Empagliflozin Improves Outcomes Irrespective of Blood Pressure
- In a post hoc analysis of a large, randomized trial, use of a SGLT2 inhibitor in HFrEF patients correlated with reduced risk for cardiac mortality, HF hospitalization, and renal deterioration irrespective of baseline SBP.
- SGLT2 inhibitor use was not associated with increased risk of hypotension compared to placebo, including patients with baseline SBP <110 mm Hg.
- In patients with SBP <110 mm Hg, SGLT2 inhibitor use led to a small increase in SBP in the first 4 weeks, but there was no appreciable change at follow-up over a longer time period compared to placebo.
What is the interplay between systolic blood pressure (SBP) and the effect of empagliflozin in patients with chronic heart failure with reduced ejection fraction (HFrEF)?
Patients with an EF of <40% were randomized to either empagliflozin or placebo in the EMPEROR-Reduced trial. Patients were grouped based on baseline SBP as <110, 110-130, or >130 mm Hg. The primary endpoint was composite of cardiovascular death or HF hospitalization. The secondary endpoint was slope of change in estimated glomerular filtration rate (eGFR) and a renal composite endpoint defined as need for chronic dialysis or renal transplant, or ≥40% sustained decrease in eGFR or sustained decrease to chronic kidney disease stage 5. Primary and secondary endpoints and occurrence of hypotension and symptomatic hypotension were assessed with empagliflozin compared to placebo in these three subgroups.
A total of 3,730 patients were randomized including 1,863 to empagliflozin and 1,867 to placebo. At baseline, patients with lower SBP had a higher severity of HF and were more likely to be on ARNI. In the placebo group, over a median of 16 months, the incidence of primary endpoint was inversely related to baseline SBP. Treatment with empagliflozin resulted in an early SBP increase in the <110 mm Hg group, no change in the 110-130 mm Hg group, and a slight decrease in >130 mm Hg group, but these changes did not persist at follow-up. Compared to placebo, there was no difference in the risk for symptomatic hypotension or hypotension with empagliflozin. Empagliflozin reduced risk for the primary endpoint and attenuated slope of eGFR decline to a similar extent in all three SBP groups. When SBP was analyzed as a time-updated covariate, changes in SBP did not influence effect of empagliflozin on the primary endpoint. The effect of empagliflozin on decreasing the renal composite endpoint was greater in patients with SBP <110 mm Hg, but the interaction effect was borderline significant likely due to sparse events.
In a large, randomized trial of HFrEF patients, an inverse relationship was noted between SBP and incidence of cardiovascular mortality. Compared to placebo, sodium-glucose cotransporter-2 (SGLT2) inhibitor use was not associated with hypotension even in patients in the lowest SBP group. Empagliflozin decreased risk for HF hospitalization, cardiovascular mortality, and eGFR decline irrespective of baseline BP.
Low baseline SBP is one of the biggest barriers with getting HFrEF patients on appropriate evidence-based medical therapy in clinical practice. Accordingly, such patients have the worst outcomes, but are least likely to receive effective treatment. In EMPEROR-Reduced, use of empagliflozin did not correlate with sustained change in SBP compared to placebo over time, including patients in the lowest SBP group with a baseline value of <110 mm Hg. However, it is noteworthy that in this highest risk subgroup with SBP <110 mm Hg, empagliflozin use was associated with a slight increase in SBP in the first 4 weeks. Reassuringly, empagliflozin use did not lead to hypotension either. Furthermore, the benefits with empagliflozin including reduced mortality, HF hospitalization, and eGFR deterioration were noted in all SBP subgroups. These data from the EMPEROR-Reduced trial show that HFrEF patients at highest risk who have the lowest BP safely tolerated a SGLT2 inhibitor with a significant reduction in cardiac mortality and HF hospitalization compared to placebo.
Keywords: Blood Pressure, Glomerular Filtration Rate, Glucosides, Heart Failure, Hypotension, Kidney Transplantation, Metabolic Syndrome, Primary Prevention, Renal Insufficiency, Chronic, Sodium-Glucose Transporter 2 Inhibitors, Stroke Volume
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