Methods of reducing the risk of cardiovascular events in patients with left ventricular hypertrophy

Abstract

Methods of reducing the risk of cardiovascular events in left ventricular hypertrophy patients without hypertension are disclosed. Preferred methods comprise administering a therapeutically effective amount of dual SGLT1 / 2 inhibitor sofogliflozin.

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202480063338.3 (22) Application Date 2024.10.03 (30) Priority Data 63 / 542,927 2023.10.06 US (85) PCT International Application Entering National Phase Date 2026.04.01 (86) PCT International Application Application Data PCT / US2024 / 049710 2024.10.03 (87) PCT International Application Publication Data WO2025 / 076165 EN 2025.04.10 (71) Applicant: Lexcare Pharmaceuticals, Inc. Address: USA (72) Inventor: Michael John Davis (74) Patent Agency: Zhongyuan Xinda Intellectual Property Agency Co., Ltd. 11219 Patent Attorney Liu Hui Jin Haixia (51) Int.Cl. A61K 31 / 70 (2006.01) A61K 31 / 7042 (2006.01) A61K 31 / 7048 (2006.01) A61P 9 / 04 (2006.01) (54) Invention Title: Method for Reducing the Risk of Cardiovascular Events in Patients with Left Ventricular Hypertrophy (57) Abstract: A method for reducing the risk of cardiovascular events in patients with left ventricular hypertrophy without hypertension is disclosed. A preferred method includes administering a therapeutically effective amount of the dual SGLT1 / 2 inhibitor soragliflozin. Claims 2 pages, Description 12 pages, Drawings 1 page, CN 122055157 A 2026.05.15 CN 1 22 05 51 57 A 1. A method for reducing the risk of cardiovascular events (e.g., heart attack, heart failure, stroke, myocardial infarction, hospitalization for heart failure, or emergency visit for heart failure) in a patient, the method comprising administering a preventively effective amount of an SGLT2 inhibitor to the patient, wherein the patient has left ventricular hypertrophy (LVH) without hypertension. 2. A method for managing heart failure (e.g., slowing the progression of heart failure or managing one or more symptoms of heart failure) in a patient at risk of heart failure, the method comprising administering a preventively effective amount of an SGLT2 inhibitor to the patient, wherein the patient has LVH without hypertension. 3. The method of claim 1 or 2, wherein the method comprises prescribing the use of the SGLT2 inhibitor prior to administering the SGLT2 inhibitor to the patient. 4. The method of claim 3, wherein the method includes determining whether the patient has LVH without hypertension before prescribing the SGLT2 inhibitor.5. The method of any of the preceding claims, wherein the SGLT2 inhibitor is dapagliflozin, canagliflozin, empagliflozin, soragliflozin, ioggliflozin, etaggliflozin, toragliflozin, or ruggliflozin, or a pharmaceutically acceptable salt or solvation thereof. 6. The method of claim 5, wherein the SGLT2 inhibitor is soragliflozin. 7. The method of claim 6, wherein the soragliflozin is administered orally at a dose of at least 200 mg / day. 8. The method of claim 7, wherein the dose is at least 400 mg / day. 9. A method for improving the hazard ratio associated with cardiovascular event risk in patients taking an SGLT2 inhibitor, the method comprising recommending the administration of the SGLT2 inhibitor to LVH patients without hypertension. 10. A method for improving the hazard ratio associated with cardiovascular event risk in patients taking an SGLT2 inhibitor, the method comprising limiting the administration of the SGLT2 inhibitor to LVH patients without hypertension. 11. A method for maximizing the efficacy of an SGLT2 inhibitor administered to a patient at risk of cardiovascular events, the method comprising recommending administration of the SGLT2 inhibitor to a non-hypertensive LVH patient. 12. A method for maximizing the efficacy of an SGLT2 inhibitor administered to a patient at risk of cardiovascular events, the method comprising limiting administration of the SGLT2 inhibitor to non-hypertensive LVH patients. 13. The method of any one of claims 9 to 12, wherein the SGLT2 inhibitor is dapagliflozin, canagliflozin, empagliflozin, soragliflozin, ioggliflozin, etaggliflozin, toragliflozin, or ruggliflozin, or a pharmaceutically acceptable salt or solvation thereof. 14. The method of claim 13, wherein the SGLT2 inhibitor is soragliflozin. 15. The method of any one of the preceding claims, wherein the patient has type 2 diabetes. 16. The method of any one of the preceding claims, wherein the patient has experienced heart failure. 17. A kit comprising: 1) a container containing at least one solid oral dosage form (e.g., tablet, capsule, or lozenge) of an SGLT2 inhibitor; and 2) a label providing prescription information recommending administration of the SGLT2 inhibitor to a non-hypertensive LVH patient. 18. The kit of claim 17, wherein the SGLT2 inhibitor is dapagliflozin, canagliflozin, empagliflozin, soragliflozin, ilagliflozin, etaggliflozin, toragliflozin, or ruggliflozin, or a pharmaceutically acceptable salt or solvation thereof. 19. The kit of claim 18, wherein the SGLT2 inhibitor is soragliflozin. 20. The kit of claim 19, wherein each of the solid oral dosage forms contains at least 200 mg of soragliflozin.Claims 1 / 2 pages 2 CN 122055157 A 21. The kit of claim 20, wherein each of the solid oral dosage forms contains at least 400 mg of sotagliflozin. Claims 2 / 2 pages 3 CN 122055157 A Method for reducing the risk of cardiovascular events in patients with left ventricular hypertrophy

