Physicians' Academy for Cardiovascular Education

Subgroup analyses in GLP1-RA trial meta-analysis to understand the varying outcomes seen with different GLP-1RAs

Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials

Literature - Kristensen SL, Rørth R, Jhund PS et al., - Lancet Diabetes Endocrinol. 2019 DOI:

Introduction and methods

GLP-1 receptor agonists (GLP-1RAs) have been demonstrated to reduce CV risk in patients with type 2 diabetes (T2DM) [1]. This class of drugs lowers HbA1c by stimulating glucose-dependent insulin secretion and by reducing glucagon secretion, gastric emptying and appetite. Moreover, treatment with a GLP-1RA is also associated with modest improvements in lipid levels and lower blood pressure and bodyweight.

Treatment is associated with a low risk of hypoglycemia [2,3]. Various GLP-1RAs have been developed, with different structure and duration of action. The trials in which their effect has been evaluated had varying sizes and were in different patient populations. Effects of these drugs on CV outcomes are not entirely consistent [4-14].

This is a systematic review and meta-analysis of all large, placebo-controlled, CV outcome trials of GLP-1RAs, with the aim to obtain robust estimates of the effects of this class on CV outcomes overall and in specific patients subgroups. Data of ELIXA (lixisenatide), LEADER (liraglutide), SUSTAIN-6 (semaglutide), EXSCEL (exenatide), Harmony Outcomes (albiglutide), REWIND (dulaglutide), and PIONEER 6 (oral semaglutide) were included (in total 56004 patients).

CV outcomes of interest were major adverse CV events (MACE), a composite of CV death, myocardial infarction (MI) and stroke. Moreover, the effects on hospitalization for heart failure (HHF) and death from any cause were studied. Regarding kidney outcomes, worsening of kidney function and a broader composite outcome (new-onset macroalbuminuria, decline in eGFR, progression to end-stage kidney disease, or death attributable to kidney causes) were considered. Severe hypoglycemia, retinopathy, pancreatitis and pancreatic cancer were monitored as key safety outcomes. By lack of individual level data, summary statistics from the included individuals trials were used. Estimated median follow-up was 3.2 years (range: 1.3- 5.4 year).

Main results


This meta-analysis shows a 12% reduction in the risk of MACE, and mostly reflected a lower risk of death from CV causes and of fatal or non-fatal stroke. Several subgroup analyses were performed to address the proposed explanations for the different effects on CV outcomes observed in different GLP-1RA trials. A hint of an interaction between the treatment effect and homology to human GLP-1 was noted, but other pharmacological characteristics or differences in patient populations between the trials did not lead to significant heterogeneity between subgroups.


Show references

Find this article online at Lancet Diabetes Endocrinol.

Share this page with your colleagues and friends: