Empagliflozin Receives Breakthrough Therapy Designation for HFpEF

The FDA has approved empagliflozin Breakthrough therapy for patients with heart failure with preserved ejection fraction (HFpEF).

Empagliflozin, a sodium-glucose co-transporter 2 inhibitor (SGLT-2 inhibitor) indicated for the treatment of type 2 diabetes (T2D), reduces the risk of cardiovascular disease (CVD) in patients with T2D and CVD, and is also approved for treatment of heart failure with reduced ejection fraction (HFrEF). Recently, FDA has assigned Breakthrough therapy for empagliflozin as an investigational therapy for adults with HFpEF (left ventricular ejection fraction (LVEF) >40%). HFpEF is about greater than half of the six million heart failures in the United States. No present treatment is recognized to significantly improve outcomes in patients with HF, especially with HFpEF. Diabetes (DM) raises the risk of heart disease in men twofold and women fivefold. 25% of patients with DM are also burdened from chronic heart failure (CHF). A previous study by Echouffo-Tcheugui et al. revealed that 45.5% of individuals with HFpEF and 41.8% of individuals with HFrEF were diagnosed with DM. Individuals with HF and DM have worse outcomes because of more significant CVD risk factors and inadequate glucose control. The CHARM program demonstrated that DM is an independent predictor of mortality and morbidity in persons with HF. Furthermore, the relative risk of death from CVD and HF hospitalization associated with DM was greater in HFpEF than those with HFrEF. There is not enough evidence that supports HFpEF drug therapy.

The EMPEROR-Preserved study is a phase III randomized, double-blind placebo-controlled trial. Five thousand nine hundred eighty-eight symptomatic patients with HFpEF with and without T2D were included in the study. The study’s objective was to assess if empagliflozin can lower the risk of HF hospitalization and whether it can improve survival. The eligibility criteria were patients ≥18 years with chronic HF (NYHA class II to IV) for not less than three months, LVEF >40% at most current evaluation, and elevated N terminal pro-B type natriuretic peptide (NT-proBNP) levels, structural heart changes, or recorded HF hospitalization within twelve months of examination. Exclusion criteria included hypotension and an eGFR of <20ml/min/1.73m2. Participants were screened 4 to 28 days following being randomized 1:1 either to placebo (n=2991) or empagliflozin 10mg a day (n=2997) in addition to routine care. The median follow-up was 26.2 months. The composite primary endpoint was the time to initial event of determined CV death or determined HF hospitalization. Secondary endpoints were the initial and recurring HF hospitalization events and the slope change in eGFR (CKD-EPI) from baseline. The previous study, EMPEROR-Reduced trial, examined the effects of empagliflozin’s mortality and morbidity in patients with HFrEF, which constitutes the foundation of FDA’s approval for HFrEF.

Patients enrolled in the study were from Asia (11%), Europe (45%), Latin America (25%), and North America (12%). The participant’s mean age was 72 years old, 45% were female, most of the patients had NYHA class II or III symptoms (99.6%), and 23% had previous HF hospitalization in twelve months. Baseline LVEF of 41% to 50% occurred in 33% of the patients. Diabetes (49%) and chronic kidney disease (CKD) (50%) were common comorbidities present. As far as medications, the main ones patients were on were ACEIs, ARBs, ARNIs (80%), beta-blockers (86%), and MRAs (37%). The median NT-proBNP (974pg/ml) was higher than previous HFpEF studies, and the median LVEF (54%) was marginally lower than earlier HFpEF studies. Nine hundred twenty-six primary outcomes were identified in the trial, including 415 among 2997 patients randomized to empagliflozin (13.8%) and 511 among 2991 patients randomized to placebo therapy (17.1%) (HR, 0.79; p <.001). Assessment of the individual elements of the composite endpoint revealed the effect was primarily determined by a lower risk of hospitalization for HF, with 407 hospitalizations occurring in the empagliflozin arm compared to 541 in the placebo arm (HR, 0.73; p <.001). Effects of empagliflozin were consistent in patients with or without DM. CV death occurred in 7.3% in the empagliflozin group compared to placebo at 8.2% (HR 0.91), not statistically significant. There was a slower rate of decline in eGFR with empagliflozin compared to placebo (-1.25 vs. -2.62 ml/min/1.73m2/year; p <.0001). As far as safety, more superficial forms of genital and urinary tract infections (UTIs) were more common in the empagliflozin arm. Moreover, adverse events that lead to discontinuation were seen more in the empagliflozin arm (19.1% vs. 18.4%).

Practice Pearls:

• Empagliflozin had a 21% relative risk reduction for the composite primary endpoint of CV death or hospitalization for HF in individuals with HFpEF compared to placebo in the EMPEROR-Preserved study.
• Empagliflozin demonstrated it decreased the combined risk of CV death or HF hospitalization in individuals with HFpEF irrespective of the presence of DM.
• Common adverse events seen with empagliflozin were UTIs and genital infections.

Anker, Stefan D et al. “Empagliflozin in Heart Failure with a Preserved Ejection Fraction.” The New England journal of medicine, 10.1056/NEJMoa2107038. August 27 2021, doi:10.1056/NEJMoa2107038. https://www-nejm-org.proxy.hsl.ucdenver.edu/doi/pdf/10.1056%2FNEJMoa2107038

Anker, Stefan D et al. “Baseline characteristics of patients with heart failure with preserved ejection fraction in the EMPEROR-Preserved trial.” European journal of heart failure vol. 22,12 (2020): 2383-2392. doi:10.1002/ejhf.2064. https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/ejhf.2064

Williams, David M, and Marc Evans. “Are SGLT-2 Inhibitors the Future of Heart Failure Treatment? The EMPEROR-Preserved and EMPEROR-Reduced Trials.” Diabetes therapy: research, treatment, and education of diabetes and related disorders vol. 11,9 (2020): 1925-1934. doi:10.1007/s13300-020-00889-9. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7434820/

Echouffo-Tcheugui, Justin B et al. “Temporal trends and factors associated with diabetes mellitus among patients hospitalized with heart failure: Findings from Get With The Guidelines-Heart Failure registry.” American heart journal vol. 182 (2016): 9-20. doi:10.1016/j.ahj.2016.07.025. https://www-sciencedirect-com.proxy.hsl.ucdenver.edu/science/article/pii/S0002870316301727

Trina Maglalang RPh, 2022 PharmD Candidate University of Colorado