KCCQ-PLS is at least 5 points higher than the score prior to SGLT2 inhibitor administration. In at least one embodiment, the higher score based on the KCCQ-PLS is at least 10 points higher than the score prior to SGLT2 inhibitor administration. In at least one embodiment, the higher score based on the KCCQ-PLS is at least 15 points higher than the score prior to SGLT2 inhibitor administration. In at least one embodiment, the KCCQ-PLS is reported by the patient, such as when the patient reports to the clinic. In at least one embodiment, the patient has T2D. In some embodiments, the patient does not have T2D.

[0035] In at least one embodiment, the improvement in exercise tolerance is characterized by a longer six-minute walk distance (6MWD) of the patient as compared to the 6MWD of the patient prior to SGLT2 inhibitor administration. In such embodiments, the longer 6MWD distance appears within 16 weeks from the start of SGLT2 inhibitor administration. In other embodiments, the longer 6MWD distance appears within 20 weeks from the start of SGLT2 inhibitor administration. In other embodiments, the longer 6MWD distance appears within 24 weeks from the start of SGLT2 inhibitor administration. In other embodiments, the longer 6MWD distance appears within 28 weeks from the start of SGLT2 inhibitor administration. In other embodiments, the longer 6MWD distance appears within 32 weeks or 8 months from the start of SGLT2 inhibitor administration. In at least one embodiment, the improvement in the six-minute walk distance (6MWD) is measured by a distance of 30 meters or more. In at least one embodiment, the patient has T2D. In some embodiments, the patient does not have T2D.

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

[0037] In some embodiments, administration of the SGLT2 inhibitor reduces the number of HF events and / or reduces the incidence of fatal cardiovascular events. In at least one embodiment, administration of the SGLT2 inhibitor reduces the number of HF events. In at least one embodiment, an HF event is hospitalization for HF or an emergency HF clinic visit. In at least one embodiment, administration of the SGLT2 inhibitor reduces the number of hospitalizations for HF. In at least one embodiment, administration of the SGLT2 inhibitor reduces the number of emergency HF clinic visits. In at least one embodiment, an emergency HF clinic visit is an outpatient visit to the emergency treatment room. In at least one embodiment, an emergency HF clinic 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, a patient being administered an SGLT2 inhibitor can be receiving one or more HF standard therapies before or during administration of the SGLT2 inhibitor. In at least one embodiment, the one or more HF standard therapies are selected from the group consisting of angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), β-blockers, mineralocorticoid receptor drugs such as mineralocorticoid receptor antagonists (MRAs), neprilysin inhibitors, antiplatelet drugs, 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, a patient being administered an SGLT2 inhibitor has a New York Heart Association (NYHA) heart failure classification of II-IV. In at least one embodiment, a patient being administered an SGLT2 inhibitor has a NYHA heart failure classification of II. In at least one embodiment, a patient being administered an SGLT2 inhibitor has a NYHA heart failure classification of III or IV.

[0041] In the methods disclosed herein, a patient being administered an SGLT2 inhibitor can have an eGFR of ≥30 ml / min / 1.73 m2 before administration of the SGLT2 inhibitor. In the methods disclosed herein, a patient being administered an SGLT2 inhibitor has an eGFR of ≥30 ml / min / 1.73 m 2 during administration of the SGLT2 inhibitor.

[0042] In the methods disclosed herein, a patient administered an SGLT2 inhibitor may have plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels 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, a patient administered an SGLT2 inhibitor can be medically diagnosed with symptomatic HFrEF prior to administration of the SGLT2 inhibitor. In at least one embodiment, the patient can be diagnosed with HFrEF at least 2 months prior to administration of the SGLT2 inhibitor.

[0044] In the methods disclosed herein, a patient administered an SGLT2 inhibitor may have atrial fibrillation and / or atrial flutter prior to administration of the SGLT2 inhibitor. In at least one embodiment, a patient administered an SGLT2 inhibitor does not have atrial fibrillation or atrial flutter prior to SGLT2 inhibitor administration. 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 SGLT2 inhibitor administration. In at least one embodiment, the methods disclosed herein reduce the incidence of atrial fibrillation in patients who do not have atrial fibrillation or atrial flutter prior to SGLT2 inhibitor administration. 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 standard HF therapy. 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 result in a hazard ratio of less than 1 for the reduction in the incidence of atrial fibrillation compared to placebo. In some embodiments, the methods disclosed herein result in a hazard ratio of less than 1 for the reduction in the incidence of atrial fibrillation compared to standard HF therapy.

[0045] In certain embodiments, the disclosed method results in a decrease in a patient's HbA1c. In certain embodiments, the disclosed method results in a decrease in a patient's systolic blood pressure. In certain embodiments, the disclosed method results in a decrease in a patient's weight. In certain embodiments, the disclosed method results in a decrease in a patient's NT-proBNP level. In any of the foregoing embodiments, the decrease can occur within 8 months from the start of SGLT2 inhibitor administration. In certain embodiments, the disclosed method results in a patient having a sustained decline of 50% or more in eGFR per ml / min / 1.73m 2 over time. In such embodiments, the sustained decline can be 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 decrease in readmission for HF or a decrease in recurrent HF events. In at least one embodiment, recurrent HF events include hospitalization for HF or an emergency HF clinic visit.

[0048] In certain embodiments, the methods disclosed herein result in a reduced incidence of death not due to cardiovascular causes.

[0049] Furthermore, this specification discloses a method for reducing the rate of a major composite endpoint of cardiovascular death, HF hospitalization, or urgent HF clinic visit in HFrEF patients being treated with an SGLT2 inhibitor and an HF standard therapy drug, which rate is reduced relative to patients being treated with the HF standard therapy drug alone. Furthermore, this specification also discloses a method for reducing the rate of a secondary composite endpoint of cardiovascular death or HF hospitalization in HFrEF patients being treated with an SGLT2 inhibitor and an HF standard therapy drug, which rate is reduced relative to patients being treated with the HF standard therapy drug alone. In any of the foregoing embodiments, the SGLT2 inhibitor is, for example, dapagliflozin or a pharmaceutically acceptable salt, solvate, mixed solvate, complex, or prodrug thereof. In at least one embodiment, the SGLT2 inhibitor is dapagliflozin administered orally to the patient once daily at 10 mg.

[0050] In some embodiments, the methods disclosed herein result in the following outcomes: (i) extending the time to the first heart failure (HF) event and / or lethal cardiovascular event; and / or (ii) reducing the worsening of HF symptoms; and / or (iii) reducing the number of HF events and / or the incidence of lethal cardiovascular events resulting in at least one of the foregoing.

[0051] Also provided herein is a method for reducing the risk of hyperkalemia in HF patients, the method comprising administering to the patient an effective amount of an SGLT2 inhibitor. In some embodiments, the methods disclosed herein reduce the risk of hyperkalemia in HF patients, which comprises 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 HF patients is disclosed.

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

[0053] In some embodiments, the present disclosure relates to a method of treating HF in a patient, the method comprising administering to the patient an effective amount of an MRA and an effective amount of an SGLT2 inhibitor. In some embodiments, the present disclosure relates to a method of treating HF in a patient, the method 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, a combination of an SGLT2 inhibitor and an MRA for use in reducing the risk of hyperkalemia in HF patients is disclosed. In some embodiments, an SGLT2 inhibitor for use in treating HF patients 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 steroid mineralocorticoid receptor antagonists (MRA), 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 apararenone.

[0055] Also disclosed in this specification 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, as disclosed in WO 2016 / 001631 pamphlet, which has the following structure. [Chemical Formula]

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

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

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

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

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

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

[0064] In some embodiments, an SGLT2 inhibitor for use in the treatment of a patient's HFrEF is disclosed, wherein said treatment comprises the 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 pharmaceutically acceptable salt thereof and an effective amount of an SGLT2 inhibitor. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt, solvate, mixed solvate, complex or prodrug thereof.

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

[0067] In some embodiments, an SGLT2 inhibitor for use in the treatment of HFpEF in a patient is disclosed, wherein said treatment comprises the individual, 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 death and hospitalization for heart failure is disclosed, the method comprising administering to a patient in need thereof an effective amount of AZD9977 or a pharmaceutically acceptable salt thereof and an effective amount of an SGLT2 inhibitor. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt, solvate, mixed solvate, complex or prodrug thereof.

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

[0070] In some embodiments, an SGLT2 inhibitor for use in reducing the risk of cardiovascular death and hospitalization for heart failure in a patient is disclosed, wherein said treatment comprises the individual, 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.

[0071] In some embodiments, a method of reducing the risk of cardiovascular death and hospitalization for heart failure, the method 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 pharmaceutically acceptable salt thereof; and an effective amount of an SGLT2 inhibitor is disclosed. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt, solvate, mixed solvate, complex or prodrug thereof.

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

[0073] In some embodiments, an SGLT2 inhibitor for use in reducing the risk of cardiovascular death and hospitalization for heart failure in a patient having an LVEF of 55% or less and an eGFR of about 15-45 ml / min / 1.73 m2 is disclosed, wherein the treatment comprises separate, sequential or simultaneous administration of the 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.

[0074] In some embodiments, a method of reducing the rate of a composite endpoint of cardiovascular death, hospitalization for heart failure, or urgent HF clinic visit, the method 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 pharmaceutically acceptable salt thereof; and an effective amount of an SGLT2 inhibitor is disclosed. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt, solvate, mixed solvate, complex, or prodrug thereof.

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

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

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

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

[0079] In some embodiments, an SGLT2 inhibitor for use in reducing the rate of any one of all-cause death, myocardial infarction, or stroke in a patient having an LVEF of 55% or less and an eGFR of about 15 - 45 ml / min / 1.73 m2 is disclosed, wherein the treatment comprises separate, sequential, or simultaneous administration of the 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.

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

[0081] In any of the foregoing embodiments, 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%. In some embodiments, 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%. In some embodiments, the patient has an LVEF of 40% or more, such as 45%, 50%, or 55% or more, and in at least one embodiment, at least 55%. In some embodiments, the patient has an estimated glomerular filtration rate (eGFR) of 45 ml / min / 1.73 m2 or less, such as 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 has type 2 diabetes (T2D). In some embodiments, the patient does not have T2D. In some embodiments, hyperkalemia is understood to mean a potassium value exceeding 5.5 mmol / L. In some embodiments, hyperkalemia can be mild (serum potassium value exceeding 5.5 mmol / L) or moderate / severe (serum potassium value exceeding 6.0 mmol / L). BRIEF DESCRIPTION OF THE DRAWINGS

[0082]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8A

Figure 8B

Figure 8C

Figure 8D

Figure 8E

Figure 8F

Figure 9A

Figure 9B

Figure 9C

Figure 9D

Figure 10A

Figure 10B

Figure 11A

Figure 11B

Figure 11C

Figure 11D

Figure 11E

Figure 12

Figure 13

Figure 14

Figure 15

Figure 16

Figure 17

Figure 18

Mode for Carrying Out the Invention

[0083] The present disclosure relates to methods of treating patients with heart failure with reduced ejection fraction (HFrEF), including patients with or without type 2 diabetes (T2D), using an SGLT2 inhibitor, such as dapagliflozin. The present disclosure also relates to treating HFrEF patients with an SGLT2 inhibitor, such as dapagliflozin, by extending the time to the 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 methods of reducing the rate of a primary composite endpoint of CV death, HF hospitalization or urgent HF outpatient visit, or a secondary composite endpoint of CV death and HF hospitalization in HFrEF patients being treated with an SGLT2 inhibitor and an HF standard of care agent, the rate being reduced as compared to patients being treated with the HF standard of care agent alone.

