Hyperglycemia Associated With Pasireotide: Results From a Mechanistic Study in Healthy Volunteers

Context: Pasireotide (SOM230) is a somatostatin analog with affinity for somatostatin receptor subtypes sst(1-3) and sst(5). 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 mu g (n = 7) sc twice a day for 7 days. Randomization to 1200 mu g 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 AUC(0-180 min) during both the hyperglycemic clamp test (-7.5%; P <.001 in both dose groups) and the OGTT (-61.9%; P <.001 in both dose groups). Suppression of glucagon levels was less pronounced. No significant changes in hepatic or peripheral insulin sensitivity were found during the hyperinsulinemic-euglycemic clamp test. Additionally, significant increases in glucose AUC(0-180 min) (+67.4%) and decreases in AUC(0-180 min) glucagon-like peptide-1 (-46.7%) and glucose-dependent insulinotropic polypeptide levels (-69.8%) were observed during the OGTT. No dose dependency or unexpected adverse events were observed. Conclusions: Pasireotide-associated hyperglycemia is related to decreases in insulin secretion and incretin hormone responses, without changes in hepatic/peripheral insulin sensitivity.