Methods of treating type 1 diabetes and kidney diseases

Abstract

Methods of treating type 1 diabetes, improving cardiovascular health, delaying renal function decline, reducing the risk of cardiovascular death and reducing the risk of heart failure hospitalization, while minimizing adverse events such as diabetic ketoacidosis and severe hypoglycemia, using sodium-glucose cotransporter 2 (SGLT2) inhibitors are disclosed. In a preferred method, the SGLT2 inhibitor is sofogliflozin. Also disclosed are prescriptions for developing sofogliflozin and methods of administering sofogliflozin.

Description

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 541,147, filed September 28, 2023, the entire contents of which are incorporated herein by reference. Technical Field

[0002] This invention relates to a method for treating cardiovascular and kidney diseases in patients with type 1 diabetes, while reducing or avoiding adverse reactions such as diabetic ketoacidosis. Background Technology

[0003] Although insulin therapy is widely used for patients with type 1 diabetes (T1D), a significant portion of the patient population still cannot achieve adequate and consistent glycemic control. Most adult patients with T1D currently have insufficient access to therapeutic services, and most cannot consistently achieve HbA1c levels with insulin therapy alone. 1C Target.

[0004] In addition to these challenges, people with type 1 diabetes (T1D) face a high risk of kidney and cardiovascular disease. Diabetic kidney disease occurs in approximately 20%–40% of people with T1D and is associated with kidney failure as well as cardiovascular disease morbidity and mortality. In fact, cardiovascular disease (CVD) is the leading cause of death in people with type 1 diabetes. Stougaard, EB, et al., “Sotagliflozin, a Dual Sodium-glucose Co-transporter-1 and Sodium-Glucose Co-transporter-2 Inhibitor, Reduces the Risk of Cardiovascular and Kidney Disease, as Assessed by the Steno T1 Risk Engine in Adults with Type 1 Diabetes” Diabetes Obes. Metab. 2023;25:1874–1882.

[0005] Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to be safe and effective in treating type 2 diabetes, and can reduce the risk of cardiovascular death, hospitalization for heart failure, and emergency heart failure visits. See, for example, Bhatt, DL, et al., “Sotagliflozin in Patients with Diabetes and Chronic Kidney Disease”. N. Engl. J. Med., 2021 Jan 14;384(2):129-139. SGLT2 inhibitors have been shown to be effective in treating kidney disease in patients with and without type 2 diabetes. See, for example, Heerspink, HJL, et al., “Dapagliflozin in Patients with Chronic Kidney Disease”. N. Engl. J. Med. 2020;383:1436-46. Unfortunately, patients with T1D often cannot obtain the extraordinary benefits of these drugs.

[0006] When administered to patients with type 1 diabetes mellitus (T1D), SGLT2 inhibitors can improve glycemic control, weight, blood pressure, and time-in-range glycemic control without increasing the risk of hypoglycemia. (Stougaard, ibid., 1874). For example, in T1D patients, administration of the dual SGLT1 / 2 inhibitor sotagliflozin "lowered blood pressure and induced mild hemoconcentration, and was associated with acute changes in eGFR and a reduction in albuminuria." (Van Raalte, DH, et al., "The Impact of Sotagliflozin on Renal Function, Albuminuria, Blood Pressure, and Hematocrit in Adults With Type 1 Diabetes"). Diabetes Care 2019;42:1921–1929,1927. However, its administration also increases the risk of diabetic ketoacidosis (DKA), an excess of ketone bodies in the blood that can cause nausea, pain, and discomfort, potentially requiring hospitalization and even leading to death. The risk of DKA "is a major limiting factor preventing the widespread use of SGLT2 inhibitors in patients with type 1 diabetes mellitus (T1DM)." (Liu, H., et al., "SGLT2 Inhibition in Type 1 Diabetes with Diabetic Kidney Disease: Potential Cardiorenal Benefits Can Outweigh Preventable Risk of Diabetic Ketoacidosis") Current Diabetes Reports , 2022;22:317–332, 327. In fact, the increased risk of DKA is precisely why SGLT2 inhibitors have not yet been approved for use in patients with type 1 diabetes in the United States. See, for example, the US Food and Drug Administration, 2022;22:317–332, 327. Proposal To Refuse To Approve a New Drug Application for Sotagliflozin Oral Tablets, 200 Milligrams and 400 Milligrams; Opportunity for a Hearing, Federal Register , 2021;86(20):12471-12473, 12472. Summary of the Invention

[0007] This invention relates in part to a method for treating type 1 diabetes (T1D) while minimizing the risk of diabetic ketoacidosis (DKA), the method comprising: 1) identifying patients with type 1 diabetes and chronic kidney disease (CKD) (i.e., those with an estimated glomerular filtration rate (eGFR) <60 mL / min / 1.73 m 2 And / or patients with a urine albumin-to-creatinine ratio (UACR) ≥30 mg / g for at least three months); and 2) administering a therapeutically effective dose of a sodium-glucose cotransporter 2 (SGLT2) inhibitor to the patient.

[0008] In another embodiment, the present invention relates to a method for improving the cardiorenal health of a patient with type 1 diabetes while minimizing the risk of DKA, the method comprising: 1) identifying a patient with both type 1 diabetes and CKD; and 2) administering a therapeutically effective amount of an SGLT2 inhibitor to the patient. Examples of improvements in cardiorenal health include decreased blood glucose, decreased systolic blood pressure, weight loss, increased diuresis / sodium excretion, decreased intraglomerular pressure, and reduced proteinuria.

[0009] In another embodiment, the present invention relates to a method for slowing the decline of renal function in a patient with T1D while minimizing the risk of DKA, the method comprising: 1) identifying a patient with type 1 diabetes and CKD; and 2) administering a therapeutically effective amount of an SGLT2 inhibitor to the patient.

[0010] In another embodiment, the present invention relates to a method for improving the safety of administering an SGLT2 inhibitor to a patient with T1D, the method comprising restricting the administration to T1D patients with CKD.

[0011] In another embodiment, the present invention relates to a kit comprising a container (e.g., box, bottle, blister pack) containing a single dosage form of an SGLT2 inhibitor, which can facilitate implementation of any of the various methods described herein. One embodiment encompasses a kit comprising: 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 the administration of an SGLT2 inhibitor to a patient with type 1 diabetes and CKD.

[0012] In another embodiment, the present invention relates to a container containing at least one solid oral dosage form of an SGLT2 inhibitor, the container having a label providing prescription information (e.g., printed on the container or affixed to the outside of the container) that recommends the administration of an SGLT2 inhibitor to a patient with type 1 diabetes and CKD. Attached Figure Description

[0013] Figure 1 The cumulative incidence of first-onset cardiac and renal events is shown from laboratory (eGFR) and non-eGFR data obtained from the SCORED clinical trial.

[0014] Figure 2A This shows placebo-adjusted HbA1c levels in patients with chronic kidney disease (CKD) and the overall cohort, obtained by pooling data from the InTandem1 and InTandem2 clinical trials. 1C Changes. The results shown are for oral administration of soragliflozin (200 mg / day and 400 mg / day) after 24 weeks. For all comparisons, P ≤ 0.005.

[0015] Figure 2B The placebo-adjusted changes in patient weight for CKD and the overall cohort are shown, obtained by pooling data from the InTandem1 and InTandem2 clinical trials. Results are shown for oral administration of soragliflozin (200 mg / day and 400 mg / day) after 24 weeks. For all comparisons, P ≤ 0.003.

[0016] Figure 3A The changes in placebo-adjusted systolic blood pressure (SBP) in patients with CKD and the overall cohort are shown by pooling data from the InTandem1 and InTandem2 clinical trials. Results are shown for oral administration of soragliflozin (200 mg / day and 400 mg / day) after 24 weeks. For the 400 mg / day data, P ≤ 0.005.

[0017] Figure 3B The percentage change in placebo-adjusted total daily insulin dose for patients with CKD and the overall cohort is shown, obtained by pooling data from the InTandem1 and InTandem2 clinical trials. Results are shown for oral administration of soragliflozin (200 mg / day and 400 mg / day) after 24 weeks. For overall comparisons, P ≤ 0.05.

[0018] Figure 4AThe changes in daily bolus insulin dose for CKD and the overall cohort, obtained by pooling data from the InTandem1 and InTandem2 clinical trials, are shown as placebo-adjusted. Results are shown for oral administration of soragliflozin (200 mg / day and 400 mg / day) after 24 weeks. For the 400 mg / day data, P ≤ 0.005. For overall comparisons, P ≤ 0.001.

[0019] Figure 4B The percentage change in placebo-adjusted daily basal insulin dose in patients with CKD and the overall cohort, obtained by pooling data from the InTandem1 and InTandem2 clinical trials, is shown. Results are shown for oral administration of soragliflozin (200 mg / day and 400 mg / day) after 24 weeks. For overall comparisons, P ≤ 0.05. For overall comparisons, P ≤ 0.001. Detailed Implementation

[0020] 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. .

[0021] Soragliflozin is a dual inhibitor of sodium-glucose cotransporters 1 and 2 (SGLT1 and SGLT2), marketed in the United States under the brand name INPEFA™, for the purpose of reducing 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. The compound can be prepared according to methods disclosed in the art (e.g., U.S. Patent No. 7,781,577) and can be formulated as described, for example, in U.S. Patent Publication No. US 20230218650. The crystalline form of the compound is disclosed in U.S. Patent No. 8,217,156.

[0022] The terms “sodium glucose cotransporter 2 inhibitor” and “SGLT2 inhibitor” are used interchangeably to refer to compounds that inhibit SGLT2. Examples of SGLT2 inhibitors include dapagliflozin, canagliflozin, empagliflozin, sotagliflozin (which also inhibits SGLT1), ipragliflozin, ertugliflozin, tofogliflozin, and luseogliflozin, as well as their pharmaceutically acceptable salts and solvates.

[0023] As used in this article, the terms “type 1 diabetes”, “T1D”, “type 1 diabetes mellitus”, and “T1DM” are used interchangeably.

