Interim analysis of the effects of exenatide treatment on A1C, weight and cardiovascular risk factors over 82 weeks in 314 overweight patients with type 2 diabetes

Abstract

Aim: Exenatide, an incretin mimetic for the adjunct treatment of type 2 diabetes (DM2), reduced A1C and weight in 30-week placebo-controlled trials. This analysis examined the effects of exenatide on glycaemic control and weight over an 82-week period in patients with DM2 unable to achieve adequate glycaemic control with sulphonylurea (SU) and/or metformin (MET). [À0.9 AE 0.1% (mean AE SE)] was sustained to week 82 (À1.1 AE 0.1%), with 48% of patients achieving A1C 7% at week 82. At week 30, exenatide reduced body weight (a secondary endpoint) from baseline (À2.1 AE 0.2 kg), with progressive reduction at week 82 (À4.4 AE 0.3 kg). Similar results were observed for the intent-to-treat population (n ¼ 551), with reductions in A1C and weight at week 82 of À0.8 AE 0.1% and À3.5 AE 0.2 kg respectively. The 82-week completer cohort showed statistically significant improvement in some cardiovascular risk factors. The most frequent adverse events were generally mild-to-moderate nausea and hypoglycaemia. Conclusion: In summary, 82 weeks of adjunctive exenatide treatment in patients with DM2 treated with SU and/or MET resulted in sustained reduction in A1C and progressive reduction in weight, as well as improvement in some cardiovascular risk factors.

Mechanisms of action of glucagon-like peptide 1 in the pancreas

“…Furthermore, in subjects with T2DM, twice-daily subcutaneous injections of Ex-4 (daily dose 12 to 96 pmol/kg) for 1 month reduced post-prandial glucose levels and stimulated insulin secretion, leading to a reduction in HbA 1c from 9.1 % to 8.3 % . Ex-4 is a potent inhibitor of gastric emptying and it causes a progressive decline in weight in subjects that have been followed out to 82 weeks (Blonde et al, 2006;Buse et al, 2004;DeFronzo et al, 2005;Kendall et al, 2005). Attempts to develop DPP-1V-resistant GLP-1 analogs are well under way but none are yet approved by regulatory agencies for long-term use (see Table 5).…”

Genetic variation inGlp1rexpression influences the rate of gastric emptying in mice

“…With regard to GLP-1, its ability to stimulate glucose-dependent insulin secretion has led to the development of therapeutic agents to treat Type 2 diabetes. For example, pharmacological activation of the GLP-1R with exenatide reduces body weight and improves glycemic control in diabetes, yet there is a gradation in the clinical response (4). Similarly, some patients treated with GLP-1R agonists experience nausea; however, the relation between the presence of nausea and the degree of inhibition of gastric emptying following these drugs remains poorly understood.…”

The nucleus tractus solitarius: a portal for visceral afferent signal processing, energy status assessment and integration of their combined effects on food intake

“…Further support for the contribution of GI signals and their CNS-mediated effects to the physiological control of energy balance comes from the recent success of the GLP-1 analog, exendin-4 (Ex-4), a modified peptidaseresistant GLP-1 analog, in the treatment of type 2 diabetes and from the indications that this treatment also results in body weight loss. 4,5 This paper focuses on CNS neurons that mediate the intake-reducing effects that arise from the action of nutrients on the GI tract. Ligand activation of glucagonlike peptide-1 receptors (GLP-1R) in the abdomen serves as a model.…”