Methods of treating type 1 diabetes and kidney disease

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

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202480062356.X (22) Application Date 2024.09.26 (30) Priority Data 63 / 541,147 2023.09.28 US (85) PCT International Application Entering National Phase Date 2026.03.27 (86) PCT International Application Application Data PCT / US2024 / 048524 2024.09.26 (87) PCT International Application Publication Data WO2025 / 072413 EN 2025.04.03 (71) Applicant: Lexcare Pharmaceuticals, Inc. Address: USA (72) Inventor: Michael John Davis (74) Patent Agency: Zhongyuan Xinda Intellectual Property Agency Co., Ltd. 11219 Patent Attorneys Liu Hui and Jin Haixia (51) Int.Cl. A61K 31 / 70 (2006.01) A61K 31 / 7042 (2006.01) A61K 31 / 7048 (2006.01) A61P 3 / 10 (2006.01) A61P 13 / 12 (2006.01) (54) Invention Title: Method for Treating Type 1 Diabetes and Kidney Disease (57) Abstract: A method is disclosed for treating type 1 diabetes, improving cardiovascular health, delaying the decline of renal function, reducing the risk of cardiovascular death and reducing the risk of hospitalization for heart failure using a sodium-glucose cotransporter 2 (SGLT2) inhibitor, while minimizing adverse events such as diabetic ketoacidosis and severe hypoglycemia. In a preferred method, the SGLT2 inhibitor is soragliflozin. Prescribing soragliflozin and methods for administering soragliflozin are also disclosed. Claims (3 pages), Description (14 pages), Drawings (4 pages), CN 121985950 A 2026.05.05 CN 1 21 98 59 50 A 1. A method for treating type 1 diabetes (T1D) while minimizing the risk of diabetic ketoacidosis (DKA), comprising: 1) identifying a patient with T1D and chronic kidney disease (CKD) (i.e., a patient with an estimated glomerular filtration rate (eGFR) < 60 mL / min / 1.73 m2 and / or a urine albumin-to-creatinine ratio (UACR) ≥ 30 mg / g for at least three months); and 2) administering a therapeutically effective amount of a sodium-glucose cotransporter 2 (SGLT2) inhibitor to said patient. 2. A method for improving the cardiorenal health of a patient with T1D while minimizing the risk of DKA, comprising: 1) identifying a patient with T1D and CKD; and 2) administering a therapeutically effective amount of an SGLT2 inhibitor to said patient.3. The method of claim 2, wherein the improvement in central renal health is manifested by decreased blood glucose, decreased systolic blood pressure, decreased weight, increased diuretic / sodium excretion, decreased intraglomerular pressure, and / or reduced proteinuria. 4. A method for slowing the decline in renal function in a patient with type 1 disease (T1D) while minimizing the risk of diabetic ketoacidosis (DKA), 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. 5. The method of any of the preceding claims, wherein the SGLT2 inhibitor is dapagliflozin, canagliflozin, empagliflozin, soragliflozin, ioggliflozin, erggliflozin, 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 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 of any of the preceding claims, wherein the patient has an eGFR < 60 mL / min / 1.73 m². 10. The method of claim 9, wherein the patient has an eGFR < 45 mL / min / 1.73 m². 11. The method of claim 10, wherein the patient has an eGFR < 30 mL / min / 1.73 m². 12. The method of any of the preceding claims, wherein the patient has an eGFR > 15 mL / min / 1.73 m² (i.e., not belonging to G5 in the GFR category). 