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 542,927, filed October 6, 2023, the entire contents of which are incorporated herein by reference. Technical Field

[0002] The present invention relates to a method for reducing cardiovascular events in patients with left ventricular hypertrophy. Background Art

[0003] Sotagliflozin, a dual inhibitor of sodium-glucose cotransporters 1 and 2 (SGLT1 and SGLT2), has been shown to effectively reduce the risk of cardiovascular death, hospitalization for heart failure, and emergency heart failure visits in adults with heart failure or type 2 diabetes, chronic kidney disease, and other cardiovascular risk factors. INPEFA™ Prescribing Information, May 2023. See also Bhatt, DL. et al., “Sotagliflozin in Patients with Diabetes and Worsening Heart Failure” N. Engl. J. Med., January 14, 2020; 384(2):117-128; Bhatt, D.L. et al., “Sotagliflozin in Patients with Diabetes and Chronic Kidney Disease” N. Engl. J. Med., January 14, 2021; 384(2): 129-139.

[0004] Left ventricular hypertrophy (LVH) is a disease characterized by an increase in the mass of the left ventricle due to increased wall thickness and / or enlargement of the left ventricular cavity. LVH is present in 15% to 20% of the general population. It is more common in Black people, the elderly, obese people, and people with hypertension. Cuspidi C. et al., “Italian Society of Hypertension. Prevalence of left-ventricular hypertrophy in hypertension: an updated review of echocardiographic studies” J Hum Hypertens. 2012 Jun;26(6):343-9.

[0005] Various clinical conditions can lead to the development of LVH. The most common of these include: essential hypertension; renal artery stenosis; athlete's heart with physiological LVH; aortic stenosis; aortic coarctation; hypertrophic cardiomyopathy (HOCM) with or without outflow tract obstruction; subaortic stenosis (left ventricular outflow tract obstructed by muscle or membrane); aortic regurgitation; mitral regurgitation; dilated cardiomyopathy; ventricular septal defect; and infiltrative cardiac processes (e.g., amyloidosis, Fabry disease, Danon disease). Ibid.

[0006] Hypertension and aortic stenosis are the most common causes of LVH. In both cases, the heart contracts due to increased afterload. Another cause is increased left ventricular filling, inducing diastolic overload, which is the underlying mechanism for eccentric LVH in patients with regurgitant valvular diseases (such as aortic regurgitation or mitral regurgitation) and is also seen in dilated cardiomyopathy. Coronary artery disease also plays a role in the pathogenesis of LVH, as normal myocardium attempts to compensate for tissue that has become ischemic or infarcted. Ibid.

[0007] In adults with type 2 diabetes, LVH may occur in the absence of hypertension, particularly in patients with diabetic cardiomyopathy (DbCM), and may occur in patients with hypertrophic cardiomyopathy. Summary of the Invention

[0008] This invention relates in part to a method for reducing the risk of cardiovascular events (e.g., heart attack, heart failure, stroke, myocardial infarction, hospitalization for heart failure, or emergency care for heart failure) in patients with ventricular hypertrophy (LVH), including patients with LVH but without hypertension.

[0009] One embodiment of the invention covers a method for reducing the risk of cardiovascular events in a patient, the method comprising administering a preventatively effective amount of an SGLT2 inhibitor to the patient, wherein the patient has LVH without hypertension.

[0010] Another embodiment covers a method of managing heart failure (e.g., slowing the progression of heart failure or managing one or more symptoms of heart failure) in a patient at risk of heart failure, the method comprising administering a preventatively effective amount of an SGLT2 inhibitor to a patient with LVH without hypertension.

[0011] Another embodiment covers a method of improving the hazard ratio associated with the risk of cardiovascular events in a patient taking an SGLT2 inhibitor, the method comprising limiting the administration of the SGLT2 inhibitor to LVH patients without hypertension.

[0012] Another embodiment covers a method of maximizing the efficacy of an SGLT2 inhibitor administered to a patient, the method comprising limiting the administration of the SGLT2 inhibitor to LVH patients without hypertension.

