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

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.

Figure 1.

Study Schematic for the PREVENT Trial (above) and mixed meal tolerance test (MMTT) sampling timepoints (below). Avexitide 30 mg twice daily, avexitide 30 mg dose every 12 hours; avexitide 60 mg once daily, avexitide 60 mg dose once each morning. CGM, continuous glucose monitoring; eDiary, electronic diary; SMBG, self-monitoring of blood glucose; SC, subcutaneous.

Figure 2.

Study profile (Consort). Twenty-two patients were screened and 18 were randomized and completed the study. *Evaluable set was defined as all randomized patients who received at least Treatment Period 1 placebo and Treatment Period 2 active treatment with blood glucose nadir measured during MMTT in both Treatment Periods 1 and 2, without any major protocol deviations that may confound the interpretation of efficacy. One participant was excluded from the Evaluable set analysis because glycemic rescue was not administered as indicated per protocol during the Period 1 placebo MMTT.

Figure 3.

Mean postprandial plasma glucose (A) and insulin (C) concentrations and mean postprandial plasma glucose nadir (B) and insulin peak (D) in response to MMTT provocation at the end of placebo (grey/dotted line), avexitide 30 mg twice daily (light blue/solid line), and avexitide 60 mg once daily (dark blue/dashed line) treatment periods. Inset within (A) shows an enlargement of axes detailing the glucose values during the 90-180 minute time period. The chart below (A) shows the number of evaluable patients at each sampling timepoint by treatment regimen, representing the number of participants not having required rescue by that timepoint. *P < .05; **P < .01; ***P < .001 for avexitide 30 mg twice daily vs placebo; +P < .05; ++P < .01, and +++P < .001 for avexitide 60 mg once daily vs placebo. Avexitide 30 mg twice daily, avexitide 30 mg dose every 12 hours; avexitide 60 mg once daily, avexitide 60 mg dose once each morning.

Figure 4.

Mean avexitide plasma concentration by dosing regimen: avexitide 30 mg twice daily; light blue/solid line, and avexitide 60 mg once daily; dark blue/dashed line on Days 29 and 43. On each of Days 29 and 43, a trough PK sample was collected immediately before the T = −90 minute injection of study drug. T = 0 minutes represents the start of Ensure Compact drink consumption. T = 0, 60, and 180 PK samples were collected at the same time as the plasma glucose and hormonal (insulin, C-peptide, GLP-1, glucagon) draws with PK sampling additionally obtained at T = 330 minutes.