Methods to reduce the risk of cardiovascular events in patients with left ventricular hypertrophy.

Abstract

A method for reducing the risk of cardiovascular events in patients with left ventricular hypertrophy without hypertension is disclosed. The preferred method involves administering a therapeutically effective dose of sotagliflozin, an SGLT1 / 2 dual inhibitor.

Description

TECHNICAL FIELD

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 542,927 filed on October 6, 2023, the entire contents of which are incorporated herein by reference.

[0002] The present invention relates to a method for reducing cardiovascular events in a patient with left ventricular hypertrophy. BACKGROUND ART

[0003] Sotagliflozin is a dual inhibitor of sodium-glucose cotransporter 1 and sodium-glucose cotransporter 2 (SGLT1 and SGLT2), and has been proven to be effective in reducing the risk of cardiovascular death, hospitalization for heart failure, and urgent medical visits for heart failure 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, D.L., et al., "Sotagliflozin in Patients with Diabetes and Worsening Heart Failure" N. Engl. J. Med., 2020 Jan 14; 384(2):117-128; Bhatt, D.L., et al., "Sotagliflozin in Patients with Diabetes and Chronic Kidney Disease" N. Engl. J. Med., 2021 Jan 14; 384(2):129-139.

[0004] Left ventricular hypertrophy (LVH) is a condition characterized by increased left ventricular mass 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 individuals, the elderly, obese individuals, and patients 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] There are various clinical conditions that 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 obstruction by muscle or membrane), aortic regurgitation, mitral regurgitation, dilated cardiomyopathy, ventricular septal defect, and infiltrative heart disease (e.g., amyloidosis, Fabry disease, Danon disease). (Ibid.)

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

[0007] In adults with type 2 diabetes, particularly in patients with diabetic cardiomyopathy (DbCM) and those with potential hypertrophic cardiomyopathy, LVH may occur without accompanying hypertension. [Overview of the project]

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

[0009] One embodiment of the present invention comprises a method for reducing the risk of cardiovascular events in a patient, the method comprising administering a prophylactic effective dose of an SGLT2 inhibitor to the patient, the patient having LVH without hypertension.

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

[0011] Another embodiment encompasses a method for improving hazard ratios related to the risk of cardiovascular events in patients taking an SGLT2 inhibitor, the method including restricting the administration of the SGLT2 inhibitor to patients with LVH without hypertension.

[0012] Another embodiment encompasses a method for maximizing the efficacy of an SGLT2 inhibitor administered to a patient, which includes restricting the administration of the SGLT2 inhibitor to patients with LVH without hypertension.

[0013] The present invention also includes kits (e.g., containers containing dosage form and formulation information) that are useful in the methods disclosed herein. [Brief explanation of the drawing]

[0014] [Figure 1] This demonstrates the consistent effect of sotagliflozin on the primary endpoint of the SCORED study, regardless of the presence or absence of reported LVH or hypertension at baseline. [Modes for carrying out the invention]

[0015] The present invention relates in part to a method of using sotagliflozin, which is (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol: [ka] It is the common name for [the subject].

[0016] Sotagliflozin is a dual inhibitor of sodium-glucose cotransporter 1 and sodium-glucose cotransporter 2 (SGLT1 and SGLT2), marketed in the United States under the trade name INPEFA®, and reduces the risk of cardiovascular death, hospitalization due to heart failure, and emergency visits due to heart failure in adults with heart failure or 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 can be formulated, for example, as described in U.S. Patent Publication No. 20230218650. The crystalline form of this compound is disclosed in U.S. Patent No. 8,217,156.

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

[0018] Unless otherwise specified, the term "combination" when referring to the administration of two or more medications to a patient means that both medications are administered to the patient (e.g., self-administered) so that the patient benefits from both medications (e.g., on a given day). The two or more medications do not need to be administered simultaneously or via the same route of administration.

[0019] Unless otherwise specified, 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, etc." has the same meaning as "for example, but not limited to."

[0020] Unless otherwise specified, the terms “manage,” “managing,” and “control” include preventing relapse of a particular disease or disorder in a patient who already has the disease or disorder, and / or extending the time that a patient with the disease or disorder maintains remission. This term also includes modulating the disease or disorder threshold, onset, and / or duration, or altering how a patient responds to the disease or disorder.

[0021] Unless otherwise specified, the terms “prevent,” “preventing,” and “prevention” refer to actions that occur before a patient begins to develop a particular disease or disorder, and that inhibit or reduce the severity of that disease or disorder. In other words, these terms encompass prophylaxis.

