HFpEF Management Update: SGLT2 Inhibitors

Written by Debra L. Beck, MSc, and Angela Ryan Lee, MD, FACC 

New data presented at the European Society of Cardiology Congress in August in Barcelona, went far to strengthen the case for using SGLT2 inhibitors in patients with heart failure with mildly reduced or preserved ejection fraction (HFmrEF or HFpEF).

The DELIVER trial randomly assigned 6,263 patients (mean age, 72 years, 44% women) with symptomatic heart failure with an ejection fraction of greater than 40% to dapagliflozin 10 mg once daily or placebo. The trial was conducted at 353 sites in 20 countries.

 The average left ventricular ejection fraction (LVEF) was 54%, and 18% of patients previously had an ejection fraction of 40% or less.

Over a median of 2.3 years, the primary outcome of cardiovascular death or worsening heart failure occurred in 16.4% of the dapagliflozin group and in 19.5% of the placebo group (hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.73-0.92; p<0.001).

Looking at the components of the primary endpoint individually, worsening heart failure was significantly reduced (11.8% vs. 14.5%; HR, 0.79, 95% CI, 0.69-0.91), but cardiovascular death was not (7.4% and 8.3%, respectively; HR, 0.88; 95% CI, 0.74–1.05). LVEF did not influence the observed benefits. 

 Key secondary outcomes were also reduced in dapagliflozin-treated patients, including total heart failure hospitalizations and cardiovascular death (rate ratio 0.77; p<0.001), and total symptom burden, assessed using the Kansas City Cardiomyopathy Questionnaire (mean difference in the KCCQ total symptom score at month 8 among survivors, 2.4 points; 95% CI, 1.5-3.4).

 Also at the ESC, investigators presented a pooled analysis that combined data from DELIVER and EMPEROR-Preserved, a trial that tested the effects of empagliflozin in patients with HFpEF. The analysis, simultaneously published in Lancet, included 12,251 heart failure patients with HFmrEF and HFpEF.  

 SGLT2 inhibitors reduced the risk of the primary outcome of cardiovascular death or hospitalization for heart failure by 20% (HR, 0.80; 95% CI, 0.73-0.87; p<0.001). For the individual components of the composite endpoint, cardiovascular death trended lower with empagliflozin treatment (HR, 0.88; 95% CI, 0.77-1.00; p=0.052) and hospitalization for heart failure was significantly reduced (HR, 0.74; 95% CI, 0.67–0.83; p<0.0001). No significant effect was noted for all-cause death (HR, 0.97; 95% CI, 0.88–1.06; p=0.48). The treatment effects for the composite endpoint were consistent across all subgroups of interest.

Background on HFpEF Management

HFpEF treatment has historically been focused on managing underlying comorbidities like hypertension, diabetes, and obesity, and symptom management of volume overload and atrial fibrillation.

Disappointingly, clinical trials had not shown that well-proven HFrEF therapies held the same promise of mortality benefit in HFpEF. ACE-inhibitors, ARBs, and ARNi have shown some benefit in reducing heart failure hospitalization in HFpEF. These have a class 2b recommendation in the 2022 Heart Failure guidelines, with the added note that they have more benefit in those with ejection fractions on the lower end of the spectrum.

More recently, SGLT2 inhibitors have entered the scene with more promising data for HFpEF. The phase 3 EMPEROR-Preserved trial from 2021 showed in 5,988 patients with NYHA class II to IV symptoms and an EF > 40%, that treatment with once-daily empagliflozin 10 mg on top of guideline-directed HF therapy reduced the relative risk of the composite of cardiovascular death or hospitalization for heart failure by 21% (13.8% vs. 17.1%; HR, 0.79; 95% CI, 0.69-0.90; p<0.001). 

This difference was mainly driven by a 29% lower risk of heart failure hospitalization with empagliflozin (HR, 0.71 (95% CI, 0.60–0.83), with the reduction in cardiovascular death not reaching statistical significance (HR, 0.91; 95% CI, 0.76–1.09). Based on these findings, in February 2022, the U.S. Food and Drug Administration (FDA) approved empagliflozin 10 mg for the reduction of hard outcomes in adults with HFpEF. 

The latest ACC/AHA/HFSA Heart Failure Guideline recommendations from 2022 include a Class 2 recommendation for both SGLT2 inhibitors and ARNI for HFpEF, and are summarized in the table below. To learn more about SGLT2 inhibitors, see the video on practical prescribing tips from endocrinologist Dr. Jeremy Gilbert.

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