HF is a leading cause of CV morbidity and mortality worldwide despite the advances in therapies and prevention. It affects ~26 million people worldwide and is described as a complex clinical syndrome that is caused by either functional or structural impairment of ventricles resulting in symptomatic LV dysfunction.³

It can result from disorders of the pericardium, myocardium, endocardium, heart valves, great vessels, or some metabolic abnormalities. Symptoms, caused by an inadequate cardiac output that fails to keep up with the metabolic demands of the body include dyspnoea, orthopnoea, oedema, abdominal discomfort from hepatic congestion and ascites, fatigue, anorexia, and weakness.³

Less typical symptoms include nocturnal cough, loss of appetite, wheezing, palpitations, depression, syncope, bendopnoea (shortness of breath while bending forward), and dizziness.³

In advanced HF, patients may have resting sinus tachycardia, diaphoresis, narrow pulse pressure (<25mmHg due to decreased cardiac output), and peripheral vasoconstriction (cool and pale extremities due to decreased perfusion). Volume overload manifests as peripheral oedema, elevated jugular venous pressure, and pulmonary congestion.³

Heart failure phenotypes

The three phenotypes of HF are:³

• HF with reduced EF (HFrEF): EF ≤40%
• HF with preserved EF (HFpEF): EF is ≥50%
• HF with mid-range EF: EF is 41% to 49%.

Studies that paved the way for approval of empagliflozin for heart failure

The approval of empagliflozin for the treatment of patients living with HF is based on the results of several large randomised controlled studies. The 2015 Empagliflozin Cardiovascular Outcome Event Trial in T2DM Patients showed that the agent significantly lowered rates of death from CV causes (3.7% vs 5.9% [38% relative risk reduction]), HF hospitalisation (2.7% and 4.1%, respectively [35% relative risk reduction]), and death from any cause (5.7% and 8.3%, respectively [32% relative risk reduction]), compared to placebo.²

Subsequent studies including the 2020 Empagliflozin Outcome Trial in Patients with Chronic HFrEF (EMPEROR-Reduced) and the 2021Empagliflozin Outcome Trial in Patients with Chronic HFpEF (EMPEROR-Preserved trial) confirmed the EMPA-REG findings.^4,5

In the EMPEROR-Reduced study, patients (n=3730) with New York Heart Association class II-IV HF and an EF of ≤40% were randomised to empagliflozin (10mg once daily) or placebo, in addition to recommended therapy. The primary outcome was a composite of CV death or hospitalisation for worsening HF. During a median of 16 months, a primary outcome event occurred in 19.4% of patients in the empagliflozin group and 24.7% in the placebo group. The effect of empagliflozin on the primary outcome was consistent in patients regardless of the presence or absence of diabetes. The total number of HF hospitalisation was lower in the empagliflozin group than in the placebo group (hazard ratio 0.70). The annual rate of decline in the estimated glomerular filtration rate was slower in the empagliflozin group than in the placebo group (–0.55 vs –2.28 ml per minute per 1.73 m² of body-surface area per year) and empagliflozin-treated patients had a lower risk of serious renal outcomes.⁴

In the EMPEROR-Preserved trial, patients (n=5988) with class II-IV HF and an EF of >40% were randomised to empagliflozin (10mg once daily) or placebo, in addition to recommended therapy. The primary outcome was a composite of CV death or HF hospitalisation. Over a median of 26.2 months, a primary outcome event occurred in 13.8% of patients in the empagliflozin group and 17.1% in the placebo group. The effects of empagliflozin appeared consistent in patients with or without diabetes. The total number of HF hospitalisation was lower in the empagliflozin group than in the placebo group (407 vs 541, respectively).⁵

Empagliflozin improves health status and QoL of patients

Butler et al recently assessed the impact of empagliflozin on the health-related quality of life (HRQoL) in patients living with HFpEF, while also exploring whether the clinical advantages of empagliflozin differed based on the initial health status of the patients.⁶

The study employed the Kansas City Cardiomyopathy Questionnaire (KCCQ) to measure HRQoL at baseline, as well as at 12, 32, and 52 weeks. Patients were categorised into groups according to their baseline KCCQ Clinical Summary Score (CSS) tertiles, and the effects of empagliflozin on various outcomes were analysed. Additionally, responder analyses were conducted to compare the likelihood of improvement or deterioration in KCCQ scores due to empagliflozin treatment.

The results indicated that the efficacy of empagliflozin in reducing the risk of CV death or HF hospitalisation remained consistent across all baseline KCCQ-CSS tertiles. Similarly, patients treated with empagliflozin showed significant improvements in KCCQ-CSS, Total Symptom Score, and Overall Summary Score compared to those on placebo. Notably, patients in the empagliflozin group had higher odds of improvement in KCCQ-CSS by various points at 12, 32, and 52 weeks, and lower odds of deterioration by at least five points.⁶

In conclusion, empagliflozin demonstrated a consistent reduction in major HF events across a spectrum of baseline KCCQ scores. Furthermore, empagliflozin showcased an early and sustained improvement in HRQoL, lasting for at least a year.⁶

Other approved indications for empagliflozin in South Africa include as an adjunct to diet and exercise to improve glycaemic control in adults with T2DM and as adjunct therapy in combination with glucose-lowering medicines, including metformin, a thiazolidinedione, a sulphonylurea, a dipeptidyl peptidase 4 inhibitor, or insulin, when these together with diet and exercise, do not provide adequate glycaemic control. Empagliflozin is also indicated in patients living with T2DM at high risk of death due to myocardial infarction or HF hospitalisation.²

References

1. Professional Information. [Internet]. 2022. Available at: https://pi-pil-repository.sahpra.org.za/wp-content/uploads/2022/09/pi-Eng.pdf
2. Zinman B, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. NEJM, 2015.
3. Hajouli S, Ludhwani D. Heart Failure and Ejection Fraction. [Updated 2022 Dec 23]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK553115/
4. Packer M, et al. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. NEJM, 2020.
5. Anker SD, et al. Empagliflozin in heart failure with a preserved ejection fraction. NEJM, 2021.
6. Butler J, et al. Empagliflozin, health status, and quality of life in patients with heart failure and preserved ejection fraction: the EMPEROR-Preserved trial. Circulation, 2022.