[0084] In some embodiments, the SGLT2 inhibitor, such as dapagliflozin, is administered together with an HF standard of care agent (such as a β-blocker, etc.) in the same or a different composition, either simultaneously 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 anti-diabetic agent, etc.) in the same or a different composition, either simultaneously or at different times.

[0086] I. Definitions The terms "comprising," "having," "including," and "containing" should 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 referring to one or more acute HF events (e.g., HF hospitalization and / or ER visit) and / or death due to cardiovascular causes, it is intended to include the composite items of all the explicitly stated events together, any combination of composite items of some of the events together, or each event alone.

[0089] As used herein, the term "prodrug" refers to esters and carbonates that can be converted to an SGLT2 inhibitor, for example, under physiological conditions or by solvolysis. Thus, the term "prodrug" includes pharmaceutically acceptable metabolic precursors of SGLT2 inhibitors. The term "prodrug" also includes covalently attached carriers that release the SGLT2 inhibitor in vivo when such prodrug is 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 produce, for example, 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 the following: (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,” etc. refer to a treatment (e.g., administration of a pharmaceutical to a subject) that cures, slows, alleviates, and / or halts the progression of a diagnosed pathological condition or disorder, such as symptoms of HFrEF. As used herein, a patient being treated with, or in need of treatment with, an SGLT2 inhibitor described herein includes a patient in whom a diagnosis of a disorder, such as HFrEF, has been confirmed.

[0092] “Therapeutically effective amount” or “effective amount” refers to an amount effective at the dosage and for the period required to achieve the desired therapeutic result (e.g., treatment of HFrEF).

[0093] Preventive treatment refers to measures that prevent and / or slow the onset of a targeted pathological condition or disorder (e.g., administration of an SGLT2 inhibitor described herein to a subject). Accordingly, those in need of preventive treatment include those who are susceptible to the disorder and those who seek to prevent the disorder. “Preventively effective amount” refers to an amount effective at a dosage and for a period of time necessary to achieve a desired preventive result (e.g., prevention or delay of a fatal cardiovascular event).

[0094] The terms “patient” and “subject” refer to adult individuals diagnosed with HFrEF and being treated with HF standard-of-care medications 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 terms “heart failure with reduced ejection fraction,” “HFrEF,” or “patients with HFrEF” refer to a chronic condition 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, e.g., 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 th ed., Boston, MA: Little Brown & Co (1994). The NYHA heart failure classification system was used in the enrollment of patients in the Phase 3 clinical trial described in Example 1. In some embodiments, “HFrEF patients” fall into NYHA HF class II. In some embodiments, “HFrEF patients” fall into NYHA HF class III or IV.

[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 assessment of HFrEF patients generally include cardiac imaging and physical examination, such as assessment of LVEF using echocardiogram, radionuclide angiocardiogram, angiography, or cardiac MRI.

[0097] The NYHA HF classification system classifies classes I-IV according to subjective patient symptom evaluation and classifies heart failure based on the patient's functional ability in daily life: Class I: No restriction of physical activity. Normal physical activity does not cause excessive fatigue, palpitations, or dyspnea; Class II. Some restriction of physical activity. Comfortable at rest. Normal physical activity causes fatigue, palpitations, or dyspnea; Class III. Marked restriction 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 in stages II-IV of the NYHA classification were enrolled in the Phase III DAPA-HF trial described in Example 1.

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

[0099] Other pharmaceuticals that can be used to treat HFrEF and can thus also be considered “standard HF therapeutics” include diuretics and loop diuretics (e.g., furosemide, bumetanide, torsemide, etc.), digoxin, cardiac pump therapy agents, selective sinus node inhibitors, ivabradine (a sinoatrial (SA) node modulator), aldosterone antagonists, vasodilators, calcium channel blockers (unless the patient does not have systolic heart failure), hydralazine / isosorbide dinitrate, or other HF pharmaceuticals according to the clinical guidelines. See the following: Yancy C.W. et al., “ACC / AHA / HFSA focused update of the 2013 ACCF / AHA guideline for the management of heart failure: A report of the American College of Cardiology / American Heart Association task force on clinical practice guidelines and the Heart Failure Society of America, J Am Coll Cardiol. 70(6):776 - 803 (2017).

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

[0101] The administration of an SGLT2 inhibitor "in combination with one or more other therapeutic agents" includes simultaneous (concurrent) or sequential administration in the same or different pharmaceutical compositions (e.g., pills, tablets, capsules) at the same or different times. "Other therapeutic agents" include the HF standard therapeutic agents described above or other therapeutic agents listed below, such as any of the following: antidiabetic agents, anti-obesity agents, antihyperlipidemic agents, anti-atherosclerotic agents, antihypertensive agents, antiplatelet agents, antithrombotic agents or anticoagulants. "Other therapeutic agents" may be in the form of pharmaceutically acceptable salts, solvate compounds, mixed solvate compounds, complexes or prodrugs.

[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 agent combination formulations 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 XR (registered trademark)), ertugliflozin / metformin (STEGLUROMET (registered trademark)) and ertugliflozin / sitagliptin (STEGLUJAN (registered trademark)).

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

[0104] As used herein, "hospitalization for HF" or "HF hospitalization" refers to hospitalization for at least 24 hours due to a primary diagnosis of HF. In some embodiments, the hospitalized patient presents with new symptoms or worsening of 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 receives initiation or intensification of HF-specific treatment. In some embodiments, the hospitalized patient has all of the foregoing criteria.

[0105] As used herein, "symptoms due to HF" includes at least one of dyspnea, decreased exercise tolerance, fatigue, or other symptoms of end-organ dysfunction or fluid overload. In some embodiments, the symptoms due to HF are newly developed or have worsened since a previous period, visit, or hospitalization.

[0106] As used herein, the "Kansas City Cardiomyopathy Questionnaire (KCCQ)" refers to a questionnaire used by physicians to assess a patient's HF symptoms and / or to determine whether the 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, 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). The KCCQ was performed in the DAPA-HF clinical trial (Example 1) as a measure of health-related quality of life (HRQL). The analysis shown in Example 2 reveals that dapagliflozin reduces the worsening of HF across a range of baseline KCCQ values and cardiovascular death, and improves symptom burden, physical function, and quality of life in patients with HFrEF.

[0107] As used herein, "objective evidence of new or worsening HF" refers to physical examination findings by a physician that are considered to be due to HF and / or clinical test values of new or worsening HF. In some embodiments, the objective evidence of new or worsening HF consists of at least two physical examination findings. In some embodiments, the objective evidence of new or worsening HF consists of one physical examination finding and at least one clinical test value.

[0108] As used herein, "physical examination findings considered to be due 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 / crepitations; increased jugular venous pressure and / or hepatojugular reflux; S3 gallop; and / or clinically significant or rapid weight gain related to fluid retention.

[0109] As used herein, "clinical test values of new or worsening HF" refers to at least one of the following findings: increased B-type natriuretic peptide / N-terminal pro-BNP (NT-proBNP) concentration consistent with decompensated heart failure (such as BNP > 500 pg / mL or NT-proBNP > 2,000 pg / mL); radiographic 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 significantly elevated left ventricular or right ventricular filling pressure or low cardiac output or invasive diagnostic evidence by right heart catheterization indicating.

[0110] As used herein, "initiation or intensification of HF-specific treatment" includes at least one of the following: increased oral diuretic therapy; intravenous diuretics or vasoactive drugs (e.g., inotropes, vasopressors or vasodilators); mechanical or surgical interventions (e.g., mechanical circulatory support such as intra-aortic balloon pump, assistive artificial heart, extracorporeal membrane oxygenation, total replacement artificial heart, etc.) and / or mechanical fluid removal (e.g., ultrafiltration, hemofiltration, dialysis).

[0111] As used herein, "emergency HF outpatient" refers to outpatient visits without an emergency reservation to a clinic for primary diagnosis of HF or to the emergency department / emergency treatment outpatient department, where the outpatient visit does not meet the criteria for HF hospitalization. In some embodiments, patients with emergency HF outpatient visits have HF symptoms and / or physical examination findings and / or clinical test values of new or worsening HF as described above, and / or receive initiation or intensification of HF specialized treatment as described above.

[0112] As used herein, "cardiovascular (CV) death" refers to the death of a patient receiving treatment for HFrEF due to the following, as described herein: acute myocardial infarction (MI), sudden cardiac death, heart failure or cardiogenic shock, stroke (cerebrovascular event), cardiovascular procedure, cardiovascular bleeding, other cardiovascular causes (not included in the above categories, but referring to CV death due to specific known causes (e.g., embryonic occlusion or peripheral arterial disease).

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

[0114] As used herein, the terms "primary composite assessment item" or "primary composite endpoint" refer to the following HF events (as described above) that occur in HFrEF patients administered an SGLT2 inhibitor (e.g., dapagliflozin) together with a standard HF treatment drug: · Cardiovascular (CV) death; · HF hospitalization; or · Emergency HF outpatient (including ED outpatient and outpatient visits to clinics without an emergency reservation as defined above) and refer to the determination of relative risk reduction in patients taking an SGLT2 inhibitor (e.g., dapagliflozin) compared to patients taking only the standard HF treatment drug. (See Example 1).

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

[0116] As described herein, for example, in relation to HF symptoms, HF events, HF hospitalization, CV death or non-CV death, the use of phrases indicating comparison such as "reduced", "reduction", "worsened", "decreased", "worsening", "prolonged", "prolongation", etc. is intended to indicate comparison of HFrEF patients administered an SGLT2 inhibitor (e.g., dapagliflozin) with respect to any of the following: · Patients not taking an SGLT2 inhibitor (or a group of patients); · Patients taking only HF standard medications (or a group of patients); · Patients taking a placebo over the same period (or a group of patients); · Patients taking a placebo and HF standard medications over the same period (or a group of patients); · Patients before administration of an SGLT2 inhibitor; · Average prognostic prediction for a group of HFrEF patients.

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

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

[0119] SGLT2 inhibitors that can be used in the disclosed methods for treating patients with HFrEF include dapagliflozin (FARXIGA®), canagliflozin (INVOKANA®), empagliflozin (JARDIANCE®), ertugliflozin (STEGLATRO®), sotagliflozin or ipragliflozin, or pharmaceutically acceptable salts, solvate compounds, mixed solvate compounds, complexes or prodrugs thereof.

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

[0121] In some embodiments, "dapagliflozin" may refer to the FDA-approved formulation FARXIGA® or may refer to a pharmaceutically acceptable salt, solvate compound, mixed solvate compound, complex or prodrug. In some embodiments, dapagliflozin has the structure:

Chemical formula

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

[0123] In some embodiments, "dapagliflozin" is formulated, for example, as a fixed-dose combination preparation together with another therapeutic agent such as another anti-diabetic drug. Dapagliflozin / metformin extended-release tablets (XIGDUO®), and dapagliflozin / saxagliptin (QTERN®), and dapagliflozin / saxagliptin / metformin (QTERNMET®) are examples of combination preparations containing dapagliflozin.

[0124] III. HF Standard Therapeutic Agents As used herein, "HF standard therapeutic agent" includes at least one, for example at least two, at least three or more pharmaceutical products or pharmaceutical classes other than SGLT2 inhibitors, which are used for treating HF, such as HFrEF. HF standard therapeutic agents can be used before and / or during the administration of an SGLT2 inhibitor, such as dapagliflozin, as described herein. In some embodiments, the HF standard therapeutic agent and the SGLT2 inhibitor are administered together at the same time or at different times.

