Research in context
Evidence before this study
Glucagon-like peptide-1 (GLP-1) receptor agonists are a class of glucose-lowering drugs used in the treatment of type 2 diabetes. We searched MEDLINE (via PubMed) and the Cochrane Central Register of Controlled Trials for eligible placebo-controlled trials reporting major adverse cardiovascular events (MACE; a composite of cardiovascular death, stroke, or myocardial infarction) up to June 15, 2019. Various drugs in this class with differing structures and durations of action have been studied in randomised, placebo-controlled, cardiovascular outcome trials of varying size and with different patient populations, with inconsistent effects on cardiovascular outcomes reported. Previous meta-analyses of cardiovascular outcome trials have not included some of the more recently reported major trials of drugs within the class.
Added value of this study
Our systematic review and meta-analysis includes data from seven large-scale cardiovascular outcome trials, pooling data for lixisenatide, liraglutide, injectable semaglutide, exenatide, albiglutide, dulaglutide, and oral semaglutide, making it the largest pooled study of the effect of GLP-1 receptor agonists on cardiovascular and kidney outcomes in patients with type 2 diabetes. Furthermore, compared with previous meta-analyses, it includes data for a greater number of patients without established cardiovascular disease and data for two additional drugs (dulaglutide and an oral form of semaglutide). Our results show that treatment with GLP-1 receptor agonists reduced the risk of MACE and its individual components, as well as all-cause mortality, hospital admission for heart failure, and a composite kidney outcome of development of new-onset macroalbuminuria, decline in estimated glomerular filtration rate (or increase in creatinine), progression to end-stage kidney disease, or death attributable to kidney causes. The benefit on MACE was consistent across all but one subgroup (with a suggestion of a possible lesser effect of exendin-4 based compounds), including consistent effects in subgroups defined by history of cardiovascular disease, BMI, age, baseline HbA1c, baseline estimated glomerular filtration rate, trial duration, and treatment dosing interval. The incidence of severe hypoglycaemia, pancreatitis, and pancreatic cancer did not differ between GLP-1 receptor agonist treatment and placebo.
Implications of all the available evidence
The cardioprotective effects of GLP-1 receptor agonists, as well as reductions in the risk of heart failure and worsening kidney function, represent an important treatment opportunity to reduce morbidity and mortality in patients with type 2 diabetes.