[0022] Unless otherwise specified, a "prophylactically effective amount" of a compound refers to an amount sufficient to prevent a disease or condition, or one or more symptoms associated with said disease or condition, prevent the recurrence thereof, or delay or halt the progression thereof. A "prophylactically effective amount" means an amount of a therapeutic agent that, alone or in combination with other medicaments, provides a prophylactic benefit in the prevention or delay of a disease or one or more symptoms thereof.

[0023] Unless otherwise specified, a "therapeutically effective amount" of a compound refers to an amount sufficient to provide a therapeutic benefit in the treatment or management of a disease or condition, or to delay or minimize one or more symptoms associated with the disease or condition. A "therapeutically effective amount" means an amount of a therapeutic agent that, alone or in combination with other therapies, provides a therapeutic benefit in the treatment or management of a disease or condition. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or alleviates the severity of a disease or condition or the symptoms thereof, or enhances the therapeutic effectiveness of another therapeutic agent.

[0024] Unless otherwise specified, the terms "treat", "treating" and "treatment" contemplate an action that occurs while a patient is suffering from a specific disease or disorder, which reduces the severity of the disease or disorder, or slows down or delays the progression of the disease or disorder.

[0025] Unless otherwise specified, the term "urgent visit" refers to a patient's visit to a healthcare provider (e.g., a hospital, clinic, or physician) resulting from 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 left ventricular hypertrophy (LVH) without hypertension, treated with sotagliflozin to reduce the risk of cardiovascular events (e.g., heart attack, heart failure, stroke, myocardial infarction, hospitalization due to heart failure, or emergency visit due to heart failure), exhibit a significantly lower hazard ratio than the general population of patients at risk of cardiovascular events. Accordingly, one embodiment of the present invention encompasses a method for reducing the risk of cardiovascular events in a patient, the method comprising administering a prophylactic effective dose of an SGLT2 inhibitor to the patient, the patient having LVH without hypertension.

[0027] In most cases, SGLT2 inhibitors are intended to be prescribed (e.g., by a physician) for use in a patient before administration. A particular method of the present invention includes evaluating whether the patient has LVH without hypertension before the use of an SGLT2 inhibitor is prescribed.

[0028] Another embodiment encompasses a method for managing heart failure in a patient at risk of heart failure (e.g., slowing the progression of heart failure or managing one or more symptoms of heart failure), the method comprising administering a prophylactic effective dose of an SGLT2 inhibitor to the patient, wherein the patient has LVH without hypertension.

[0029] Another embodiment encompasses a method for improving hazard ratios related to the risk of cardiovascular events in patients taking SGLT2 inhibitors, the method comprising administering SGLT2 inhibitors to patients with LVH without hypertension. In certain methods, the administration of SGLT2 inhibitors is limited to patients with LVH without hypertension.

[0030] Another embodiment includes a method for increasing the difference in hazard ratios related to 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 patients taking an SGLT2 inhibitor compared to patients taking a placebo, the method including restricting the administration of SGLT2 inhibitors to patients with LVH without hypertension.

[0031] Another embodiment encompasses a method for improving hazard ratios related to the risk of cardiovascular events in patients taking SGLT2 inhibitors, the method including recommending the administration of SGLT2 inhibitors to patients with LVH without hypertension.

[0032] Another embodiment encompasses a method for improving hazard ratios related to the risk of cardiovascular events in patients taking SGLT2 inhibitors, the method including restricting the administration of SGLT2 inhibitors to patients with LVH without hypertension.

[0033] Another embodiment encompasses a method for maximizing the efficacy of an SGLT2 inhibitor administered to patients at risk of cardiovascular events, the method including recommending the administration of an SGLT2 inhibitor to patients with LVH without hypertension.

[0034] Another embodiment encompasses a method for maximizing the efficacy of an SGLT2 inhibitor administered to patients at risk of cardiovascular events, the method including restricting the administration of the SGLT2 inhibitor to patients with LVH without hypertension.

[0035] Examples of SGLT2 inhibitors include dapagliflozin, canagliflozin, empagliflozin, sotagliflozin, ipragliflozin, erzgliflozin, tofogliflozin, or luseogliflozin, or their pharmaceutically acceptable salts or solvates. The preferred SGLT2 inhibitor is sotagliflozin.