13. The method of 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 of any of the preceding claims, wherein the patient has an eGFR < 60 mL / min / 1.73 m² and a UACR ≥ 30 mg / g. 16. The method of any of the preceding claims, wherein the patient has a BMI ≥ 27 kg / m². 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; has an HbA1c of 7.0%–11.0%; and / or has a β-hydroxybutyrate (BHB) level ≤ 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 soggliflozin is administered in the form of tablets, capsules, or pouches. 22. The method of claim 21, wherein the therapeutically effective amount of soggliflozin is at least 200 mg / day. 23. The method of claim 22, wherein the therapeutically effective amount of soggliflozin is at least 400 mg / day. 24. The method of any of the preceding claims, further comprising monitoring the patient for DKA or an increased risk of DKA. Claims 1 / 3 page 2 CN 121985950 A 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 of 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 comprises optimizing this therapy. 30. The method of claim 27, wherein the SGLT2 inhibitor is dapagliflozin, canagliflozin, empagliflozin, soragliflozin, ioggliflozin, erggliflozin, toragliflozin, 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 patients with eGFR < 60 mL / min / 1.73 m2. 33. The method of claim 32, wherein the patient has eGFR < 45 mL / min / 1.73 m2. 34. The method of claim 33, wherein the patient has eGFR < 30 mL / min / 1.73 m2. 35. The method of any one of claims 27-34, wherein the patient has an eGFR > 15 mL / min / 1.73 m² (i.e., not belonging 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 m² and a UACR ≥ 30 mg / g. 39. The method of any one of claims 27-34, wherein the patient has a BMI ≥ 27 kg / m². 40. The method of claim 27, further limiting the administration to patients meeting at least one of the following criteria: being an adult (i.e., at least 18 years of age); not pregnant; using multiple daily injections (MDI) or subcutaneous insulin infusion (SCII) for insulin delivery; having an HbA1c of 7.0%–11.0%; and / or having a β-hydroxybutyrate (BHB) level ≤ 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 meeting all of the stated criteria. 43. The method of claim 27, further comprising requiring periodic monitoring of the patient for an increased risk of DKA and / or hypoglycemia. 44. A kit comprising: 1) a container (e.g., a box, a bottle) containing at least one solid oral dosage form of an SGLT2 inhibitor; and 2) a label providing prescription information, the label suggesting administration of the SGLT2 inhibitor to a T1D patient 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, the container having a label providing prescription information (e.g., printed on the container or affixed to the outside of the container), the label suggesting administration of the 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, toragliflozin, 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 of any one of claims 44-48, wherein the solid oral dosage form is a tablet, capsule, or lozenge. 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 patients with eGFR > 15 mL / min / 1.73 m2. 53. The kit or container of any one of claims 44-52, wherein the label further suggests limiting the administration to patients meeting at least one of the following criteria: being an adult (i.e., at least 18 years of age); not pregnant; using multiple daily injections (MDI) or subcutaneous insulin infusion (SCII) for insulin delivery; and / or having HbA1c of 7.0%–11.0%; and having β-hydroxybutyrate (BHB) levels ≤ 0.6 mmol / L. Claims 3 / 3 Page 4 CN 121985950 A Method for treating type 1 diabetes and kidney disease

