A Review of the Current Literature Regarding Sodium-Glucose Cotransporter 2 Inhibitors in Heart Failure With Preserved Ejection Fraction and Timing of Initiating Therapy

Abstract

Heart failure with preserved ejection fraction (HFpEF) is a growing public health burden that now accounts for nearly half of all HF diagnoses in the United States. Modern classifications of HF divide patients into HFpEF and HF with reduced ejection fraction (HFrEF). Historically, diagnosis has relied on the Framingham Heart Failure Diagnostic Criteria, which incorporates clinical signs and symptoms including pulmonary edema, jugular venous distention, orthopnea, S3 gallop, cardiomegaly, peripheral edema, dyspnea on exertion, and tachycardia. Contemporary definitions of HF further incorporate objective evidence such as elevated natriuretic peptide levels, cardiopulmonary congestion, and echocardiographic findings including preserved left ventricular ejection fraction and evidence of diastolic dysfunction. HFpEF predominantly affects older adults and is strongly associated with hypertension, obesity, diabetes mellitus, coronary artery disease, atrial fibrillation, and chronic kidney disease. Despite advances in management, HFpEF continues to be associated with substantial morbidity, mortality, recurrent hospitalization, and healthcare utilization. Therapeutic options for HFpEF have historically been limited, with few interventions demonstrating meaningful reductions in hospitalization or cardiovascular mortality. However, sodium-glucose cotransporter 2 inhibitors (SGLT2i) have emerged as a promising cornerstone of therapy. Initially developed for glycemic control in patients with diabetes mellitus, SGLT2i have demonstrated broad cardiovascular and renal benefits extending beyond glucose lowering. Recent large randomized controlled trials evaluating empagliflozin and dapagliflozin in patients with HFpEF have shown significant reductions in HF hospitalizations and improved cardiovascular outcomes across diverse patient populations, including those without diabetes mellitus. These findings have substantially influenced contemporary guideline-directed medical therapy recommendations. Current American and European HF guidelines now support the use of SGLT2i in HFpEF, with European recommendations assigning the highest level of recommendation and evidence for their routine use in eligible patients. Contraindications to therapy remain limited and include type 1 diabetes mellitus, end-stage renal disease requiring dialysis, and pregnancy or lactation. Although evidence supporting SGLT2i use in HFpEF continues to strengthen, uncertainty remains regarding the optimal timing of therapy initiation. In particular, there is ongoing debate surrounding whether initiation during hospitalization for acute HF exacerbation confers greater clinical benefit compared with delayed outpatient initiation after discharge. Early inpatient initiation may improve medication adherence, reduce rehospitalization rates, accelerate symptomatic improvement, and optimize implementation of guideline-directed medical therapy. Conversely, concerns regarding hemodynamic stability, renal function, volume status, and transitional care logistics continue to influence clinician decision-making in the inpatient setting. This literature review aims to explore the current literature regarding SGLT2i in HFpEF, as well as the optimal time to initiate therapy.