Empagliflozin: A new dawn for heart failure treatment across the ejection fraction spectrum
Initially approved to improve glycaemic control and reduce cardiovascular death in adults with type 2 diabetes (T2D), the SGLT-2* inhibitor empagliflozin reduced hospitalization for heart failure (HFH) or cardiovascular death and delayed renal function decline when added to recommended therapy in patients with heart failure and reduced ejection fraction (HFrEF) in the EMPEROR-Reduced** trial. The EMPEROR-Preserved** trial has now shown that the benefits of empagliflozin extend to patients with heart failure and preserved ejection fraction (HFpEF).
Improved outcomes in HFpEF
In the EMPEROR-Preserved trial, 5,988 adults (mean age ~72 years, 45 percent female) with New York Heart Association functional class II–IV chronic HF, left ventricular ejection fraction (LVEF) >40 percent (median 54 percent), and N-terminal pro–B-type natriuretic peptide (NT-proBNP) level >300 pg/mL (>900 pg/mL for patients with atrial fibrillation) were randomized 1:1 to receive empagliflozin (10 mg QD) or placebo plus standard therapy.
Baseline characteristics of the patients were similar between groups. About 81 percent were NYHA class II, mean BMI was ~30 kg/m2, half the population had eGFR*** <60 mL/min/1.73 m2, and nearly half had diabetes. LVEF was ≥50 percent in two-thirds of patients.
After a median 26.2-month follow-up, the primary composite of cardiovascular death or HFH (first event) was significantly reduced with empagliflozin vs placebo (13.8 percent vs 17.1 percent; hazard ratio [HR], 0.79, 95 percent confidence interval [CI], 0.69–0.90; p<0.001). [N Engl J Med 2021;385:1451-1461]
This translated to 6.9 vs 8.7 events per 100 patient-years, with 31 patients needing treatment with empagliflozin to prevent one primary outcome event.
The results were mainly due to reduced HFH (8.6 percent vs 11.8 percent; HR, 0.71, 95 percent CI, 0.60–0.83). Cardiovascular death occurred in 7.3 and 8.2 percent of patients in the empagliflozin and placebo groups, respectively (HR, 0.91, 95 percent CI, 0.76–1.09).
The primary outcome results were generally consistent across subgroups including baseline diabetes status, kidney function, history of atrial fibrillation or flutter, and prior HFH ≤12 months. The results were also consistent regardless of baseline LVEF (HRs, 0.71, 0.80, and 0.87 for <50, ≥50 to <60, and ≥60 percent, respectively).
Total HFH (first and recurrent events) was reduced by 27 percent with empagliflozin vs placebo (n=407 vs 541; HR, 0.73, 95 percent CI, 0.61–0.88; p<0.001).
Decline in eGFR was also slower with empagliflozin vs placebo (-1.25 vs -2.62 mL/min/1.73 m2; p<0.001).
Serious adverse events (AEs) occurred in 47.9 and 51.6 percent of empagliflozin and placebo recipients, respectively, with AEs leading to treatment discontinuation in 19.1 and 18.4 percent, respectively. Uncomplicated genital and urinary tract infections and hypotension occurred more frequently in empagliflozin recipients.
Prior benefits noted with HFrEF
The benefits observed with empagliflozin in HFpEF add on to the previous benefits noted in patients with HFrEF. In the EMPEROR-Reduced trial, 3,730 patients with class II–IV HF and EF ≤40 percent were randomized to receive empagliflozin (10 mg QD) or placebo plus recommended therapy. [N Engl J Med 2021;383:1413-1424]
Over a median 16 months, cardiovascular death or hospitalization for worsening HF occurred in fewer patients in the empagliflozin than placebo arm (19.4 percent vs 24.7 percent; HR, 0.75, 95 percent CI, 0.65–0.86; p<0.001), with the benefit evident regardless of diabetes status.
Empagliflozin recipients also had a slower annual rate of eGFR decline than placebo recipients (-0.55 vs -2.28 mL/min/1.73 m2/year; p<0.001), as well as a lower risk of serious renal outcomes.
According to the 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure, treatment with a beta-blocker, ARNI/ARB/ACE# inhibitor, mineralocorticoid receptor antagonist, and an SGLT-2 inhibitor, with diuretics (as needed), is recommended to manage HFrEF with an LVEF ≤40 percent. The four classes can be initiated simultaneously at low doses. [J Am Coll Cardiol 2022;doi:10.1016/j.jacc.2021.12.012]
Clear benefits across the HF spectrum
“The pattern of benefits … is similar to that reported with empagliflozin in a similarly designed parallel trial of patients with HFrEF (EMPEROR-Reduced), which suggests that the effects of SGLT-2 inhibition on HF events do not vary meaningfully with the HF phenotype,” said the EMPEROR-Preserved authors.