[0013] This invention also covers kits (e.g., containers containing dosage forms and prescription information) useful in the methods disclosed herein. Brief Description of the Drawings

[0014] Figure 1 shows that the effect of soragliflozin on the primary endpoint of the SCORED study was consistent with the presence or absence of reported LVH or hypertension at baseline. Detailed Description

[0015] This invention relates in part to methods using soragliflozin, which is the common name for (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol.

[0016] Soragliflozin is a dual inhibitor of sodium-glucose cotransporter 1 and 2 (SGLT1 and SGLT2), marketed in the United States under the brand name INPEFA™ to reduce the risk of cardiovascular death, hospitalization for heart failure, and emergency heart failure visits in adults with heart failure or adults with type 2 diabetes, chronic kidney disease, and other cardiovascular risk factors. This compound can be prepared by methods disclosed in the art (e.g., U.S. Patent No. 7,781,577) and formulated as described, for example, in U.S. Patent Publication No. US 20230218650. U.S. Patent No. 8,217,156 discloses the crystalline form of this compound.

[0017] The terms “sodium-glucose cotransporter 2 inhibitor” and “SGLT2 inhibitor” are used interchangeably herein and refer to compounds that inhibit SGLT2, including soragliflozin, which also inhibits SGLT1. Examples of SGLT2 inhibitors include dapagliflozin, canagliflozin, empagliflozin, sotagliflozin, ipragliflozin, ertugliflozin, tofogliflozin, and luseogliflozin, and their pharmaceutically acceptable salts and solvates.

[0018] Unless otherwise stated, the term “combination” when referring to the administration of two or more drugs to a patient means the administration (e.g., self-administration) of two or more drugs to a patient so that the patient receives the benefit of two or more drugs (e.g., , 2 / 12 pages 5 CN 122055157 A during a given day). The two or more drugs need not be administered simultaneously or via the same route of administration.

[0019] Unless otherwise stated, the term "include" has the same meaning as "include but are not limited to," and the term "includes" has the same meaning as "includes but is not limited to." Similarly, the term "for example" has the same meaning as the term "such as but not limited to."

[0020] Unless otherwise stated, the terms "manage," "managing," and "management" include preventing the recurrence of a particular disease or condition in a patient who already has it, and / or prolonging the time a patient with it is in remission. These terms cover modulating the threshold, development, and / or duration of a disease or condition, or altering how a patient responds to a disease or condition.

[0021] Unless otherwise stated, the terms "prevent," "preventing," and "prevention" consider actions taken before a patient begins to develop a particular disease or condition that inhibit or reduce the severity of the disease or condition. In other words, these terms encompass prevention.

[0022] Unless otherwise stated, a “preventively effective amount” of a compound means sufficient to prevent a disease or ailment, or one or more symptoms associated with a disease or ailment, to prevent its recurrence, or to slow or stop its worsening. A “preventively effective amount” of a compound means an amount of a therapeutic agent, used alone or in combination with other agents, that provides preventive benefit in preventing or delaying one or more symptoms of a disease or ailment.

[0023] Unless otherwise stated, a “therapeutically effective amount” of a compound means an amount sufficient to provide therapeutic benefit in treating or controlling a disease or ailment, or sufficient to delay or minimize one or more symptoms associated with a disease or ailment. A “therapeutically effective amount” of a compound means an amount of a therapeutic agent, used alone or in combination with other therapies, that provides therapeutic benefit in treating or controlling a disease or ailment. The term “therapeutically effective amount” may encompass an amount that improves overall treatment, reduces or alleviates the severity of a disease or ailment or its symptoms, or enhances the therapeutic efficacy of another therapeutic agent.

[0024] Unless otherwise stated, the terms “treat”, “treating” and “treatment” refer to actions taken when a patient has a particular disease or condition that may reduce the severity of the disease or condition or delay or slow its progression.

[0025] Unless otherwise stated, the term “emergency visit” refers to a patient’s visit to a healthcare provider (e.g., a hospital, clinic, or doctor) due to an acute cardiovascular event (e.g., heart attack, stroke) or one or more symptoms associated with a cardiovascular event.

[0026] This invention is based on the finding that patients with non-hypertensive left ventricular hypertrophy (LVH) treated with soragliflozin to reduce their risk of cardiovascular events (e.g., heart attack, heart failure, stroke, myocardial infarction, hospitalization for heart failure, or emergency visit for heart failure) exhibit significantly lower hazard ratios than the general patient population at risk of cardiovascular events. Therefore, one embodiment of the invention covers a method for reducing the risk of cardiovascular events in a patient, the method comprising administering a preventatively effective amount of an SGLT2 inhibitor to a patient with non-hypertensive LVH.

[0027] Considering that in most cases, SGLT2 inhibitors are prescribed to patients prior to administration (e.g., by a physician), a particular method of the invention includes assessing whether a patient has non-hypertensive LVH before prescribing the use of an SGLT2 inhibitor.