[0125] Exemplary HF standard therapeutic agents include angiotensin-converting enzyme (ACE) inhibitors; angiotensin receptor blockers (ARBs); β-blockers; mineralocorticoid receptor drugs such as mineralocorticoid receptor antagonists (MRAs) and neprilysin inhibitors. HF standard therapeutic agents and their dosages are well known to cardiologists and other physicians who examine and treat HFrEF patients. A brief description of these HF standard therapeutic agents 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 drugs also block the enzyme necessary to convert angiotensin I to angiotensin II. Angiotensin II is a potent vasoconstrictor that raises 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 the adrenal gland. In blood vessels, ARBs cause venous and arterial dilation, reducing both preload and afterload. Blockade of angiotensin II receptors in the adrenal gland reduces the release of aldosterone, which in turn increases the excretion of sodium and water. Representative examples of ARBs include valsartan, losartan, and irbesartan.

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

[0129] Mineralocorticoid receptor antagonists (MRAs) or "aldosterone antagonists" are diuretics that antagonize the action of aldosterone at the mineralocorticoid receptor. This group of drugs is often used as adjuvant 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 (MRMs) are used to represent compounds that exhibit either tissue- or cell-specific receptor antagonism, full antagonism, or partial antagonism.

[0131] Neprilysin inhibitors break down natriuretic peptides and, when the ventricles are overloaded, are responsible for reducing sodium and water. By delaying their breakdown to sustain their effect, more sodium and water are removed from the body, reducing preload and afterload by decreasing intravascular volume and blood pressure. A typical 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 medication, sacubitril / valsartan, combines an ARB (valsartan) with a neprilysin enzyme inhibitor (sacubitril).

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

[0133] IV. Other Therapeutic Agents As described herein, administration of an SGLT2 inhibitor can be carried out in combination with one or more "other therapeutic agents". As used herein, the phrase "other therapeutic agent" typically does not include the HF standard therapeutic agents discussed above, unless otherwise indicated by the context.

[0134] Examples of other therapeutic agents that can be administered together with the SGLT2 inhibitors described herein include anti-diabetic agents, anti-obesity agents, anti-hyperlipidemic agents, anti-atherosclerotic agents, anti-hypertensive agents, antiplatelet agents, antithrombotic agents or anticoagulants. The "other therapeutic agent" can be in the form of a pharmaceutically 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 in the same or different pharmaceutical compositions (e.g., pills, tablets, capsules) at the same or different times.

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

[0137] Method for treating HFrEF by administering an SGLT2 inhibitor 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 has type 2 diabetes. In some embodiments, the patient does not have type 2 diabetes.

[0138] The present disclosure also provides a method for 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 insufficiency during treatment.

[0139] The present disclosure also provides a method for 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 insufficiency during treatment.

[0140] In some embodiments, "no adverse events associated with renal insufficiency" includes no change or only a slight decrease in the estimated glomerular filtration rate (eGFR) level of the patient during SGLT2 inhibitor therapy, no end-stage renal disease (ESRD), and / or no death due to the kidney.

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

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

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

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

[0145] In some embodiments, the at least one other therapeutic agent is an anti-diabetic agent, an anti-obesity agent, an anti-hyperlipidemic agent, an anti-atherosclerotic agent, an anti-hypertensive agent, an antiplatelet agent, an antithrombotic agent, or an anticoagulant.

[0146]

[0147] In some embodiments, the at least one other therapeutic agent is an anti-diabetic agent. In some embodiments, the anti-diabetic 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.In some embodiments, HFrEF patients are receiving one or more HF standard therapies for treating HF before or during administration of an SGLT2 inhibitor. In some embodiments, the HF standard therapies 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, at least one HF standard therapy is a therapeutically effective amount of an angiotensin-converting enzyme (ACE) inhibitor.

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

[0150] In certain embodiments, at least one HF standard therapy is a beta blocker.

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

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

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

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

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

[0156] In some embodiments, a 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. The total number of hospitalizations for HF includes initial and / or readmissions.

[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 specialized HF treatment. In some embodiments, hospitalization for HF is due to all of the criteria listed above. 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 dysfunction or fluid overload. In some embodiments, objective evidence of new or worsening symptoms of HF includes physical examination findings and / or clinical test values for new or worsening HF that are considered to be due to HF. In some embodiments, physical examination findings include at least two of the following findings: peripheral edema, increasing abdominal distension or ascites, pulmonary rales / crackles / crepitations, 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, clinical test values for new or worsening HF include at least one of the following findings: increased B-type natriuretic peptide (BNP) / N-terminal pro-BNP (NT-proBNP) concentration consistent with decompensated heart failure; radiographic evidence of pulmonary congestion; non-invasive diagnostic evidence of clinically significantly elevated left ventricular or right ventricular filling pressure or low cardiac output or invasive diagnostic evidence by right heart catheterization. In some embodiments, initiation or intensification of specialized HF treatment includes at least one of the following: increased 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, the acute HF outpatient visit is an outpatient visit outside the emergency department for primary diagnosis of HF and does not require hospitalization. In some embodiments, the acute HF outpatient visit is an urgent, unscheduled outpatient visit to a clinic for primary diagnosis of HF. In some embodiments, the patient has experienced HF symptoms and / or has physical examination findings and / or new or worsening clinical test values for HF. 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 receives initiation or intensification of specialized HF treatment. In some embodiments, the acute HF outpatient visit requires intravenous therapy.

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

[0161] In some embodiments, the time to the first heart failure event and / or a fatal cardiovascular event can be delayed from 6 months to 24 months from the first administration of the SGLT2 inhibitor. In some embodiments, the time to the first heart failure event can be delayed from 6 months to 24 months from the first administration of the SGLT2 inhibitor. In some embodiments, the time to a fatal cardiovascular event can be delayed from 6 months 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 the treated patient. In some embodiments, the reduced worsening of the patient's heart failure symptoms occurs 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 in the patient. In some embodiments, the reduced worsening of heart failure symptoms is characterized by a reduced number of acute HF outpatient visits in the patient. In some embodiments, the acute HF outpatient visit is an outpatient visit outside the emergency department or an outpatient visit to a clinic for emergency patients.

[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 score of the patient before SGLT2 inhibitor administration. In some embodiments, the higher score based on the KCCQ appears within 8 months from the start of SGLT2 inhibitor administration. In some embodiments, the higher score based on the KCCQ is at least 5 points higher than the score before SGLT2 inhibitor administration. In some embodiments, the higher score based on the KCCQ is at least 10 points higher than the score before SGLT2 inhibitor administration. In some embodiments, the higher score based on the KCCQ is at least 15 points higher than the score before SGLT2 inhibitor administration.

[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 score of the patient before SGLT2 inhibitor administration. In some embodiments, the higher score based on the PGIC appears within 8 months from the start of SGLT2 inhibitor administration. In some embodiments, the higher score based on the PGIC is at least 1 point higher than the score before SGLT2 inhibitor administration. In some embodiments, the higher score based on the PGIC is at least 2 points higher than the score before SGLT2 inhibitor administration. In some embodiments, the higher score based on the PGIC is at least 3 points or more higher than the score before SGLT2 inhibitor administration.

[0166] In some embodiments, the reduced worsening of heart failure symptoms is characterized by a higher score for the patient's global impression (PGIS) questionnaire of severity 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 from the start of SGLT2 inhibitor administration. In some embodiments, the higher score based on the PGIS is at least 1 point higher than the score before SGLT2 inhibitor administration. In some embodiments, the higher score based on the PGIS is at least 2 points higher than the score before SGLT2 inhibitor administration. In some embodiments, the higher score based on the PGIS is at least 3 points or more higher than the score before SGLT2 inhibitor administration.

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

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

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

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

[0171] In some embodiments, administration of the 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 before 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 plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels of at least 400 pg per milliliter, at least 600 pg per milliliter, or at least 900 pg per milliliter before administration of the SGLT2 inhibitor.

[0174] In some embodiments, the patient is medically diagnosed with symptomatic HFrEF before administration of the SGLT2 inhibitor. In some embodiments, the patient is diagnosed with HFrEF at least two months before administration of the SGLT2 inhibitor.

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

[0176] In some embodiments, administration of the SGLT2 inhibitor reduces the HbA1c of the HFrEF patient. In some embodiments, administration of the SGLT2 inhibitor reduces the systolic blood pressure of the HFrEF patient. In some embodiments, administration of the SGLT2 inhibitor reduces the weight of the HFrEF patient. In certain embodiments, the disclosed method results in a decrease in the patient's NT-proBNP levels. In some embodiments, this decrease appears within eight months of the start of administration of the SGLT2 inhibitor. In certain embodiments, the disclosed method results in a sustained decrease in the patient's eGFR (ml / min / 1.73m 2 per).

[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 decrease in readmissions for HF or a decrease in recurrent HF events. In some embodiments, recurrent HF events include hospitalizations for HF or urgent HF clinic visits.

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

[0180] In another aspect, the present disclosure provides a method of reducing the rate of a major composite endpoint of cardiovascular death, HF hospitalization, or urgent HF clinic visit in HFrEF patients being treated with an SGLT2 inhibitor and an HF standard of care agent, the rate being reduced relative to patients being treated with the HF standard of care agent alone. In another aspect, the present disclosure provides a method of reducing the rate of a secondary composite endpoint of cardiovascular death or HF hospitalization in HFrEF patients being treated with an SGLT2 inhibitor and an HF standard of care agent, the rate being reduced relative to patients being treated with the HF standard of care agent alone. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharmaceutically 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 present disclosure provides a method of preventing or delaying fatal CV events in patients with HFrEF without T2D, the method comprising administering to the patient an effective amount of an SGLT2 inhibitor as described herein.

[0182] The present disclosure also provides a method for preventing or delaying fatal CV events in HFrEF patients with T2D, the method comprising administering to a 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 pharmaceutically 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, dapagliflozin is administered at a dose of 2.5 mg, 5 mg or 10 mg once daily. In at least one embodiment, dapagliflozin is administered at a dose of 10 mg once daily.

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

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

[0187] In some embodiments, by administering to an HFrEF patient an effective amount of an SGLT2 inhibitor as described herein, the patient can reduce the total number of HF standard therapeutic agents the patient takes. In some embodiments, the total number of HF standard therapeutic agents is reduced to 2, 3 or 4. Reducing the total number of HF standard therapeutic agents a patient has to take improves the quality of life related to the health of TD2-combined and non-combined HFrEF patients.

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

Example

[0189] Example 1 Results of the DAPA-HF Phase III Clinical Trial Introduction Large-scale clinical trials involving participants with type 2 diabetes (T2D) have demonstrated that inhibitors of sodium-glucose cotransporter 2 (SGLT2) reduce the risk of hospitalization for heart failure (HF). 1~4 However, in particular, most patients in these trials did not have HF at baseline, so the benefits of SGLT2 inhibitor therapy were largely attributed to the prevention of HF events that are likely to occur. Notably, the reduction in hospitalizations for heart failure was observed early after randomization, raising the possibility of a different mechanism or mode of action than that normally assumed to explain the cardiovascular benefits of glucose-lowering therapy. 5~9 In addition to the diuretic effect and related hemodynamic effects of SGLT2 inhibitors, effects on myocardial metabolism, ion transporters, fibrosis, adipokines, and uric acid have also been reported. 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) in whom SGLT2 inhibitor trials have not been conducted. 4、10、11

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

[0191] Methods Trial Design and Oversight AstraZeneca served as the sponsor of the clinical 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 ethics committee of each research facility. The safety of the patients participating in the trial was regularly reviewed by an independent data monitoring committee. The analysis by the sponsor was replicated by an independent academic group at the University of Glasgow.

