Efficacy and safety of avexitide for treatment of hypoglycemia following bariatric and other upper gastrointestinal surgeries: a phase 2b study.

CONTEXT: Post-bariatric Hypoglycemia (PBH), complicating up to 30% of Roux-en-Y (RYGB) and up to 10% of Sleeve Gastrectomy (SG) procedures, is characterized by recurrent severe postprandial hypoglycemia and neuroglycopenic events. Similar clinical presentations occur following total gastrectomy, esophagectomy, and Nissen fundoplication. All are characterized by postprandial hypersecretion of GLP-1. Avexitide, a first-in-class GLP-1 receptor antagonist, has shown promise in reducing hypoglycemia events in patients with PBH after RYGB. OBJECTIVES: Evaluate the efficacy and safety of avexitide 45 mg BID and 90 mg QD for reducing the risk of hypoglycemia associated with bariatric and other upper-gastrointestinal surgeries. METHODS: Adults with clinically important hypoglycemia following RYGB, SG, total gastrectomy, or Nissen fundoplication completed a 14-day run-in period (baseline) followed by 14 days each of subcutaneous avexitide 45 mg BID and 90 mg QD in random order. Hypoglycemia was assessed by blinded continuous glucose monitoring (CGM), self-monitored blood glucose (SMBG), and electronic diary. The primary endpoint was rate of diurnal Level 2 events (<54 mg/dL by CGM between the hours of 8 am and 10 pm); secondary endpoints included Level 2 events by SMBG, Level 3 (severe) events by central adjudication, percent time < 54 and < 70 mg/dL by CGM, and patient-reported quality-of-life (QOL) outcomes (HFS-II, EQ-5D-5L). Linear mixed-effects models compared each treatment with baseline. RESULTS: Sixteen participants completed the study. Compared with baseline, avexitide 45 mg BID and 90 mg QD significantly reduced diurnal Level 2 hypoglycemia events by CGM (-47.7% and - 59.0%, both p ≤ 0.0001), Level 2 events by SMBG (-56.8%, p = 0.0027; -53.3%, p = 0.0043), Level 3 events (-67.5% and - 66.1%, both p = 0.0003), and percent time < 54 mg/dL (CGM) by 45% (p = 0.0007) and 64% (p < 0.0001), respectively. Improvements were consistent across surgical subtypes. Avexitide 90 mg QD significantly improved HFS-II Total Score (p = 0.0095) and EQ-5D-5L Index Score (p = 0.0067). Avexitide was well tolerated, with no serious adverse events and no discontinuations due to adverse events. CONCLUSIONS: Avexitide significantly reduced hypoglycemia events and improved QOL in patients with hypoglycemia following bariatric and other upper GI surgeries. Avexitide may represent an effective and targeted therapeutic approach for this patient population. CLINICAL TRIAL REGISTRATION: ClinicalTrials.govNCT04652479.