Cardiovascular Risk Associated With SGLT-2 Inhibitors

Study Questions:

What are the cardiovascular (CV) outcomes in patients initiated on sodium-glucose cotransporter-2 inhibitors (SGLT-2i) versus other glucose-lowering drugs (oGLD) across six countries in the Asia Pacific, the Middle East, and North America?


The CVD-REAL 2 study investigators identified new users of SGLT-2i and oGLD via claims, medical records, and national registries in South Korea, Japan, Singapore, Israel, Australia, and Canada. Propensity scores for SGLT-2i initiation were developed in each country, with 1:1 matching. Hazard ratios (HRs) for death, hospitalization for heart failure (HHF), death or HHF, myocardial infarction (MI), and stroke were assessed by country and pooled using weighted meta-analysis.


After propensity-matching, there were 235,064 episodes of treatment initiation in each group; approximately 27% had established CV disease (CVD). Patient characteristics were well-balanced between groups. Dapagliflozin, empagliflozin, ipragliflozin, canagliflozin, tofogliflozin, and luseogliflozin accounted for 75%, 9%, 8%, 4%, 3%, and 1% of exposure time in the SGLT-2i group, respectively. Use of SGLT-2i versus oGLDs was associated with a lower risk of death (hazard ratio [HR], 0.51; 95% confidence interval [CI], 0.37-0.70; p < 0.001), HHF (HR, 0.64; 95% CI, 0.50–0.82; p = 0.001), death or HHF (HR, 0.60; 95% CI, 0.47–0.76; p < 0.001), MI (HR, 0.81; 95% CI, 0.74–0.88; p < 0.001), and stroke (HR, 0.68; 95% CI, 0.55–0.84; p < 0.001). Results were directionally consistent both across countries and patient subgroups, including those with and without CVD.


The authors concluded that initiation of SGLT-2i was associated with a lower risk of CV events, across a broad range of outcomes and patient characteristics.


This international study reports that initiation of SGLT-2i, as compared with oGLDs, was associated with significantly lower risk of all-cause death, HF events, as well as MI and stroke. Furthermore, the results were also consistent across various patient subgroups, including those with and without established CVD. These findings suggest that CV benefits of SGLT-2i may extend both across various patient ethnic and racial backgrounds, as well as across the CV risk continuum, and is likely a class effect. These findings, if confirmed in the ongoing DECLARE-TIMI 58 trial, will have substantial implications for optimal diabetes therapy.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Lipid Metabolism, Acute Heart Failure

Keywords: Diabetes Mellitus, Glucose, Heart Failure, Medical Records, Metabolic Syndrome X, Myocardial Infarction, Myocardial Ischemia, Primary Prevention, Sodium-Glucose Transport Proteins, Sodium-Glucose Transporter 2, Stroke, Vascular Diseases

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