[0192] Patients in the trial The eligibility criteria included being at least 18 years of age, having symptoms of New York Heart Association (NYHA) class II, III or IV, 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, if the patient had been hospitalized for heart failure within the past 12 months, at least 400 pg of NT-proBNP per milliliter. Patients with atrial fibrillation or atrial flutter on the baseline electrocardiogram were required to have an NT-proBNP level of at least 900 pg / mL regardless of their history of hospitalization for heart failure. Patients were required to receive standard medical and device therapies for heart failure, such as beta blockers and mineralocorticoid receptor (MR) drugs if considered appropriate, as well as angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs) or sacubitril / valsartan, unless contraindicated or intolerant. The doses were individually optimized according to the targets recommended in the guidelines and were required to be stable for at least 4 weeks (except for diuretics where dosing could be flexible). The trial physician was recommended that type 2 diabetic patients continue to take their blood glucose-lowering medications, which could be adjusted as needed. In particular, the protocol stated that, for example, the dose of insulin, sulfonylurea treatment or both could be reduced to minimize the risk of hypoglycemia in patients with a baseline hemoglobin Alc (HbAlc) value of less than 7%.

[0193] Exclusion criteria included recent treatment with an SGLT2 inhibitor or intolerance to it, type 1 diabetes, low blood pressure or symptoms of systolic blood pressure less than 95 mmHg, recent worsening of heart failure or other cardiovascular events or surgery (or planned surgery), and a body surface area of 1.73 m 2 estimated glomerular filtration rate (eGFR) of less than 30 ml per minute per 1.73 m2 of body surface area (or rapid decline in renal function) was included.

[0194] Trial procedures After all patients had submitted written informed consent, they entered a 14-day enrollment period during which trial participation and exclusion criteria were reviewed and baseline information was collected, including findings from clinical examinations and laboratory measurements. After this period, patients were randomly assigned to receive dapagliflozin 10 mg once daily or corresponding placebo according to a stratified, fixed randomization schedule using permuted blocks to ensure a nearly 1:1 ratio of the two treatments. The trial responsible physician performed the treatment assignment using an automated voice or web response system. Randomization was stratified based on the diagnosis of type 2 diabetes defined as any HbA1c value of 6.5% or greater (≥48 mmol / mol) confirmed at the central research facility at the time of definitive diagnosis or screening. Patients were evaluated 14 and 60 days after randomization, focusing on the assessment of heart failure and volume status, adverse events, and renal function and potassium tests. Further trial visits were conducted 4 months later and then every 4 months thereafter. The protocol required that the study drug be discontinued immediately if pregnancy or diabetic ketoacidosis occurred. In the event of any rapid, unexpected decline in eGFR, reduction in fluid volume, or low blood pressure (or to avoid these), dose reduction (to dapagliflozin 5 mg once daily or corresponding placebo) or temporary interruption was permitted, and subsequent dose increases (or resumption of treatment) were recommended if possible.

[0195] Trial evaluation items The primary evaluation item was a composite of the first episode of heart failure worsening or death due to cardiovascular causes. An episode of heart failure worsening was either an unexpected hospitalization due to heart failure or an emergency outpatient visit for heart failure requiring intravenous therapy. 14 The first secondary evaluation item was a composite of heart failure hospitalization or cardiovascular death. Another secondary evaluation item was as follows: the total number of readmissions for recurrent heart failure (including readmissions) and cardiovascular death; the change in the total symptom score of the Kansas City Cardiomyopathy Questionnaire (KCCQ) using a scale of 0 - 100 from baseline to 8 months (a higher score indicates fewer symptoms, and a change of 5 points or more is considered clinically significant). 15 ; a sustained decrease of 50% or more in eGFR, end-stage renal disease (defined as a sustained eGFR < 15 mL / min / 1.73m 2 , the incidence of a composite renal function worsening evaluation item consisting of sustained dialysis treatment or renal transplantation, or renal system death; and death from all causes; in all cases, "sustained" meant lasting for at least 28 days. 12

[0196] The evaluation items were determined by a clinical endpoint committee that was not informed about the treatment allocation according to pre-specified criteria.

[0197] Statistical Analysis For the primary evaluation item, a hazard ratio (HR) of 0.80 for dapagliflozin compared to placebo was estimated. Using a two-sided α of 5%, the inventors calculated that 844 primary endpoints would provide 90% power for the hypothesis test. Based on an annual predicted event rate of 11% in the placebo treatment group, an expected recruitment period of 18 months, and an average follow-up period of about 24 months, it was estimated that approximately 4,500 patients would result in the required number of primary events. A closed testing procedure was used, including a pre-specified hierarchical test for the primary and secondary endpoints in the order specified above. The type I error was controlled at a two-sided 0.0499α level for multiplicity across all primary and secondary endpoints, and one intermediate effect analysis was considered.

[0198] Data from all patients randomly assigned were introduced into the analysis of primary and secondary evaluation items in accordance with the principle of intention to treat. Baseline characteristics were summarized as mean and standard deviation, median and interquartile range, or percentage. Longitudinal measurements such as glycated hemoglobin level (HbAlc) and body weight were analyzed using a mixed model for repeated measures, and the least-squares mean difference between treatment groups was estimated together with the 95% confidence interval. Time-to-event data were evaluated using Kaplan-Meier estimates and the Cox proportional hazards model, stratified by diabetes status with history of hospitalization and treatment for heart failure as fixed-effect coefficients (in the case of 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 the Cox model.

[0199] All (including recurrences) events were analyzed using a semiparametric proportional rate model to verify treatment effects and quantify treatment differences. 16

[0200] The KCCQ total symptom score was analyzed as a composite rank-based endpoint incorporating the change in score from baseline to 8 months and the patient's vital status at 8 months, using rank analysis of covariance with the corresponding win ratio used to estimate the magnitude of treatment effect in surviving patients. 17The consistency of treatment effects among 14 pre-specified groups was evaluated. The pre-specified safety analyses included: serious adverse events; adverse events related to discontinuation of the investigational treatment; "adverse events of special interest", namely volume depletion, renal events, major hypoglycemic events, fractures, diabetic ketoacidosis, amputations; Fournier gangrene; and clinical laboratory tests of note. Other adverse events were not routinely collected, taking into account a large amount of past collected data on the past safety data for dapagliflozin. Safety analyses were performed on patients who had received at least one dose of dapagliflozin or placebo after randomization. Fisher's exact test was used to compare adverse event rates. 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] Results Study patients From February 15, 2017, to August 17, 2018, 4,744 patients were randomly assigned to receive 10 mg of dapagliflozin once daily or matching placebo at 410 sites in 20 countries (Figure 1). Patient characteristics and heart failure therapies were well balanced between the study groups at baseline (Table 1).

[0202] [Table 1]

[0203] [Table 2]

[0204] Study drug administration and follow-up Except for discontinuation due to death, the study drug was discontinued in 249 patients (10.5%) who received dapagliflozin and 258 patients (10.9%) who received placebo (P = 0.71). At the last assessment, among the patients who took the study drug, 2,039 patients (98.1%) in the dapagliflozin group maintained 10 mg once daily; 1,993 patients (98.2%) received placebo at the equivalent dose. At the end of the trial, there were no patients with unknown vital status in the dapagliflozin group, and 2 patients in the placebo group (Figure 1). The median follow-up period was 18.2 months.

[0205] Trial evaluation items Events of worsening heart failure or death due to cardiovascular causes (primary endpoint) 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 - 0.85; P < 0.001 (Figure 2A and Table 2). The event rates for all three components of the composite evaluation item were favorable for dapagliflozin; the most events of worsening heart failure were hospitalizations (Figure 2 and Table 2). 231 patients (9.7%) who received dapagliflozin were hospitalized due to heart failure, compared with 318 patients (13.4%) who received placebo (hazard ratio, 0.70; 95% CI, 0.59 - 0.83; P < 0.001) (Figure 2B and Table 2). Deaths due to cardiovascular causes occurred in 227 patients (9.6%) in the dapagliflozin group and 273 patients (11.5%) in the placebo group (hazard ratio, 0.82; 95% CI, 0.69 - 0.98; P < 0.03) (Figure 2C and Table 2). Over the course of the trial, the number of patients who would need to be treated with dapagliflozin to prevent one major event was 21.

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

[0207] The total KCCQ symptom score increased by a median of 6.1 ± 18.6 points in the dapagliflozin group and 3.3 ± 19.2 points in the placebo group from baseline to 8 months (between-group difference, 2.8 points; 95% CI, 1.6 - 4.0 (Winc ratio, 1.18; 95% CI, 1.11, 1.26; P < 0.001) (Table 2). Compared with placebo, more patients in the dapagliflozin group had a score improvement of 5 points or more (58% vs 51%; OR 1.15, 95% CI, 1.08, 1.23; P < 0.001), and fewer had deterioration (25% vs 33%; OR 0.84, 95% CI, 0.78, 0.90; P < 0.001).

[0208] The pre-specified composite renal evaluation items occurred in 28 patients (1.2%) taking dapagliflozin and 39 patients (1.6%) taking placebo (hazard ratio, 0.71; 95% CI, 0.44 - 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 - 0.97) (Figure 2D and Table 2). The effects of dapagliflozin on heart failure worsening and death are summarized in Figure 3.

[0210] The effect of dapagliflozin on the primary evaluation items was generally consistent among the pre-specified subgroups, including patients without diabetes at baseline. However, the benefit was found to be lower in patients with NYHA functional class III and IV compared to class II (Figure 4). In the post hoc subgroup analysis of patients taking sacubitril-valsartan at baseline, the hazard ratio of dapagliflozin versus placebo for the primary evaluation items was 0.75 (95% CI, 0.50, 1.13), while in patients not taking sacubitril-valsartan, it was 0.74 (0.65, 0.86).

[0211]

Table 3

[0212]

Table 4

[0213] Other evaluation items The changes in hemoglobin A1c, hematocrit, plasma potassium, systolic blood pressure, and body weight from baseline to 8 months are shown in Table 3. The mean creatinine concentration increased by 0.08 ± 0.19 mg per deciliter in the dapagliflozin group and by 0.01 ± 0.17 mg per deciliter in the placebo group from baseline to 2 weeks (between-group difference, 0.07 mg per deciliter; 95% CI, 0.05 - 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 - 0.04; P = 0.04). The change in eGFR per year per ml / min / 1.73 from baseline to 720 days was also measured and shown in Figures 15 and 16. 2 The change in eGFR per year per ml / min / 1.73 from baseline to 720 days was also measured and shown in Figures 15 and 16.

[0214]

Table 5

[0215] Safety Table 2 shows the pre-specified safety evaluation items that deserve special attention. Five patients assigned to dapagliflozin and three assigned to placebo did not receive the investigational drug and were 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%) in the placebo group (P = 0.40). Serious adverse events related to volume depletion occurred in 29 dapagliflozin-treated patients (1.2%) and 40 patients in the placebo group (1.7%) (P = 0.23).

[0216] Adverse events related to renal insufficiency occurred in 153 patients (6.5%) in the dapagliflozin group compared with 170 patients (7.2%) in the placebo group (P = 0.36) (Table 2). Serious renal adverse events occurred in 38 dapagliflozin-treated patients (1.6%) and 65 patients in the placebo group (2.7%) (P = 0.009).

