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Abstract

CONTEXT:Pasireotide (SOM230) is a somatostatin analog with affinity for somatostatin receptor subtypes sst1-3 and sst5. Clinical trials have demonstrated pasireotide's efficacy in treating Cushing's disease and acromegaly, but have also shown adverse effects on glucose metabolism.OBJECTIVE:Evaluate the mechanism of pasireotide-associated hyperglycemia.DESIGN:Randomized, single-center, open-label study.SUBJECTS:45 healthy male volunteers.INTERVENTION:Subjects were randomized to pasireotide 600 (n=19), 900 (n=19) or 1200 μ g (n=7) sc bid for 7 days. Randomization to 1200 μ g was discontinued because of increased severity of gastrointestinal adverse events in this arm. An oral glucose tolerance test (OGTT), a hyperglycemic clamp test (HGCT) and a hyperinsulemic-euglycemic clamp test (HECT) were performed on three consecutive days at baseline and treatment end.MAIN OUTCOME MEASURE:Effect of pasireotide on insulin secretion and hepatic/peripheral insulin sensitivity. The secondary objective was to evaluate the effects of pasireotide on oral glucose absorption.RESULTS:Pasireotide treatment resulted in significant decreases in insulin AUC0-180min during both the HGCT (-77.5%, P<0.001 in both dose groups) and the OGTT (-61.9%, P<0.001 in both dose groups). Suppression of glucagon levels was less pronounced. No significant changes in hepatic or peripheral insulin sensitivity were found during the HECT. Additionally, significant increases in glucose AUC0-180min (+67.4%) and decreases in AUC0-180min glucagon-like peptide-1 (-46.7%) and glucose-dependent insulinotropic polypeptide levels (-69.8%) were observed during the OGTT. No dose dependency or unexpected AEs were observed.CONCLUSIONS:Pasireotide-associated hyperglycemia is related to decreases in insulin secretion and incretin hormone responses, without changes in hepatic/peripheral insulin sensitivity.