[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 methods for treating cardiovascular and kidney diseases in patients with type 1 diabetes, while reducing or avoiding adverse reactions such as diabetic ketoacidosis. Background Art

[0003] Although insulin therapy is widely used in patients with type 1 diabetes (T1D), a large proportion of the patient population still cannot consistently achieve adequate glycemic control. Most adult patients with T1D currently have inadequate therapeutic services available, and most patients cannot consistently achieve HbA1c targets with insulin therapy alone.

[0004] In addition to these challenges, people with T1D face a high risk of developing kidney and cardiovascular diseases. 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 patients 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 to 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, Herspink, H.J.L., et al., “Dapagliflozin in Patients with Chronic Kidney Disease” N. Engl. J. Med. 2020; 383:1436-46. Unfortunately, patients with T1D often do not receive the remarkable 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 of glycemic control without increasing the risk of hypoglycemia. Stougaard, ibid., 1874. For example, in patients with T1D, 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, D.H., 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, Instructions for Use, 1 / 14 pages, CN 121985950, A 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, US Food and Drug Administration, 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.

[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 a patient with type 1 diabetes and chronic kidney disease (CKD) (i.e., a patient with an estimated glomerular filtration rate (eGFR) <60 mL / min / 1.73 m2 and / or a urine albumin-to-creatinine ratio (UACR) ≥ 30 mg / g for at least three months); and 2) administering a therapeutically effective amount of a sodium-glucose cotransporter 2 (SGLT2) inhibitor to the patient.

[0008] In another embodiment, this 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 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, the kit being helpful in implementing 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) recommending the administration of an SGLT2 inhibitor to a patient with type 1 diabetes and CKD.

[0013] Figure 1 shows the cumulative incidence of first-onset cardiorenal events derived from laboratory (eGFR) and non-eGFR data obtained from the SCORED clinical trials.

[0014] Figure 2A shows placebo-adjusted changes in HbA1c in patients with chronic kidney disease (CKD) and the overall cohort, obtained by pooling data from the InTandem1 and InTandem2 clinical trials. 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 shows placebo-adjusted changes in patient weight in patients with CKD and the overall cohort, obtained by pooling data from the InTandem1 and InTandem2 clinical trials. The results shown are those of oral administration of soragliflozin (200 mg / day and 400 mg / day) after 24 weeks. For all comparisons, P ≤ 0.003.

[0016] Figure 3A shows the placebo-adjusted changes in systolic blood pressure (SBP) for CKD and the overall cohort obtained by pooling data from the InTandem1 and InTandem2 clinical trials. The results shown are those of 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 shows the percentage change in placebo-adjusted total daily insulin dose for patients in the CKD and overall cohorts obtained by pooling data from the InTandem1 and InTandem2 clinical trials. The results are shown for oral administration of soragliflozin (200 mg / day and 400 mg / day) after 24 weeks. For overall comparison, P ≤ 0.05.

[0018] Figure 4A shows the change in placebo-adjusted daily bolus insulin dose for patients in the CKD and overall cohorts obtained by pooling data from the InTandem1 and InTandem2 clinical trials. The 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 comparison, P ≤ 0.001.

[0019] Figure 4B shows the percentage change in placebo-adjusted daily basal insulin doses in patients with CKD and the overall cohort, obtained by summarizing data from the InTandem1 and InTandem2 clinical trials. The results shown are 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 Description

[0020] This invention relates in part to a method of 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 cotransporter 1 and 2 (SGLT1 and SGLT2), marketed in the United States under the trade 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, ergliflozin, tofogliflozin, and luseogliflozin, as well as their pharmaceutically acceptable salts and solvates.

[0023] As used herein, 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 a patient’s kidney structure or function abnormality that has lasted for more than three months and has an impact on 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 GFR categories are: G1 (normal or high) ≥90 ml / min / 1.73 m2; G2 (mildly decreased) 60–89 ml / min / 1.73 m2; G3a (mild to moderately decreased) 45–59 ml / min / 1.73 m2; G3b (moderate to severe decreased) 30–44 ml / min / 1.73 m2; G4 (severely decreased) 15–29 ml / min / 1.73 m2; and G5 (kidney failure) <15 ml / min / 1.73 m2. CGA 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 eGFR equation based on serum creatinine (SCr) (rather than SCr alone) is sensitive for detecting GFR <60 mL / min / 1.73 m².If necessary, the reduction in eGFR obtained using 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 invention have eGFR <60 mL / min / 1.73 m2 (e.g., <45 mL / min / 1.73 m2) and / or a urinary 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, patients have both eGFR <60 mL / min / 1.73 m2 and UACR ≥30 mg / g (3 mg / mmol) for more than three months. In some embodiments, patients have eGFR <45 mL / min / 1.73 m2 and >15 mL / min / 1.73 m2 (i.e., not belonging 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 invention, the terms “safe,” “safely,” “enhanced safety,” “minimize the risk,” and “minimizing the risk” mean a method of reducing the relative risk of DKA and / or hypoglycemia compared to 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), compared to placebo.