[0217] Adverse events that required treatment discontinuation were rare (Table 2). Lower limb amputations and fractures occurred only rarely, and the incidence rates were 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 gangrene in the dapagliflozin group, while one case was reported in the placebo group. In the dapagliflozin group, there were no significant excesses of any serious adverse events (SAEs).

[0218] Discussion In this multicenter, randomized, placebo-controlled trial of patients with chronic heart failure and a low left ventricular ejection fraction, dapagliflozin reduced the risk of the primary composite endpoint of first episode of heart failure worsening (urgent heart failure outpatient visits requiring hospitalization or intravenous therapy for heart failure) or death due to cardiovascular causes. Each of the three components of this endpoint was similarly reduced, as was the total number of heart failure hospitalizations and deaths due to cardiovascular causes. Dapagliflozin also improved symptoms of heart failure, as measured by the total symptom score of the Kansas City Cardiomyopathy Questionnaire (KCCQ). The observed benefits, which were substantial and clinically important, emerged early after randomization and were seen in participants receiving recommended background therapy for heart failure, including renin-angiotensin system blockers, β-blockers, and mineralocorticoid receptor antagonists, in a high percentage of patients.

[0219] In particular, dapagliflozin was effective in 55 percent of patients without type 2 diabetes, similar to participants with diabetes. This first demonstration of cardiovascular benefit of an SGLT2 inhibitor in patients without diabetes provides support for past suggestions that this type of treatment may have beneficial effects beyond glucose lowering. 4~11 Therefore, the findings from DAPA-HF may potentially expand the therapeutic role of dapagliflozin beyond diabetes.

[0220] Reduction in the primary endpoint was generally consistent across the remaining prespecified subgroups, although one subgroup suggested that patients with NYHA functional classes III and IV had smaller benefits and potentially heterogeneous treatment effects compared with class II. However, other subgroups with more advanced disease, such as lower ejection fraction, worsening renal function, and higher NT-proBNP, did not conform to the NYHA class findings.

[0221] The population tested in the DAPA-HF trial was quite different from previous SGLT2 inhibitor trials in that patients with DAPA-HF had a much higher risk of hospitalization for heart failure and death due to cardiovascular causes. Most patients were already being treated with loop diuretics and mineralocorticoid receptor antagonists, so it was unclear whether dapagliflozin would cause the expected initial natriuresis and diuresis observed in other patient groups. These effects were thought to be able to cause fluid volume reduction and worsening renal function, especially since many of the patients in this trial had chronic kidney disease. Neither of these two adverse effects was common (occurring in less than 8 percent of patients in each treatment group), and serious renal adverse events were generally rare and significantly less frequent in the dapagliflozin group. Overall, very few patients discontinued the trial treatment due to any adverse event (less than 5 percent in each treatment group). Similar to diabetic ketoacidosis, life-threatening hypoglycemia was rare, and all cases of both adverse events occurred in patients with diabetes mellitus.

[0222] With regard to the reduction of hospitalization for heart failure and death due to cardiovascular causes, the baseline use of sacubitril-valsartan, which was more effective than renin-angiotensin system blockade alone, was low. 18 However, the hypothesized mechanisms of action of SGLT2 inhibition and neprilysin inhibition are different, and in a post hoc subgroup analysis, the benefits of dapagliflozin were similar in patients treated with and without concomitant sacubitril-valsartan. 19、20

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

[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 D.Y. et al., “Semiparametric regression for the mean and rate functions of recurrent events,” J R 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 J.J. et al., “Angiotensin-neprilysin inhibition versus enalapril in heart failure,” N Engl J Med. 371:993-1004(2014). 19 McMurray J.J., “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 of disease progression, leading to clinical deterioration, repeated hospitalizations, and death. Bui, A. L. et al., Nat Rev Cardiol 8:30 - 41 (2011). Importantly, these patients also experience a high burden of debilitating symptoms, which affect their daily function and quality of life. Indeed, some of the treatments for HFrEF that have favorable effects on death and hospitalization do not improve health status (Reddy, P. and Dunn, A. B., Pharmacotherapy 20:679 - 689 (2000)), highlighting the high unmet need for another effective therapy that not only improves clinical events but also reduces symptom burden and physical limitations and improves quality of life. In fact, improvement in patients' health status is a major goal of heart failure management and is increasingly recognized by clinical guidelines (Tsevat, J. et al., J Gen Intern Med. 9:576 - 582 (1994); Lewis, E. F. et al., J Heart Lung Transplant 20:1016 - 1024 (2001)) and is recognized as an important evaluation item 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, J.J.V. et al., N Engl J Med, doi:10.1056 / NEJMoa1911303 [Epub ahead of print] (Sep 19, 2019); McMurray, J.J.V. et al., Eur J Heart Fail 21:665-675 (2019); McMurray J.J.V. et al., Eur J Heart Fail., doi:10.1002 / ejhf.1548. [Epub ahead of print] (Jul 15, 2019) (incorporated by reference in their entirety). To better understand the effect of dapagliflozin on a wide range of health status assessment items, its effect on various domains of the KCCQ (an approved self-administered means of quantifying heart failure-related symptoms, function, and quality of life) was examined.

[0227] Methods The design of the DAPA-HF trial, the baseline characteristics of the study patients, and the primary results were as described in Example 1 and in McMurray, J. J. V. et al., N Engl J Med, doi:10.1056 / NEJMoa1911303 [Epub ahead of print] (2019 Sep 19); McMurray, J. J. V. et al., Eur J Heart Fail 21:665-675 (2019); and McMurray J. J. V. 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 urgent HF clinic visit) or cardiovascular (CV) death (whichever occurred first). Other clinical endpoints that were evaluated were the occurrence of HF hospitalization or CV death; worsening HF events (HF hospitalization or urgent HF clinic visit), hospitalizations for HF, CV death, and all-cause death.

[0228] Kansas City Cardiomyopathy Questionnaire The KCCQ was electronically completed (as verified) by patients without assistance from local trial staff and was evaluated 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 change) over the past 2 weeks, physical function, quality of life, and social function. For the KCCQ, the total symptom score (TSS) quantifies symptom frequency and severity, the KCCQ clinical summary score (KCCQ-CSS) includes physical function and the symptom domain, and the KCCQ overall summary score (OSS) is derived from the following domains (total symptom score, physical function, quality of life, and social function). For each domain, validity, reproducibility, responsiveness, and interpretability have been established independently. Scores are converted to a scale of 0 to 100, where higher scores represent better health status.

[0229] Statistical Analysis In this trial, patients were divided into three subgroups based on the tertiles of baseline KCCQ-TSS (a KCCQ domain pre-specified as a secondary endpoint): (i) ≤ 65.6, (ii) 65.7 - 87.5, (iii) > 87.5 points. Characteristics at baseline were summarized as mean and standard deviation, median and interquartile range, or percentage. CV mortality and HF worsening rates (regardless of treatment allocation) were calculated across the tertiles of KCCQ-TSS and compared using Kaplan-Meier estimates.

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

[0231] Using a mixed model for repeated measures, the differences between treatment groups in mean KCCQ-TSS, CSS, and OSS at 4 and 8 months in surviving patients were analyzed, and the difference in least-squares means between treatment groups adjusted for baseline values was estimated. The proportion of patients with worsening and clinically important improvement in KCCQ at 8 months was examined, and responder analysis was performed. For all responder analyses across this KCCQ domain, clinically important thresholds established for KCCQ (≥ 5 points (small at least), ≥ 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, 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 values); these models used complementary data to account for missing KCCQ values and pooled estimates using Rubin's rule. Missing data were imputed using the assumption of random missingness and the predictive mean matching multiple imputation model and the method of full conditional specification implemented in SAS Procedure MI (FCS statement). The imputation model included the treatment group, type 2 diabetes randomization strata, baseline, 4-month, and 8-month KCCQ scores, and categorical variables representing the number of HF events (0, 1, ≥2 events) reported by the study physicians from randomization to 4 months and from 4 to 8 months. Death was handled by assigning the lowest value. Patients with baseline KCCQ scores that were too high to experience improvement according to a specific threshold (e.g., for a 5-point threshold, baseline score ≥95 points) were defined as improved if the score remained high (i.e., ≥95 points) at 8 months. Similarly, patients with baseline KCCQ scores that were too low to experience worsening were defined as worsened if the score 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] Results Overall, 4,744 patients were randomized. Baseline KCCQ TSS was available for 4,443 (93.7%) patients. The median KCCQ TSS was 77.1 (IQR 58.3 - 91.7). The number and percentage of patients in the KCCQ TSS tertiles are shown in Table 4.

[0234] [Table 6]

[0235]

Table 7

[0236] Characteristics of the patients Compared with participants with a higher KCCQ-TSS score at baseline, participants with a lower score were younger, more frequently female, white, and enrolled in Europe and North and South America. These participants also had a higher body mass index and natriuretic peptide values; and a lower eGFR as well (Table 4); and had a higher tendency to fall into NYHA functional class III / IV rather than class II and a tendency to have type 2 diabetes and atrial fibrillation. Regarding the baseline HF therapy, patients with a low baseline KCCQ-TSS were more frequently treated with mineralocorticoid receptor antagonists (MRAs) and diuretics. The baseline use of angiotensin receptor neprilysin inhibitors (ARNI) was generally low but similar across age groups. The proportion of patients treated with implantable cardiac devices was generally equivalent across the KCCQ-TSS subgroups.

[0237] Clinical evaluation items Patients with a lower baseline KCCQ-TSS experienced CV mortality or HF worsening at a higher rate (25.0%, 17.3%, and 13.6% in patients across the KCCQ-TSS tertiles of ≤65.6, 65.7 - 87.5, and >87.5 respectively; p < 0.001). In the Cox proportional hazards model, patients with a lower baseline KCCQ-TSS had a higher risk of CV death or HF worsening (tertile >87.5: reference; 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 effects of dapagliflozin on the range of clinical evaluation items are summarized in Figure 6. Dapagliflozin reduced the primary evaluation items of CV death or HF worsening across the entire range of KKCQ-TSS, and there was no evidence of treatment effect heterogeneity (HR (95% CI) for the lowest to highest tertiles: 0.70 (0.57 - 0.86), 0.77 (0.61 - 0.98), and 0.62 (0.46 - 0.83), respectively; P = 0.52 for heterogeneity). Similar results were observed for hospitalization for CV death or HF, HF worsening events, HF hospitalization, CV death, and all-cause death (Figure 6; all P-values for heterogeneity were 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 were modest at the 4-month time point in mean KCCQ-TSS, CSS, and OSS, but there were significant improvements (1.9, 1.8, and 1.7 points higher than placebo, respectively; P < 0.0001 for all). These beneficial effects were amplified over time, and the corresponding mean differences at the 8-month time point were 2.8, 2.5, and 2.3 points higher for dapagliflozin than for placebo (P < 0.0001 for all).

[0240] The results of responder analysis are shown in Figures 8A - 8F. Fewer patients treated with dapagliflozin had a clinically beneficial worsening (≥5 - point decrease in KCCQ - TSS (25.3% vs 32.9%; OR 0.84, 95% CI 0.78 - 0.90; p < 0.0001)); fewer had at least small (58.3% vs 50.9%), moderate (54.5% vs 47.6%) and large (54.0% vs 48.2%) improvements, and more patients treated with dapagliflozin had these 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 KCCQ - CSS and OSS (Figures 8C - 8F).

