Endocrine Abstracts (2011) 26 P260

Mechanism and management of hyperglycemia associated with pasireotide: results from studies in healthy volunteers

R R Henry1, S Mudaliar1, K Wetli-Hermosillo2, M Ligueros-Saylan3, S Chenji4 & G Golor5

1University of California at San Diego and VA San Diego Healthcare System, San Diego, California, USA; 2Novartis Pharma AG, Basel, Switzerland; 3Novartis Pharmaceuticals Corporation, Florham Park, New Jersey, USA; 4Novartis Healthcare Pvt Ltd, Hyderabad, India; 5Parexel International GmbH, Berlin, Germany.

Introduction: The multi-receptor targeted somatostatin analogue pasireotide has high affinity for sst5; this receptor may play an important role in glucose metabolism. Two studies in healthy male volunteers evaluated the mechanism and management of hyperglycemia associated with pasireotide.

Methods: A randomized, Phase II study assessed insulin secretion and glucose metabolism during 8 days of pasireotide 600 or 900 μg sc bid (n=19 for both) with oral glucose tolerance test (OGTT), hyperglycemic clamp (HC) with arginine stimulation, and hyperinsulinemic–euglycemic clamp (HIEC). A randomized, 1-week, five-arm Phase I study evaluated glucose metabolism following OGTT with pasireotide 600 μg sc bid co-administered with four classes of antihyperglycemic drugs (metformin, nateglinide, vildagliptin or liraglutide) or pasireotide alone (n=18 each).

Results: Following OGTT (Phase II study), significant decreases in mean plasma insulin AUC (P<0.001) and increases in mean plasma glucose AUC (P<0.001) were observed during treatment in both dose groups. Following HC, final plasma insulin levels were ~50% those at baseline; decreases in AUC were significant (P<0.001) in both dose groups. Significant decreases (P<0.01) in glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP) AUC were observed. Following HIEC there were no statistically significant changes in basal endogenous glucose production or glucose disposal rate (i.e. insulin sensitivity). The plasma glucose AUC0–4 h on day 7 (Phase I study) decreased by a mean of 2, 10, 15, and 29%, respectively, when pasireotide was co-administered with metformin, nateglinide, vildagliptin and liraglutide, compared with pasireotide alone. Treatment was generally well tolerated in these groups.

Conclusions: Hyperglycemia associated with pasireotide is related to decreases in insulin secretion, with no changes in insulin sensitivity. Pasireotide also significantly decreased incretin hormone response. The mechanism of action of GLP-1 analogues (e.g. liraglutide), DPP-4 inhibitors (e.g. vildagliptin) and insulin secretagogues (e.g. nateglinide) can effectively address the hyperglycemia on pasireotide therapy.

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