Meta-Analysis of Incretin Agents Suggests Modest Efficacy in Type 2 Diabetes

July 11, 2007 — In type 2 diabetes mellitus, agents that enhance the incretin effect appear to be modestly effective and favorable with respect to weight change, according to the findings of ameta-analysis published in the July 11 issue of the Journal of the American Medical Association.
To date, 2 incretin-enhancing therapies, exenatide and sitagliptin, have been approved by the US Food and Drug Administration for the adjunctive treatment of type 2 diabetes mellitus. The first agent to be approved was exenatide, an injectable glucagonlike peptide 1 (GLP-1) analogue resistant to degradation by the enzyme dipeptidyl peptidase 4 (DPP4). The other agent, sitagliptin, is an oral agent that inhibits the GLP-1–destroying actions of DPP4. Other incretin-based agents, including liraglutide and vildagliptin, are in late-stage development. The incretin pathway promotes insulin release and appears to be impaired in type 2 diabetes mellitus.
Renee E. Amori, MD, and colleagues from the Tufts-New England Medical Center in Boston, Massachusetts, assessed the efficacy and safety of incretin-based therapy in nonpregnant adults with type 2 diabetes mellitus. The researchers searched several sources including MEDLINE and the Cochrane Central Register of Controlled Trials for English-language randomized controlled trials investigating incretin agents.
A total of 29 randomized controlled trials met the inclusion criteria. The trials were all at least 12 weeks in duration and compared incretin therapy with placebo or other treatments of diabetes mellitus and reported hemoglobin A1c (HbA1c) data.
With respect to long-term glucose control, incretin therapy was at least noninferior to other hypoglycemic agents. Incretins modestly lowered HbA1c level compared with placebo, with a weighted mean difference for GLP-1 analogues of -0.97% (95% confidence interval [CI], -1.13% to -0.81%) and -0.74% (95% CI, -0.85% to -0.62%) for DPP4 inhibitors.
According to the researchers, the modest effectiveness observed for incretin therapy may have partly resulted from participants' relatively low baseline HbA1c level (about 8%) compared with older trials in which baseline HbA1c level was often in the range of 9% to 10%.
They also found that the magnitude of the reduction in HbA1c level with incretin therapy was dependent on the baseline HbA1c level, such that greater declines were observed among patients with higher baseline HbA1c levels.
Notably, the weight-loss effects with incretin therapy were neutral to favorable, whereas nearly all other available hypoglycemic agents cause weight gain. The GLP-1 analogues resulted in a weight loss of 1.4 and 4.8 kg vs placebo and insulin, respectively, and DPP4 inhibitors were weight neutral. Weight loss with the agents was continuous and did not appear to plateau during the studies.
"The weight loss may, in part, be due to nausea; however, nausea decreased over the course of the trials and participants who did not report any nausea also had weight loss," the authors note.
In addition, incretin therapy decreased both fasting and postprandial glycemia, especially postprandial glycemic excursions, a finding that "addresses an important limitation of currently available pharmacologic therapies," the authors point out.
Adverse effects of GLP-1 analogues were mostly gastrointestinal: risk ratio (RR), 2.9 (95% CI, 2.0 - 4.2) for nausea and 3.2 (95% CI, 2.5 - 4.4) for vomiting. By contrast, DPP4 inhibitors were associated with an increased risk for infection (RR, 1.2 [95% CI, 1.0 - 1.4] for nasopharyngitis and 1.5 [95% CI, 1.0 - 2.2) for urinary tract infection) and headache (RR, 1.4 [95% CI, 1.1 - 1.7]). Of the 29 trials, 26 trials were 30 weeks or less in duration; therefore, long-term efficacy and safety could not be determined.
"Individuals with mild diabetes, suggesting an adequate pancreatic β cell reserve, who are at risk of hypoglycemic sequelae and in need of weight loss may benefit from this new class," Dr. Amori and colleagues conclude. "However, these new classes of hypoglycemic agents will need continued evaluation both in long-term efficacy and safety controlled trials and in clinical practice to assess their effectiveness and safety profile to determine their role among the many available and well-established therapies for type 2 diabetes."
JAMA. 2007;298:194-206.