[0241] Discussion In this prospective study evaluating pre - specified health state assessment items using 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 entire range of baseline KCCQ, indicating that the beneficial effect of dapagliflozin on HF assessment items is independent of baseline health state impairment. Furthermore, dapagliflozin significantly improved KCCQ - TSS, CSS and OSS (comprehensively including impairment, physical function, quality of life and social function), and these effects were amplified over time. Finally, significantly fewer patients treated with dapagliflozin experienced a clinically important worsening, and significantly more experienced at least small, moderate and large clinically important improvements in health state. These effects were substantial, with the number needed to treat in the range of 12 - 18 after only 8 months of treatment.

[0242] These results have several important implications. First, the analysis of clinical evaluation items across subgroups of the baseline KCCQ-TSS did not show evidence of heterogeneity in the benefits of dapagliflozin by severity of symptom impairment at baseline. A previously reported pre-specified subgroup analysis for the primary endpoint (CV death or HF worsening) suggested that the benefits of dapagliflozin may be more prominent in patients with NYHA functional class II compared to class III-IV. However, the NYHA class, while important for prognosis, presents a more subjective, arbitrary, and non-patient-centered assessment of symptom burden; considering this report, the observations from previous NYHA class subgroup analyses were likely opportunistic.

[0243] Second, the findings substantially elaborate on 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 Heart Failure Patients With Reduced Ejection Fraction (DEFINE-HF) trial, a moderately sized randomized, placebo-controlled trial conducted at 26 US sites, dapagliflozin was also demonstrated to have favorable effects on several domains of the KCCQ, and the mean difference of dapagliflozin versus placebo was slightly larger than that observed in the DAPA-HF trial, but the responder analysis and number needed to treat were comparable after only 12 weeks of treatment. Nassif, M.E. et al., Circulation 140:1463-1476 (Sept. 2019). These findings confirm the beneficial effects on symptoms, function, and quality of life in much larger worldwide trials with longer follow-up periods. Collectively, the findings from both the DEFINE-HF and DAPA-HF trials show that dapagliflozin significantly improves heart failure-related health status as measured by the KCCQ, and these benefits appear early and persist over the long term.

[0244] Third, the degree of improvement in KCCQ observed with dapagliflozin compared to placebo in the DAPA-HF trial is favorably comparable to other effective therapies for HFrEF. As an example, in the Systolic Heart Failure Treatment with Ivabradine (SHIFT) trial using the If inhibitor ivabradine, ivabradine showed an average improvement in KCCQ-OSS of 2.4 points and an average improvement in 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, E. F. et al., Circ Heart Fail. 10: doi:10.1161 / CIRCHEARTFAILURE.116.003430 (2017), sacubitril / valsartan showed improvements in KCCQ-OS and KCCQ-CS of 1.3 and 0.9 points, respectively, compared to enalapril after 8 months of treatment. In HF-ACTION, Flynn, K. E. et al., JAMA 301:1451-1459 (2009), exercise therapy for HFrEF resulted in an improvement in KCCQ-OSS of 1.9 points. In the MADIT-CRT trial of cardiac resynchronization therapy (CRT) in patients with HFrEF and prolonged QRS duration, Veazie, P. J. et al., J Am Coll Cardiol. 60:1940-1944 (2012), treatment with CRT resulted in improvements in KCCQ-TSS, CSS, and OSS of 2.0, 2.0, and 2.4 points, respectively, in patients with left bundle branch block (LBBB), and no significant improvement in KCCQ in patients without LBBB. Responder analyses have been conducted only very rarely to date, but the degree of benefit (such as the number of times treatment was required) observed with dapagliflozin in the responder analysis of DAPA-HF is very favorably comparable to results observed in the past. Ekman, I. et al., Eur Heart J 32:2395-2404 (2011). The number of times treatment was required for a clinically important improvement in KCCQ is based on a comparison between dapagliflozin-treated patients and placebo-treated patients (both in our trial and the DEFINE-HF trial, who also experienced an improvement in health status consistent with a fairly large "placebo effect").Therefore, the degree of the dapagliflozin effect on health status in clinical practice (clearly without using a placebo) may be greater than that observed. Considering the reduction of symptom burden and physical limitations as well as the improvement of quality of life (the main goals of HF management recognized by clinical guidelines and regulatory agencies), the findings of the present inventors provide further support for dapagliflozin as a new treatment option for HFrEF patients.

[0245] Conclusion In the DAPA-HF trial, treatment with dapagliflozin reduced death and hospitalization for heart failure across the range of baseline KCCQ values and improved the symptom burden, functional status, and quality of life of HFrEF patients. 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 Results of the DAPA-HF Phase III Clinical Trial - Effects of Dapagliflozin on Clinical, Metabolic, Hemodynamic, and Renal Assessment Items in Diabetic and Nondiabetic HF Patients Introduction As described in Example 1, in the DAPA-HF trial, SGLT2 inhibition resulted in a similar reduction in the primary assessment of HF worsening events or death due to cardiovascular causes in diabetic and nondiabetic HF patients. See also McMurray, J.J.V. et al., Eur J Heart Fail 21:665-675 (2019); McMurray, J.J.V. et al., N Engl J Med doi:10.1056 / NEJMoa1911303 [Epub ahead of print] (Sep 19, 2019) (incorporated herein by reference in its entirety). In the pre-specified analysis described in this example, in HF patients, the effects and safety of dapagliflozin are described together with changes in metabolism and hemodynamics across the range of baseline glycated hemoglobin (also known as hemoglobin Alc or HbAlc) in DAPA-HF.

[0247] Method The inclusion criteria, baseline characteristics, and exclusion criteria for the DAPA-HF trial patients were as described in Example 1 and McMurray, J.J.V. et al., Eur J Heart Fail 21:665-675 (2019); McMurray, J.J.V. et al., N Engl J Med doi:10.1056 / NEJMoa1911303 [Epub ahead of print] (2019 Sep 19). The trial procedures, trial evaluation items, and statistical analysis were also as described in Example 1 and McMurray, J.J.V. et al., Eur J Heart Fail 21:665-675 (2019); McMurray, J.J.V. et al., N Engl J Med doi:10.1056 / NEJMoa1911303 [Epub ahead of print] (2019 Sep 19).

[0248] Baseline classification of diabetes status The trial responsible physician recorded whether the patient had a history of diabetes at the time of registration visit (visit 1). The patient also had a measured glycated hemoglobin (HbAlc) value at the central research facility at visit 1 and at visit 2 (randomization visit) 14 (±7) days after visit 1. For this pre-specified subgroup analysis, patients were classified as having diabetes if they had a history of diabetes or a glycated hemoglobin of at least 6.5% (≥48 mmol / mol) at both visits 1 and 2. Patients with a glycated hemoglobin value <5.7% (<39 mmol / mol) at both visits 1 and 2 were considered to have normal glycated hemoglobin. For the purposes of this trial, patients with a glycated hemoglobin value ≥5.7% and <6.5% were considered to have prediabetes. Ibid.

[0249] Results Patients Blood glucose status at baseline Of the 4,744 patients who participated, 2,605 (55%) had no diabetes. Of the remainder, 1,983 (41.8%) had a history of diabetes at the time of screening, and an additional 156 (3.3%) had diabetes that had not been previously diagnosed, i.e., had a glycated hemoglobin ≥6.5% at Visit 1 (registration) and Visit 2 (randomization). Of the 2,605 patients without diabetes, 1,748 (67.1%) had a glycated hemoglobin value ≥5.7% at either Visit 1 or 2, and 839 patients (32.2%) had a glycated hemoglobin value <5.7% at both Visit 1 and 2. In addition, 12 patients had only a single glycated hemoglobin measurement <5.7%, and 6 patients had missing baseline glycated hemoglobin measurements for both (these 18 were included in the normal hemoglobin group).

[0250] Characteristics of patients by baseline glycemic status Table 5 shows the baseline characteristics of patients with and without diabetes, and these were well balanced between patients randomized to dapagliflozin or placebo within each patient group (Table 6). Patients without diabetes were less likely to be black and less likely 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 to those with diabetes. Mean eGFR was higher in participants without diabetes compared to those with diabetes. The mean glycated hemoglobin value in patients without diabetes was 5.8% compared to 7.4% in patients with diabetes. The mean duration of diabetes was 7.41 years (IQR 2.75, 13.5).

[0251] At baseline, both NYHA functional class and KCCQ-TSS were better in patients without diabetes compared to those 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 Evaluation items based on baseline glycemic status Patients without diabetes had low pre-specified mortality and HF worsening rates (Table 7, Figures 9A - 9D, and Figure 10A). Among patients without diabetes, the rates of evaluation items were highest in those in the upper one-third of baseline glycated hemoglobin (≥6.0%), i.e., individuals with prediabetes (Figure 10A). The risk of renal composite endpoints 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 and without diabetes.

[0260]

Table 15

[0261]

Table 16

[0262] Effect of dapagliflozin versus placebo according to baseline glycemic status The effects of dapagliflozin on the primary composite endpoint and on the individual mortality and hospitalization endpoints, and on urgent outpatient visits due to worsening heart failure requiring intravenous therapy are shown in Table 7 and Figure 10B. The effects of dapagliflozin on each endpoint were similar in patients with and without diabetes, and the effects of the study drug on the renal composite endpoint were also similar.

[0263] At baseline, in patients without diabetes, when divided into three equal groups, the effect of dapagliflozin on the primary endpoint was consistent across the range of hemoglobin A1c (Figure 10A). In particular, for patients in the lower third (hemoglobin A1c value ≤5.6%), the hazard ratio for dapagliflozin versus placebo was 0.74 (95% CI 0.53, 1.04), in the middle third (>5.6 to <6.0%) it was 0.71 (0.48, 1.04), and in the upper third (≥6.0%) it was 0.72 (0.52, 1.00); P interaction = 0.837. Another analysis using hemoglobin A1c as a continuous variable demonstrated the benefit of dapagliflozin across the range included (Figures 12A–12D).

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

[0265] In individuals without diabetes, more patients in the dapagliflozin group than in the placebo group reported an increase of at least 5 points in 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. The corresponding rates in individuals with diabetes were as follows: improvement of ≥5 points - 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 interaction for improvement and P = 0.075 for interaction for worsening).

[0266] In individuals without diabetes, 157 developed T2D during the trial, and 150 of them (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 a higher baseline Alc (6.2±0.3 vs 5.7±0.4%; p<0.001), higher BMI (28.5±5.9 vs 27.1±5.7 kg / m 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) than those who remained diabetes-free. 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, body weight, and blood pressure Figures 11A - 11E show the changes in clinical test measurements, body weight, and blood pressure, adjusted for baseline values. In patients without diabetes, there was little change in hemoglobin A1c, but in patients with diabetes, there was a slight decrease by 60 days (P interaction < 0.0001) (Figure 11A). Body weight and systolic blood pressure decreased in both patient groups (Figures 11B and 11C, respectively). Hematocrit increased with dapagliflozin in both patient groups and reached a plateau after about 4 months; this increase was lower in patients without diabetes than in patients with diabetes (P interaction = 0.0002) (Figure 11D). The difference between treatments attenuated by 6 months, but there was a slight initial increase in creatinine with dapagliflozin in both groups; this increase was lower in patients without diabetes than in patients with diabetes (P interaction = 0.0005) (Figure 11E).

[0268] N - terminal pro - B - type natriuretic peptide In patients without diabetes, NT - proBNP decreased by 144 ± 2286 pg / ml in the dapagliflozin group and increased by 84 ± 2993 pg / ml in the placebo group from baseline to 8 months; the between - treatment difference was - 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; the between - treatment difference was - 333 (- 562 to - 104) pg / ml; p = 0.004 (P interaction = 0.728).