[0028] Another embodiment covers a method of managing heart failure (e.g., slowing the progression of heart failure or managing one or more symptoms of heart failure) in a patient at risk of heart failure, the method comprising administering a preventatively effective amount of an SGLT2 inhibitor to a patient with LVH without hypertension.

[0029] Another embodiment covers a method of improving the hazard ratio associated with the risk of cardiovascular events in a patient taking an SGLT2 inhibitor, the method comprising administering an SGLT2 inhibitor to a patient with LVH without hypertension. In a particular method, administration of the SGLT2 inhibitor is limited to patients with LVH without hypertension.

[0030] Another embodiment covers a method of increasing the difference between patients taking an SGLT2 inhibitor and patients taking a placebo in the hazard ratio associated with the risk of cardiovascular events (e.g., heart attack, heart failure, stroke, myocardial infarction, hospitalization for heart failure, or emergency care for heart failure), the method comprising limiting administration of the SGLT2 inhibitor to patients with LVH without hypertension.

[0031] Another embodiment covers a method for improving the hazard ratio associated with the risk of cardiovascular events in patients taking SGLT2 inhibitors, the method comprising recommending the administration of SGLT2 inhibitors to LVH patients without hypertension.

[0032] Another embodiment covers a method for improving the hazard ratio associated with the risk of cardiovascular events in patients taking SGLT2 inhibitors, the method comprising limiting the administration of SGLT2 inhibitors to LVH patients without hypertension.

[0033] Another embodiment covers a method for maximizing the efficacy of an SGLT2 inhibitor administered to a patient at risk of cardiovascular events, the method comprising recommending the administration of the SGLT2 inhibitor to a non-hypertensive LVH patient.

[0034] Another embodiment covers a method for maximizing the efficacy of an SGLT2 inhibitor administered to a patient at risk of cardiovascular events, the method comprising limiting the administration of the SGLT2 inhibitor to non-hypertensive LVH patients.

[0035] Examples of SGLT2 inhibitors include dapagliflozin, canagliflozin, empagliflozin, soragliflozin, ioggliflozin, etaggliflozin, toragliflozin, or ruggliflozin, or pharmaceutically acceptable salts or solvates thereof. A preferred SGLT2 inhibitor is soragliflozin.

[0036] In a particular method, the SGLT2 inhibitor is administered orally (e.g., as a capsule, tablet, or capsule). In a particular method, soragliflozin is administered orally at a dose of at least 200 mg / day or 400 mg / day.

[0037] In a particular method of the invention, the patient has type 2 diabetes. In a particular method of the present invention, the patient has experienced heart failure or is at risk of heart failure.

[0038] The present invention covers a kit comprising a container (e.g., box, bottle, blister pack) containing a single dosage form of an SGLT2 inhibitor. In one embodiment, the kit comprises: 1) a container containing at least one solid oral dosage form (e.g., tablet, capsule, or blister pack) of an SGLT2 inhibitor; and 2) a label providing prescription information recommending administration of the SGLT2 inhibitor to LVH patients without hypertension. In the context of the present invention, a label stating that an SGLT2 inhibitor can be administered to LVH patients without hypertension is considered "recommended" for administration to these patients.

[0039] The present invention also covers a container containing: 1) at least one solid oral dosage form of an SGLT2 inhibitor, and 2) a label providing prescription information recommending administration of the SGLT2 inhibitor to LVH patients without hypertension.

[0040] In the kits or containers of the present invention, the label may be printed on or affixed to the exterior of the container.

[0041] Preferred solid dosage forms contain 200 mg or 400 mg of soragliflozin (e.g., as tablets, capsules, or capsules).

[0042] Examples

[0043] Example 1. Study in patients with diabetes and chronic kidney disease

[0044] A multicenter, double-blind clinical trial (SCORED) was conducted in which patients with type 2 diabetes (glycated hemoglobin level ≥7%), chronic kidney disease (estimated glomerular filtration rate of 25 to 60 ml / min / 1.73 m2 body surface area) and cardiovascular disease risk were randomized in a 1:1 ratio to receive soragliflozin or placebo.During the trial, the primary endpoint was changed to the composite of the total number of deaths from cardiovascular causes, hospitalizations for heart failure, and emergency visits for heart failure.

