It could be said that 2021 was the year of the SLGT2 inhibitor. Empagliflozin was shown in the EMPEROR-Reduced trial to improve cardiovascular function and renal outcomes. This article, originally published Sept. 21, 2021, outlines the results of this trial. Click here to read the original article and obtain CME/CE credit for the activity.
Empagliflozin—an SLGT2 inhibitor—provided similar benefits for heart failure (HF) patients with reduced ejection fractions (HFrEF) and systolic blood pressures (SBP) <110 mmHg, who are typically at highest risk of HF, compared with patients with higher SBPs. Importantly, empagliflozin did not increase their risks for hypotension, according to the most recent results from the EMPEROR-Reduced trial published in the Journal of the American College of Cardiology.
Treatment with empagliflozin reduced the risk of cardiovascular death and hospitalization for heart failure, as well as renal function decline independently of both baseline and trial SBPs, concluded the authors, led by Michael Böhm, MD, of the Universitätsklinikum des Saarlandes, Klinik für Innere Medizin III, Saarland University, Homburg, Germany.
These results mirror and expand on previous findings from sister trials, including EMPEROR-Pooled, in which empagliflozin reduced hospitalizations from HF over a wide range of ejection fractions, but had less clear renoprotective benefits; and EMPEROR-Preserved, where empagliflozin effected significant reductions in HF hospitalizations.
Nicolas Girerd, MD, PhD, of the Institut Lorrain du Cœur et des Vaisseaux Louis Mathieu, CHRU de Nancy, France, provided some context for this latest research.
“Effective novel interventions continue to be of benefit in heart failure with reduced ejection fraction (HFrEF). However, a major limitation in the implementation of optimized treatment for HFrEF is low blood pressure as most HF drugs can induce hypotension, thus incurring symptoms and/or concerns for potential complications. As recently highlighted, the proportion of patients with HF actually receiving the target dose (or receiving at least 50% of the target dose) is low overall, partly due to hypotension,” he wrote in an accompanying editorial.
Böhm and colleagues sought to assess the influence of SBP on the effects of empagliflozin on the primary outcome (cardiovascular death or hospitalization for HF), and secondary outcomes including HF hospitalization, rate of decline in estimated glomerular filtration rate (eGFR), renal outcomes, and effects on SBP.
They included 3,730 patients with HFrEF from the EMPEROR-Reduced study who had been randomized to treatment with either empagliflozin (10 mg once daily) or placebo. Patients were grouped and assessed according to baseline SBP as follows:
- <110 mmHg: n=928.
- 110-130 mmHg: n=1,755.
- >130 mmHg; n=1,047.
“Those with lower SBP had a greater severity of heart failure, as evidenced by a lower ejection fraction, higher N-terminal pro–B-type natriuretic peptide plasma concentrations, and a higher likelihood of having experienced a heart failure hospitalization in the last 12 months. Patients with lower SBP were more likely to be treated with a neprilysin inhibitor or have received an implanted cardioverter-defibrillator and/or cardiac resynchronization therapy device,” noted these researchers.
Böhm and colleagues found an inverse relationship between baseline SBP and the risk of cardiovascular death or HF hospitalization in patients receiving placebo (P trend=0.0015). In patients with SBP >130 mmHg, the event rate for total hospitalizations increased from 17.9 per 100 patient years of follow-up, to 22.0 in those with SPBs of 110-130 mmHg, to 28.1 in those with SBP <110 mmHg (P trend=0.0075).
But baseline SBP, they found, had no effect on the ability of empagliflozin to reduce the risk of HF events or renal endpoints. Relative risk reductions in the primary outcome were similar across all SBP groups (P for interaction trend=0.83).
“SBP also did not influence the magnitude of the risk reduction produced by empagliflozin on total (first and recurrent) hospitalizations for heart failure (P for interaction trend=0.96),” these researchers noted.
Reductions in eGFR decline were also unaffected by SBP, and were similar in all SBP groups with treatment with empagliflozin (P for interaction trend=0.68), even when assessed 23-45 days after treatment discontinuation (P for interaction trend=0.63).
“The effect of SBP on the ability of empagliflozin to reduce the risk of the renal composite was somewhat greater in patients with SBP ˂110 mm Hg, but the P for interaction trend was borderline significant (P=0.088), and this analysis is based on sparse events,” noted Böhm et al.
Finally, they found that patients with SBPs ˂110 mmHg treated with empagliflozin did not have an increased incidence of symptomatic hypotension. When adjusted for placebo, empagliflozin effected only a slight, early increase in SBP at <110 mmHg, no changes at 110-130 mmHg, and a slight reduction at >130 mmHg. After 4 and 12 weeks, the between-group differences in these rates were only of borderline significant (P for interaction trend=0.05-0.10), and after these timepoints, not significant.
“Because patients with SBP ˂110 mm Hg did not experience a decline in SBP or an increased risk of hypotension or symptomatic hypotension with empagliflozin, the benefit-to-risk relationship for empagliflozin would seem to be particularly favorable in patients with SBP ˂110 mm Hg. These observations are relevant, as physicians are often reluctant to initiate treatment with outcome-modifying drugs in patients with heart failure whose SBP is low,” noted Böhm et al.
“It is genuinely hoped that the paper by Böhm et al will reassure physicians regarding the good BP tolerability of SGLT2 inhibitors. Importantly, this proven hemodynamic tolerability, along with a considerable renal-protective effect, should probably prompt an early/initial initiation of SGLT2 inhibitors in patients with HFrEF, along with other pharmacologic pillars of HF treatment. We believe that a voluntarist approach, favoring the implementation of the major therapeutic advances obtained in the field of HF in the past decade, can actually change the face of HF in the next decade,” concluded editorialist Girerd.
Limitations of the study are that results were not confined to patients not meeting exclusion criteria, including eGFR <20 mL/min/1.73 m2, symptomatic hypotension, or SBP <100 mmHg.
Liz Meszaros, Deputy Managing Editor, BreakingMED™
The EMPEROR trial was funded by Boehringer Ingelheim and Eli Lilly.
Böhm is supported by Deutsche Forschungsgemeinschaft (German Research Foundation); and has received personal fees from Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Medtronic, Novartis, Servier, and Vifor during the conduct of the study
Girerd is supported by the French National Research Agency Fighting Heart Failure, by the French PIA project Lorraine Université d’Excellence GEENAGE programs, and the Contrat de Plan Etat Région Lorraine and FEDER IT2MP; and has received honoraria from AstraZeneca, Bayer, Boehringer, Lilly, Novartis, and Vifor.
Cat ID: 446
Topic ID: 74,446,730,446,6,914,127,410,411,192,669,916,918,925