[0269] Tolerance 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 investigational drug. In patients with diabetes, these numbers were 105 (9.8%) and 117 (11.0%), respectively.

[0270] The most common notable adverse events were those related to volume depletion and kidney impairment, but these were less frequent 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] Doubling of serum creatinine occurred in 22 (1.7%) patients without diabetes randomized to dapagliflozin and 36 (2.8%) patients randomized 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 presumed diabetic ketoacidosis during the trial, and all were diabetic patients randomized to dapagliflozin. Eight patients (0.17%) experienced life-threatening hypoglycemia during the trial, and all eight had diabetes: four were randomized to dapagliflozin and four were randomized to placebo. Overall, 25 patients (0.53%) underwent amputations, one of the patients without diabetes belonged to the dapagliflozin group and three to the placebo group, and among the diabetic patients, 12 patients belonged to the dapagliflozin group and nine to the placebo group.

[0275] Discussion The key findings from this analysis of patients with HF and a low ejection fraction were that the SGLT2 inhibitor dapagliflozin improved all pre-specified mortality and hospitalization endpoints to a similar extent in both diabetic and non-diabetic people. Furthermore, among individuals without diabetes, the reduction in the primary endpoint with dapagliflozin was consistent across the range of baseline hemoglobin A1c values, regardless of whether it was evaluated as a categorical or continuous measure. Indeed, serendipitously, in the tertile analysis of participants without diabetes, quartiles reflecting the prediabetes U.S. (≥5.6%) and European (≥6.0%) definitions based on hemoglobin A1c criteria were selected. (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 benefits of dapagliflozin were similar in individuals with prediabetes diagnosed using either definition and in those with normal hemoglobin A1c. This data provides compelling evidence that the benefits of SGLT2 inhibition are not limited to people with diabetes or prediabetes and are applicable to patients with heart failure and a low ejection fraction, regardless of glycemic status. Furthermore, the observed benefits were also obtained in participants who were already receiving therapies recommended for HF, including renin - angiotensin system blockers, β - blockers, and mineralocorticoid receptor antagonists.

[0276] This analysis also demonstrated the effects of dapagliflozin on metabolism, hemodynamics, and anthropometric measures in both diabetic and non - diabetic people. As predicted, dapagliflozin reduced hemoglobin A1c in patients with type 2 diabetes but had no effect on this measure in non - diabetic patients. However, the effects of dapagliflozin on weight, blood pressure, hematocrit, creatinine, and NT - proBNP were directionally similar in both diabetic and non - diabetic people, although they were somewhat more pronounced in the former group.

[0277] From the findings of this clinical trial, it can be inferred that the benefits of dapagliflozin were independent of the reduction in plasma glucose. Other mechanisms of action of SGLT2 inhibitors have been presented, including diuretic effects. (Hallow, K.M. et al., Diabetes Obes Metab 20: 479-487 (2018); McMurray, J., J Diabetes Complications 30: 3-4 (2016)). This mechanism was not directly measured in this trial, but the early reduction in systolic blood pressure and body weight, as well as the increase in creatinine, were consistent with a diuretic effect. However, particularly in HF patients, especially those without diabetes, little is known about the effect of SGLT2 inhibitors on urinary sodium and water excretion when added to conventional diuretic therapy. (Hallow, K.M. et al., supra; Devineni, D. et al., Clin Ther 36: 698-710 (2014); Nassif, M.E. 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 cause tubuloglomerular feedback independently of diuresis, which promotes constriction of the glomerular afferent arterioles and a decrease in glomerular filtration. (Heerspink, H.K. et al., Circulation 134: 752-72 (2016); Kidokoro, K. et al., Circulation 140: 303-315 (2019). Similarly, the increase in hematocrit is thought to be due to an increase in renal erythropoietin secretion due to the improvement in renal function mediated by SGLT2 inhibitors. (Yanai, H. et al., J Clin Med Res 9: 178-179 (2017)). The time-course changes in creatinine and hematocrit observed by the inventors were quite different, with the initial increase in creatinine reversing after 14 days, while hematocrit gradually increased during the first 4 months and then leveled off. Volume contraction due to diuresis does not seem likely to explain such diverse changes.

[0278] Other diuretic-independent effects have also been reported, such as effects on ion transporters, fibrosis, adipokines, sympathetic nervous system activity, and vascular function, but the clinical evidence to support these is scarce. (Thomas, M.C. 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 volume, and the effect on cardiac remodeling may explain the reduction in NT-proBNP observed with dapagliflozin. (Verma, S. et al., Circulation (2019 Aug. 22)). Recent experimental studies have further revealed the benefits of SGLT2 inhibitors on the cardiac structure and function of animals without diabetes. (Thomas, M.C. et al., Diabetologia 61:2098-2107 (2018); Yurista, S.R. 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 worthy of note in relation to those associated with heart failure and reduced fluid volume were low and similar in diabetic and non-diabetic participants. This finding is also consistent with the view that diuresis may not be the main mechanism underlying the beneficial effects of dapagliflozin. Other pre-specified safety assessment items were rare in both patient groups, and discontinuation of the investigational drug was also rare in both groups. Neither life-threatening hypoglycemia nor diabetic ketoacidosis occurred in the non-diabetic patients. Although no significant effect on the inventors' pre-specified renal assessment items was revealed, this occurred in few patients. However, doubling of serum creatinine was found to be significantly less in patients receiving dapagliflozin in both diabetic and non-diabetic patients. Serious renal adverse events were also less in patients assigned to dapagliflozin compared to placebo.

[0280] In conclusion, in patients with HF and reduced ejection fraction, the SGLT2 inhibitor dapagliflozin reduced the risk of worsening heart failure and cardiovascular death and improved symptoms regardless of baseline diabetes and independently of hemoglobin A1c levels. These benefits were observed to be superior to those of excellent standard-of-care drugs in both diabetic and non-diabetic individuals. Collectively, these data support the use of dapagliflozin as a treatment for heart failure with reduced ejection fraction in both diabetic and non-diabetic individuals regardless of glycemic status.

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

[0282] Unless otherwise indicated, the description of a range of values herein is intended merely as a concise way to refer individually to each separate value falling within the range, and each separate value is incorporated herein as if it were individually recited 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 exemplary language provided herein (e.g., "such as") are intended merely to clarify the disclosure and do not otherwise limit the scope of the disclosure unless otherwise claimed. No language in this specification should be construed as indicating any non-claimed element as essential to the practice of the disclosure.

[0283] This specification describes various embodiments of the disclosure, including the best mode known to the inventors for practicing the disclosure. Variations of these embodiments will be apparent to those skilled in the art upon reading the above description. The inventors expect those skilled in the art to employ such variations as appropriate, and the inventors intend for the disclosure to be practiced otherwise than as specifically described herein. Accordingly, this disclosure includes any variations and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Furthermore, any combination of the above-described elements in all possible variations thereof is included in the disclosure unless otherwise indicated herein or otherwise clearly contradicted by context.

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

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

[0286] Results Overall, 3370 (70.1%) patients in DAPA-HF were treated with MRA. Mild hyperkalemia 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 who received placebo (Table 8 and Figures 18A - 18B). This yielded 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 when 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 method for 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.

2. A method for 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.

3. A method for treating HFrEF in a patient with T2D, the method comprising administering to the patient an effective amount of an SGLT2 inhibitor.

4. A method for preventing or delaying fatal cardiovascular events in a patient with HFrEF without T2D, the method comprising administering to the patient an effective amount of an SGLT2 inhibitor.

5. A method for preventing or delaying fatal cardiovascular events in a patient with HFrEF with T2D, the method comprising administering to the patient an effective amount of an SGLT2 inhibitor.

6. A method for treating HFrEF in a patient without T2D, the method comprising administering to the patient an effective amount of an SGLT2 inhibitor, wherein the patient does not experience adverse events associated with renal insufficiency during treatment.

7. A method for treating HFrEF in a patient with T2D, the method comprising administering to the patient an effective amount of an SGLT2 inhibitor, wherein the patient does not experience adverse events associated with renal insufficiency during treatment.

8. The method according to claim 6 or 7, wherein the absence of adverse events associated with renal insufficiency includes no or only slight reduction in eGFR level, no end-stage renal disease (ESRD), and / or no kidney-related death.

9. A method for reducing the total number of standard heart failure (HF) therapeutics taken by a patient with HFrEF without T2D, the method comprising administering to the patient an effective amount of an SGLT2 inhibitor.

10. A method for reducing the total number of HF standard therapeutics taken by a patient with HFrEF with T2D, the method comprising administering to the patient an effective amount of an SGLT2 inhibitor.

11. The method according to any one of claims 1 to 10, wherein the SGLT2 inhibitor is dapagliflozin, canagliflozin, empagliflozin, sotagliflozin, ipragliflozin or ertugliflozin, or a pharmaceutically acceptable salt, solvate, mixed solvate, complex or prodrug thereof.

12. The method according to claim 11, wherein the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt, solvate, mixed solvate, complex or prodrug thereof.

13. The method according to claim 12, wherein dapagliflozin is in the form of an amorphous solid.

14. The method according to claim 12, wherein dapagliflozin is in the form of a crystalline solid.

15. The dapagliflozin has the structure: 【Chemical 1】 and is in the form of (S)-propylene glycol ((S)-(PG) solvate), and the method according to any one of claims 12 to 14.

16. The method according to any one of claims 1 to 15, further comprising administering to the patient at least one other therapeutic agent.

17. The method according to claim 16, wherein the other therapeutic agent is administered in the same or a different pharmaceutical composition and at the same or a different time point together with the SGLT2 inhibitor.

18. The method according to claim 16 or 17, wherein the other therapeutic agent is an anti-diabetic agent, an anti-obesity agent, an anti-hyperlipidemic agent, an anti-atherosclerotic agent, an anti-hypertensive agent, an antiplatelet agent, an antithrombotic agent or an anticoagulant.

19. The method according to claim 18, wherein the other therapeutic agent is an anti-diabetic agent.

20. The method according to claim 19, wherein the anti-diabetic agent is a biguanide and / or a DPP4 inhibitor.

21. The method according to claim 20, wherein the biguanide is metformin or a pharmaceutically acceptable salt thereof.

22. The method according to claim 20, wherein the DPP4 inhibitor is saxagliptin, linagliptin or sitagliptin, or a pharmaceutically acceptable salt thereof.

23. The method according to any one of claims 1 to 22, wherein the patient has a left ventricular ejection fraction (LVEF) of 40% or less.

24. The method according to claim 23, wherein the LVEF is 35%, 30% or 25% or less.

25. The method according to claim 24, wherein the LVEF is at least 20%.

26. The method according to any one of claims 23 to 25, wherein the LVEF is determined using echocardiogram, radionuclide angiocardiogram, angiography or cardiac MRI.

27. The method according to any one of claims 12 to 26, wherein dapagliflozin is orally administered to the patient once a day at a dose of 2.5 mg, 5.0 mg or 10 mg.

28. The method according to claim 27, wherein the dose of dapagliflozin is 10 mg.

29. The administration of the SGLT2 inhibitor results in at least one of the following outcomes: (i) extending the time to the first heart failure (HF) event and / or fatal cardiovascular event; and / or (ii) reducing the worsening of HF symptoms; and / or (iii) reducing the number of HF events and / or the incidence of fatal cardiovascular events The method according to any one of claims 1 to 28.

