Recent clinical trials with SGLT2 inhibitors like empagliflozin and dapagliflozin have shown significant cardiovascular benefits and reduced heart failure hospitalizations in HFpEF patients, expanding the potential application of these drugs beyond type 2 diabetes and heart failure with reduced ejection fraction (HFrEF).

Heart Failure with Preserved Ejection Fraction (HFpEF) is a diverse syndrome characterized by various phenotypes and comorbidities, demanding personalized therapies for each patient. Gliflozins, notably SGLT2 inhibitors, stand out as the sole drug class consistently improving cardiovascular outcomes in HFpEF patients, regardless of factors like ejection fraction, age, functional class, or diabetes status. Ongoing clinical studies investigating SGLT2 inhibitors’ impact on biomarkers, overall health, functional status, and diastolic function offer an exciting opportunity to gain deeper insights into HFpEF management, potentially opening new horizons in this field of research.

Several limitations should be acknowledged when interpreting the current evidence on SGLT2 inhibition in HFpEF. The exact multifaceted mechanisms behind the cardioprotective effects of SGLT2 inhibitors remain incompletely understood, necessitating further investigation.

Furthermore, trials hold promises for shedding light on how SGLT2 inhibitors influence various HFpEF phenotypes, quality of life, and exercise capacity.

Additionally, comparing results across different HFpEF trials can be challenging due to varying definitions and left ventricular ejection fraction (LVEF) cut-offs. Trials often encompass patients with HFmrEF (LVEF between 41–49%), whose clinical course may resemble HFrEF more than HFpEF. Future trials should consider evolving HF classifications and present results in a manner that facilitates meaningful comparisons.

Unraveling the Potential Cardioprotective Mechanisms of SGLT2 Inhibition in HFpEF:

• SGLT2 inhibitors may functionally mimic renal denervation by mitigating renal sympathetic overactivity.

Therapeutic Potential of SGLT2 Inhibitors in Managing Comorbidities Associated with HFpEF:

• SGLT2 inhibitors hold promise in addressing the comorbidities often linked with HFpEF. By promoting natriuresis, glycosuria, and osmotic diuresis, these medications can contribute to notable reductions in body weight, blood pressure, blood glucose levels, uric acid levels, and lipid profiles.

Cardiovascular Benefits of SGLT2 Inhibitors: Beyond HF Hospitalizations:

• The utilization of SGLT2 inhibitors significantly influences cardiovascular outcomes, particularly in terms of their role in reducing HF hospitalizations. Recent findings emphasize the multifaceted and pleiotropic nature of SGLT2 inhibition, with numerous studies highlighting its favorable impact on diastolic function and cellular metabolism.

Source: Aguiar-Neves I, Santos-Ferreira D, Fontes-Carvalho R. SGLT2 Inhibition in Heart Failure with Preserved Ejection Fraction—The New Frontier. Reviews in Cardiovascular Medicine. 2023 Jan 3;24(1):1.

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