SGLT2 Inhibitors Show Success Against HFpEF in New UK Study

This new investigation into the use of sodium-glucose co-transporter 2 (SGLT2) inhibitors for heart failure shows significant benefit in persons with heart failure with preserved ejection fraction (HFpEF).

Using statistical modeling, a new investigation of sodium-glucose co-transporter 2 (SGLT2) inhibitors—the class of medication originally developed for patients with diabetes—from the United Kingdom shows these pharmacotherapeutic agents may benefit patients with heart failure with preserved ejection fraction (HFpEF).

With EMPEROR-Preserved results previously showing benefit for this subtype of heart failure, the study authors thought the time was optimal to conduct a new meta-analysis of data on SGLT2 use in HFpEF. Their findings appear today in ESC Heart Failure.

With a date range of inception to August 27, 2021, the team used SGLT2, sodium-glucose cotransporter-2 inhibitors, canagliflozin, dapagliflozin, empagliflozin, or ertugliflozin and heart failure for searches of PubMed, Embase, Cochrane, and Web of Science. Five studies (EMPEROR-Preserved, VERTIS CV, DECLARE-TIMI 58, SOLOIST-WHF, SCORED) of 9726 patients (n = 5046 who received SGLT2 inhibitors; n = 4680 who received a placebo) were included in the final analysis. All had at least 6 months of follow-up.

“For many years there was not a single medicine that could improve the outcome in patients with heart failure with preserved ejection fraction, as every medicine tested showed no benefit,” said lead investigator Vassilios S. Vassiliou MBBS, PhD, University of East Anglia Norwich Medical School, in a statement. “Previous studies had shown that SGLT2 inhibitors would be beneficial in heart failure with reduced ejection fraction. But we found they can also help heart failure patients with preserved ejection fraction.”

For their primary outcome of cardiovascular (CV) death and hospitalization for heart failure (HHF), this new analysis shows an overall 22% reduction (HR, 0.78; 95% CI, 0.69-0.87; I2, 0%) in CV death or HHF among patients who received SGLT2 inhibitors compared with placebo. The rate for HHF alone dropped 29% (HR, 0.71; 95% CI, 0.61-0.84; I2, 0%).

However, no significant between-group differences were seen for either CV death (HR, 1.01; 95% CI, 0.80-1.28; I2, 23%) or all-cause mortality (HR, 1.01; 95% CI, 0.89-1.14; I2, 0%).

A subanalysis of data on patients with left ventricular ejection fraction (LVEF) above 50%, because “some studies included patients with LVEF 40%-50%, not fulfilling the definition of HFpEF according to the recent ESC Heart Failure guidelines,” reiterated the investigators’ findings. SGLT2 inhibitors again showed benefit toward a reduction in CV death or HF, for a 23% drop in this outcome (HR, 0.77; 95% CI, 0.66-0.91; I2, 22%), which “remained significant even after sensitivity analysis removing each study sequentially,” the authors wrote.

Noting the challenges that accompany HFpEF—high morbidity and mortality rates, diagnostic and treatment difficulties—they add that SGLT2 inhibitors appear to have benefit for this subtype of heart failure because of the class’ favorable cardiometabolic profile on HFpEF’s complex pathophysiological mechanisms and because the cardioprotective effects are independent of diabetes status. “Therefore their effect is applicable to patients without diabetes,” the authors noted.

Yet, they add, challenges remain for several reasons. Despite reductions in CV death and HHF among patients with an LVEF of 40% to 50% following treatment with SGLT2 inhibitors, overall mortality did not improve. In addition, the benefits were lessened among individuals with an LVEF above 50%.

“In order to draw robust conclusions safely regarding these efficacy outcomes, further large trials need to evaluate the effect of the SGLT2 inhibitors in a sufficient number of patients with HFpEF,” the authors determined. “The journey for an optimal and effective medication for HFpEF still continues.”


Tsampasian V, Elghazaly H, Chattopadhyay R, et al. Sodium glucose co-transporter 2 (SGLT2) inhibitors in heart failure with preserved ejection fraction: a systematic review and meta-analysis. ESC Heart Fail. Published online November 30, 2021.

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