[0024] The term "chronic kidney disease" (CKD) generally refers to structural or functional abnormalities of the kidneys that have existed for more than three months and are impacting the patient's health. (KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease) Kidney International Supplements ,2013;3,page x. This disease is classified according to etiology, glomerular filtration rate (GFR) category, and proteinuria (CGA) category. The glomerular filtration rate (GFR) category is: G1 (normal or high) ≥90 ml / min / 1.73 m 2 G2 (mildly decreased) 60 – 89 ml / min / 1.73 m 2 G3a (mild to moderate decrease) 45 – 59 ml / min / 1.73 m 2 G3b (moderate to severe reduction) 30–44 ml / min / 1.73 m 2 G4 (severely reduced) 15 – 29 ml / min / 1.73 m 2 ; and G5 (renal failure) <15ml / min / 1.73 m 2CGA is categorized as follows: A1 (normal to mildly elevated) <30 mg / g (<3 mg / mmol); A2 (moderately elevated) 30–300 mg / g (3–30 mg / mmol); and A3 (severely elevated) >300 mg / g (>30 mg / mmol). Both GFR and CGA can be measured using established techniques. The estimating GFR equation based on serum creatinine (SCr) (rather than SCr alone) is used for detecting GFR <60 mL / min / 1.73 m 2 GFR is highly sensitive. If necessary, the reduction in eGFR obtained with SCr can be confirmed by estimating GFR using an alternative filtration marker (cystatin C) or by measuring GFR. Ibid., page 21.

[0025] Unless otherwise stated, CKD patients according to the present invention have eGFR < 60 mL / min / 1.73 m 2 (For example, <45 mL / min / 1.73m) 2 And / or a urine albumin to creatinine ratio (ACR or UACR) ≥30 mg / g (3 mg / mmol) (e.g., >300 mg / g (>30 mg / mmol)) for more than three months. In some embodiments of the invention, the patient has an eGFR <60 mL / min / 1.73 m 2 Both UACR ≥30 mg / g (3 mg / mmol) and eGFR exceeding three months. In some implementations, patients with eGFR <45 mL / min / 1.73 m 2 and >15 mL / min / 1.73 m 2 (That is, it does not belong to G5 in the GFR category).

[0026] This invention covers methods for safely treating T1D, improving cardiovascular health, slowing the decline in renal function, reducing the risk of cardiovascular death, and reducing the risk of hospitalization for heart failure, methods comprising administering a therapeutically effective amount of an SGLT2 inhibitor (e.g., soragliflozin).

[0027] Unless otherwise stated, when used herein to describe the method of using an SGLT2 inhibitor to describe the present invention, the terms “safe,” “safely,” “enhanced safety,” “minimize the risk,” and “minimizing the risk” refer to a method of reducing the relative risk of DKA and / or hypoglycemia compared to placebo and the relative risk observed when administering an SGLT2 inhibitor to T1D patients without CKD (e.g., patients belonging to G1 or G2 in the GFR category and A1 in the CGA category).

[0028] One embodiment of the present invention relates to a method for treating type 1 diabetes (T1D) while minimizing the risk of diabetic ketoacidosis (DKA), the method comprising: 1) identifying patients with both T1D and chronic kidney disease (CKD) (i.e., those with an estimated glomerular filtration rate (eGFR) <60 mL / min / 1.73 m 2 (and / or patients with a urine albumin-to-creatinine ratio (UACR) ≥ 30 mg / g for at least three months); and 2) administering a therapeutically effective dose of a sodium-glucose cotransporter 2 (SGLT2) inhibitor to the patient.

[0029] Another embodiment of the invention relates to a method for improving the cardiorenal health of a patient with type 1 diabetes mellitus (T1D) while minimizing the risk of diabetic ketoacidosis (DKA), the method comprising: 1) identifying a patient with both T1D and chronic kidney disease (CKD); and 2) administering a therapeutically effective amount of an SGLT2 inhibitor to the patient. Examples of improvements in cardiorenal health include decreased blood glucose, decreased systolic blood pressure, weight loss, increased diuresis / sodium excretion, decreased intraglomerular pressure, and reduced proteinuria.

[0030] Another embodiment of the invention relates to a method for slowing the decline in renal function in a patient with T1D while minimizing the risk of DKA, the method comprising: 1) identifying a patient with both T1D and CKD; and 2) administering a therapeutically effective amount of an SGLT2 inhibitor to the patient.

[0031] Another embodiment of the invention relates to a method for reducing the risk of persistent eGFR decline, end-stage renal disease, cardiovascular death or hospitalization for heart failure in at-risk patients, while minimizing the risk of DKA, the method comprising: 1) identifying patients with T1D and CKD; and 2) administering a therapeutically effective amount of an SGLT2 inhibitor to the patient.

[0032] Another embodiment of the invention covers a method for improving the safety of administering an SGLT2 inhibitor to a patient with T1D, the method comprising restricting the administration to T1D patients with CKD.

[0033] In a specific embodiment of the invention, the SGLT2 inhibitor is dapagliflozin, canagliflozin, empagliflozin, soragliflozin, ioggliflozin, erggliflozin, toragliflozin, or ruggliflozin, or a pharmaceutically acceptable salt or solvation thereof. A preferred SGLT2 inhibitor is soragliflozin.

[0034] In a particular embodiment of the invention, a patient is receiving optimized insulin therapy. In a particular method of the invention, a patient is receiving insulin therapy, and the method further includes optimizing this therapy.

