SAN FRANCISCO — The new incretin mimetic exenatide and the incretin enhancer sitagliptin both have unique properties that need to be taken into account when prescribing them, American Diabetes Association president Dr. John B. Buse said at a meeting sponsored by the association.
Injections of exenatide (Byetta) were approved in 2005 as adjunctive therapy for patients with type 2 diabetes. Orally administered sitagliptin (Januvia) was approved in 2006 for use as monotherapy or in combination with metformin or thiazolidinedione for patients who have type 2 diabetes.
Dr. Buse has received research funds from Amylin Pharmaceuticals and from Eli Lilly & Co., which market exenatide. He is an adviser and speaker for those companies and for Merck & Co., which markets sitagliptin.
Incretin augments glucose-stimulated insulin secretion by intestinally derived peptides. Exenatide and sitagliptin augment the incretin pathway, which appears to be attenuated in type 2 diabetes. The incretin effect is composed mainly of the peptides glucose-dependent insulinotropic polypeptide and glucagonlike peptide-1 (GLP-1), which are normally inactivated by the enzyme dipeptidyl peptidase-4 (DPP-4). Exenatide is a GLP-1 receptor analogue resistant to DPP-4 degradation and slows gastric emptying. Sitaglip- tin selectively inhibits DPP-4, giving the incretin enzymes a longer half-life to enhance their effects.
“We don't have long-term safety and efficacy data” for these medications “as we do with the other four classes of medications for diabetes mellitus,” cautioned Dr. Buse, who discussed several aspects of the use of these drugs.
▸ Combination with insulin. “This is a very exciting combination,” he said, though it has not been adequately studied in clinical trials. Sparse data on five patients treated for 5 days with exenatide and insulin at his institution are buried in a larger study published in 2001, said Dr. Buse, professor of medicine at the University of North Carolina, Chapel Hill. However, he warned against combining exenatide with rapid-acting insulin. “I'd be exceptionally cautious about doing [that].”
▸ Fitting exenatide into the diabetes care algorithm. Experts are wondering whether exenatide might be a reasonable alternative to sulfonylureas or glitazones. Decisions on whether to include exenatide in treatment algorithms will depend “on whether we have data demonstrating its long-term safety and efficacy, and what the effects are on ?-cell biology,” he said.
▸ Rhinorrhea as a side effect of sitagliptin. Studies of sitagliptin persistently show an elevated but low rate of rhinorrhea—around 11%, compared with 7% in placebo groups—and few other side effects. The drug affects chemokine levels, which has raised concerns that the rhinorrhea is “a hint that there are immune effects that we haven't been able to measure yet.” But many drugs are associated with an increased rate of rhinorrhea, so it could be something more benign, he added.
▸ Which patients will respond to these agents. Because exenatide dramatically increases GLP-1 levels, “my guess is that virtually anybody would respond” to it, though it's unclear whether the level of response would justify two injections daily and a cost of around $200 per day, said Dr. Buse. Sitagliptin produces more modest increases in GLP-1 levels, but “I don't know what the effects would be in a patient who has severely impaired β-cell function.”
▸ Their use in bariatric surgery patients. “Part of the benefit of bariatric surgery is you actually increase the levels of GLP-1 and perhaps other incretin hormones, so it's an intriguing notion,” Dr. Buse said. “The concern with exenatide would be the nausea from the surgery plus the nausea from the exenatide maybe getting somebody in a bad place in that regard.”
▸ Effects on gastroparesis patients. The clinical trials excluded patients with chronic, serious GI issues, “so we don't really know” the answer, he said. For some patients whose intermittent “gastroparesis” is a result of overeating that produces bloating and nausea, exenatide may limit their eating and help them feel better, “but you want to be cautious.”