Is Empagliflozin Safe and Effective for Patients with HFrEF and Low Blood Pressure?

The interaction between systolic blood pressure (SBP) and the effects of empagliflozin in patients with heart failure with reduced ejection fraction (HFrEF).

Empagliflozin is a sodium-glucose cotransporter-2 (SGLT-2) inhibitor approved to treat type 2 diabetes and reduce the risk of cardiovascular mortality plus hospitalization for heart failure in adults with heart failure with reduced ejection fraction. Previous clinical trials, such as the PARADIGM-HF and DAPA-HF trials, showed an inverse relationship between blood pressure and risk for severe heart failure complications. Nevertheless, low blood pressure is a factor that prevents many patients with HFrEF from therapy optimization. 

The EMPEROR-Reduced study’s goal is to evaluate the interplay of SBP and the effects on empagliflozin in patients with HFrEF with or without type 2 diabetes (T2D). This phase III multination, randomized, double-blind, parallel-group, placebo-controlled trial studied 3,730 randomly assigned participants to receive either empagliflozin 10mg daily or placebo (in 1:1 ration, stratified based on SBP of <110 mmHg, 110-130 mmHg, and >130 mmHg) for 16 months. The EMPEROR-Reduced trial included adult participants who have had chronic heart failure (functional class II, III, or IV) for at least three months, left ventricular EF ≤40%, and were currently on appropriate therapy for heart failure per local guidelines. 

The primary endpoint was the time-to-first-event analysis of the combined risk of adjudicated cardiovascular death or adjudicated hospitalization for heart failure and assessed by the Cox proportional hazards model. In a stepwise hierarchical manner, the secondary endpoints included the first occurrence of adjudicated hospitalization for heart failure and the slope of change in eGFR from baseline. 

The baseline characteristics in the SBP <110 mmHg (group A), SBP 110-130 mmHg (group B), and SBP > 130 mmHg (group C), respectively, were: mean age 64.9 ± 11.4, 66.9 ± 11.1 and 68.4 ± 10.3; NYHA class II 73.3% 75.7% and 75.5%; NYHA class III 26.2%, 24.0%, and 23.5%; NYHA class IV 0.5%, 0.3% and 1.0%; mean SBP 104.0 mmHg, 119.4 mmHg and 142.3 mmHg; and mean eGFR 62.2, 52.2 and 61.5 ml/min/1.73m². 

In the results, the relative risk reduction of the primary outcome by empagliflozin was similar across all three groups (p trend = 0.83). However, the incidence rate per 100 patient-years follow-ups for the primary endpoint increased from 16.5 to 20.8 and 26.3 (p trend = 0.0015) in placebo groups C, B, and A, respectively. Therefore, the changes in SBP did not influence the effect of empagliflozin on the primary endpoint. 

In the first secondary outcome, the incidence rate for the total hospitalization for heart failure increased from 17.9 to 22.0 and 28.1 in placebo groups C, B, and A, respectively (respective HRs of 0.82, 0.71, and 0.76; p trend = 0.0075). The HRs for all heart failure hospitalization were 0.74 (95% CI 0.51 to 1.07), 0.66 (95% CI 0.50 to 0.88) and 0.74 (95% CI 0.51 to 1.06) for group C, B, and A, respectively. Therefore, SBP did not influence the magnitude of risk reduction on total hospitalization for HF (p for interaction trend = 0.96). The slope differences in eGFR changes from baseline slope were 1.56 (95% CI 0.39 to 2.74), 1.79 (95% CI 0.87 to 2.71), and 1.85 (95% CI 0.55 to 3.15) for groups C, B, and A, respectively. Hence, empagliflozin has no treatment effect on the eGFR changes (p interaction trend = 0.63).

There was a slight early increase in blood pressure in group A and a slight reduction in blood pressure in group C. The differences were borderline significant at week four and week 12 but were not significant later. Additionally, the incidence rate in 100 patient-years of symptomatic hypotension increased from 2.9 to 4.0 and 8.2 in the placebo groups C, B, and A, respectively. As a result, empagliflozin did not increase the risk for hypotension or symptomatic hypotension. 

Practice Pearls:

• Empagliflozin reduced the risk of the primary outcome independently of baseline systolic blood pressure.
• SBP does not influence the treatment effect of empagliflozin in reducing the risk for total hospitalization for HF.
• Empagliflozin has no treatment effect on the eGFR changes from baseline to off-treatment and the risk of hypotension in all three groups.

References for “Is Empagliflozin Safe and Effective for Patients with HFrEF and Low Blood Pressure?”:
Böhm, Michael et al. “Empagliflozin Improves Cardiovascular and Renal Outcomes in Heart Failure Irrespective of Systolic Blood Pressure.” Journal of the American College of Cardiology vol. 78,13 (2021): 1337-1348.

Böhm, Michael et al. “Systolic blood pressure, cardiovascular outcomes and efficacy and safety of sacubitril/valsartan (LCZ696) in patients with chronic heart failure and reduced ejection fraction: results from PARADIGM-HF.” European heart journal vol. 38,15 (2017): 1132-1143. 

Serenelli, Matteo et al. “Effect of dapagliflozin according to baseline systolic blood pressure in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure trial (DAPA-HF).” European heart journal vol. 41,36 (2020): 3402-3418. 

Ding Nguyen, PharmD Candidate, University of South Florida Taneja College of Pharmacy