[0035] In a specific embodiment of the invention, the patient has an eGFR < 60 mL / min / 1.73 m 2 eGFR < 45 mL / min / 1.73 m 2 or eGFR < 30 mL / min / 1.73 m 2 In a specific embodiment of the invention, the patient has an eGFR > 15 mL / min / 1.73 m 2 (That is, it does not belong to G5 in the GFR category).

[0036] In a particular embodiment of the invention, the patient has a UACR ≥ 30 mg / g. In some embodiments, the patient has a UACR ≥ 300 mg / g.

[0037] In a specific embodiment of the invention, the patient has an eGFR < 60 mL / min / 1.73 m 2 Both and UACR ≥ 30mg / g.

[0038] In a specific embodiment of the invention, the patient has a BMI ≥ 27 kg / m². 2 .

[0039] In a particular embodiment of the invention, the SGLT2 inhibitor is administered to the patient for more than 52 weeks (e.g., 1.5 years, 2 years, 5 years, or 10 years). In such embodiments, monitoring and / or reporting of DKA events are performed throughout the entire period of administration of the drug, preferably periodically (e.g., daily, weekly, or monthly).

[0040] In a specific embodiment of the invention, the patient meets at least one of the following criteria: is an adult (i.e., at least 18 years old); is not pregnant; is using multiple daily injections (MDI) or subcutaneous insulin infusion (SCII) for insulin delivery; and has HbA1c levels. 1C The range is 7.0%–11.0%; β-hydroxybutyrate (BHB) levels are ≤0.6 mmol / L. In some implementations, the patient is an adult. In some implementations, the patient meets all of these criteria.

[0041] In certain embodiments of the invention, the SGLT2 inhibitor (e.g., soggliflozin) is administered orally. In some embodiments, the SGLT2 inhibitor is administered in the form of tablets, capsules, or pouches. In embodiments including the use of soggliflozin, the therapeutically effective amount of soggliflozin is at least 200 mg / day. In some embodiments, the therapeutically effective amount of soggliflozin is at least 400 mg / day.

[0042] Specific methods of the present invention include monitoring a patient for DKA or an increased risk of DKA. This can be done by methods known in the art, such as testing the patient's blood glucose, arterial pH, and / or serum bicarbonate levels. Specific methods of the present invention also include monitoring a patient for hypoglycemia or an increased risk of hypoglycemia, which can also be done by methods well known in the art.

[0043] The present invention also covers a kit comprising a container (e.g., box, bottle, blister tab) 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 the administration of an SGLT2 inhibitor to a patient with CKD and T1D.

[0044] In one embodiment, the kit further includes a device for measuring and / or reporting DKA events to a healthcare provider. The device for measuring DKA events includes a ketone body test kit and a meter (e.g., a glucose meter) for measuring blood ketone body levels. The device for reporting DKA events includes information containing instructions for email or message delivery (e.g., SMS delivery). Other devices include mobile applications that can wirelessly connect to the glucose meter and store and / or report ketone body levels to a healthcare provider or their agent.

[0045] Another implementation encompasses a container (e.g., box, bottle, blister cap) containing at least one solid oral dosage form of an SGLT2 inhibitor, the container having a label providing prescription information (e.g., printed on the container or affixed to the outside of the container) that recommends the administration of an SGLT2 inhibitor to a T1D patient with CKD.

[0046] The kits and containers of the present invention may contain any SGLT2 inhibitor, such as dapagliflozin, canagliflozin, empagliflozin, soragliflozin, ioggliflozin, erggliflozin, toggliflozin, or ruggliflozin, or pharmaceutically acceptable salts or solvates thereof. A preferred SGLT2 inhibitor is soragliflozin (e.g., in dosage forms containing 200 mg or 400 mg of the drug).

[0047] In a particular embodiment of the invention, the label suggests limiting the application to the presence of eGFR > 15 mL / min / 1.73 m 2 Patients for whom this treatment is intended. In some implementations, the label recommends limiting administration to patients who meet at least one of the following criteria: are adults (i.e., at least 18 years of age); are not pregnant; are using multiple daily injections (MDI) or subcutaneous insulin infusions (SCII) for insulin delivery; have HbA1c levels.1C The levels ranged from 7.0% to 11.0%; β-hydroxybutyric acid (BHB) levels were ≤ 0.6 mmol / L.

[0048] Example Example 1. Analysis of cardiac and renal endpoint events in patients with type 2 diabetes. The cardioprotective and renal-protective properties of soragliflozin in patients with type 2 diabetes provided the basis for the research that led to this invention. In patients with type 2 diabetes (glycated hemoglobin level ≥7%) and an estimated glomerular filtration rate (eGFR) of 1.73 mcg / min... 2 These characteristics were observed in a phase 3, multicenter, double-blind clinical trial in patients with a body surface area of ​​25 ml to 60 ml. During the trial, the primary endpoint was changed to a composite endpoint of total cardiovascular deaths, hospitalizations for heart failure, and emergency visits for heart failure.

