A multiplicity of targets: evaluating composite endpoint studies of the GLP-1 receptor agonists in type 2 diabetes

Objective: Current type 2 diabetes (T2D) treatment guidelines include weight maintenance or loss, avoidance of hypoglycemia, and targets for blood pressure and circulating lipids, in addition to glycemic control. Increasingly, clinical trials and meta-analyses employ composite endpoints to capture the net clinical benefit of a given T2D intervention. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) represent a new class of injected antihyperglycemic agents that may be well suited to reaching many of these targets among patients failing on metformin monotherapy. Research designs and methods: Using MEDLINE, Embase and Google Scholar, studies were sought that employed composite endpoints and that reported outcomes with exenatide and/or liraglutide. Bibliographies of relevant review articles were consulted to search for additional reports. Results: Many trials have used the combination of HbA1c<7%, no weight gain and no hypoglycemic episodes as the composite endpoint in evaluating T2D therapies; however, at least 15 other distinct composite endpoints have been reported. Findings were relatively consistent across studies, regardless of how the composite endpoint was defined. Specifically, the GLP-1 RAs appear to be superior to other agents in their efficacy in providing T2D patients failing on metformin with a net clinical benefit, which can include avoidance of hyperglycemia and maintenance or improvement in body weight. Conclusions: Use of composite endpoints represents an important advance in T2D. While no single such endpoint has achieved dominance in the field, widely used composite endpoints capture efficacy in glycemic control as well as safety and effects on markers of cardiovascular risk.