Glucagon-Like Peptide-1 Receptor (GLP-1R) Agonists and Dipeptidyl Peptidase-4 (DPP-4) Inhibitors: How Do They Exert Their Metabolic Actions? Part 7

Incretin Therapy and Type 2 Diabetes Mellitus

Normalization of Diurnal Plasma Glucose Concentrations by Continuous IV GLP-1 Rachman et al demonstrated that continuous infusion of GLP-1 maintained a constant level of hormone in plasma-augmented insulin secretion, inhibited glucagon secretion, and normalized fasting and postprandial glucose levels in study participants with type 2 diabetes mellitus (T2DM).   Rachman J, Barrow BA, Levy JC, et al. Diabetologia. Near-normalisation of diurnal glucose concentrations by continuous administration of glucagon-like peptide-1 (GLP-1) in subjects with NIDDM. 1997;40(2):205-211.

Dose-Response Effectc of Exenatide on Plasma Glucose, Insulin, and Glucagon Concentration in T2DM Dose-response effect of exenatide to stimulate insulin secretion (right), inhibited glucagon secretion (left), and reduced the plasma glucose concentration (middle) in patients with patients. For clarity, the intermediate doses of exenatide (0.05 and 0.1 ng/kg) are not shown on the plasma glucagon and glucose curves.   Kolterman OG, Buse JB, Fineman MS, et al. Synthetic exendin-4 (exenatide) significantly reduces postprandial and fasting plasma glucose in subjects with type 2 diabetes. J Clin Endocrinol Metab. 2003;88(7):3082-3089

Effect of Exenatide on Glycemic Control in Metformin-Treated Type 2 Diabetes Subjects: 336 metformin-treated patients with type 2 diabetes Age: 53±10y; BMI: 34.2±5.9 A1C: 8.2±1.1% Protocol: 4-week placebo run-in 4 weeks of exenatide (5 µg BID) or placebo 26 weeks of exenatide (10 µg BID) or placebo Metformin dose kept constant DeFronzo RA, Ratner RE, Han J, et al. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care. 2005;28(5):1092-1100. DeFronzo RA, et al. Diabetes Care. 2005;28:1092-1100.

Effect of Exenatide on A1C In a double-blind, placebo-controlled study, 30 weeks of exenatide, 5 µg bid and 10 µg bid, reduced A1C by 1.0% and 1.2%, respectively. At week 30, all patients with T2DM were switched to exenatide, 10 mg bid. After 82 weeks of open-label therapy, the reduction in A1C was similar, 1.2% in all groups.

Effect of Exenatide on Body Weight Change in body weight in participants with T2DM treated with placebo and exenatide, 5 µg bid (see footnote in previous slide).

Effect of Exenatide on Postprandial Glucose and Insulin Concentrations Participants with T2DM received a meal tolerance test before and after 30 weeks of treatment with placebo, exenatide 5 µg bid, and exenatide 10 µg bid. Exenatide caused a marked dose-related decline in the postprandial plasma glucose concentration (middle) without change in the plasma insulin response (right). Consequently, the incremental insulin response (I) per incremental glucose response (G) increased dramatically in both exenatide-treated groups. These results demonstrate a potent effect of exenatide to augment insulin secretion.

Change in Weight by Quartile at 82 Weeks Not all participants treated with exenatide lose weight. Approximately one-quarter lose no weight (quartile 4), while one-quarter experience marked weight loss (quartile 1) (11.4 kg). Other participants have intermediate weight loss (quartiles 2 and 3).

Change in A1C as a Function of Change in Weight at 82 Weeks The decrease in A1C in exenatide-treated participants with diabetes is related to the magnitude of the weight loss. In participants who experienced no weight loss, the decline in A1C is 0.7% (quartile IV). This reflects the effect of exenatide to augment insulin secretion, to inhibit glucagon secretion, and to delay gastric emptying. In participants who experienced a large weight loss (quartile I), an additional drop in A1C (0.8%) can be expected secondary to the beneficial effects of weight reduction on glucose homeostasis.

Change in Triglycerides and HDL-C as Function of Weight-Change Quartile at 82 Weeks Exenatide per se has no effect to reduce the plasma triglyceride concentration. However, with progressive weight loss, there was a progressive decline in the group with the greatest weight loss (quartile I). With respect to HDL cholesterol, it appears that exenatide per se may have a modest effect to increase the levels of this lipoprotein (quartile IV). With increasing weight loss, there is a progressive further rise in HDL.