[0036] In certain methods, SGLT2 inhibitors are administered orally (e.g., as capsules, caplets, or tablets). In certain methods, sotagliflozin is administered orally at a dose of at least 200 mg / day or 400 mg / day.

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

[0038] The present invention encompasses a kit comprising a container (e.g., a box, bottle, or blister tab) containing individual dosage forms of SGLT2 inhibitors. In one embodiment, the kit comprises: 1) a container containing at least one oral solid dosage form of an SGLT2 inhibitor (e.g., a tablet, caplet, or capsule); and 2) a label providing prescription information recommending the administration of the SGLT2 inhibitor to patients with LVH without hypertension. In the context of the present invention, a label stating that an SGLT2 inhibitor may be administered to patients with LVH without hypertension is considered to “recommend” administration to such patients.

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

[0040] In either the kit or the container of the present invention, the label may be printed or affixed to the outside of the container.

[0041] The preferred solid dosage form is sotagliflozin in an amount of 200 mg or 400 mg (for example, as a tablet, caplet, or capsule). [Examples]

[0042] Example 1. Study of patients with diabetes and chronic kidney disease A multicenter, double-blind clinical trial (SCORED) was conducted, and participants with type 2 diabetes (glycated hemoglobin levels, ≥7%) and chronic kidney disease (estimated glomerular filtration rate, body surface area 1.73 m²) were identified. 2Patients with a blood flow rate of 25–60 mL / min and those at risk of cardiovascular disease were randomly assigned in a 1:1 ratio to receive either sotagliflozin or placebo. The primary endpoint was changed during the study to a composite of the total number of cardiovascular deaths, hospitalizations due to heart failure, and emergency visits due to heart failure.

[0043] Of the 19,188 patients screened, 10,584 were enrolled, with 5,292 assigned to the sotagliflozin group and 5,292 to the placebo group, followed for a median of 16 months. The incidence of the primary endpoint event was 5.6 events per 100 patient-years in the sotagliflozin group and 7.5 events per 100 patient-years in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.63–0.88; P<0.001). The incidence of cardiovascular mortality per 100 patient-years was 2.2 in the sotagliflozin group and 2.4 in the placebo group (hazard ratio, 0.90; 95% CI, 0.73–1.12; P=0.35). The initial joint primary endpoint of first-time cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke had a hazard ratio of 0.84 (95% CI, 0.72–0.99), and the initial joint primary endpoint of first-time cardiovascular death or hospitalization due to heart failure had a hazard ratio of 0.77 (95% CI, 0.66–0.91). Diarrhea, genital fungal infections, fluid depletion, and diabetic ketoacidosis were more common with sotagliflozin than with placebo.

[0044] In patients with diabetes and chronic kidney disease, regardless of the presence or absence of albuminuria, sotagliflozin was found to reduce the composite risk of cardiovascular death, hospitalization due to heart failure, and emergency visits due to heart failure compared to placebo.

[0045] Test design This study was a phase 3, randomized, double-blind, placebo-controlled trial comparing sotagliflozin (200 mg once daily, 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 factors. All patients also received standard care. Randomization was stratified according to criteria for heart failure (ejection fraction ≤40% recorded within the past year, or hospitalization for heart failure within the past two years) and geographical region (North America, Latin America, Western Europe, Eastern Europe, or other regions).

[0046] patient Individuals aged 18 or older with type 2 diabetes (glycated hemoglobin level of 7% or higher) or chronic kidney disease (eGFR, 1.73m²) 2 Participants were enrolled if they had a blood flow rate of 25-60 ml / min per body surface area and additional cardiovascular risk factors. Risk factors consisted of at least one major cardiovascular risk factor for those 18 years of age or older, and at least two minor cardiovascular risk factors for those 55 years of age or older. One of the exclusion criteria was having a plan to initiate SGLT2 inhibitor therapy during the study. Written informed consent was obtained from all patients.

[0047] Evaluation items The initial joint primary endpoints, assessed using time-versus-event analysis, were the first occurrence of major adverse cardiovascular events (MACE, defined as cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) and the first occurrence of cardiovascular death or hospitalization due to heart failure (HHF). The primary endpoint was the total number of cardiovascular deaths, hospitalizations due to heart failure, and emergency visits due to heart failure (UVHF).