[0049] Of the 19,188 patients screened, 10,584 were enrolled, with 5,292 assigned to the soragliflozin group and 5,292 to the placebo group. The median follow-up was 16 months. The primary endpoint event rate 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. Cardiovascular mortality was 2.2 per 100 patient-years in the soragliflozin group and 2.4 in the placebo group (hazard ratio, 0.90; 95% CI, 0.73 to 1.12; P = 0.35). For the original co-primary endpoint of first-time cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke, the hazard ratio was 0.84 (95% CI, 0.72 to 0.99); for the original co-primary endpoint of first-time cardiovascular death or hospitalization for heart failure, the hazard ratio was 0.77 (95% CI, 0.66 to 0.91). Compared with placebo, the soragliflozin group was more likely to experience diarrhea, genital yeast infection, and volume depletion.

[0050] like Figure 1 As shown, soragliflozin significantly reduced the risk of cardiac and renal endpoint events compared to placebo. Table 1 lists the number and type of cardiac and renal events observed during the trial, with each of the soragliflozin and placebo groups containing 5292 patients.

[0051] Table 1. Effects of soragliflozin on cardiac and renal endpoints in patients with type 2 diabetes and CKD

[0052] This study clearly demonstrates that patients with diabetes and kidney disease (regardless of proteinuria) who took soragliflozin daily had a lower risk of the composite endpoint of death from cardiovascular cause, hospitalization for heart failure, and emergency visits for heart failure compared to patients taking a placebo. See, for example, U.S. Patent Application No. 17 / 574,977, filed January 13, 2022; Bhatt, DL, et al. supra ;Sridhar, VS, et al., “Sotagliflozin and KidneyOutcomes, Kidney Function, and Albuminuria in Type 2 Diabetes and CKD” CJASN 2024;19:557–564. Soragliflozin has been approved by the U.S. Food and Drug Administration (FDA) for the purpose of reducing the risk of cardiovascular death, hospitalization for heart failure, and emergency heart failure visits in patients with heart failure or type 2 diabetes, chronic kidney disease, and other cardiovascular risk factors. INPEFA™ Prescribing Information May 2023.

[0053] Example 2. InTandem1 and InTandem2 studies in patients with type 1 diabetes. Two multicenter, double-blind clinical studies, InTandem1 and InTandem2, evaluated the efficacy of soragliflozin as adjunctive therapy in adult patients with inadequate glycemic control on insulin therapy. Patients were randomized to three treatment groups: those treated with soragliflozin 200 mg / day, those treated with soragliflozin 400 mg / day, and those treated with placebo.

[0054] Details of the InTandem1 study have been published. See, for example, Buse, JB, et al., “Sotagliflozin in Combination With Optimized Insulin Therapy in Adults With Type 1 Diabetes: The North American InTandem1 Study”. Diabetes Care2018;41:1970–1980. Details of the InTandem2 study have also been published. See, for example, Danne, T., et al., “HbA and Hypoglycemia 1c Reductions at 24 and 52 Weeks With Sotagliflozin in Combination With Insulin in Adults With Type 1 Diabetes: The European InTandem2 Study” Diabetes Care 2018;41:1981–1990. Both studies included patients receiving insulin delivery via multiple daily injections (MDI) or subcutaneous insulin infusion (SCII) and whose HbA1c levels were high at screening. 1C The prevalence of type 1 diabetes (T1D) was 7.0%–11.0% in men aged ≥18 years and non-pregnant women. Patients with β-hydroxybutyrate (BHB) levels >0.6 mmol / L at screening were excluded.

[0055] In both studies, insulin therapy was optimized for six weeks prior to randomization, and the optimized insulin was used continuously until the end of week 52. After a two-week placebo induction period, patients were randomized to receive a 52-week double-blind treatment regimen of soragliflozin 200 mg or 400 mg or placebo. Insulin optimization was defined as adjusting insulin to achieve standard of care glycemic targets, initiated six weeks prior to randomization and continued throughout the study. The independent insulin dose monitoring committee (IDMC) assessed adherence to standards of care and provided feedback to the principal investigator when deviations from standards of care were observed before week 24. During this period, HbA1c was assessed in the investigators. 1c Blinding was performed. Insulin optimization continued without input from the IDMC between weeks 24 and 52, and HbA1c values ​​were unblinded. Safety was monitored for 30 days after the last dose of the study drug.

[0056] The primary endpoint for both studies was the change in HbA1C from baseline to week 24 in either soragliflozin (400 mg or 200 mg) treatment group compared to placebo. Other endpoints included changes in soragliflozin relative to baseline in the following areas compared to placebo: the proportion of patients with A1C < 7.0% and without severe hypoglycemia or DKA; body weight, bolus insulin dose, fasting plasma glucose (FPG), Diabetes Treatment Satisfaction Questionnaire (DTSQ) score; and Diabetes Distress Screening Scale (DDS2) score.

[0057] Efficacy analyses were based on the mITT (modified intention-to-treat) population. The primary efficacy analysis was based on data collected during the core treatment period (from baseline to the week 24 visit assessment, including the week 24 visit assessment). As shown in Table 2 below, in the pooled inTandem1 / inTandem2 study results, after the core treatment and long-term extension periods, soragliflozin achieved its primary endpoint compared to placebo by causing a statistically significant reduction in A1C levels at both doses.

