Exenatide for diagnosing endogenous hyperinsulinemic hypoglycemia – a randomized placebo-controlled, double-blind, cross-over proof-of-principle study

Objective The 72-hour fasting test, gold standard for diagnosing endogenous hyperinsulinemic hypoglycemia (EHH), is cumbersome and costly. We evaluated exenatide, a GLP-1 receptor agonist, as a faster, less burdensome alternative diagnostic tool. Design & Methods In this prospective, placebo-controlled, double-blind, randomized cross-over, proof-of-principle study, 10 μg intravenous exenatide was compared to placebo in 14 patients with confirmed EHH in a fasting test. 14 matched controls received 10 μg exenatide unblinded. Clinical monitoring and measurements of glucose, insulin, C-peptide, and proinsulin were performed for 4 hours. Follow-up for EHH patients included imaging and histology. Results Exenatide induced diagnostic hypoglycaemia in 6 of 14 EHH patients (42%) compared to none with placebo (p=0.005). In patients with EHH glucose nadir occurred earlier after exenatide (67 min [95%CI 50–142] vs. 210 min [95%CI 174–219], p<0.0001) and at lower glucose levels (2.68 mmol/L [95%CI 2.26–3.02] vs. 3.2 mmol/L [95%CI 2.92–3.77], p<0.0001) compared to placebo. Proinsulin levels 120 minutes post-exenatide were higher in patients with EHH (69 pmol/L [95%CI 3.8–232]) compared to controls (9 pmol/L [95%CI 4.5–16.9], p=0.0001). Compared to the fasting test, exenatide significantly shortened time to hypoglycaemia (1.38 hours [95%CI 0.67–2.99] vs. 12 hours [95%CI 1.44–36.1] respectively, p=0.032). Exenatide was well tolerated and preferred by patients over the fasting test. Conclusion Exenatide is a promising, faster, less cumbersome and less expensive diagnostic tool for EHH compared to the fasting test. Larger trials are warranted to confirm its diagnostic utility. Trial Registration Clinicaltrials.gov (NCT04909333)