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

Abstract

Context Post-bariatric 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 GLP-1 antagonist, for treatment of PBH. Design Phase II, randomized, placebo-controlled crossover study (PREVENT). Setting Multicenter. Participants Eighteen female patients with PBH. Intervention Placebo for 14 days followed by avexitide 30 mg BID and 60 mg QD, each for 14 days in random order. Main Outcome Measures 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 monitor (CGM). Results Compared to placebo, avexitide 30 mg BID and 60 mg QD raised the glucose nadir by 21% (p=0.001) and 26% (p=0.0002) and lowered the insulin peak by 23% (p=0.029) and 21% (p=0.042), corresponding to 50% and 75% fewer participants requiring rescue during MMTT, respectively. Significant reductions in rates of Levels 1-3 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. Conclusions 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.

European guideline on obesity care in patients with gastrointestinal and liver diseases – Joint ESPEN/UEG guideline

“…In contrast, pasireotide often causes continuous hyperglycemia [514,515]. More recent drug treatments for post-bariatric hypoglycemia are canagliflozin [516], avexitide [517], or a Closed-Loop Glucagon System [518]. Endoscopic techniques may reduce the diameter of the anastomotic mouth and help to maintain weight reduction.…”

Exendin-(9-39) Effects on Glucose and Insulin in Children With Congenital Hyperinsulinism During Fasting and During a Meal and a Protein Challenge

“…Available medical treatments for HI are currently limited, insufficiently effective, and associated with significant side effects ( 22 – 24 ); by targeting the underlying pathophysiology, exendin-(9-39) offers potential therapeutic advantages over currently available therapies for HI, particularly for cases due to inactivating K ATP channel mutations that are not responsive to diazoxide. Furthermore, exendin-(9-39) has been well tolerated without significant treatment-related side effects in children with HI and also in adults with post–bariatric surgery hypoglycemia ( 25 , 26 ). Exendin-(9-39) has been granted breakthrough therapy designation for the treatment of HI ( 27 ), and future studies to evaluate efficacy and safety of multiple dose regimens are under development.…”

The Role of GLP-1 Signaling in Hypoglycemia due to Hyperinsulinism

“…Incidence of hypoglycemia measured by continuous glucose monitor and number of hypoglycemic events were decreased in the subjects treated with exendin-(9-39). There was a statistically significant increase in glucose nadir and decrease in insulin peak during the mixed meal tolerance test ( 49 ). Another study found a reduction in symptomatic hypoglycemic events, as well as decreased insulin peak and increased glucose nadir during oral glucose tolerance tests in subjects receiving exendin-(9-39) ( 50 ).…”