Cardiovascular and microvascular outcomes of glucagon-like peptide-1 receptor agonists in type 2 diabetes: a meta-analysis of randomized controlled cardiovascular outcome trials with trial sequential analysis

Abstract

BackgroundEfficacy trials showed that glucagon-like peptide–1 receptor (GLP1R) agonists reduced metabolic risk factors in addition to glucose lowering, but the cardiovascular and microvascular efficacy of this drug class remains to be determined. We aimed to evaluate the overall cardiovascular and microvascular efficacy of GLP1R agonists by performing a meta-analysis with trial sequential analysis.MethodsRandomized controlled, cardiovascular outcomes trials including at least 2000 patient-years’ follow-up and 100 composite cardiovascular events were included. Trial sequential analysis (TSA) was performed and the quality of evidence was graded.ResultsThirty-three thousand four hundred fifty-seven patients and 4105 cardiovascular events from 4 large trials were included. GLP1R agonists were associated with a statistically significant reduction in risks for all-cause mortality (hazard ratio [HR]: 0.88, 95% CI: 0.81 to 0.95; number needed to treat [NNT]: 286 person-years), cardiovascular mortality (HR: 0.87, 95% CI: 0.79 to 0.96; NNT: 412 person-years), stroke (HR: 0.87, 95% CI: 0.76 to 0.98; NNT: 209 person-years) and the composite adverse cardiovascular outcome (MACE; HR: 0.91, 95% CI: 0.85 to 0.96; NNT: 241 person-years). The magnitude of benefit on MACE was attenuated in patients with a history of congestive heart failure (HR: 0.96, 95% CI: 0.85 to 1.08 with; HR: 0.87, 95% CI: 0.77 to 1.00 without). The risks for hospitalization for heart failure and myocardial infarction were not significantly different. The quality of the evidence was deemed as moderate to high based on GRADE approach. TSA provided firm evidence for a 10% reduction in all-cause mortality, a 15% reduction in MACE, and lack of a 15% reduction in hospitalization for heart failure, but evidence remains inconclusive for cardiovascular mortality and myocardial infarction. GLP1R agonists numerically reduced the rates for nephropathy but the risk for retinopathy was similar.ConclusionsMeta-analysis with trial sequential analysis suggested that GLP1R agonists significantly reduced the risk for all-cause mortality and composite cardiovascular outcomes, but the reduction of cardiovascular mortality remains to be confirmed.Electronic supplementary materialThe online version of this article (10.1186/s40360-018-0246-x) contains supplementary material, which is available to authorized users.

New hypoglycemic agents and the kidney: what do the major trials tell us?

“…Meta-analysis of these studies has demonstrated a reduction in risk of all-cause mortality (HR 0.88 [95% CI 0.81, 0.95]), cardiovascular mortality (HR 0.87 [95% CI 0.79, 0.96]), and major adverse cardiovascular events (HR 0.90 [95% CI 0.82, 0.99]) 17 . Favorable reductions in HbA1c (–0.57% [95% CI –0.74, –0.40]), body weight (–2.25 kg [95% CI –3.09, –1.41]), and systolic blood pressure (–1.33 mmHg [95% CI –1.80, –0.86]) were also reported in a separate meta-analysis 18 . In addition to these metabolic benefits, previous studies suggest that GLP-1 receptor agonists have complex intra-renal effects, including natriuresis and afferent arteriolar vasodilation 12 .…”

Cardiovascular outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes mellitus: A systematic review and meta-analysis

“…6 and Zhang et al. 17 showed a reduction in the composite adverse cardiovascular outcome. We propose that the significant difference detected by our analysis is likely to be due to the increased power from the inclusion of additional newer RCTs.…”

“…11–13 Prior meta-analyses evaluating the effect of GLP1RAs on cardiovascular outcomes have shown a statistically significant reduction in all-cause mortality and cardiovascular mortality, while most of these studies showed no significant reduction in non-fatal myocardial infarction (MI) or the rate of hospitalization for heart failure. 14–17 The last reported meta-analysis showed a significant difference in mortality, major adverse cardiac events (MACE) but did not perform a per patient-year analysis to account for the variation in study duration between RCTs, which ranged from 17 to 64 months. 18 It is also unclear if the cardiovascular benefits of GLP1RAs extend to DM patients with chronic kidney disease (CKD).…”

CVOTs: What did the endocrinologist learn?

“…According to the large meta-analysis including data from five CVOTs, GLP-1RA treatment is associated with a favourable effect on albuminuria progression [20]. Some trials had also reported a reduction risk for composite outcome combining macroalbuminuria and decline kidney function parameters but this result was mainly driven by the benefit on albuminuria [23,24]. Thus, CVOTs pointed out positive signals for GLP-1RAs at early stages of diabetic nephropathy, with a class effect.…”