[0028] One embodiment of the present invention relates to a method for treating T1D while minimizing the risk of diabetic ketoacidosis (DKA), the method comprising: 1) identifying a patient with T1D and chronic kidney disease (CKD) (i.e., a patient with an estimated glomerular filtration rate (eGFR) <60 mL / min / 1.73 m2 and / or a urine albumin-to-creatinine ratio (UACR) ≥ 30 mg / g for at least three months); and 2) administering a therapeutically effective amount of a sodium-glucose cotransporter 2 (SGLT2) inhibitor to the patient.

[0029] Another embodiment of the present invention relates to a method for improving the cardiorenal health of a patient with T1D while minimizing the risk of DKA, the method comprising: 1) identifying a patient with T1D and CKD; and 2) administering a therapeutically effective amount of an SGLT2 inhibitor to the patient.Examples of improved 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 a patient with both T1D and CKD; and 2) administering a therapeutically effective amount of an SGLT2 inhibitor to the patient. Specification 4 / 14 pages 8 CN 121985950 A

[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 limiting 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, toggliflozin, or ruggliflozin, or a pharmaceutically acceptable salt or solvation thereof. A preferred SGLT2 inhibitor is soragliflozin.

[0034] In a specific embodiment of the invention, the patient is receiving optimized insulin therapy. In a specific method of the invention, the 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 m2, an eGFR < 45 mL / min / 1.73 m2, or an eGFR < 30 mL / min / 1.73 m2. In a specific embodiment of the invention, the patient has an eGFR > 15 mL / min / 1.73 m2 (i.e., not belonging to G5 in the GFR category).

[0036] In a specific 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 particular embodiment of the invention, the patient has both an eGFR < 60 mL / min / 1.73 m2 and a UACR ≥ 30 mg / g.

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

[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 particular embodiment of the invention, 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; has an HbA1c of 7.0%–11.0%; and has a β-hydroxybutyrate (BHB) level ≤0.6 mmol / L. In some embodiments, the patient is an adult. In some embodiments, the patient meets all of these criteria.

[0041] In a particular embodiment 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 dose of soggliflozin is at least 200 mg / day. In some embodiments, the therapeutically effective dose 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 by testing a patient's blood glucose, arterial pH, and / or serum bicarbonate levels. Specific methods of the present invention 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 T1D patient with CKD.

[0044] In one embodiment, the kit further comprises means for measuring and / or reporting DKA events to a healthcare provider. The means for measuring DKA events includes a ketone body test kit and a meter (e.g., a glucose meter) for measuring blood ketone body levels. Devices for reporting DKA events include information containing instructions for sending emails or messages (such as text messages). Other devices include mobile applications that can wirelessly connect to glucose meters and store and / or report ketone levels to healthcare providers or their agents.Instructions for Use, Page 5 / 14, CN 121985950 A

[0045] Another embodiment covers 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 administration of an SGLT2 inhibitor to a patient with CKD and T1D.

[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 recommends limiting the administration to patients with eGFR > 15 mL / min / 1.73 m2. In some implementations, the label suggests 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 an HbA1c of 7.0%–11.0%; or have a β-hydroxybutyrate (BHB) level ≤ 0.6 mmol / L.

[0048] Examples Example 1. Analysis of Cardiac and Renal Endpoint Events in Patients with Type 2 Diabetes The cardioprotective properties of sorafenib in patients with type 2 diabetes provided the basis for the study that led to this invention. These properties were observed in a phase 3 multicenter, double-blind clinical trial in patients with type 2 diabetes (glycated hemoglobin level ≥7%) and an estimated glomerular filtration rate (eGFR) of 25 ml to 60 ml per minute per 1.73 m2 body surface area. 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, with a median follow-up of 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 to placebo, the soragliflozin group was more likely to experience diarrhea, genital yeast infection, and volume depletion.

