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Click to add/remove this article to your list of 'My Favorites' Single Doses of the Glucagon Receptor Antagonist LY2409021 Reduce Blood Glucose in Healthy Subjects and Patients with Type 2 Diabetes Mellitus (T2DM)

Year: 2011

Abstract Number: 1004-P


Institutions: Singapore, Singapore, Indianapolis, IN

Results: LY2409021 (LY) is a potent, selective antagonist of the glucagon receptor. In T2DM, glucagon levels are inappropriately elevated and contribute to hyperglycemia. This Phase 1, randomized, double-blind, placebo (PBO)-controlled, crossover study examined the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single escalating doses of LY in healthy subjects (HS; 2.5, 10, 30, 100, 250, and 500 mg LY; N=23 males) and patients with T2DM treated with diet and exercise (T2DM; 75, 200, and 500 mg LY; N=9 [5M and 4F]; fasting blood glucose [FBG] 93.6 to 207.0 mg/dL; HbA1c 5.6 to 8.7%). In each dosing period, serial blood samples were collected for measurement of LY PK and PD and standardized meals were provided. Safety was assessed by medical exams, laboratory tests, vital signs, ECGs, and adverse events (AEs).

PK parameters tmax, t1/2, and apparent clearance (CL/F) were comparable across dose levels and between HS and T2DM, ranging from 4 to 8 h, 50.8 to 58.6 h, and 0.232 to 0.396 L/h, respectively. Plasma exposure of LY increased in proportion to dose in HS and T2DM.

Least squares (LS) mean changes from baseline in FBG vs. PBO ranged from +2.9 to -11.5 mg/dL in HS and from -21.9 to -33.3 mg/dL in T2DM. Across LY dose groups in HS, the mean predinner (10-h post-dose) glucose value appeared 0.11 to 11.4 mg/dL lower than PBO; in T2DM, mean premeal glucose values at lunch (4-h), dinner (10-h), and breakfast (24-h), respectively, appeared from 3.6 to 42.9 mg/dL, 8.4 to 29.8 mg/dL, and 14.0 to 48.5 mg/dL lower than PBO. There were no consistent dose-related changes in postprandial glucose.

In general, LY reduced fasting serum insulin, with significant LS mean changes vs. PBO (p≤.02) observed at higher dose levels (250 and 500 mg in HS at 24-h, and 200 mg [24-h] and 500 mg [48-h] in T2DM).

Notably, hypoglycemia did not occur in HS or T2DM after LY administration. There were no significant changes in laboratory tests, vital signs, or ECGs, and review of AEs indicated LY was generally well tolerated.

This first-in-man study demonstrated clinically significant glucose-lowering by single doses of LY in T2DM.