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Small Differences in GLP-1 Agonists Identified

Differences in four GLP-1 receptor agonists are noted, such as reductions in HbA1c, but are better studies needed to get a meaningful comparison?

A meta-analysis looking at once-weekly glucagon-like peptide (GLP)-1 receptor agonists has identified several differences in outcomes and safety associated with the type 2 diabetes (T2DM) treatments.1

Specifically, Franceso Zaccardi, MD, and colleagues reported in Annals of Internal Medicine that compared with other once-weekly GLP-1 receptor agonists, dulaglutide 1.5 mg, once-weekly exenatide and taspoglutide 20 mg – which has been withdrawn from the market – had the greatest reductions in HbA1c, fasting plasma glucose, and body weight.

According to the authors there are currently no head-to-head trials comparing the safety and efficacy of once-weekly GLP-1 receptor agonists. Therefore, they conducted this meta-analysis to summarize available evidence of the efficacy of these drugs in patients with T2DM. They identified 34 trials of once-weekly GLP-1 receptor agonists for use in the review.

Results of the review showed that all of the once-weekly GLP-1 receptor agonists reviewed – albiglutide, dulaglutide, once-weekly exenatide, semaglutide, and taspoglutide – reduced HbA1c and fasting plasma glucose compared with placebo. In addition, dulaglutide 1.5 mg, once-weekly exenatide, and taspoglutide 20 mg also reduced body weight.

Looking at safety endpoints, the researchers found no clinically meaningful differences between the drugs for blood pressure, blood lipid levels, and C-reactive protein levels. In addition, the risk for hypoglycemia was similar between all of the drugs. However, taspoglutide 20 mg was found to have a significantly increased risk for nausea among the drugs examined, with an 8.3-fold increased risk.

In an editorial that accompanied the review, Victor M. Montori, MD, from the Mayo Clinic, Rochester, MN, discussed the growing number of treatment options available to patients with T2DM and how these choices can make it difficult to select the best treatment for a patient.2 Making the appropriate decision on treatment will require high-quality evidence, he wrote. However, the meta-analysis by Zaccardi and colleagues highlights that this evidence may still be lacking.

“They found these trials to have inadequate blinding (which could affect co-interventions that may affect hemoglobin A1c level and weight outcomes) and substantial loss to follow-up,” Montori wrote. “The estimates for each direct, indirect, and network comparison and their quality ratings were not reported separately and hindered appraisal. Data on outcomes of importance to patients, including quality of life, treatment burden, and morbidity and mortality, were sparse or nonexistent.”

“The triumph of innovation will be a triumph for patients only when patients and clinicians have high quality evidence of the comparative effectiveness of various treatment options. . . Zaccardi and colleagues' network meta-analysis shows that meeting this basic standard in diabetes care remains, frustratingly and unfairly, a work in progress,” Montori wrote.

The primary source of funding for the meta-analysis was Sanofi Aventis.



1. Zaccardi F, et al. Benefits and harms of once-weekly glucagon-like peptide-1 receptor agonist treatments: a systematic review and network meta-analysis. Ann Intern Med.2015;epub ahead of print.

2. Montori VM, Rodriquez-Gutierrez R. The triumph of innovation and the hard work of caring for patients with diabetes. Ann Intern Med. 2015;epub ahead of print.