[0050] As shown in Figure 1, 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 Sotagliflozin on Cardiac and Renal Endpoint Events in Patients with Type 2 Diabetes and CKD (Presentation 6 / 14 pages, 10 CN 121985950 A)

[0052] This study clearly demonstrates that patients with diabetes and kidney disease (with or without proteinuria) who took sotagliflozin daily had a lower risk of the composite endpoint of death from cardiovascular cause, hospitalization for heart failure, and emergency visit for heart failure compared to patients taking 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 Kidney Outcomes, Kidney Function, and Albuminuria in Type 2 Diabetes and CKD” CJASN2024;19:557–564. Soragliflozin has been approved by the U.S. Food and Drug Administration (FDA) for reducing the risk of cardiovascular death, heart failure hospitalization, 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 In two multicenter, double-blind clinical studies, “InTandem1” and “InTandem2”, the efficacy of soragliflozin as adjunctive therapy in adult patients with type 1 diabetes whose glycemic control was inadequate on insulin therapy was evaluated. Patients were randomized to three treatment groups: patients treated with soragliflozin 200 mg / day, patients treated with soragliflozin 400 mg / day, and patients treated with placebo.

[0054] Details of the InTandem1 study have been published.See, for example, B use, J.B., et al., “Sotagliflozin in Combination With Optimized Insulin Therapy in Adults With Type 1 Diabetes: The North American InTandem1 Study”, Diabetes Care 2018;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 men aged ≥18 years with type 1 diabetes mellitus (T1D) and non-pregnant women with HbA1c of 7.0%–11.0% at screening, who received insulin delivery via multiple daily injections (MDI) or subcutaneous insulin infusions (SCII). 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 the study at 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 starting six weeks prior to randomization and continuously adjusting insulin throughout the study to achieve standard care glycemic targets. Independent Insulin Dose Monitoring Committee (IDMC) assesses adherence to standards of care and provides feedback to the principal investigator when deviations from the standards of care are observed before week 24. During this period, HbA1c blinding is performed on investigators. Insulin optimization continues without input from the IDMC between weeks 24 and 52, and HbA1c values ​​are unblinded. Safety is monitored for 30 days following the last dose of the study drug.

[0056] The primary endpoint for both studies was the change in glycated hemoglobin A1C 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 ways compared to placebo: the proportion of patients with A1C < 7.0% and no severe hypoglycemic episodes or DKA episodes; 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 results of the inTandem1 / inTandem2 studies, after core treatment and long-term extended periods, soragliflozin achieved its primary endpoint by causing a statistically significant reduction in A1C levels at both doses compared to placebo.

[0058] Table 2. Pooled efficacy and safety results from randomization to week 52 8 / 14 pages 12 CN 121985950 A

[0059] Additional data from these combined studies 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, subgroups distinguished by baseline BMI < 27 kg / m2 and baseline BMI ≥ 27 kg / m2 were found to exhibit different efficacy profiles.

[0060] At baseline, no significant differences were observed between the high BMI and low BMI groups, but overweight and obese patients with BMI ≥27 kg / m2 tended to have higher baseline SBP. Overall, at week 24, soragliflozin was significantly more effective than placebo in the overweight and obese subgroup with BMI ≥27 kg / m2, particularly for A1C, weight, time to target glycemic control, DTSQ, and two DDS2 measurements. Using the same statistical model, the treatment-subgroup interaction test for changes in A1C, weight, and DTSQ relative to baseline scores was associated with a p-value <0.05. This implies that soragliflozin is systematically more effective than the lower BMI subgroup in these variables. The differences in A1C, weight, and time to target glycemic control were often greater in the 400 mg group.At a dose of 400 mg only, the decrease in fasting plasma glucose was greater in overweight and obese patients. The decrease in SBP and 2-hour postprandial glucose was tended to be smaller in these patients. A similar trend was also observed at week 52.

[0061] This invention is not focused on BMI, but is based on findings surrounding renal 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 pooled population

[0063] Although most patients exhibited relatively healthy renal function, 15% of the patients enrolled in these studies had CKD defined as eGFR < 60 mL / min / 1.73 m2 and / or UACR ≥ 30 mg / g, as shown in Table 4 below.

