A Single Dose Trial of Mizagliflozin for the Treatment of Post-bariatric Hypoglycemia

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Abstract Context Post-bariatric hypoglycemia (PBH) is a complication of bariatric surgery characterized by severe postprandial hypoglycemia for which there is no approved therapy. Objective To evaluate efficacy and safety of mizagliflozin, an SGLT1 inhibitor, for treatment of PBH. Methods This was a Phase 2, open label, randomized, single dose, crossover study. Nine participants with PBH were randomized to receive a baseline mixed meal tolerance test (MMTT), and single doses of mizagliflozin before each of two additional MMTTs. Doses included 2.5 mg liquid formulation, and 2.5 mg, 5 mg and 10 mg capsules. The primary outcome was change from baseline in glucose nadir, and the main secondary outcomes were change from baseline peak glucose and peak insulin. Results Compared to baseline, all individual doses of mizagliflozin raised the glucose nadir: 6.2 mg/dL (2.5 mg capsule), 17.5 md/dL (2.5 mg liquid), 4.0 mg/dL (5 mg capsule) and 31.5 mg/dL (10 mg capsule). In a post-hoc analysis of participants that exhibited hypoglycemia (<70 mg/dL) during the baseline MMTT, mizagliflozin (all capsule doses combined) raised the glucose nadir by 38% (p = 0.03). Treatment with mizagliflozin also lowered both peak glucose by 21% (p = 0.03) and peak insulin by 53% (P = 0.016). Gastric inhibitory polypeptide (GIP) AUC0-3h was reduced by 45% from baseline (p = 0.048). Conclusions Mizagliflozin resulted in improved glucose nadir, reduction in both postprandial peak glucose and peak insulin, and reduction in postprandial GIP. The results from this proof-of-concept study suggest mizagliflozin represents a promising novel oral treatment for PBH that warrants further clinical development.