[0045] Of the 19,188 patients screened, 10,584 were recruited, of whom 5,292 were assigned to the soragliflozin group and 5,292 to the placebo group, with a median follow-up of 16 months. The rate of the primary endpoint event was 5.6 events per 100 patient-years in the soragliflozin group and 7.5 events per 100 patient-years in the placebo group (hazard ratio 0.74; 95% confidence interval [CI] 0.63 to 0.88; P < 0.001). The rate of death from cardiovascular causes per 100 patient-years was 2.2 for soragliflozin and 2.4 for placebo (hazard ratio 0.90; 95% CI, 0.73 to 1.12; P = 0.35). For the initial co-primary endpoint of first-time death from cardiovascular causes, non-fatal myocardial infarction, or non-fatal stroke, the hazard ratio was 0.84 (95% CI, 0.72 to 0.99); for the initial co-primary endpoint of first-time death from cardiovascular causes or hospitalization for heart failure, the hazard ratio was 0.77 (95% CI, 0.66 to 0.91). Diarrhea, genital fungal infections, volume exhaustion, and diabetic ketoacidosis were more common with soragliflozin than with placebo.

[0046] The study found that, compared with placebo, soragliflozin resulted in a lower composite risk of death from cardiovascular causes, hospitalization for heart failure, and emergency room visits for heart failure in patients with diabetes and chronic kidney disease (with or without proteinuria).

[0047] Trial Design

[0048] This was a phase 3, randomized, double-blind, placebo-controlled trial comparing soragliflozin (200 mg once daily, which could be increased to 400 mg once daily if no unacceptable side effects occurred) with placebo in patients with type 2 diabetes, chronic kidney disease, and additional cardiovascular risk; all patients also received standard care. Randomization was stratified according to heart failure criteria (ejection fraction ≤40% recorded in the previous year or hospitalization for heart failure in the previous 2 years) and geographic region (North America, Latin America, Western Europe, Eastern Europe, or other parts of the world).

[0049] Patients

[0050] Recruitment is made of individuals aged 18 years or older with type 2 diabetes mellitus with a glycated hemoglobin level of 7% or higher, chronic kidney disease (eGFR, 25 to 60 ml / min / 1.73 m2 body surface area), and additional cardiovascular risk factors. Risk factors consist of at least one major cardiovascular risk factor in individuals aged 18 years or older, or at least two minor cardiovascular risk factors in individuals aged 55 years or older.One exclusion criterion was any plan to start an SGLT2 inhibitor during the trial. Written informed consent was obtained from all patients.

[0051] Endpoints

[0052] The initial co-primary endpoints assessed in the time-event analysis were the first major adverse cardiovascular event (MACE, defined as death from cardiovascular cause, non-fatal myocardial infarction, or non-fatal stroke) and the first hospitalization for death from cardiovascular cause or heart failure (HHF). The primary endpoint was the total number of deaths from cardiovascular cause, hospitalizations for heart failure, and emergency visits for heart failure (UVHF).

[0053] Secondary endpoints were the total number of hospitalizations and emergency visits due to heart failure; the total number of deaths from cardiovascular causes; the total number of deaths from cardiovascular causes, hospitalizations due to heart failure, non-fatal myocardial infarctions, and non-fatal strokes; the total number of deaths from cardiovascular causes, hospitalizations due to heart failure, emergency visits due to heart failure, and heart failure events during hospitalization; the first occurrence of a sustained decrease in eGFR of at least 50% relative to baseline for at least 30 days, long-term dialysis, kidney transplantation, or a composite of persistent eGFR below 15 ml / min / 1.73 m2 for at least 30 days; deaths from any cause; and the total number of deaths from cardiovascular causes, non-fatal myocardial infarctions, and non-fatal strokes. Using total events allowed for multiple events to be included in the analysis for a single patient. Subgroup analyses were pre-specified.

[0054] Statistical Analysis

[0055] All efficacy analyses followed the intention-to-treat principle. To allow for analysis of total events, a competing risk marginal model stratified recurrent events according to heart failure criteria and geographic region (mortality was excluded from a given endpoint treated as a competing end event) was used to generate hazard ratios with Wald 95% confidence intervals and p-values. The interaction term between the trial group allocation and the logarithm of time confirmed proportionality. Event ratios were summarized by the number of events followed per 100 patient-years, and events were accumulated over time using a cumulative occurrence function. For subgroup analyses, the reported 95% confidence intervals were not adjusted for multiple comparisons, and no conclusions could be drawn from these data.

[0056] Total events of myocardial infarction and total events of stroke were evaluated post-hoc. Differences in adverse events between the two groups were tested post-hoc; p-values ​​were obtained from the Pearson chi-square test. Changes in eGFR, glycated hemoglobin levels, systolic blood pressure, diastolic blood pressure, and body weight over time were analyzed post-hocly using a repeated measures mixed-effects model. The absolute change relative to baseline was used as the outcome, with random effects set for the intercept and fixed effects set for group assignment, baseline values, and time. Changes in these outcomes were also co-modeled with mortality from any cause to account for competing risks.Data from patients who discontinued the trial were reviewed for time-event endpoints and sensitivity analyses were performed, including imputation for events that occurred at the last known date of patient survival, and the same imputation was performed only in the soragliflozin group.