[0048] Secondary endpoints include: total number of hospitalizations and emergency visits due to heart failure; deaths due to cardiovascular causes; total number of deaths due to cardiovascular causes, hospitalizations due to heart failure, non-fatal myocardial infarctions, and non-fatal strokes; total number of deaths due to cardiovascular causes, hospitalizations due to heart failure, emergency visits due to heart failure, and heart failure events during hospitalization; sustained decline of at least 50% of eGFR from baseline for 30 days or longer, long-term dialysis, kidney transplantation, or 15 ml / min / 1.73m² 2 The total number of events included the first occurrence of a composite event in which eGFR remained below 30 days for 30 days or more; all-cause deaths; and the total number of cardiovascular deaths, non-fatal myocardial infarctions, and non-fatal strokes. Using the total number of events allowed a single patient to contribute multiple events to the analysis. Subgroup analyses were pre-specified.

[0049] statistical analysis All efficacy analyses followed the intention-to-treat principle. To enable analysis of total events, a competing risk marginal model for recurrent events (treating deaths not included in a given endpoint as competing final events) was applied, stratified by heart failure criteria and geographical region, to calculate hazard ratios with Wald 95% confidence intervals and p-values. Proportionality was confirmed by an interaction term between trial group allocation and the logarithm of time. Event rates were summarized by the number of events per 100 patient-year follow-up, and the occurrence of events over time was summarized by a cumulative occurrence function. For subgroup analyses, 95% confidence intervals were reported without adjustment for multiple comparisons, and conclusions cannot be drawn from these data.

[0050] The total number of myocardial infarction and stroke events was assessed retrospectively. Differences between the two groups in adverse events were tested retrospectively. P-values ​​were obtained using Pearson's chi-square test. Changes in eGFR, glycated hemoglobin levels, systolic blood pressure, diastolic blood pressure, and body weight over time were analyzed retrospectively using a repeated measures mixed-effects model with fixed effects on random effects in the intercept, treatment group assignment, baseline values, and time, with absolute changes from baseline as outcomes. These outcomes were modeled in conjunction with all-cause mortality to account for competing risks. Data from patients who discontinued the study were censored for the time to event endpoint, and sensitivity analyses were performed. This sensitivity analysis included imputation, where events were assumed to have occurred on the date the patient was last confirmed to be alive, and similar imputation was performed only in the sotagliflozin group.

[0051] Patient characteristics A total of 19,188 patients were screened, of which 10,584 were enrolled, and 5,292 were assigned to each study group. The median age of the patients was 69 years, 44.9% were female, and 82.7% were Caucasian. The vital status was available for 99.4% of the patients, with 142 (1.3%) not completing the final study visit, of which 67 had an unknown vital status at the end of the study. The median duration of exposure to sotagliflozin was 14.2 months (interquartile range, 10.3–18.9), and the median duration of exposure to placebo was 14.3 months (interquartile range, 10.3–18.9). The median follow-up period was 16.0 months (interquartile range, 12.0–20.3) in the sotagliflozin group and 15.9 months (interquartile range, 11.9–20.3) in the placebo group. In the sotagliflozin group, 3,944 patients (74.5%) had their dose increased from 200 mg to 400 mg, while in the placebo group, 4,002 patients (75.6%) had an apparent dose increase. Early discontinuation of the trial regimen for reasons other than death or early termination occurred in 578 patients (10.9%) in the sotagliflozin group and 597 patients (11.3%) in the placebo group. Baseline characteristics, as shown in Table 1, were similar between the two groups. [Table 1-1] [Table 1-2] [Table 1-3]

[0052] Of all patients randomly assigned, 19.9% ​​had an ejection fraction of 40% or less within the past year or had been hospitalized for heart failure within the past two years, with a median left ventricular ejection fraction of 60% (interquartile range, 51–65). The median glycated hemoglobin level was 8.3%, the median body mass index (kg weight divided by the square of height in meters) was 31.8, and the median eGFR was 44.5 ml / min / 1.73m². 2 (Interquartile range, 37.0–51.4), and the median urinary albumin-to-creatinine ratio was 74 (interquartile range, 17–481).

[0053] Evaluation items There were 701 primary endpoint events on the first trial, and a total of 930 events. The incidence of total primary endpoint events was 5.6 events per 100 patient-years in the sotagliflozin group and 7.5 events per 100 patient-years in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.63–0.88; P<0.001).

