Lack of effect of LAF237 on C-peptide clearance in patients with type 2 diabetes

Abstract

Background LAF237 is potent DPP-4 inhibitor and under development as an oral anti-diabetic agent. It is expected to stimulate glucose-dependent insulin secretion. Deconvolution of C-peptide (C-Pep) levels is used to estimate insulin secretion rates (ISR).1 The objective of the present work was to assess the effect of LAF237 on C-pep clearance (CL) in patients with type 2 diabetes (T2D). Methods In a randomized placebo-controlled study, 20 patients with T2D received either LAF237 (100 mg bid, n=9) or placebo (PBO n=11) for 28 days. Blood samples were collected for measuring C-pep, insulin, glucose and other variables. The present work focuses on C-pep levels and DPP-4 activity. The endogenous C-pep levels were measured for 24 hr before and after in both groups. DPP-4 activity was measured 2 hr after each dose. Results DPP-4 activity was inhibited 98 and 97% 2 hr after morning and evening doses. C-pep levels vs. time over 24 hr on day-1 (predose) and day1 were superimposible. AUCs for C-pep were 48.3±18.1 and 47.0±15.6 nM.hr for the LAF237 group on days -1 and 1, respectively (p=0.783). When comparing the C-pep AUCs in patients treated with LAF237 to PBO on day 1, no difference was observed either (p=0.54). Conclusions DPP-4 activity was completely inhibited by LAF237. C-pep levels remained unchanged after a single day treatment with LAF237. LAF237 did not alter C-pep CL, supporting the use of C-pep levels to estimate ISR during LAF237 treatment. Clinical Pharmacology & Therapeutics (2005) 77, P56–P56; doi: 10.1016/j.clpt.2004.12.105