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CN-121985950-A - Methods for treating type 1 diabetes and kidney disease

CN121985950ACN 121985950 ACN121985950 ACN 121985950ACN-121985950-A

Abstract

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

Inventors

  • MICHAEL JOHN DAVIS

Assignees

  • 莱西肯医药有限公司

Dates

Publication Date
20260505
Application Date
20240926
Priority Date
20230928

Claims (20)

  1. 1. A method of treating type 1 diabetes (T1D) while minimizing the risk of Diabetic Ketoacidosis (DKA) comprising 1) identifying a patient having T1D and Chronic Kidney Disease (CKD) (i.e., a patient having an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m 2 and/or a Urinary Albumin Creatinine Ratio (UACR) > 30 mg/g for at least three months) and 2) administering to the patient a therapeutically effective amount of a sodium-glucose cotransporter 2 (SGLT 2) inhibitor.
  2. 2. A method of improving heart and kidney health while minimizing DKA risk in a patient suffering from T1D comprising 1) identifying a patient suffering from T1D and CKD, and 2) administering to said patient a therapeutically effective amount of an SGLT2 inhibitor.
  3. 3. The method of claim 2, wherein the improvement in central renal health is manifested by reduced blood glucose, reduced systolic blood pressure, reduced body weight, increased diuretic/natriuresis, reduced intraglomerular pressure, and/or reduced proteinuria.
  4. 4. A method of slowing the decline in renal function in a patient with T1D while minimizing the risk of DKA comprising 1) identifying a patient with T1D and CKD, and 2) administering to the patient a therapeutically effective amount of an SGLT2 inhibitor.
  5. 5. The method of any one of the preceding claims, wherein the SGLT2 inhibitor is dapagliflozin, canagliflozin, enggliflozin, soligliflozin, iggliflozin, tolgliflozin, or Lu Gelie, or a pharmaceutically acceptable salt or solvate thereof.
  6. 6. The method of claim 5, wherein the SGLT2 inhibitor is soligliflozin.
  7. 7. The method of any one of the preceding claims, wherein the patient is receiving insulin therapy.
  8. 8. The method of claim 7, further comprising optimizing insulin therapy.
  9. 9. The method of any one of the preceding claims, wherein the patient has an evfr <60 mL/min/1.73: 1.73 m 2 .
  10. 10. The method of claim 9, wherein the patient has an evfr <45 mL/min/1.73m 2 .
  11. 11. The method of claim 10, wherein the patient has an evfr < 30 mL/min/1.73: 1.73 m 2 .
  12. 12. The method of any one of the preceding claims, wherein the patient has an eGFR > 15 mL/min/1.73: 1.73 m 2 (i.e., does not belong to G5 in the GFR category).
  13. 13. The method of any one of the preceding claims, wherein the patient has a UACR ≡30-mg/g.
  14. 14. The method of claim 13, wherein the patient has a UACR ≡300 mg/g.
  15. 15. The method of any one of the preceding claims, wherein the patient has an evfr < 60 mL/min/1.73 m 2 and a UACR ≡30 mg/g.
  16. 16. The method of any one of the preceding claims, wherein the patient has a BMI ≡27 kg/m 2 .
  17. 17. The method of any of the preceding claims, wherein the patient meets at least one of the criteria of being an adult (i.e., at least 18 years old), not a pregnant woman, being insulin delivery using Multiple Daily Injections (MDI) or subcutaneous insulin infusion (SCII), hbA 1C of 7.0-11.0%, and/or having a beta-hydroxybutyrate (BHB) level of less than or equal to 0.6 mmol/L.
  18. 18. The method of claim 17, wherein the patient is an adult.
  19. 19. The method of claim 17, wherein the patient meets all of the criteria.
  20. 20. The method of claim 6, wherein the soligliflozin is administered orally.

Description

Methods for treating type 1 diabetes and kidney disease The present application claims priority from U.S. provisional patent application No. 63/541,147, filed on 9/28 of 2023, the entire contents of which are incorporated herein by reference. Technical Field The present invention relates to methods of treating cardiovascular and renal disease in type 1 diabetics while reducing or avoiding adverse effects such as diabetic ketoacidosis. Background Although insulin therapy has been widely used in type 1 diabetes (T1D) patients, a significant portion of the patient population is still unable to continue to achieve adequate glycemic control. Most T1D adult patients are currently under-serviced by available therapies, and most patients cannot continue to achieve the HbA 1C target by insulin therapy alone. In addition to these challenges, people with T1D are also at high risk of suffering from kidney and cardiovascular diseases. Diabetic kidney disease occurs in approximately 20% -40% of people with T1D and is associated with renal failure and cardiovascular disease morbidity and mortality. In fact, cardiovascular disease (CVD) is the major cause of death in type 1 diabetics. Stougaard, e.b., 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. Sodium glucose cotransporter 2 (SGLT 2) inhibitors have proven to be safe and effective in the treatment of type 2 diabetes and can reduce the risk of cardiovascular death, hospitalization for heart failure, and in emergency care for heart failure. See, e.g., bhatt, d.l., et al , "Sotagliflozin in Patients with Diabetes and Chronic Kidney Disease"N. Engl. J. Med., 2021 Jan 14;384(2):129-139.SGLT2 inhibitors have been shown to be effective in treating kidney disease in patients with and without type 2 diabetes. See, e.g., HEERSPINK, H.J.L., et al, "Dapagliflozin IN PATIENTS WITH Chronic KIDNEY DISEASE" N.Engl. J.Med.2020; 383:1436-46. Unfortunately, T1D patients often fail to obtain the remarkable benefits of these drugs. SGLT2 inhibitors, when administered to T1D patients, can improve glycemic control, body weight, blood pressure, and time to glucose (time-in-range) without increasing the risk of hypoglycemia. Stougaard, supra, 1874. For example, in T1D patients, administration of the dual SGLT1/2 inhibitor, soligliflozin (sotagliflozin), "reduced blood pressure and induced mild blood concentration, and correlated with acute changes in eGFR and 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 Care2019;42:1921–1929, 1927. however, its administration also increases the risk of patients suffering from Diabetic Ketoacidosis (DKA), which is excessive ketone bodies in the blood that can cause nausea, pain and discomfort, may require hospitalization, and even lead to death. The risk of DKA "is a major limiting factor in preventing the broad uptake and use of SGLT2 inhibitors by T1DM patients. 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, that the increased risk of DKA is why SGLT2 inhibitors have not been approved for use in type 1 diabetics in the united states. See, for example ,U.S. 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. Disclosure of Invention The present invention relates in part to a method of treating type 1 diabetes (T1D) while minimizing the risk of Diabetic Ketoacidosis (DKA), the method comprising 1) identifying a patient suffering from type 1 diabetes and Chronic Kidney Disease (CKD) (i.e., a patient having an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m 2 and/or a Urinary Albumin Creatinine Ratio (UACR) > 30 mg/g for at least three months) and 2) administering to the patient a therapeutically effective amount of a sodium-glucose cotransporter 2 (SGLT 2) inhibitor. In another embodiment, the invention relates to a method of improving heart and kidney health while minimizing DKA risk in a patient with type 1 diabetes, comprising 1) identifying a patient with type 1 diabetes and CKD, and 2) administering to the patient a therapeutically effective amount of an SGLT2 inhibitor. Examples of improvements in heart and kidney health include reduced blood glucose, reduced systolic blood pressure, reduced weight, increased diuretic/natriuresis, reduced intraglomerular pressure, and reduced proteinuria. In another embodiment, the invention relates to