[0057] Patient Characteristics

[0058] A total of 19,188 patients were screened, of whom 10,584 were recruited; 5,292 were assigned to each trial group. The median age of the patients was 69 years; 44.9% were female and 82.7% were white. 99.4% of patients achieved a vital status; 142 (1.3%) did not complete the final trial visit, of whom 67 had unknown vital status at trial end. The median duration of exposure to soragliflozin was 14.2 months (interquartile range, 10.3 to 18.9), and the median duration of exposure to placebo was 14.3 months (interquartile range, 10.3 to 18.9). The median follow-up duration was 16.0 months (interquartile range, 12.0 to 20.3) in the soragliflozin group and 15.9 months (interquartile range, 11.9 to 20.3) in the placebo group. In the soragliflozin group, 3944 patients (74.5%) had their dose increased from 200 mg to 400 mg; in the placebo group, 4002 patients (75.6%) had their dose increased. Early discontinuation of the trial protocol for reasons other than death or early termination of the trial occurred in 578 patients (10.9%) in the soragliflozin group and 597 patients (11.3%) in the placebo group. Baseline characteristics were similar in both groups, as shown in Table 1.

[0059] Table 1. Baseline characteristics of patients Instructions 6 / 12 pages 9 CN 122055157 A Instructions 7 / 12 pages 10 CN 122055157 A Due to rounding, the sum of percentages may not equal 100. ACE represents angiotensin-converting enzyme, DPP-4 represents dipeptidyl peptidase-4, GLP-1 represents glucagon-like peptide-1, IQR represents interquartile range, and NT-proBNP represents N-terminal pro-brain natriuretic peptide. † Race and ethnicity are reported by the investigator. ‡ Ejection fraction was measured within 1 year prior to screening or during screening. § This ratio is calculated using albumin in milligrams and creatinine in grams. ¶ Some patients are taking more than one renin-angiotensin-aldosterone system (RAAS) inhibitor.

[0060] Among all randomly assigned patients, 19.9% ​​had an ejection fraction of 40% or less in the previous year or had been hospitalized for heart failure in the past two years, and the median left ventricular ejection fraction was 60% (interquartile range 51 to 65).The median glycated hemoglobin level was 8.3%, the median body mass index (body weight in kilograms divided by the square of height in meters) was 31.8, the median eGFR was 44.5 ml / min / 1.73 m2 (interquartile range, 37.0 to 51.4), and the median urine albumin / creatinine ratio was 74 (interquartile range, 17 to 481).

[0061] Endpoints

[0062] There were 701 primary endpoint events and 930 total primary endpoint events. The rates of total primary endpoint events were 5.6 and 7.5 per 100 patient-years in the soragliflozin group and the placebo group, respectively (hazard ratio 0.74; 95% confidence interval [CI] 0.63 to 0.88; P < 0.001).

[0063] For the total number of hospitalizations and emergency visits for heart failure (the first primary endpoint), the rate was 3.5 events per 100 patient-years in the soragliflozin group and 5.1 events per 100 patient-years in the placebo group (hazard ratio 0.67; 95% CI, 0.55 to 0.82; P < 0.001) (Table 2). Regarding death from cardiovascular causes (the second primary endpoint), there was no significant difference between the soragliflozin and placebo groups (2.2 and 2.4 per 100 patient-years, respectively; hazard ratio 0.90; 95% CI, 0.73 to 1.12), and the stratified analysis ended thereafter. However, there was no significant difference in the composite renal endpoint between the two groups, nor in all-cause mortality. The initial co-primary endpoint of death from cardiovascular causes or hospitalization for heart failure showed a hazard ratio of 0.77 (95% CI, 0.66 to 0.91). The initial co-primary endpoint of death due to cardiovascular causes, non-fatal myocardial infarction, or non-fatal stroke showed a hazard ratio of 0.84 (95% CI, 0.72 to 0.99). For cases reported by investigators that were submitted for adjudication before trial funding loss, 337 out of 501 events (67.3%) in the soragliflozin group and 460 out of 664 events (69.3%) in the placebo group were adjudicated.

[0064] Table 2. Primary and secondary endpoints. eGFR represents estimated glomerular filtration rate; HF represents heart failure. †Results are presented as point estimates and 95% confidence intervals, without adjustment for multiple comparisons, therefore no definitive conclusions can be drawn regarding significant differences. ‡Stratified analysis was stopped after the first p-value indicated no significance.