[0058] Table 2. Summary efficacy and safety results from randomization to week 52

[0059] Further data from studies of these combinations are given in U.S. Patent Application Publication No. US 2024-0226125 A1, published July 11, 2024, which focuses on the observed correlation between body mass index (BMI) and efficacy. Specifically, data were found with a baseline BMI <27 kg / m². 2 and baseline BMI ≥ 27 kg / m 2 The distinct subgroups exhibited different efficacy profiles.

[0060] At baseline, no significant differences were observed between the high BMI group and the low BMI group, but for BMI ≥27 kg / m²... 2 Overweight and obese patients often have higher baseline SBP. Overall, at week 24, soragliflozin, compared with placebo, was significantly lower in patients with a BMI ≥27 kg / m². 2 The efficacy was more significant in the overweight and obese subgroups, particularly for A1C, weight, time to target glycemic control, DTSQ, and two DDS2 measurements. Using the same statistical model, the treatment-subgroup interaction for changes in A1C, weight, and DTSQ relative to baseline scores was correlated with p-values ​​<0.05. This implies that for these variables, soragliflozin is more effective in individuals with a BMI ≥27 kg / m². 2The efficacy was systematically superior in patients with lower BMI compared to the subgroup. The differences in A1C, weight, and time to target glycemic control were often greater in the 400 mg group. Only at the 400 mg dose were the fasting plasma glucose decreases greater in overweight and obese patients. These patients tended to have smaller decreases in SBP and 2-hour postprandial glucose. Similar trends were observed at week 52.

[0061] This invention does not focus on BMI, but rather on research findings surrounding kidney function. In this regard, Table 3 lists the baseline characteristics (after insulin therapy optimization) of participants randomly assigned in the pooled analysis groups (InTandem1 and InTandem2 patients).

[0062] Table 3. Baseline characteristics of the summarized population

[0063] Although most patients exhibited relatively healthy renal function, 15% of the patients recorded in these studies had a condition defined as eGFR < 60 mL / min / 1.73 m 2 And / or CKD with UACR ≥30 mg / g, as shown in Table 4 below.

[0064] Table 4. Summary of patients with and without CKD by dosage

[0065] Below are some baseline characteristics of CKD subgroups. Unless otherwise stated, these values ​​are mean values ​​(standard deviations are in parentheses).

[0066] Table 5. Baseline characteristics of the CKD population

[0067] The figure illustrates some characteristics of the CKD and overall (i.e., total pooled) study populations after 24 weeks of oral administration of soragliflozin at 200 mg / day or 400 mg / day. Figure 2A The patient's HbA1c was shown after placebo adjustment. 1C Change, and Figure 2B The changes in patient weight after placebo adjustment are shown. Figure 3A and Figure 3B The figures show comparisons between placebo-adjusted systolic blood pressure (SBP) and changes in total daily insulin dose in the populations. Figure 4A and Figure 4B The differences between the changes in daily bolus insulin dose and daily basal insulin dose in placebo-adjusted patients were clearly visible.

[0068] Of particular note is that the study found that the CKD subgroup had a lower relative risk of developing DKA (an adverse event that has so far prevented the FDA from approving soragliflozin for the treatment of T1D) and severe hypoglycemia after 52 weeks, as shown in Table 6.

[0069] Table 6. Incidence of diagnosed severe hypoglycemia and DKA

[0070] These data suggest that, compared to the overall cohort, treatment in patients with CKD has a better benefit-risk profile, with similar efficacy and improved safety. Soragliflozin significantly reduced A1C and BW in the CKD subgroup, to a similar degree as in the overall cohort, but the relative risk of severe hypoglycemia was lower in the CKD cohort when using soragliflozin compared to placebo. Similarly, the relative risk of DKA with soragliflozin was not significantly increased relative to placebo in the CKD cohort, contrasting with the substantial increase in DKA risk in the overall cohort.

[0071] Example 3. InTandem3 study in patients with type 1 diabetes The InTandem3 study was a phase 3, double-blind trial conducted at 133 centers worldwide. In this study, 1402 patients with type 1 diabetes receiving insulin therapy (pump or injection) were randomized to receive sotagliflozin (400 mg daily) or placebo for 24 weeks. The primary endpoint was a HbA1c level below 7.0% at week 24, and the absence of severe hypoglycemia or diabetic ketoacidosis after randomization. Secondary endpoints included changes in HbA1c level, body weight, systolic blood pressure, and the mean daily insulin bolus dose relative to baseline. Further details of the study were published in Garg, SK et al., “Sotagliflozin Added to Insulin in Patients with Type 1 Diabetes”. N. Engl. J. Med. 2017;377:2337-48.

[0072] In this study, the proportion of patients meeting the primary endpoint was significantly higher in the soragliflozin group than in the placebo group (200 out of 699 patients [28.6%] vs. 107 out of 703 patients [15.2%], P < 0.001). Compared with the placebo group, the soragliflozin group showed significantly greater least-squares mean changes in glycated hemoglobin (difference -0.46 percentage points), body weight (-2.98 kg), systolic blood pressure (-3.5 mm Hg), and mean daily insulin bolus dose (-2.8 units / day) (P ≤ 0.002 for all comparisons). The incidence of severe hypoglycemia was similar in the soragliflozin and placebo groups (3.0% [21 patients] and 2.4% [17 patients], respectively). The incidence of hypoglycemia (blood glucose levels of 55 mg / dL (3.1 mmol / L) or below) was significantly lower in the soragliflozin group than in the placebo group. The incidence of DKA was higher in the soragliflozin group than in the placebo group (3.0% [21 patients] vs. 0.6%, respectively). Ibid., p. 2337.

