As previously reported by heartwire, exenatide is an incretin mimetic, a synthetic version of exendin-4, a hormone found in the saliva of the Gila monster, a lizard native to the Southwest US, that eats only four times a year. Early studies of the drug showed that it works through the GLP-1 receptor but is much more potent and has similar actions to human GLP-1, including stimulation of insulin secretion, slowing of gastric emptying, and inhibition of glucagon production by the alpha cells of the pancreas. Clinical studies of exenatide have shown that it is as effective as insulin glargine in patients who fail to reach blood glucose targets with common oral antidiabetics. While no cardiovascular-outcome studies have been performed with exenatide, the drug also appears to improve several important cardiovascular risk factors, likely due to its effects on body weight.

In DURATION-1, Drucker et al sought to compare a long-acting-release formulation of exenatide (2 mg, injected once weekly) with 10-µg exenatide injected twice per day in 295 patients with type 2 diabetes. Patients could be on either no other antidiabetic drug or one or more oral agents.

At 30 weeks, Drucker et al reported that patients taking the once-a-week regimen had significantly greater changes in HbA_1c than patients taking the twice-a-day regimen; they also were more likely to reach target HbA_1c levels (7.0% or less).

Authors also reported important changes in CVD risk factors. Compared with the twice-a-day regimen, patients receiving the once-per-week injections had greater reductions from baseline in mean total and LDL cholesterol. Both groups experienced similar reductions in triglycerides from baseline, similar reductions in blood pressure, and similar weight loss.

Commenting on the study for heartwire, Drucker emphasized that this is the first once-weekly diabetes therapy to demonstrate beneficial effects on weight loss and blood pressure, with very low risk of hypoglycemia. "This has favorable implications for improvement of cardiometabolic risk," he noted.

Dr John Buse

Likewise, Dr John Buse (University of North Carolina, Chapel Hill), a coauthor on the study who is presenting some of the results tomorrow here at the European Association for the Study of Diabetes 2008 Meeting, told heartwire that while it's too soon to appreciate the long-term effects of exenatide on the heart, at least some of the early signals are promising.

"This is an area where there is a lot of hope that, associated with the weight loss, there will be improvements in cardiovascular risk markers," he said. "Enough hope that many people, including myself, have called for the need for CV-outcomes studies, not because anyone thinks there will be any surprise in terms of safety, but because of all of the therapies we have in diabetes, this is the one that is perhaps most likely to improve CV outcomes. If the major focus or concern was to look at cardiovascular safety, then you would do a noninferiority trial comparing exenatide [with another antidiabetic drug]. But in this case, I think this is drug where it's probably worth doing a superiority trial with cardiovascular end points."

Whether the signal of benefit in terms of lipid and blood-pressure parameters is due completely to weight loss or is directly related to drug effects "has not been sorted out," he added.

In a Comment accompanying the DURATION-1 results [2], Dr Andre J Scheen (University of Liège, Belgium) warns that longer-term data are needed for this new regimen. "Caution is needed as with any new drug developed for the treatment of type 2 diabetes. . . . Many glucose-lowering drugs were withdrawn from the market or their use became controversial despite early positive results. The success of any antidiabetic agent depends on efficacy for glucose control, good tolerance and safety profile, ease of use, cost (unknown for long-acting exenatide), and capacity to reduce complications."

That said, Scheen acknowledged that avoiding twice-daily injections would be a welcome change for diabetes patients. "When the once-a-week exenatide formulation becomes available, after confirmation and extension of today's positive results, this new strategy might substantially change the management of type 2 diabetes," he writes.

Exenatide is already approved for twice-daily injections in the US for use on top of metformin, sulfonylurea, or a thiazolidinedione (TZD) alone, on top of metformin plus sulfonylureas, or on top of metformin plus a TZD. It is not approved for monotherapy.