Abstract
BackgroundBesides providing reassurance about cardiovascular (CV) safety of newer diabetes drugs, cardiovascular outcome trials (CVOTs) have also shown encouraging benefits on some CV endpoints. The contribution of the better glycemic control in the reduction of major cardiovascular events (MACE) remains an open question. The aim of this study is to evaluate the associations between the reduction of HbA1c and risk of MACE, MACE components, hospitalization for heart failure (HF) and all-cause death in CVOTs.MethodsAn electronic search up to July 2021 was conducted to determine eligible trials. Systematic review identified eighteen CVOTs reporting prespecified CV outcomes. Pooled summary estimates and 95% confidence intervals (CI) were calculated according to the random effects model using the Paule-Mandel method; restricted maximum likelihood estimators were used to estimate model parameters in the metaregression.ResultsThe eighteen CVOTs evaluated 161,156 patients and included four trials with dipeptidyl-peptidase-4 inhibitors (DPP-4i), eight trials with glucagon-like peptide-1 receptor agonists (GLP-1RA) and six trials with sodium-glucose cotransporter-2 inhibitors (SGLT-2i). Random-effects model meta-analysis showed an association between treatment and risk of MACE (hazard ratio [HR] 0.90; 95% CI 0.86, 0.94, P < 0.001), with significant heterogeneity between studies (I2 = 45.2%, Q statistic P = 0.040). In meta-regression, there was an association between the reduction in HbA1c at the end of the trial and the HR reduction for MACE (beta = − 0.298, P = 0.007), with significant heterogeneity (I2 = 40%, Q statistic P = 0.04); this association was totally driven by the risk reduction of non-fatal stroke, which explained 100% of between-study variance (beta = − 0.531, R2 = 100%), without heterogeneity (I2 = 24%, Q statistic P = 0.206). There was no association between the reduction in HbA1c and the HR for heart failure or all-cause death.ConclusionsThe reduction of HbA1c in eighteen CVOTs was significantly associated with reduction of non-fatal stroke, explaining all (R2 = 100%) of the between-study variance. While the contribution of glucose lowering in some CV benefits of newer agents does not influence their indications for the patient with type 2 diabetes, it may hopefully facilitate their use.
Highlights
All the dedicated cardiovascular outcome trials (CVOTs), designed to ensure cardiovascular (CV) safety of the newer glucose-lowering drugs, have provided reassurance about their overall CV safety, and have shown some encouraging benefits on CV endpoints
The results of the meta-regression analysis of the 18 CVOTs in 161,156 patients with type 2 diabetes show that the reduction of HbA1c during treatment with dipeptidyl-peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 receptor agonists (GLP-1RA) or sodium-glucose cotrasporter-2 inhibitors (SGLT-2i) is associated with reduction of major cardiovascular events (MACE), explaining almost all (R2 = 97%) of the between-study variance
In the pooled analysis of the 18 CVOTs, we found a 10% reduction of MACE risk in patients treated with the newer antihyperglycemic drugs, which remained significant for GLP-1RA and SGLT-2i (14% and 11% risk reduction, respectively), and was null for DPP-4i
Summary
All the dedicated cardiovascular outcome trials (CVOTs), designed to ensure cardiovascular (CV) safety of the newer glucose-lowering drugs, have provided reassurance about their overall CV safety, and have shown some encouraging benefits on CV endpoints. In some CVOTs, the imbalance of glycemic control between groups was equal to or greater than that obtained in the UKPDS 34 study [9], the first trial of intensive glycemic control to explore the supposed beneficial effects of near normal hyperglycemia. This imbalance may have masked potential benefits of the glycemic control per se on the CV endpoint. The aim of this study is to evaluate the associations between the reduction of HbA1c and risk of MACE, MACE components, hospitalization for heart failure (HF) and all-cause death in CVOTs
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