30. The method according to claim 29, wherein the administration of the SGLT2 inhibitor extends the time to the first heart failure (HF) event.

31. The method according to claim 30, wherein the HF event is hospitalization for HF or an emergency HF clinic visit.

32. The method according to claim 31, wherein the hospitalization for HF includes a hospitalization lasting at least 24 hours along with the primary diagnosis of HF.

33. The method according to any one of claims 1 to 32, wherein the administration of the SGLT2 inhibitor reduces the total number of hospitalizations for HF.

34. The method according to claim 33, wherein the total number of hospitalizations for HF includes the first and / or readmissions.

35. The hospitalization for HF is based on 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) the initiation or intensification of specialized HF treatment The method according to any one of claims 32 to 34.

36. The method according to claim 35, wherein the new or worsening symptoms of HF experienced by the patient include dyspnea, reduced exercise tolerance, fatigue and / or other symptoms of worsening end-organ damage or fluid overload.

37. The method according to claim 35 or 36, wherein the objective evidence of new or worsening symptoms of HF includes physical examination findings considered to be due to HF and / or clinical test values of new or worsening HF.

38. The physical examination findings of claim 37, wherein the method comprises at least two of the following findings: peripheral edema, increasing abdominal distension or ascites, pulmonary rales / crackles / crepitations, increased jugular venous pressure and / or hepatojugular reflux, S3 gallop, and / or clinically significant or rapid weight gain associated with fluid retention.

39. The clinical test values of the new or worsening HF of claim 37, wherein the method comprises at least one of the following findings: increased B-type natriuretic peptide (BNP) / N-terminal pro-BNP (NT-proBNP) concentration consistent with decompensated heart failure; radiographic evidence of pulmonary congestion; non-invasive diagnostic evidence of clinically significantly elevated left ventricular or right ventricular filling pressure or low cardiac output, or invasive diagnostic evidence by right heart catheterization.

40. The initiation or intensification of the HF-specific treatment of claims 35 to 39, wherein the method comprises at least one of the following: increased oral diuretic therapy, intravenous administration of diuretics or vasoactive agents, or mechanical or surgical intervention.

41. The mechanical or surgical intervention of claim 40, wherein the method comprises mechanical circulatory support or mechanical fluid removal.

42. The emergency HF outpatient clinic of claim 31, which is an outpatient clinic outside the emergency department for primary diagnosis of HF but does not require hospitalization.

43. The emergency HF outpatient clinic of claim 31, which is an emergency walk-in clinic without prior reservation at a clinic for primary diagnosis of HF.

44. The method of claim 42 or 43, wherein the patient has experienced HF symptoms and / or has physical examination findings and / or clinical test findings of new or worsening HF.

45. The method of claim 44, wherein 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 deteriorated end-organ damage or fluid overload.

46. The method of any one of claims 42 to 45, wherein the patient receives initiation or intensification of HF-specific treatment.

47. The method of any one of claims 42 to 46, wherein the emergency HF outpatient clinic requires intravenous therapy.

48. The method of any one of claims 29 to 47, wherein the administration of the SGLT2 inhibitor prolongs the time to lethal cardiovascular events.

49. The time to the first heart failure event and / or fatal cardiovascular event is delayed from 8 weeks to 2 years from the first administration of the SGLT2 inhibitor, the method according to any one of claims 29 to 48.

50. The time to the first heart failure event is delayed from 8 weeks to 2 years from the first administration of the SGLT2 inhibitor, the method according to claim 49.

51. The time to fatal cardiovascular event is delayed from 8 weeks to 2 years from the first administration of the SGLT2 inhibitor, the method according to claim 49.

52. The administration of the SGLT2 inhibitor reduces the worsening of HF symptoms in the patient being treated, the method according to claim 29.

53. The reduced worsening of the heart failure symptoms in the patient is over a period of 12 to 36 months, the method according to claim 52.

54. The reduced worsening of the heart failure symptoms is characterized by a reduced number of hospitalizations for HF in the patient, the method according to any one of claims 52 or 53.

55. The reduced worsening of the heart failure symptoms is characterized by a reduced number of visits to the emergency HF clinic in the patient, the method according to any one of claims 52 to 54.

56. The emergency HF clinic is an outpatient emergency department or a clinic outpatient department for emergency outpatients, the method according to claim 55.

57. The reduced worsening of the heart failure symptoms is characterized by a higher score of the patient based on the Kansas City Cardiomyopathy Questionnaire (KCCQ) compared to the score of the patient before SGLT2 inhibitor administration, the method according to any one of claims 52 to 56.

58. The higher score based on the KCCQ appears within 8 months from the start of SGLT2 inhibitor administration, the method according to claim 57.

59. The higher score based on the KCCQ is at least 5 points higher than the score before SGLT2 inhibitor administration, the method according to claim 57 or 58.

60. The higher score based on the KCCQ is at least 10 points higher than the score before SGLT2 inhibitor administration, the method according to claim 57 or 58.

61. The higher score based on the KCCQ is at least 15 points higher than the score before SGLT2 inhibitor administration, the method according to claim 57 or 58.

62. The method according to any one of claims 57 to 61, wherein the KCCQ score is the KCCQ total symptom score (TSS).

63. The method according to claim 62, wherein the higher score based on the KCCQ-TSS is obtained regardless of the threshold KCCQ-TSS score of the patient before administration of the SGLT2 inhibitor.

64. The method according to any one of claims 57 to 61, wherein the KCCQ score is the KCCQ-clinical symptom score (CSS).

65. The method according to any one of claims 57 to 61, wherein the KCCQ score is the KCCQ-overall summary score (OSS).

66. The method according to claim 29, wherein the administration of the SGLT2 inhibitor reduces the number of HF events and / or reduces the incidence of cardiovascular events.

67. The method according to claim 66, wherein the administration of the SGLT2 inhibitor reduces the number of HF events.

68. The method according to claim 67, wherein the HF event is hospitalization for HF or an emergency HF outpatient visit.

69. The method according to claim 68, wherein the administration of the SGLT2 inhibitor reduces the number of hospitalizations for HF.

70. The method according to claim 68, wherein the administration of the SGLT2 inhibitor reduces the number of emergency HF outpatient visits.

71. The method according to claim 70, wherein the emergency HF outpatient visit is an outpatient visit outside the emergency treatment room.

72. The method according to claim 70 or 71, wherein the emergency HF outpatient visit requires intravenous therapy.

73. The method according to claim 66, wherein the administration of the SGLT2 inhibitor reduces the incidence of fatal cardiovascular events.

74. The method according to any one of claims 66 to 73, wherein the administration of the SGLT2 inhibitor reduces the composite item of hospitalization for HF or fatal cardiovascular events.

75. The method according to any one of claims 1 to 74, wherein the patient is receiving one or more HF standard therapeutic agents before or during the administration of the SGLT2 inhibitor.

76. The method according to claim 75, wherein the one or more HF standard therapeutic agents are selected from the group consisting of an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin II receptor blocker (ARB), a β-blocker, a mineralocorticoid receptor antagonist (MRA), a neprilysin inhibitor, and a diuretic.

77. The method according to claim 75 or 76, wherein at least one of the HF standard therapeutic agents is a therapeutically effective amount of an angiotensin-converting enzyme (ACE) inhibitor.

78. The method according to any one of claims 75 to 77, wherein at least one of the HF standard therapeutic agents is a therapeutically effective amount of an angiotensin II receptor blocker (ARB).

79. The method according to any one of claims 75 to 78, wherein at least one of the HF standard therapeutic agents is a β-blocker.

80. The method according to any one of claims 75 to 79, wherein at least one of the HF standard therapeutic agents is a mineralocorticoid receptor antagonist (MRA).

81. The method according to any one of claims 75 to 80, wherein at least one of the HF standard therapeutic agents is a neprilysin inhibitor.

82. The method according to any one of claims 75 to 81, wherein at least one of the HF standard therapeutic agents is a loop diuretic.

83. The method according to any one of claims 1 to 82, wherein the patient administered the SGLT2 inhibitor has a New York Heart Association (NYHA) heart failure classification of II to IV.

84. The method according to any one of claims 1 to 83, wherein the patient has a NYHA heart failure classification of II.

85. The method according to any one of claims 1 to 83, wherein the patient has a NYHA heart failure classification of III or IV.

86. The method according to any one of claims 1 to 85, wherein the patient has an eGFR of ≧ 30 ml / min / 1.73 m2 before administration of the SGLT2 inhibitor.

87. The patient maintains an eGFR of ≥ 30 ml / min / 1.73 m ２ during administration of the SGLT2 inhibitor, according to any one of claims 1 to 86.

88. The method according to any one of claims 1 to 87, wherein the 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 before administration of the SGLT2 inhibitor.

89. The method according to any one of claims 1 to 88, wherein the patient has been medically diagnosed with symptomatic HFrEF before administration of the SGLT2 inhibitor.

90. The method according to claim 89, wherein the patient was diagnosed with HFrEF at least two months before administration of the SGLT2 inhibitor.

91. The method according to any one of claims 1 to 90, wherein the patient has atrial fibrillation and / or atrial flutter before administration of the SGLT2 inhibitor.

92. The method according to any one of claims 1 to 90, wherein the patient does not have atrial fibrillation and / or atrial flutter before administration of the SGLT2 inhibitor.

93. The method according to any one of claims 1 to 92, wherein the administration of the SGLT2 inhibitor reduces the HbA1c of the patient.

94. The method according to any one of claims 1 to 93, wherein the administration of the SGLT2 inhibitor reduces the systolic blood pressure of the patient.

95. The method according to any one of claims 1 to 94, wherein the administration of the SGLT2 inhibitor reduces the body weight of the patient.

96. The method according to any one of claims 1 to 95, wherein the administration of the SGLT2 inhibitor reduces the NT-proBNP level of the patient.

97. The method according to any one of claims 94 to 96, wherein the reduction occurs within 8 months from the start of the administration of the SGLT2 inhibitor.

98. The method according to any one of claims 84 to 96, wherein the administration of the SGLT2 inhibitor results in an improvement in the NYHA HF classification.

99. The method according to any one of claims 1 to 98, wherein the administration of the SGLT2 inhibitor results in a reduction in readmission for HF or a reduction in recurrent HF events.

100. The method according to claim 99, wherein the recurrent HF event includes hospitalization for HF or an emergency HF outpatient visit.

101. The method according to any one of claims 1 to 100, wherein the administration of the SGLT2 inhibitor results in a reduced incidence of death due to non-cardiovascular causes.

102. A method for reducing the rate of a major composite endpoint of cardiovascular death, HF hospitalization or emergency HF outpatient visit in HFrEF patients being treated with an SGLT2 inhibitor and an HF standard treatment drug, wherein the rate is reduced compared to patients being treated with the HF standard treatment drug alone.

103. A method for reducing the rate of a secondary composite endpoint of cardiovascular death or HF hospitalization in HFrEF patients being treated with an SGLT2 inhibitor and an HF standard treatment drug, wherein the rate is reduced compared to patients being treated with the HF standard treatment drug alone.

104. The method according to claim 102 or 103, wherein the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt, solvate, mixed solvate, complex or prodrug thereof.

105. The method according to claim 104, wherein the dapagliflozin is administered once a day at a dose of 10 mg. **Claim 106** A method for reducing the incidence of all-cause death in patients with HFrEF being treated with an SGLT2 inhibitor. **Claim 107** The method according to claim 106, wherein the all-cause death includes deaths due to cardiovascular and non-cardiovascular causes.

Images