For the Treatment of HFpEF, are SGLT2is continuing to DELIVER?
For the Treatment of HFpEF, are SGLT2is continuing to DELIVER?
Erin Salo, PharmD
CentraCare - Paynesville
Background: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) seem to be all the rage right now. They have become a mainstay in the management of type 2 diabetes and are now a pillar of treatment for heart failure with a reduced ejection fraction (HFrEF), classified as having an ejection fraction (EF) ≤40%. SGLT2is have been shown to reduce heart failure (HF) progression in patients with type 2 diabetes and HFrEF, and recent studies suggest they may provide some benefit for patients with HF with a preserved ejection fraction (HFpEF).
Prior to the 2022 AHA/ACC/HFSA guidelines there were little to no guideline-directed medication therapies for the treatment of HFpEF. Roughly 50% of HF cases are HFpEF, and commonly these patients are older adults. Patients with HF, regardless of EF, are at risk of greater mortality compared to patients who do not have HF. With few treatment recommendations for half of HF patients, some recent studies bring both excitement and suspicion to the treatment of HFpEF.
Evidence & Discussion: The 2022 AHA/ACC/HF Guideline for the Management of Heart Failure is the newest reference for the treatment of HF. HFpEF in this guideline is defined as having an EF ≥50%. This guideline provides 2a and 2b recommendations, representing moderate and weak strengths of recommendation respectively, for all medication treatment options for HFpEF. Angiotensin receptor/neprilysin inhibitors (ARNis) and mineralocorticoid receptor antagonists (MRAs) are now considered a 2b treatment recommendation with SGLT2is securing a 2a recommendation. Previous guideline renditions contained primarily recommendations for only management of other conditions that can affect HF such as hypertension, this revision provides broadened recommendations for treating HF more directly.
The trial that played a primary role in SGLT2is receiving the 2a recommendation was the 2021 EMPEROR-Preserved trial. This trial concluded that the SGLT2i, empagliflozin 10 mg daily, reduced the combined risk of cardiovascular death or HF hospitalization regardless of the presence or absence of diabetes for patients with symptomatic HFpEF (EF>40%) (hazard ratio, 0.79; 95% CI, 0.69 to 0.90; P<0.001). However, the study did not find a significant difference in cardiovascular mortality between placebo or empagliflozin (hazard ratio, 0.91; 95% CI, 0.766 to 1.09). A subgroup analysis of EMPEROR-Preserved noted more favorable outcomes for patients with a EF<50% (hazard ratio 0.71; 95% CI, 0.57 to 0.88) and EF ≥50% to <60% (hazard ratio 0.80; 95% CI, 0.64 to 0.99).
In 2022 the DELIVER trial was published. This trial looked at the SGLT2i, dapagliflozin 10 mg daily, and its effectiveness in treating patients with preserved EF or mildly reduced EF. Like EMPEROR-Preserved, DELIVER reached its primary outcome and concluded that dapagliflozin reduced the composite risk of cardiovascular death and worsening HF (hazard ratio 0.82; 95% CI, 0.73 to 0.92). Unlike EMPEROR-Preserved, DELIVER did not find any significant heterogeneity in benefit for dapagliflozin based on EF subgroup analysis.
A prespecified analysis looking at safety and efficacy with regard to frailty of patients in the DELIVER trial was also published in 2022. As a large portion of patients with HFpEF are older and frailty is common among patients with HF, these are patients whom providers may be hesitant to start on new medications. This analysis found increasing frailty was associated with worse outcomes. However, it also found greater improvement with dapagliflozin in patients with a larger degree of frailty. Older patients may not always receive the newest therapy options, but with evidence for improvements in symptoms and quality of life near the end of life, SGLT2is are becoming an appealing option.
Clinical Impact: Both empagliflozin and dapagliflozin have been shown to reduce HF hospitalizations with promising safety profiles. However, neither therapy has been shown to decrease mortality for patients with HFpEF. The decision to treat HFpEF with a SGLT2i is highly patient specific involving a variety of factors including EF and comorbidities. SGLT2is provide a promising treatment avenue for patients with HFpEF who otherwise have few treatment options.
References:
- Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022;145:e895–e1032.
- Anker SD, Butler G, Gilippatos JP, et al. Empagliflozin in heart failure with a preserved ejection fraction. NEJM. 2021;385:1451-1461.
- Solomon SD, McMurray JJV, Claggett, et al. Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction. NEJM. 2022;387:1089-1898.
- Butt JH, Jhund PS, Belohlávek J, et al. Efficacy and safety of dapagliflozin according to frailty in patients with heart failure: a prespecified analysis of the DELIVER trial. Circulation. 2022; 146:1210-1224.