[0073] Table 7 lists some baseline characteristics of the overall population and the CKD patient population: Table 7. Baseline characteristics of the total population

[0074] To conduct this invention, we compared data from CKD patients with data from the overall cohort. As shown below, 16% of patients had CKD at baseline: Table 8. Summary of patients with and without CKD by dosage

[0075] After 24 weeks, the placebo-adjusted HbA1C changes were similar in the CKD group and the general population: the least squares mean was -0.46% in the CKD group (standard error (SE) = 0.120, p < 0.001) and the least squares mean was -0.46% in the general population (SE = 0.042, p < 0.001).

[0076] After 24 weeks, placebo-adjusted weight changes were observed in both groups, and the values ​​were similar: the least squares mean was -2.82 kg in the CKD group (SE = 0.464, p < 0.001), and the least squares mean was -2.98 kg in the overall population (SE = 0.166, p < 0.001).

[0077] After 16 weeks, the least squares mean change in placebo-adjusted systolic blood pressure in the two groups was -7.1 mm Hg for the CKD group (SE = 1.81, p < 0.001) and -3.8 mm Hg for the entire population (SE = 0.57, p < 0.001).

[0078] Of particular note is the observation of a significant difference in the incidence of DKA between the two groups after 24 weeks, as shown in Table 9.

[0079] Table 9. Incidence of diagnosed severe hypoglycemia and DKA

[0080] Although the risk of DKA with soggliflozin was numerically higher than that with placebo, the relative risk of DKA in the CKD cohort was lower (3.5) compared with the overall cohort (5.5).

[0081] In summary, the analysis of the results of the three clinical trials indicates that, compared to the overall T1D patient population evaluated in the trials, soragliflozin treatment for T1D has a better benefit / risk profile, with similar efficacy and improved safety in the cohort of patients with CKD.

[0082] All publications cited above (such as patents and patent applications) are incorporated herein by reference in their entirety.

Claims

1. A method for treating type 1 diabetes (T1D) while minimizing the risk of diabetic ketoacidosis (DKA), comprising: 1) Identify patients with type 1 diabetes (T1D) and chronic kidney disease (CKD) (i.e., those with an estimated glomerular filtration rate (eGFR) < 60 mL / min / 1.73 m 2 And / or patients with a urine albumin-to-creatinine ratio (UACR) ≥ 30 mg / g for at least three months; and 2) administering a therapeutically effective dose of a sodium-glucose cotransporter 2 (SGLT2) inhibitor to the patients.

2. A method for improving the cardiac and renal health of patients with T1D while minimizing the risk of DKA, comprising: 1) Identify patients with T1D and CKD; And 2) administer a therapeutically effective dose of the SGLT2 inhibitor to the patient.

3. The method of claim 2, wherein the improvement in heart and kidney health is manifested in decreased blood glucose, decreased systolic blood pressure, decreased weight, increased diuresis / sodium excretion, decreased intraglomerular pressure and / or reduced proteinuria.

4. A method for slowing the decline in renal function in patients with type 1 disease (T1D) while minimizing the risk of diabetic ketoacidosis (DKA), comprising: 1) Identify patients with T1D and CKD; And 2) administer a therapeutically effective dose of the SGLT2 inhibitor to the patient.

5. The method of any of the preceding claims, wherein the SGLT2 inhibitor is dapagliflozin, canagliflozin, empagliflozin, soragliflozin, ioggliflozin, erggliflozin, 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 as described in any of the preceding claims, wherein the patient is receiving insulin therapy.

8. The method of claim 7, further comprising optimizing insulin therapy.

9. The method as described in any of the preceding claims, wherein the patient has an eGFR < 60 mL / min / 1.73 m 2 .

10. The method of claim 9, wherein the patient has an eGFR < 45 mL / min / 1.73 m 2 .

11. The method of claim 10, wherein the patient has an eGFR < 30 mL / min / 1.73 m 2 .

12. The method as described in any of the preceding claims, wherein the patient has an eGFR > 15 mL / min / 1.73 m 2 (That is, it does not belong to G5 in the GFR category).

13. The method as described in any of the preceding claims, wherein the patient has a UACR ≥ 30 mg / g.

14. The method of claim 13, wherein the patient has a UACR ≥ 300 mg / g.

15. The method as described in any of the preceding claims, wherein the patient has an eGFR < 60 mL / min / 1.73 m 2 And UACR ≥ 30 mg / g.

16. The method as described in any of the preceding claims, wherein the patient has a BMI ≥ 27 kg / m². 2 .

17. The method of any of the preceding claims, wherein the patient meets at least one of the following criteria: is an adult (i.e., at least 18 years of age); is not pregnant; is using multiple daily injections (MDI) or subcutaneous insulin infusion (SCII) for insulin delivery; and has HbA1c levels. 1C The levels are 7.0%–11.0%; and / or the levels of β-hydroxybutyrate (BHB) are ≤ 0.6 mmol / L.