[0065] Adverse Events

[0066] The percentage of patients who experienced adverse events or worsened during treatment or had events leading to withdrawal from the trial protocol did not differ significantly between the two groups. The percentage of patients with serious adverse events was 23.4% in the soragliflozin group and 25.2% in the placebo group.Compared with placebo, the more common adverse events of particular concern with soragliflozin were diarrhea (8.5% vs. 6.0%; P<0.001), diabetic ketoacidosis (0.6% vs. 0.3%; P=0.02), genital fungal infection (2.4% vs. 0.9%; P<0.001), and volume failure (5.3% vs. 4.0%; P=0.003). There were no significant differences between groups in fracture, urinary tract infection, severe hypoglycemia, acute kidney injury (2.2% in the soragliflozin group vs. 2.1% in the placebo group; P=0.55), or amputation. The percentage of patients developing hypertension with soragliflozin was lower than with placebo (2.6% vs. 4.1%), while the percentage of patients developing hypotension with soragliflozin was higher than with placebo (2.6% vs. 1.9%; P=0.009).

[0067] Discussion

[0068] In this trial, compared with placebo, the SGLT1 / 2 inhibitor soragliflozin had a lower risk of the composite primary endpoint of death from cardiovascular causes, hospitalization for heart failure, and emergency visits for heart failure (5.6 vs. 7.5 per 100 patient-years). There were no significant differences in death from cardiovascular causes and renal endpoints between the trial groups. Diarrhea, genital fungal infections, volume exhaustion, and diabetic ketoacidosis occurred with soragliflozin.

[0069] This trial did not consider the urine albumin / creatinine ratio for patient recruitment, and the trial examined cardiovascular events in a population with a median albumin / creatinine ratio of 75 mg / g. A history of heart failure or a reduced baseline ejection fraction was also not required for this trial. Despite a lower eGFR in the trial population (median 44.5 ml / min / 1.73 m2), there was no significant difference in renal injury between the soragliflozin and placebo groups.

[0070] Potential mechanisms of action of SGLT2 inhibition include renal and systemic natriuretic effects, enhanced myocardial energy properties, adaptive cell reprogramming, increased erythrocyte count with improved oxygen delivery, weight loss, reduced blood pressure and left ventricular hypertrophy, reduced uric acid, and beneficial effects on endothelial progenitor cells. Soragliflozin also provides some degree of SGLT1 inhibition, slows intestinal glucose uptake, and lowers postprandial blood glucose. Mendelian randomization data increase the likelihood that SGLT1 inhibition may be associated with a reduced rate of cardiovascular events. In this trial, SGLT1 blockade may have resulted in an increase in reported diarrhea.

[0071] Researcher-defined endpoint events were used in all analyses. Approximately 31% of adjudicated heart failure hospitalizations or emergency visits were not identified as major events, leading to an overestimation of the number of events.Furthermore, hospitalization for reasons other than heart failure would exempt patients from the risk of the primary endpoint event, but the total number of hospitalizations in the soragliflozin group was less than that in the placebo group (1923 vs. 2094), spanning fewer total patient-years (104 vs. 119), indicating no bias favorable to soragliflozin in terms of the primary endpoint.

[0072] In patients with diabetes and chronic kidney disease with or without proteinuria, the SGLT1 / 2 inhibitor soragliflozin posed a lower composite risk of death from cardiovascular causes, hospitalization for heart failure, and emergency visits for heart failure compared to placebo. There was no significant difference between the results in the soragliflozin group and the placebo group in terms of the rate of death from cardiovascular causes or the renal endpoint.

[0073] Example 2. Analysis of patients with left ventricular hypertrophy without hypertension

[0074] A post-hoc analysis was performed on the data from the SCORED trial described in Example 1 to determine the effect of soragliflozin on cardiovascular outcomes in patients who reported LVH but did not report hypertension.

[0075] In this analysis, patients who reported LVH but did not report hypertension were identified based on the CV Risk Factor Questionnaire (CVRFQ) and medical history [n=418]. LVH patients were identified through analysis of CVRFQ data, and their history of hypertension was determined through medical history data.

[0076] Sensitivity analysis was performed based on CVRFQ [n=361] by identifying patients as in the main method, minus patients who reported aortic stenosis and patients with uncontrolled blood pressure (BP). Aortic stenosis data were obtained from medical history data. Patients with systolic blood pressure (SBP) >140 mmHg and diastolic blood pressure (DBP) >90 mmHg (BP uncontrolled) despite taking antihypertensive medication were identified from the CVRFQ data. Table 3 shows the baseline characteristics of patients who reported LVH but did not report hypertension.

[0077] Table 3. Baseline Characteristics Description 10 / 12 pages 13 CN 122055157 A

[0078] Table 4 presents events of particular concern in patients who reported LVH but did not report hypertension.

[0079] Table 4. Events of Special Concern

[0080] As shown in Figure 1, the effect of soragliflozin on the primary endpoint of the SCORED study was consistent with the presence or absence of reported LVH or hypertension at baseline.