“Whereas HFrEF can be treated with drugs that act to attenuate the overactivation of endogenous neurohormonal systems, therapeutic options for patients with HFpEF are limited,” they pointed out. Although there were previously no approved therapies with a clear mortality benefit in HFpEF, [Drugs 2021;81:1243-1255] empagliflozin recently received FDA approval for use in patients with HF regardless of LVEF. [https://www.fda.gov/news-events/press-announcements/fda-approves-treatment-wider-range-patients-heart-failure; https://www.boehringer-ingelheim.us/press-release/us-fda-approves-jardiance-empagliflozin-treat-adults-heart-failure-regardless-left]
What do the experts say?
Clin Assoc Prof David Sim Kheng Leng
Senior Consultant & Director of Heart Failure Programme
National Heart Centre Singapore
Dato’ Dr Azmee Mohd Ghazi
Consultant Cardiologist & Deputy Head, Department of Cardiology
Clinical Director of Heart Failure and Heart Transplant
National Heart Institute, Malaysia
What is the usual treatment regimen for patients with HFpEF?
AMG: Trial data on HFpEF are limited. Therefore, the management remains empiric and focuses mainly on symptom control with diuretics. Moreover, since patients tend to be elderly with several comorbidities, management of these comorbidities (eg, hypertension, diabetes, myocardial ischaemia, CKD***) is an important component of the overall management of HFpEF.
How do patients fare on these treatments?
DS: The treatments help with symptom improvement but there is no impact on mortality and rehospitalization.
AMG: The main side effects of diuretics are electrolyte depletion, hypotension, and renal function impairment. Patients with HFpEF are highly sensitive to volume changes and susceptible to hypotension and azotaemia with overdiuresis, making optimal diuretic use vital. While diuretics help to improve symptoms in HFpEF patients, there is limited evidence to show their effect on long-term morbidity and mortality in HFpEF.
How would SGLT-2 inhibitors fit into the HFpEF treatment algorithm?
DS: SGLT-2 inhibitors are the only treatment to have impact on rehospitalization for HF. Previously, there were no approved treatments for HFpEF that impacted mortality or hospitalization. The recent FDA approval of empagliflozin has changed that. The 2022 ACC/AHA guidelines just conferred a class 2a indication for SGLT-2 inhibitors in HFpEF treatment. In March 2022, the Singapore Health Sciences Authority also approved empagliflozin for HFpEF, which is to my knowledge, the first approval of an SGLT-2 inhibitor for HFpEF in Asia.
How do the EMPEROR-Preserved findings factor in for patients with HF?
AMG: Diabetes and CKD are commonly present in HF patients and both comorbidities are strongly associated with the risk of both incident HF and adverse clinical outcomes. Empagliflozin improves glycaemic control and significantly reduces CV death and HF events in diabetic patients. In patients with CKD, empagliflozin also decreases the risk of renal disease progression in a manner additive to RAAS# inhibitors.
The EMPEROR-Reduced and EMPEROR-Preserved trials demonstrated that empagliflozin reduced the risk of a composite of CV death or HFH in HF patients across the spectrum of EF, regardless of presence of T2D. Empagliflozin also slowed kidney function decline in patients in both trials.
Based on this evidence, empagliflozin could be considered as a disease-modulating drug that simultaneously targets all three diseases (HF, T2D, and CKD).
How important is the kidney benefit of empagliflozin in patients with HFpEF and HFrEF?
AMG: CKD is present in >50 percent of HF patients. CKD is not only associated with higher all-cause mortality and risk of rehospitalization but may complicate HF management and, in some cases, prevent optimal use of HF therapies.
In both the EMPEROR-Preserved and EMPEROR-Reduced trials, empagliflozin protected the kidney by significantly slowing kidney function decline. Empagliflozin could potentially address most of the challenges faced in managing HF with CKD.
Are there certain subgroups of patients who would most benefit from empagliflozin?
DS: All subgroups would benefit from empagliflozin regardless of age, sex, LVEF, renal function, or background therapy.
AMG: The beneficial effects of empagliflozin are consistent in all HF subgroups in the EMPEROR-Reduced and EMPEROR-Preserved trials. Given the complexity of HF treatment, SGLT-2 inhibitors are especially important in the pre-HF stage to reduce disease onset in those with known diabetes.
How would the approval of empagliflozin impact HF treatment?
DS: For HFpEF, the approval of empagliflozin would be the first as the only proven therapy in a HFpEF clinical trial. For HFrEF, the approval of empagliflozin would provide more options and incremental benefit on top of current medications.
AMG: EMPEROR-Preserved represents a major breakthrough for patients with HFpEF. For the first time in medical history, a treatment showed beneficial outcomes in patients with HFpEF by reducing the risk of HFH or CV death. We expect that guideline committees will review all available clinical evidence in the process of updating recommendations.