No clear-cut choice among once-weekly GLP-1 receptor agonists

All once-weekly GLP-1 receptor agonists reduced HbA1c and fasting plasma glucose levels, and either no differences or clinically marginal differences were found among the drugs for blood pressure, blood lipid levels, and C-reactive protein levels, according to the systematic review and network meta-analysis.


A systematic review and network meta-analysis comparing once-weekly glucagon-like peptide-1 (GLP-1) receptor agonists for type 2 diabetes found some differences but no clear superiority in cardiometabolic efficacy or adverse effects.

Researchers looked at electronic databases and congress abstracts published from inception through Sept. 26, 2015, and selected randomized, controlled, phase 3 clinical trials that involved at least 24 weeks of follow-up; reported cardiometabolic or safety outcomes; and evaluated albiglutide, dulaglutide, once-weekly exenatide, semaglutide, or taspoglutide. The primary cardiometabolic outcome reported was HbA1c; the secondary outcomes were fasting plasma glucose, body weight, systolic and diastolic blood pressure, heart rate, C-reactive protein level, and blood lipid values. Safety outcomes included the following: documented or symptomatic hypoglycemic events, severe hypoglycemic events, nausea and injection-site reaction events, fatal and nonfatal cardiovascular and cancer events, and all-cause mortality. Trials in patients with chronic kidney disease were excluded. The study results were published online Dec. 8 by Annals of Internal Medicine.

A total of 34 trials involving 21,126 participants were included. The authors found that all once-weekly GLP-1 receptor agonists reduced HbA1c and fasting plasma glucose levels when compared with placebo. Taspoglutide, 20 mg; once-weekly exenatide; and dulaglutide, 1.5 mg, also reduced body weight. When data on each of the drugs were compared, the authors found the greatest differences between dulaglutide, 1.5 mg, and taspoglutide, 10 mg, for HbA1c (−0.4% [95% CI, −0.7% to −0.2%]); between once-weekly exenatide and albiglutide for fasting plasma glucose level (−12.6 mg/dL [95% CI, −19.8 to −3.6 mg/dL]); and between taspoglutide, 20 mg, and dulaglutide, 0.75 mg, for body weight (−1.5 kg [95% CI, −2.2 to −0.8]).

Either no differences or clinically marginal differences were found among the drugs for blood pressure, blood lipid levels, and C-reactive protein levels. Heart rate was increased with once-weekly exenatide versus albiglutide and dulaglutide (1.4 to 3.2 beats/min). All of the once-weekly drugs appeared to have similar risk for hypoglycemia, while taspoglutide, 20 mg, was associated with the greatest risk for nausea.

The study authors noted that they didn't collect data on potential improvements in patient satisfaction, quality of life, or adherence related to once-weekly injections; that data were unavailable for semaglutide; that different definitions of outcomes were used in the studies; and that 73% of the studies used the last-observation-carried-forward imputation method, among other limitations. They concluded, however, that based on their results, different GLP-1 receptor agonists have a similar effect on several cardiometabolic outcomes and some “appreciable differences” in their effects on HbA1c, fasting plasma glucose levels, and body weight. They called for future randomized, controlled trials directly comparing these agents to “help better clarify their comparative tolerability and efficacy” and help inform treatment choice.

The authors of an accompanying editorial said that the growing number of available treatments for type 2 diabetes has made diabetes care more complex. In addition, they noted that selecting a drug from a particular class is often difficult because useful evidence of differences among drugs is not always available, reliable head-to-head comparisons are rare, and marketing claims can cause confusion. “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,” the editorialists wrote, adding that such evidence would help inform patient-clinician discussions and that ideally treatment would be affordable and easily implemented. The current study “shows that meeting this basic standard in diabetes care remains, frustratingly and unfairly, a work in progress,” they concluded.