[0081] The event rates of the primary endpoint, three major adverse cardiovascular events (MACE: cardiovascular (CV) death, nonfatal myocardial infarction, or nonfatal stroke), and MACE+HHF were determined, and the rates of soragliflozin and placebo were compared. The hazard ratio (HR) and 95% confidence interval (CI) of the endpoints were calculated. Table 5 shows the primary endpoint and selected CV endpoints for patients who reported LVH but did not report hypertension.

[0082] Table 5. Primary endpoint and selected endpoint

[0083] HHF: Hospitalization due to heart failure; UVHF: Emergency visit due to heart failure. Specification 11 / 12 pages 14 CN 122055157 A

[0084] These findings demonstrate that patients reporting LVH but not hypertension were at a higher risk for the primary endpoint (9.5 events per 100 PY with placebo) compared to the overall cohort (7.5 events per 100 PY with placebo). However, even in these patients, soragliflozin significantly reduced the risk of CV events.

[0085] All publications cited above (e.g., patents and patent applications) are incorporated herein by reference in their entirety. Specification 12 / 12 pages 15 CN 122055157 A Figure 1 Specification Figure 1 / 1 page 16 CN 122055157 A

Claims

1. A method for reducing the risk of cardiovascular events (e.g., heart attack, heart failure, stroke, myocardial infarction, hospitalization for heart failure, or emergency medical attention for heart failure) in a patient, the method comprising administering a preventatively effective amount of an SGLT2 inhibitor to the patient, wherein the patient has left ventricular hypertrophy (LVH) without hypertension.

2. A method of managing heart failure (e.g., slowing the progression of heart failure or managing one or more symptoms of heart failure) in a patient at risk of heart failure, the method comprising administering a preventatively effective amount of an SGLT2 inhibitor to the patient, wherein the patient has LVH without hypertension.

3. The method of claim 1 or 2, wherein the method comprises prescribing the use of the SGLT2 inhibitor prior to administering the SGLT2 inhibitor to the patient.

4. The method of claim 3, wherein the method includes determining whether the patient has LVH without hypertension before prescribing the SGLT2 inhibitor.

5. The method of any of the preceding claims, wherein the SGLT2 inhibitor is dapagliflozin, canagliflozin, empagliflozin, soragliflozin, ilagliflozin, etaggliflozin, toggliflozin or ruggliflozin, or a pharmaceutically acceptable salt or solvation thereof.

6. The method of claim 5, wherein the SGLT2 inhibitor is soragliflozin.

7. The method of claim 6, wherein the soggliflozin is administered orally at a dose of at least 200 mg / day.

8. The method of claim 7, wherein the amount is at least 400 mg / day.

9. A method for improving the hazard ratio associated with the risk of cardiovascular events in patients taking an SGLT2 inhibitor, the method comprising recommending the administration of the SGLT2 inhibitor to LVH patients without hypertension.

10. A method for improving the hazard ratio associated with the risk of cardiovascular events in patients taking an SGLT2 inhibitor, the method comprising limiting the administration of the SGLT2 inhibitor to LVH patients without hypertension.

11. A method for maximizing the efficacy of an SGLT2 inhibitor administered to a patient at risk of cardiovascular events, the method comprising recommending administration of the SGLT2 inhibitor to a non-hypertensive LVH patient.

12. A method for maximizing the efficacy of an SGLT2 inhibitor administered to a patient at risk of cardiovascular events, the method comprising limiting the administration of the SGLT2 inhibitor to LVH patients without hypertension.

13. The method of any one of claims 9 to 12, wherein the SGLT2 inhibitor is dapagliflozin, canagliflozin, empagliflozin, soragliflozin, ilagliflozin, etaggliflozin, toggliflozin or ruggliflozin, or a pharmaceutically acceptable salt or solvation thereof.

14. The method of claim 13, wherein the SGLT2 inhibitor is soragliflozin.

15. The method as claimed in any of the preceding claims, wherein the patient has type 2 diabetes.

16. The method as described in any of the preceding claims, wherein the patient has experienced heart failure.

17. A kit comprising: 1) A container containing at least one solid oral dosage form (e.g., tablet, capsule, or capsule) of an SGLT2 inhibitor; 2) A label providing prescription information recommending the administration of the SGLT2 inhibitor to LVH patients without hypertension.

18. The kit of claim 17, wherein the SGLT2 inhibitor is dapagliflozin, canagliflozin, empagliflozin, soragliflozin, ilagliflozin, etaggliflozin, toggliflozin or ruggliflozin, or a pharmaceutically acceptable salt or solvation thereof.

19. The kit of claim 18, wherein the SGLT2 inhibitor is soragliflozin.

20. The kit of claim 19, wherein each of the solid oral dosage forms contains at least 200 mg of soragliflozin.

21. The kit of claim 20, wherein each of the solid oral dosage forms contains at least 400 mg of soragliflozin.

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