Exenatide was the first GLP-1 receptor agonist to reach the market was exenatide which was approved by the U.S. Food and Drug Administration in 2005 and by European Medicines Agency in 2007. Exenatide is a synthetic version of exendin-4, and is resistant to inactivation by DPP-4. Exenatide is primarily cleared in the kidneys by glomerular filtration, and the half-life after subcutaneous injection is approximately 2 to 3 hours. Exenatide therefore has to be administered twice daily to achieve 24 hour pharmacological plasma concentrations.
In the early clinical Diabetes Management for Improving Glucose Outcome (AMIGO) trials the effects of exenatide were investigated in a total of 1,446 randomised patients. Exenatide was given as add-on therapy to metformin, sulphonylurea, or both and these studies reported statistically significant improvement of glycaemic control in the exenatide treatment groups (change of HbA1c of -1.0% (baseline of 8.2%) vs. an increase of approximately 0.2% in the placebo groups) and change in fasting plasma glucose (-0.5 mM vs. an increase of nearly 1 mM in the placebo groups). On average, the weight loss in the three studies comparing exenatide to oral anti-diabetics amounted to 1.6 kg (baseline of 95 kg) in the exenatide-treated patients. Additionally, significant reduction in systolic blood pressure compared with placebo (difference of 2.8 mmHg) or insulin (difference of 3.7 mmHg) have been reported after 6 month of treatment with exenatide. In 2011, a large retrospective database analysis looking at the relative incidence of cardiovascular disease events in patients with type 2 diabetes either treated with exenatide twice-daily (n=39,275) or with other glucose lowering agents (n=381,218) was published. The study reported that treatment with exenatide twice-daily was associated with a significantly lower risk of cardiovascular disease events than treatment with other glucose-lowering agents.
^ Sivertsen J, Rosenmeier J, Holst JJ, Vilsbøll T. The effect of glucagon-like peptide 1 on cardiovascular risk. Nature Reviews. Cardiology [Internet]. 2012 Jan 31 [cited 2012 Mar 6]; Available //www.ncbi.nlm.nih.gov/pubmed/22290234
^ Best JH, Hoogwerf BJ, Herman WH, Pelletier EM, Smith DB, Wenten M, et al. Risk of cardiovascular disease events in patients with type 2 diabetes prescribed the glucagon-like peptide 1 (GLP-1) receptor agonist exenatide twice daily or other glucose-lowering a retrospective analysis of the LifeLink database. Diabetes Care. 2011 Jan;34(1):90–5.