18. The method of claim 17, wherein the patient is an adult.

19. The method of claim 17, wherein the patient meets all of the stated criteria.

20. The method of claim 6, wherein the soggliflozin is administered orally.

21. The method of claim 20, wherein the soragliflozin is administered in the form of tablets, capsules, or pouches.

22. The method of claim 21, wherein the therapeutically effective amount of sorafenib is at least 200 mg / day.

23. The method of claim 22, wherein the therapeutically effective amount of sorafenib is at least 400 mg / day.

24. The method as described in any of the preceding claims, the method further comprising monitoring the patient for DKA or an increase in DKA risk.

25. The method of claim 24, wherein the monitoring is performed by testing the patient's blood glucose, arterial pH and / or serum bicarbonate levels.

26. The method as described in any of the preceding claims, further comprising monitoring the patient for hypoglycemia or an increased risk of hypoglycemia.

27. A method for improving the safety of administering an SGLT2 inhibitor to a patient with T1D, comprising restricting the administration to T1D patients with CKD.

28. The method of claim 27, wherein the patient is receiving optimized insulin therapy.

29. The method of claim 27, wherein the patient is receiving insulin therapy, and the method further includes optimizing the therapy.

30. The method of claim 27, wherein the SGLT2 inhibitor is dapagliflozin, canagliflozin, empagliflozin, soragliflozin, ioggliflozin, erggliflozin, toggliflozin, or ruggliflozin, or a pharmaceutically acceptable salt or solvation thereof.

31. The method of claim 30, wherein the SGLT2 inhibitor is soragliflozin.

32. The method of claim 27, further comprising limiting the administration to eGFR < 60 mL / min / 1.73 m 2 The patient.

33. The method of claim 32, wherein the patient has an eGFR < 45 mL / min / 1.73 m 2 .

34. The method of claim 33, wherein the patient has an eGFR < 30 mL / min / 1.73 m 2 .

35. The method of any one of claims 27-34, wherein the patient has an eGFR > 15 mL / min / 1.73 m 2 (That is, it does not belong to G5 in the GFR category).

36. The method of claims 27-34, wherein the patient has a UACR ≥ 30 mg / g.

37. The method of claim 36, wherein the patient has a UACR ≥ 300 mg / g.

38. The method of any one of claims 27-34, wherein the patient has an eGFR < 60 mL / min / 1.73 m 2 And UACR ≥ 30 mg / g.

39. The method of any one of claims 27-34, wherein the patient has a BMI ≥ 27 kg / m². 2 .

40. The method of claim 27, further limiting the administration to a patient who meets at least one of the following criteria: is an adult (i.e., at least 18 years of age); is not pregnant; is using multiple daily injections (MDI) or subcutaneous insulin infusion (SCII) for insulin delivery; has HbA1c 1C The levels are 7.0%–11.0%; and / or the levels of β-hydroxybutyrate (BHB) are ≤ 0.6 mmol / L.

41. The method of claim 40, wherein the administration is limited to adult patients.

42. The method of claim 40, wherein the administration is limited to patients who meet all of the stated criteria.

43. The method of claim 27, further comprising requiring regular monitoring of the patient for an increased risk of DKA and / or hypoglycemia.

44. A reagent kit comprising: 1) A container (e.g., a box, a bottle) containing at least one solid oral dosage form of an SGLT2 inhibitor; 2) A label providing prescription information recommending the administration of the SGLT2 inhibitor to T1D patients with CKD.

45. The kit of claim 44, further comprising means for measuring and / or reporting DKA events to a healthcare provider.

46. ​​A container (e.g., a box, a bottle) containing at least one solid oral dosage form of an SGLT2 inhibitor, said container having a label providing prescription information (e.g., printed on said container or affixed to the outside of said container) that recommends the administration of said SGLT2 inhibitor to a T1D patient with CKD.

47. The kit or container of any one of claims 44-46, wherein the SGLT2 inhibitor is dapagliflozin, canagliflozin, empagliflozin, soragliflozin, ioggliflozin, erggliflozin, toggliflozin or ruggliflozin, or a pharmaceutically acceptable salt or solvation thereof.

48. The kit or container of claim 47, wherein the SGLT2 inhibitor is soragliflozin.

49. The kit or container according to any one of claims 44-48, wherein the solid oral dosage form is a tablet, capsule, or capsule.

50. The kit or container of claim 49, wherein each of the solid oral dosage forms contains at least 200 mg of soragliflozin.

51. The kit or container of claim 50, wherein each of the solid oral dosage forms contains at least 400 mg of soragliflozin.

52. The kit or container of any one of claims 44-51, wherein the label further suggests limiting the administration to the presence of eGFR > 15 mL / min / 1.73 m 2 The patient.

53. The kit or container of any one of claims 44-52, wherein the label further suggests limiting the administration to patients who meet at least one of the following criteria: are adults (i.e., at least 18 years of age); are not pregnant; are using multiple daily injections (MDI) or subcutaneous insulin infusions (SCII) for insulin delivery; and / or have HbA1c. 1C The levels ranged from 7.0% to 11.0%; β-hydroxybutyric acid (BHB) levels were ≤ 0.6 mmol / L.

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