Hyperglycemia associated with pasireotide: Results from a mechanistic study in healthy volunteers

Abstract

Context: Pasireotide (SOM230) is a somatostatin analog with affinity for somatostatin receptor subtypes sst1-3 and sst5. Clinical trials have demonstrated the efficacy of pasireotide in treating Cushing's disease and acromegaly but have also shown adverse effects on glucose metabolism. Objective: The aim of the study was to evaluate the mechanism of pasireotide-associated hyperglycemia. Design: We conducted a randomized, single-center, open-label study. Subjects and Intervention: Forty-five healthy male volunteers were randomized to pasireotide 600 (n = 19), 900 (n = 19), or 1200 μg (n = 7) sc twice a day for 7 days. Randomization to 1200 μg was discontinued because of increased severity of gastrointestinal adverse events in this arm. An oral glucose tolerance test (OGTT), a hyperglycemic clamp test, and a hyperinsulinemic-euglycemic clamp test were performed on 3 consecutive days at baseline and treatment end. Main Outcome Measure: The effect of pasireotide on insulin secretion and hepatic/peripheral insulin sensitivity was measured. The secondary objective was to evaluate the effects of pasireotide on oral glucose absorption. Results: Pasireotide treatment resulted in significant decreases in insulin AUC0-180 min during both the hyperglycemic clamp test (-77.5%; P < .001 in both dose groups) and the OGTT (-61.9%; P