[0054] The total number of hospitalizations and emergency visits due to heart failure (first secondary endpoint) was 3.5 events per 100 patient-years in the sotagliflozin group and 5.1 events per 100 patient-years in the placebo group (hazard ratio, 0.67; 95% CI, 0.55~0.82; P<0.001) (Table 2). There was no significant difference between the sotagliflozin and placebo groups in cardiovascular mortality (second secondary endpoint) (2.2 and 2.4 per 100 patient-years, respectively; hazard ratio, 0.90; 95% CI, 0.73~1.12), and hierarchical analysis was stopped at this point. However, there was no significant difference between the two groups in the composite renal endpoint, and the same was true for all-cause mortality. The initial joint primary endpoint, first-time death or hospitalization due to cardiovascular causes or heart failure, showed a hazard ratio of 0.77 (95% CI, 0.66–0.91). The initial joint primary endpoint, first-time death, non-fatal myocardial infarction, or non-fatal stroke due to cardiovascular causes, showed a hazard ratio of 0.84 (95% CI, 0.72–0.99). Of the investigator-reported events submitted for determination before the loss of study funding, 337 out of 501 events (67.3%) in the sotagliflozin group and 460 out of 664 events (69.3%) in the placebo group were confirmed by determination. [Table 2]

[0055] Harmful events There were no significant differences between the two groups in the proportion of patients experiencing adverse events that occurred or worsened during the treatment period, or in the proportion of patients experiencing events that led to discontinuation of the study regimen. The proportion of patients experiencing serious adverse events was 23.4% in the sotagliflozin group and 25.2% in the placebo group. Adverse events of particular interest that were more frequently observed in the sotagliflozin group than in the placebo group 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 fluid volume reduction (5.3% vs. 4.0%; P=0.003). There were no significant differences between the groups in fractures, urinary tract infections, severe hypoglycemia, acute kidney injury (2.2% in the sotagliflozin group vs. 2.1% in the placebo group; P=0.55), or amputation. The proportion of patients who developed hypertension was lower in the sotagliflozin group than in the placebo group (2.6% vs. 4.1%), while the proportion of patients who developed hypotension was higher in the sotagliflozin group than in the placebo group (2.6% vs. 1.9%; P=0.009).

[0056] Consideration In this study, sotagliflozin, an SGLT1 / 2 inhibitor, reduced the risk of the composite primary endpoint—the total number of cardiovascular deaths, hospitalizations due to heart failure, and emergency visits due to heart failure—compared to placebo (5.6 events per 100 patient-years vs. 7.5 events). Cardiovascular deaths and renal outcomes did not differ significantly between the study groups. Diarrhea, genital fungal infections, fluid depletion, and diabetic ketoacidosis occurred in patients treated with sotagliflozin.

[0057] This study enrolled patients regardless of their urinary albumin-to-creatinine ratio and investigated cardiovascular events in a population with a median albumin-to-creatinine ratio of 75 mg / g. The study also did not require a history of heart failure or reduced ejection fraction at baseline. Low eGFR (median, 44.5 ml / min / 1.73 m²) was present in the study population. 2 Despite this, renal impairment did not differ significantly between the sotagliflozin group and the placebo group.

[0058] Potential mechanisms of action of SGLT2 inhibition include renal and systemic natriuretic effects, enhanced myocardial energy, adaptive cellular reprogramming, increased red blood cell volume affecting oxygen delivery, weight loss, reduced blood pressure and left ventricular hypertrophy, reduced uric acid, and beneficial effects on endothelial progenitor cells. Sotagliflozin also provides some degree of SGLT1 inhibition, slowing glucose absorption in the intestines and lowering postprandial blood glucose. Mendelian randomized data suggest that SGLT1 inhibition may be associated with a reduced incidence of cardiovascular events. SGLT1 blockade may have contributed to the increased reporting of diarrhea in this study.

[0059] All analyses used endpoint events as defined by the investigators. Approximately 31% of determined hospitalizations or emergency visits due to heart failure were not confirmed as primary events, leading to an overestimation of the number of events. Furthermore, while hospitalizations for reasons other than heart failure exclude patients from the risk of primary endpoint events, the lower total number of hospitalizations in the sotagliflozin group (1923 vs. 2094) and the lower total patient years (104 vs. 119) compared to the placebo group suggest that there is no bias favoring sotagliflozin with respect to the primary endpoint.

[0060] Sotagliflozin, an SGLT1 / 2 inhibitor, reduced the composite risk of cardiovascular death, hospitalization due to heart failure, and emergency visits due to heart failure compared to placebo in patients with diabetes and chronic kidney disease, regardless of the presence of albuminuria. The results in the sotagliflozin group were not significantly different from those in the placebo group in terms of the incidence of cardiovascular death or renal endpoints.