[0064] Table 4. Summary of Patients with and without CKD by Dosage 10 / 14 pages 14 CN 121985950 A

[0065] Some baseline characteristics of CKD subgroups are provided below. Unless otherwise stated, these values ​​are mean (standard deviation in parentheses).

[0066] Table 5. Baseline Characteristics of the CKD Population

[0067] The figures show some characteristics of the CKD and overall (i.e., total summation) study populations after 24 weeks of oral administration of sorafenib at 200 mg / day or 400 mg / day. Figure 2A shows the placebo-adjusted changes in HbA1c, while Figure 2B shows the placebo-adjusted changes in patient weight. Figures 3A and 3B show comparisons between placebo-adjusted changes in systolic blood pressure (SBP) and total daily insulin dose, respectively. The difference between the changes in daily bolus insulin dose and daily basal insulin dose in placebo-adjusted patients is clearly visible in Figures 4A and 4B.

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

[0069] Table 6. Judged Incidence of Severe Hypoglycemia and DKA (Instructions for Use, Pages 11 / 14, CN 121985950 A)

[0070] These data suggest that treatment in patients with type 1 diabetes has a better benefit-risk profile, with similar efficacy and improved safety, compared to the overall cohort. Soragliflozin significantly reduced A1C and BW in the CKD subgroup, to a similar degree to the overall cohort, but the relative risk of severe hypoglycemia was lower in the CKD cohort when using soragliflozin compared to placebo.Similarly, in the CKD cohort, the relative risk of DKA with soragliflozin was not significantly increased compared to placebo, in contrast to the significant 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 soragliflozin (400 mg daily) or placebo for 24 weeks. The primary endpoint was a glycated hemoglobin level below 7.0% at week 24 and no severe hypoglycemia or diabetic ketoacidosis after randomization. Secondary endpoints included changes in glycated hemoglobin level, body weight, systolic blood pressure, and mean daily insulin bolus dose relative to baseline. The specific details of this study are 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 who met the primary endpoint in the sotagliflozin group was significantly higher than that 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 sotagliflozin group had significantly greater least squares mean changes in glycated hemoglobin (difference of -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 group and the placebo group (3.0% [21 patients] and 2.4% [17 patients], respectively). The incidence of hypoglycemia (blood glucose level of 55 mg / dL (3.1 mmol / L) or below) recorded in the soragliflozin group was significantly lower than that in the placebo group. The incidence of DKA in the soragliflozin group was higher than that in the placebo group (3.0% [21 patients] and 0.6%, respectively). Ibid., p. 2337.

[0073] Some baseline characteristics of the overall population and the CKD patient population are listed in Table 7: Table 7. Baseline characteristics of the overall population Description 12 / 14 pages 16 CN 121985950 A

[0074] For the purposes of 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 dose

[0075] After 24 weeks, the placebo-adjusted HbA1c changes were similar in the CKD and overall populations: the least squares mean observed in the CKD group was -0.46% (standard error (SE) = 0.120, p < 0.001), and the least squares mean observed in the overall population was -0.46% (SE = 0.042, p < 0.001).

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

[0077] After 16 weeks, the least squares mean change in placebo-adjusted systolic blood pressure for 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 overall population (SE = 0.57, p < 0.001).

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

[0079] Table 9. Judged Severe Hypoglycemia and Incidence of DKA

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

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

[0082] All publications cited above (e.g., patents and patent applications) are incorporated herein by reference in their entirety. Specification 14 / 14 pages 18 CN 121985950 A Figure 1 Specification Figure 1 / 4 pages 19 CN 121985950 A Figure 2A Figure 2B Specification Figure 2 / 4 pages 20 CN 121985950 A Figure 3A Figure 3B Specification Figure 3 / 4 pages 21 CN 121985950 A Figure 4A Figure 4B Specification Figure 4 / 4 pages 22 CN 121985950 A.

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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