GLP‐1 receptor agonists for prevention of cardiorenal outcomes in type 2 diabetes: An updated meta‐analysis including the REWIND and PIONEER 6 trials

Abstract

A meta‐analysis of cardiovascular outcome trials (CVOTs) comparing glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) and placebo concerning cardiorenal outcomes in patients with type 2 diabetes (T2D) is presented. An electronic search without language restrictions up to June 15, 2019 was conducted to determine eligible trials. A meta‐analysis of available trial data was undertaken, using a random‐effects model to calculate overall hazard ratios (HRs) and 95% confidence intervals (CIs). Data from seven CVOTs, comprising 56 004 patients (68.9% with established cardiovascular disease) were included. GLP‐1RA reduced major cardiovascular events (MACE) by 13% (HR, 0.87; 95% CI, 0.80–0.96; P = 0.011) with a non‐significant heterogeneity between subgroups of patients with and without cardiovascular disease (CVD) (P = 0.220). GLP‐1RA also reduced the risk of cardiovascular death by 12%, of non‐fatal stroke by 16%, of hospitalization for heart failure by 9%, of all‐cause mortality by 11%, and the broad composite kidney outcome by 17%; the latter appeared to be driven only by a reduction in macroalbuminuria (HR, 0.76 [0.68–0.86]; P = 0.003). GLP‐1RAs have moderate benefits concerning MACE, and also reduce hospitalization for heart failure and all‐cause mortality; they also robustly reduce the incidence of macroalbuminuria, without affecting the progression of diabetic renal disease.

Effects of semaglutide on risk of cardiovascular events across a continuum of cardiovascular risk: combined post hoc analysis of the SUSTAIN and PIONEER trials

“…Our results are consistent overall with a post hoc analysis of pooled SUSTAIN and PIONEER data, which also showed that the effect of semaglutide vs comparators on MACE was largely consistent across different CV subgroups [35]. Furthermore, a meta-analysis including CVOTs for all GLP-1 receptor agonists found no significant heterogeneity in the effect of these therapies in subgroups with a history of CVD vs those with no history of CVD [36]. Although there were no significant subgroup interactions in the meta-analysis, there was a numerically lower risk of MACE in subjects with a history of CVD (−14%, hazard ratio 0.86) vs those without such a history (−6%, hazard ratio 0.94) [36].…”

2019 Update to: Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)

“…Some meta-analyses (5,13,14) suggest the presence of heterogeneity in estimates for MACE and CV death with GLP-1 receptor agonists, although this is mostly due to the results of a single trial with lixisenatide. Likewise, there is some heterogeneity in the estimate for CV death with SGLT2 inhibitors.…”

CVOTs: What did the endocrinologist learn?

“…While a chance effect may not be excluded saxagliptin should be avoided in such patients. Two recent meta-analyses including data from 7 CVOTs showed that GLP-1 RAs afford a 9% relative risk reduction of hHF as compared to placebo [19,20]. This effect is much greater with SGLT-2is which have shown a relative risk reduction of 31% over a similar median duration of follow-up [5] (Table 1).…”