SGLT2 Inhibitors Improve Cardiovascular Outcomes Across Groups

Miriam E. Tucker

January 06, 2022

Sodium-glucose cotransporter 2 (SGLT2) inhibitors show "remarkable consistency of class benefit" for improving cardiovascular outcomes in high-risk people across age, sex, and race/ethnicity categories.

The findings, from a meta-analysis of 10 major randomized clinical trials, were published online January 5 in JAMA Network Open by Mukul Bhattarai, MD, a cardiology fellow at the Southern Illinois University School of Medicine, Springfield, Illinois, and colleagues.

"Our meta-analysis evaluated a wide spectrum of efficacy outcomes, further characterizing the primary outcome in different subgroups from several well-designed large clinical trials. It supports that SGLT2 inhibitors have emerged as an effective class of drugs for improving cardiovascular morbidity and mortality, including the prevention of [hospitalization for heart failure] and reducing all-cause mortality in selected patients," Bhattarai and colleagues write.

The cardiovascular outcomes of SGLT2 inhibitor therapy, they note, "can be compared across all trials, and it demonstrates remarkable consistency of class benefit, despite the variations in populations enrolled."

However, they also note that SGLT2 inhibitors did not reduce the risk of acute myocardial infarction overall, and that most of the trials were short term, with a mean follow-up of just 2.3 years.

Ten Trials, Consistent Cardiovascular Benefits

Bhattarai and colleagues searched the literature through January 10, 2021, as well as meeting presentations and other sources. They identified 10 placebo-controlled randomized clinical trials in which participants had atherosclerotic cardiovascular disease (ASCVD) or ASCVD risk factors, diabetes, or heart failure. Among a total of 71,553 high-risk patients, 39,053 received an SGLT2 inhibitor and 32,500 received a placebo.

The primary outcome of cardiovascular death or hospitalization for heart failure occurred in 8.10% randomized to SGLT2 inhibitors compared with 11.56% in the placebo group, a significant difference with odds ratio 0.67 (P < .001). Both individual outcomes were lower in the SGLT2 inhibitor group, with a number needed to treat of 5.7 (P < .001).

Patients receiving SGLT2 inhibitors also had significantly lower rates of major adverse cardiovascular events, defined as death due to cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Those events occurred in 9.82% vs 10.22%, with an odds ratio of 0.90 (P = .03).

Hospitalizations and emergency department visits with heart failure were also reduced with SGLT2 inhibitors (4.37% vs 6.81%; odds ratio, 0.67; P < .001), as was cardiovascular death (4.65% vs 5.14%; odds ratio, 0.87; P = .009). The reduction in heart failure is likely due to a combination of a natriuretic effect and reduced interstitial fluid, along with inhibition of cardiac fibrosis, the authors say.

On the other hand, no reductions were seen in acute myocardial infarction, evaluated in five of the studies. That event occurred in 4.66% taking SGLT2 inhibitors compared with 4.70% of the placebo group, a nonsignificant difference with an odds ratio of 0.95 (P = 0.22). This is likely due to the fact that SGLT2 inhibitors don't have known antianginal properties or vasodilatory effects, they don't reduce myocardial oxygen consumption, and they don't prevent cardiac muscle remodeling, they note.

All-cause mortality was significantly lower with SGLT2 inhibitors, though, at 7.09% vs 7.86% (odds ratio, 0.87; P = .004).

Benefits Seen Across Age, Sex, and Race/Ethnicity Subgroups

While no differences in benefit were found between men and women when compared to placebo groups, the rates of cardiovascular death or heart failure hospitalizations were slightly higher in men than in women (9.01% [odds ratio, 0.75; P < .001] vs 5.34% [0.78; P = .002]).

By age, SGLT2 inhibitors benefited people both those younger than 65 years and those aged 65 years and older, although the primary outcome was slightly lower in the younger group (6.94% [0.79; P < 0.001] vs 10.47% [0.78; P < .001]).

And by race, similar benefits from SGLT2 inhibitors were seen among individuals who were White compared to those who were Asian, Black, or of other race/ethnicity, with event rates of 8.77% (0.82; P < .001) and 8.75% (0.66; P = .06), respectively.

"Owing to the short-term trial durations, future long-term prospective studies and post-marketing surveillance studies are warranted to discover the rate of cardiovascular outcomes," Bhattarai and colleagues conclude.

The authors have no disclosures.

JAMA Netw Open. Published online January 5, 2021. Full text

Miriam E. Tucker is a freelance journalist based in the Washington DC area. She is a regular contributor to Medscape, with other work appearing in the Washington Post, NPR's Shots blog, and Diabetes Forecast magazine. She is on Twitter @MiriamETucker.

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