DefinePK

Abstract

Heart failure with reduced ejection fraction (HFrEF) remains a major clinical challenge worldwide and is a pressing public health issue in Pakistan. Patients here often present at an advanced stage, are typically younger than their Western counterparts, and carry a higher burden of comorbidities such as diabetes and hypertension. Despite therapeutic advances, hospitals continue to report high readmission and mortality rates.
Over the last decade, sodium–glucose cotransporter-2 (SGLT2) inhibitors have emerged as a transformative drug class—not only for type 2 diabetes but also for HFrEF regardless of glycemic status. Landmark randomized controlled trials, including DAPA-HF and EMPEROR-Reduced, consistently demonstrated reductions in hospitalizations and cardiovascular deaths [1–3]. However, validation in South Asian populations—where socioeconomic and clinical characteristics differ markedly from trial cohorts—remains limited.
The study by Yaqoob et al. helps address this critical evidence gap. Conducted at a tertiary public hospital in Karachi, this prospective observational study showed that empagliflozin use was associated with significant clinical benefit: a 60% relative reduction in rehospitalization within 90 days (9.2% vs. 23%), a 74% reduction in cardiac mortality over six months (4.6% vs. 17.6%), and marked preservation of renal function (3.1% vs. 23% incidence of renal insufficiency). Importantly, these outcomes were achieved even though the empagliflozin group had a higher proportion of NYHA class IV patients, highlighting benefit in advanced disease [4].
These findings align closely with global evidence. Both EMPEROR-Reduced and DAPA-HF demonstrated significant reductions in heart failure hospitalization and renal decline [1,3]. Likewise, EMPA-REG OUTCOME confirmed reductions in cardiovascular mortality among high-risk diabetic patients [5].
Renal benefits are particularly significant in Pakistan, where diabetic nephropathy and cardiorenal syndrome are prevalent [6,7].
Mechanistically, empagliflozin’s actions extend well beyond glycemic control. Through osmotic diuresis and natriuresis, it reduces preload and afterload. At the myocardial level, it enhances energetics by modulating intracellular sodium and calcium, thereby potentially improving contractility [8]. Anti-inflammatory and antifibrotic properties may further support reverse remodeling [9]. In the kidney, empagliflozin reduces intraglomerular pressure, thereby attenuating hyperfiltration injury and slowing progression of chronic kidney disease [10].
Despite these encouraging results, certain limitations must be acknowledged. The non-randomized design introduces potential confounding, follow-up was limited to six months, and adherence data were self-reported, raising concerns about recall bias. Furthermore, as a single-center study, generalizability remains restricted. Nonetheless, the magnitude and consistency of the observed benefit in a resource-constrained, real-world setting strongly support the validity of these findings.
The clinical message is clear: empagliflozin should be considered early in the treatment pathway for HFrEF, in accordance with the 2021 ESC and 2022 AHA/ACC/HFSA guidelines [11,12]. To ensure equitable access, barriers such as drug cost, availability, and limited prescriber awareness must be addressed through coordinated efforts involving clinicians, policymakers, and health insurers.
Looking ahead, multicenter registries with longer follow-up, inclusion of HFpEF populations, and local cost-effectiveness analyses are needed. Evidence from EMPEROR-Preserved suggests benefit across the full ejection fraction spectrum [13], which could further expand the role of SGLT2 inhibitors in heart failure care.
Overall, the study by Yaqoob et al. [4] provides timely and robust real-world evidence that empagliflozin improves outcomes in HFrEF patients in Pakistan, irrespective of diabetes status. It bridges the gap between clinical trial efficacy and everyday practice and underscores the need to integrate SGLT2 inhibitors into routine heart failure management nationwide.
References

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