TREATMENT OF POST-BARIATRIC HYPOGLYCEMIA WITH GLP-1 ANTAGONISTS

• US 20180147261A1
• Filed: 05/23/2016
• Published: 05/31/2018
• Est. Priority Date: 05/22/2015
• Status: Active Grant

• Current Assignee: Board of Trustees of the Leland Stanford Junior University (Stanford University)
• Original Assignee: Board of Trustees of the Leland Stanford Junior University (Stanford University)
• Inventors: McLaughlin, Tracey L., Craig, Colleen M.
• Granted Patent: US 10,660,937 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 38/17 from animals; from humans enzyme inhibitors A61K38/005
• CPC Class Codes: A61K 38/22 Hormones derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin A61K38/33, e.g. corticotropin A61K38/35
• CPC Class Codes: A61K 38/2278 Vasoactive intestinal peptide [VIP]; Related peptides (e.g. Exendin)
• CPC Class Codes: A61K 38/26 Glucagons
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/08 Solutions composition of solutions A61K47/00
• CPC Class Codes: A61K 9/10 Dispersions; Emulsions A61K9/06 takes precedence; composition of dispersions, emulsions A61K47/00
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48

Abstract

Treatment of hyperinsulinemic hypoglycemia comprises administration of an effective amount of a glucagon-like peptide-1 receptor antagonist (GLP1RA) alone or in combination with an amylinomimetic agent or any anti-gastric emptying agent. Patients suffering from hyperinsulinemic hypoglycemia after bariatric surgery experience particular benefit, as there is no current method effective for their treatment. Prevention or reduction of acute adverse effects of postprandial hypoglycemia, such as palpitations, tremor, weakness, sweating, confusion, fatigue, blurred vision, seizures, or loss of consciousness, and prevention of chronic adverse effects of hyperinsulinemic hypoglycemia, such as cognitive impairment, can be achieved by treatment with GLP1RA.

Claims

1. A method for treating and preventing hyperinsulinemic hypoglycemia and associated acute and chronic symptoms and outcomes, said method comprising subcutaneous administration of a GLP-1 antagonist (“

GLP1A”

) to a patient in need of treatment.

2. The method of claim 1, wherein said patient treated has previously had bariatric surgery.

4. The method of claim 1, wherein said patient has previously had a gasterointestinal surgery selected from the group consisting of Roux-en-Y Gastric Bypass, Vertical Sleeve Gastrectomy, placement of an endosleeve device, duodenal mucosal resurfacing, partial bypass of the duodenum, vagal nerve blockade, and pyloroplasty.

5. The method of claim 1 wherein the GLP1A is selected from the group consisting of exendin(9-39), a derivative of the exendin-4 peptide, a small molecule allosteric ligand, and a derivative of an endogenous GLP-1 peptide.

9. The method of claim 4, wherein the GLP1A is administered by a syringe, a pen, or a pump.

10. The method of claim 9, wherein the patient has been previously treated by intravenous (IV) infusion of exendin(9-39).

11. The method of claim 4, wherein the GLP1A is co-administered or co-formulated with an amylinomimetic, an antacid, a H2 receptor antagonist, or a proton pump inhibitor.

20. The method of claim 1, wherein said hyperinsulinemic hypoglycemia results from an endogenous hyperinsulinemia, and wherein said GLP1A is exendin(9-39), and wherein said method comprises treating said patient with an extended-release formulation of exendin(9-39) administered no more frequently than once per week.

21. The method of claim 1, wherein said hyperinsulinemic hypoglycemia results from post-bariatric surgery, and wherein said GLP1A is exendin(9-39), and wherein the method comprises administering to the patient a therapeutically effective amount of exendin(9-39), wherein the exendin(9-39) is administered at a dose in the range from 2.5 mg to 10 mg twice per day (BID).

22. The method of claim 21, wherein the exendin(9-39) is administered at a dose in the range from 2.5 mg to 7.5 mg BID.

23. The method of claim 21, wherein the exendin(9-39) is subcutaneously administered.

24. The method of claim 22, wherein the exendin(9-39) is subcutaneously administered.

3. (canceled)

6. (canceled)

7. (canceled)

8. (canceled)

12. A method for treating a patient with hyperinsulinemic hypoglycemia resulting from post-bariatric surgery, said method comprising treating said patient with an immediate-release formulation of exendin(9-39), wherein said exendin(9-39) in said formulation is at a concentration ranging from 5 to 30 mg/mL, and said patient is administered from 7.5 mg to 15 mg per dose, and said dose is administered twice a day, once in the morning before a morning meal and once in the evening before an evening meal.

13. The method of claim 12, wherein the morning administration is administered at least sixty minutes before the morning meal.

14. The method of claim 12, wherein said patient has received, prior to said dose in said 7.5 mg to 15 mg dose range, a lower dose of exendin(9-39) as a starting or initial dose.

15. The method of claim 14, wherein said starting or initial dose is an a range of 4 mg to 8 mg per dose

19. The method of claim 14, wherein said starting or initial dose is an a range of 10 mg to 20 mg per dose.

16. A method for treating a patient with hyperinsulinemic hypoglycemia resulting from post-bariatric surgery, said method comprising treating said patient with an extended-release formulation of exendin(9-39), wherein said exendin(9-39) in said formulation is at a concentration ranging from 15 to 45 mg/mL, and said patient is administered a once daily dose from 15 mg to 45 mg, either once in the morning or once in the evening.

17. The method of claim 16, wherein the administration of said once daily dose is in the evening.

18. The method of claim 16, wherein said patient has received, prior to receiving said once daily dose, a lower dose of exendin(9-39) as a starting or initial dose.