Twice-daily exenatide added to basal insulin improves glycemic control without excess hypoglycemia or weight gain

Adding twice-daily exenatide injections to (basal) insulin glargine improved glycemic control without increasing the risk for hypoglycemia or weight gain in patients with uncontrolled type 2 diabetes, according to a randomized and placebo-controlled trial.

The complete findings of this trial along with a detailed online appendix can be found on the Annals of Internal Medicine website (http://www.annals.org).

Exenatide, a glucagon-like peptide-1 (GLP-1) analog originally approved by FDA in 2005, supplies biologic activity similar to naturally occurring GLP-1. GLP-1 is rapidly released after meals and is responsible for increasing glucose-dependent insulin secretion, suppressing glucagon secretion, delaying gastric emptying, and decreasing appetite.

Currently, accepted treatment algorithms for type 2 diabetes suggest adding pre-prandial insulin, not a GLP-1 analog, to basal insulin when glucose goals are not being met. 

In this trial, investigators sought to evaluate whether exenatide reduced HbA_1c levels more than placebo in people already receiving insulin glargine. In order to test this hypothesis, 261 patients with type 2 diabetes, HbA_1c level of 7.1% to 10.5%, and who were receiving insulin glargine alone or in combination with metformin, pioglitazone, or both oral agents were randomly assigned to receive exenatide 10-μg injections twice daily or placebo.

After 30 weeks, investigators found that HbA_1c levels decreased by 1.74% in those receiving exenatide and 1.04% in those receiving placebo (between-group difference, -0.69% [95% CI, -0.93% to -0.46%]; P<.001). This was despite less insulin use in the exenatide group compared to placebo (13 U/d vs 20 U/d, between-group difference, -6.5 [95% CI, -12.3 to -0.8]; P=.03).

Moreover, weight decreased by 1.8 kg with exenatide use, but increased by 1.0 kg in the placebo group (between-group difference, -2.7 kg [95% CI, -3.7 to -1.7]; P<.001). No significant differences were seen in the rates of major (0% vs 1%) or minor (25% vs 29%) hypoglycemic events (P>.05 for both) between the 2 treatment strategies. A greater number of exenatide patients withdrew from the trial due to adverse events (13 exenatide vs 1 placebo, P<.01); mostly due to increased rates of gastrointestinal adverse effects or headache.

David M. Nathan, MD, from the Diabetes Center at Massachusetts General Hospital and lead author on the American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) consensus statement on the pharmacologic management of type 2 diabetes remarked in an accompanying editorial, “Because they chose a placebo comparator instead of an active comparator, one can only conclude that exenatide added to insulin decreases HbA_1c levels by about 0.7% (similar to the effect of exenatide in other combination drug studies) when compared with substandard therapy-and at the expense of 2 additional injections per day, very common gastrointestinal side effects, and an estimated additional cost of $3,500 per year.”

However, the authors of this latest trial argued, “Before this study, information on the use of insulin with exenatide was limited to data from small clinical trials and observational analyses.”

Among United States residents 20 years of age or older, 23.5 million or 10.7% are thought to have diabetes mellitus, of which, 90% to 95% have type 2 diabetes.