Sodium-glucose co-transporter 2 inhibitors and cardiovascular outcomes: A systematic review and meta-analysis

Abstract

Background The risks and benefits of sodium-glucose co-transporter 2 (SGLT2) inhibitors on cardiovascular outcomes have not been well established. We pooled evidence from all available clinical trials to assess the cardiovascular effects of this drug. Design A systematic review and meta-analysis of randomised controlled trials. Methods We queried electronic databases (MEDLINE, Scopus, CENTRAL and clinicaltrials.gov) from their inception to July 2017 for published and unpublished placebo controlled trials of SGLT2 inhibitors. Only studies with a follow-up period of at least 24 weeks and reporting at least one cardiovascular outcome were included. Results from trials were presented as odds ratios (ORs) with 95% confidence intervals (CIs) and were pooled using a random-effects model. Results Thirty-five eligible studies (canagliflozin, nine; empagliflozin, eight; dapagliflozin, 18), consisting of 34,987 patients with type 2 diabetes mellitus were included. Pooled results show that SGLT2 inhibitors, when compared to placebo, significantly reduce all-cause mortality (OR 0.79, 95% CI 0.70-0.89; P < 0.001), major adverse cardiac events (OR 0.8, 95% CI 0.76-0.92; P < 0.001), non-fatal myocardial infarction (OR 0.85, 95% CI 0.73-0.98; P = 0.03) and heart failure/hospitalisation for heart failure (OR 0.67, 95% CI 0.59-0.76; P < 0.001) in patients with type 2 diabetes mellitus. No significant difference was noted in the occurrence of stroke (OR 1.02, 95% CI 0.85-1.21; P = 0.87), atrial fibrillation (OR 0.61, 95% CI 0.31-1.19; P = 0.15) or unstable angina (OR 0.95, 95% CI 0.73-1.25; P = 0.73). In addition, there was no heterogeneity between different drugs in the SGLT2 inhibitor class for all of the clinical outcomes studied ( I= 0). Conclusions SGLT2 inhibitors significantly reduce the incidence of mortality, major adverse cardiac events, non-fatal myocardial infarction and heart failure in patients with type 2 diabetes mellitus. Subtypes of SGLT2 inhibitors appear to have similar cardiovascular effects.

Do most patients with obesity or type 2 diabetes, and atrial fibrillation, also have undiagnosed heart failure? A critical conceptual framework for understanding mechanisms and improving diagnosis and treatment

“…[161][162][163][164] Newer glucose-lowering drugs have been evaluated in large-scale trials, but, in most cases, these investigations did not systematically identify AF events and hence the number of captured AF events was too small to allow for meaningful analysis. 165 Nevertheless, it is noteworthy that the risk for AF appears to be numerically reduced by sodium-glucose cotransporter 2 inhibitors, 166 which are known to reduce the mass and inflammation of epicardial adipose tissue [167][168][169][170] and which have been shown to decrease the incidence of HF events, including those caused by HFpEF. 4…”

The importance of dyslipidaemia in the pathogenesis of cardiovascular disease in people with diabetes

“…In absolute terms the benefits reduced CHD events more modestly than blood pressure lowering or low density lipoprotein cholesterol (LDL‐C) reduction. More recently several trials of sodium glucose co‐transporter 2 (SGLT2) inhibitors and glucagon‐like peptide 1 (GLP‐1) agonist have shown significant reductions in cardiovascular events despite achieving about only 1/3 of the difference in HbA1c as earlier studies . In contrast, trials with DDP4 inhibitors which achieved similar reductions in HbA1c have failed to show any cardiovascular benefits .…”

“…More recently several trials of sodium glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 (GLP-1) agonist have shown significant reductions in cardiovascular events despite achieving about only 1/3 of the difference in HbA1c as earlier studies. 30,31 In contrast, trials with DDP4 inhibitors which achieved similar reductions in HbA1c have failed to show any cardiovascular benefits. 32 Taken together these data suggest that it matters how you reduce HbA1c with GLP-1 agonists and SGLT2 inhibitors offering benefits beyond the magnitude of glucose reduction and may be related to pleiotropic effects of these therapies.…”

Increases in circulating levels of ketone bodies and cardiovascular protection with SGLT2 inhibitors: Is low‐grade inflammation the neglected component?

“…However, these trials were not designed to detect an effect on singular endpoints . Later meta‐analyses and real‐world studies involving up to 400 000 patients using SGLT2 inhibitors showed a significant reduction in the rate of myocardial infarction, stroke, heart failure and CV death . Several hypotheses have been formulated to explain these marked cardioprotective effects .…”