Sodium-Glucose Cotransporter-2 Inhibition Benefits in Cardiorenal Risk in Men and Women

Abstract

Introduction In addition to their antihyperglycemic action, sodium-glucose cotransporter-2 (SGLT2) inhibitors are used in patients with Type 2 Diabetes due to their cardioprotective effects. Meta-analyses of large clinical trials have reported mixed results when examining sex differences in their cardioprotective effects. For example, some studies reported that, compared to women, men had a greater reduction in cardiovascular risk with SGLT2 inhibition. Taking advantage of several recently-completed large-scale randomized controlled clinical trials, we tested the hypothesis that women have an attenuated response in primary cardiorenal outcomes to SGLT2 inhibition compared to men. Methods We performed a systematic search using PubMed and the Cochrane Library to find completed large-scale, prospective, randomized-controlled Phase III clinical trials with primary outcomes testing cardiovascular or renal benefit. Studies had to include at least 1,000 participants and report data about sex differences in their primary cardiovascular or renal outcomes. Results The present meta-analysis confirmed that SGLT2 inhibition decreased adverse cardiorenal outcomes in a pooled sex analysis using 13 large-scale clinical trials. SGLT2 inhibition exhibited similar reduction in hazard ratios for both men (0.79, 95% confidence interval 0.73-0.85) and women (0.78, 95% confidence interval 0.72-0.84) for adverse cardiorenal outcomes. Conclusion In contrast to previous findings, our updated meta-analysis suggests that women and men experience similar cardiorenal benefit in response to SGLT2 inhibition. These findings strongly suggest that SGLT2 inhibition therapy should be considered in patients with high risk for cardiovascular disease irrespective of the patient sex.

Sex Differences in Therapies against Myocardial Ischemia-Reperfusion Injury: From Basic Science to Clinical Perspectives

“…Interestingly, multiple trials showed that SGLT2 inhibitors also decrease MACE in type 2 diabetes patients, however to a far lesser extent in women compared with men [ 185 , 186 ]. However, there are also reports of similar protection against cardiovascular events between the sexes with SGLT2 inhibitor use [ 187 , 188 , 189 , 190 ]. SGLT2 expression patterns may explain the observed sex differences in the clinical setting.…”

“…Additionally, a hormonal upregulation of SGLT2 takes place after puberty in female rats but not in male rats [ 152 , 153 ]. Several trials involving HF patients showed that SGLT2 inhibitors also significantly reduce MACE regardless of diabetic status [ 154 , 188 , 189 ]. However, the exact mechanism by which SGLT2 inhibitors exert these protective effects is yet unclear.…”