[0061] Example 2. Analysis of a patient with left ventricular hypertrophy without hypertension. A post-hoc analysis was performed using data from the SCORED trial described in Example 1 to determine the effect of sotagliflozin on cardiovascular outcomes in patients with reported LVH but without reported hypertension.

[0062] In this analysis, patients with reported LVH but without reported hypertension [n=418] were identified through the Cardiovascular Risk Factor Questionnaire (CVRFQ) and medical history. LVH patients were identified from the analysis of CVRFQ data, and their history of hypertension was determined from medical history data.

[0063] Sensitivity analysis was performed by identifying patients, as in the primary approach, and then excluding those with reported aortic stenosis and poorly controlled blood pressure (BP) based on the CVRFQ [n=361]. Aortic stenosis data were obtained from medical history data. Patients with systolic blood pressure (SBP) >140 mmHg and diastolic blood pressure (DBP) >90 mmHg (poorly controlled BP) despite taking antihypertensive medication were identified from CVRFQ data. Baseline characteristics of patients with reported LVH and no reported hypertension are shown in Table 3. [Table 3]

[0064] Table 4 lists the events of particular interest in patients with reported LVH but no reported hypertension. [Table 4]

[0065] As shown in Figure 1, the effect of sotagliflozin on the primary endpoint of the SCORED study was consistent regardless of the presence or absence of reported LVH or hypertension at baseline.

[0066] Event rates were determined for the primary endpoint, 3-point major adverse cardiovascular events (MACE: cardiovascular (CV) death, non-fatal myocardial infarction, or non-fatal stroke), and MACE+HHF, and the incidence rates of sotagliflozin and placebo were compared. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated for the endpoints. Table 5 shows the primary and selected CV endpoints in patients with reported LVH and without reported hypertension. [Table 5]

[0067] These findings demonstrate that patients with reported LVH but without reported hypertension had a higher risk of the primary endpoint (9.5 events per 100 patient-years with placebo) compared to the overall cohort (7.5 events per 100 patient-years with placebo). However, even in these patients, sotagliflozin significantly reduced the risk of cardiovascular events.

[0068] All publications cited above (e.g., patents and patent applications) are incorporated herein by reference in their entirety.

Claims

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

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

3. The method according to claim 1 or 2, comprising prescribing the use of the SGLT2 inhibitor before the SGLT2 inhibitor is administered to the patient.

4. The method according to claim 3, comprising determining whether the patient has LVH without hypertension before prescribing the use of the SGLT2 inhibitor.

5. The method according to any one of the prior claims, wherein the SGLT2 inhibitor is dapagliflozin, canagliflozin, empagliflozin, sotagliflozin, ipragliflozin, erzgliflozin, tofogliflozin, or luseogliflozin, or a pharmaceutically acceptable salt or solvate thereof.

6. The method according to claim 5, wherein the SGLT2 inhibitor is sotagliflozin.

7. The method according to claim 6, wherein sotagliflozin is administered orally in an amount of at least 200 mg / day.

8. The method according to 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, comprising recommending the administration of the SGLT2 inhibitor to patients with LVH without hypertension.

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

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

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

13. The method according to any one of claims 9 to 12, wherein the SGLT2 inhibitor is dapagliflozin, canagliflozin, empagliflozin, sotagliflozin, ipragliflozin, erzgliflozin, tofogliflozin, or luseogliflozin, or a pharmaceutically acceptable salt or solvate thereof.

14. The method according to claim 13, wherein the SGLT2 inhibitor is sotagliflozin.

15. The method according to any one of the prior claims, wherein the patient has type 2 diabetes.

16. The method according to any one of the prior claims, wherein the patient has a history of heart failure.

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

18. The kit according to claim 17, wherein the SGLT2 inhibitor is dapagliflozin, canagliflozin, empagliflozin, sotagliflozin, ipragliflozin, erzgliflozin, tofogliflozin, or luseogliflozin, or a pharmaceutically acceptable salt or solvate thereof.

19. The kit according to claim 18, wherein the SGLT2 inhibitor is sotagliflozin.

20. The kit according to claim 19, wherein each of the oral solid preparations contains at least 200 mg of sotagliflozin.

21. The kit according to claim 20, wherein each of the oral solid preparations contains at least 400 mg of sotagliflozin.

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