PREVENT: A Randomized, Placebo-controlled Crossover Trial of Avexitide for Treatment of Postbariatric Hypoglycemia

Colleen M Craig; Helen Margaret Lawler; Clare Jung Eun Lee; Marilyn Tan; Dawn Belt Davis; Jenny Tong; Michele Glodowski; Elisa Rogowitz; Rowan Karaman; Tracey L McLaughlin; Lisa Porter

doi:10.1210/clinem/dgab103

PREVENT: A Randomized, Placebo-controlled Crossover Trial of Avexitide for Treatment of Postbariatric Hypoglycemia

J Clin Endocrinol Metab. 2021 Jul 13;106(8):e3235-e3248. doi: 10.1210/clinem/dgab103.

Authors

Affiliations

¹ Eiger BioPharmaceuticals, Inc., Palo Alto, CA 94306, USA.
² Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado School of Medicine, Aurora, CO 80045, USA.
³ Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
⁴ Division of Endocrinology, Gerontology, and Metabolism, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁵ Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Wisconsin, Madison, WI 53705, USA.
⁶ Division of Endocrinology, Metabolism, and Nutrition, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.

Abstract

Context: Postbariatric hypoglycemia (PBH), characterized by enteroinsular axis overstimulation and hyperinsulinemic hypoglycemia, is a complication of bariatric surgery for which there is no approved therapy.

Objective: To evaluate efficacy and safety of avexitide [exendin (9-39)], a glucagon-like peptide-1 antagonist, for treatment of PBH.

Methods: A multicenter, Phase 2, randomized, placebo-controlled crossover study (PREVENT). Eighteen female patients with PBH were given placebo for 14 days followed by avexitide 30 mg twice daily and 60 mg once daily, each for 14 days in random order. The main outcome measures were glucose nadir and insulin peak during mixed-meal tolerance testing (MMTT) and hypoglycemic events captured by self-monitoring of blood glucose (SMBG), electronic diary, and blinded continuous glucose monitoring (CGM).

Results: Compared with placebo, avexitide 30 mg twice daily and 60 mg once daily raised the glucose nadir by 21% (P = .001) and 26% (P = .0002) and lowered the insulin peak by 23% (P = .029) and 21% (P = .042), corresponding to 50% and 75% fewer participants requiring rescue during MMTT, respectively. Significant reductions in rates of Levels 1 to 3 hypoglycemia were observed, defined, respectively, as SMBG <70 mg/dL, SMBG <54 mg/dL, and a severe event characterized by altered mental and/or physical function requiring assistance. CGM demonstrated reductions in hypoglycemia without induction of clinically relevant hyperglycemia. Avexitide was well tolerated, with no increase in adverse events.

Conclusion: Avexitide administered for 28 days was well tolerated and resulted in robust and consistent improvements across multiple clinical and metabolic parameters, reinforcing the targeted therapeutic approach and demonstrating durability of effect. Avexitide may represent a first promising treatment for patients with severe PBH.

Trial registration: ClinicalTrials.gov NCT03373435.

Keywords: GLP-1 antagonist; PBH; Postbariatric hypoglycemia; avexitide; exendin (939); hyperinsulinemic hypoglycemia.

Publication types

Clinical Trial, Phase II
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Bariatric Surgery / adverse effects*
Blood Glucose*
Cross-Over Studies
Female
Humans
Hypoglycemia / drug therapy*
Hypoglycemia / etiology
Male
Middle Aged
Peptide Fragments / therapeutic use*
Postoperative Complications / drug therapy
Postoperative Complications / etiology
Treatment Outcome

Substances

Blood Glucose
Peptide Fragments
exendin (9-39)

Associated data

ClinicalTrials.gov/NCT03373435