Off‑Label Use of Empagliflozin for Heart Failure in Patients Without Diabetes

Heart Failure with Reduced Ejection Fraction (HFrEF)

Empagliflozin 10 mg daily significantly lowers the composite of cardiovascular death or hospitalization for worsening heart failure by 21 % (hazard ratio 0.79, 95 % CI 0.69–0.90) in NYHA class II–IV patients with left‑ventricular ejection fraction ≤ 40 %【1】.
The benefit is observed in both diabetic and non‑diabetic participants; roughly half of the EMPEROR‑Reduced cohort had type 2 diabetes, demonstrating efficacy in patients without diabetes【1】.
Across the EMPEROR‑Reduced trial, empagliflozin reduced cardiovascular mortality and heart‑failure hospitalizations regardless of diabetes status, confirming a robust off‑label indication【2】【3】.

In the EMPEROR‑Preserved trial, empagliflozin reduced the risk of cardiovascular death or heart‑failure hospitalization by 21 % (HR 0.79, 95 % CI 0.69–0.90) in patients with LVEF > 40 %【2】【3】.
The study enrolled 5,988 adults with NYHA class I–IV chronic HFpEF; about 50 % had type 2 diabetes, indicating the effect extends to non‑diabetic patients【2】.
The therapeutic benefit was consistent irrespective of baseline diabetes diagnosis, supporting its use off‑label in HFpEF without diabetes【2】【3】.

A meta‑analysis of five large SGLT2‑inhibitor trials (EMPEROR‑Reduced, EMPEROR‑Preserved, DAPA‑HF, DELIVER, SOLOIST‑WHF) comprising 21,947 participants showed significant reductions in:
- cardiovascular death or heart‑failure hospitalization,
- cardiovascular death alone,
- first heart‑failure hospitalization, and
- all‑cause mortality【4】【2】.
These pooled data confirm that SGLT2 inhibition lowers the risk of heart‑failure hospitalization and cardiovascular death across a wide range of heart‑failure phenotypes, independent of diabetes status【4】【2】.

The recommended regimen for heart‑failure benefit is empagliflozin 10 mg taken orally once daily, which is the lowest dose proven effective in cardiovascular outcome trials【5】.
No dose escalation is required to achieve cardiovascular or heart‑failure risk reduction【5】.
Renal‑function‑based adjustments: the drug is not advised for glycaemic control when eGFR < 45 mL/min/1.73 m² and is contraindicated in patients on dialysis or with severe renal impairment【5】.

SGLT2 inhibitors increase susceptibility to DKA, including euglycaemic presentations, especially in contexts such as insulin‑pump malfunction, substantial insulin dose reductions, or prolonged fasting【6】.

Empagliflozin induces osmotic diuresis, which can lead to intravascular volume contraction; clinicians should consider reducing or pausing concomitant diuretics when initiating therapy, particularly in older adults (≥ 65 years), patients on low‑sodium diets, those with renal impairment, or those already receiving diuretics【5】.

Use is associated with a higher incidence of genital mycotic infections and urinary‑tract infections【5】.

Empagliflozin is contraindicated in individuals with hypersensitivity to the drug, patients receiving dialysis, and during pregnancy or lactation【5】.

The 2025 Canadian Cardiovascular Society (CCS) guidelines give a Class I recommendation for SGLT2‑inhibitor therapy in patients with heart failure with non‑reduced ejection fraction (HFnrEF), encompassing early diastolic dysfunction and concentric left‑ventricular hypertrophy. 7
The 2022 Canadian guideline on structural heart disease advises early integration of SGLT2 inhibitors into cardiovascular management for patients with objective cardiac remodeling but no symptoms. 8

In adults with cardiovascular risk factors or early structural heart disease, empagliflozin reduces the incidence of symptomatic heart failure compared with usual care. Evidence comes from a 2022 Diabetes Care trial and a 2021 Canadian cardiology study. [9][10]
The EMPEROR‑Preserved randomized trial showed that empagliflozin decreases the composite of cardiovascular death or heart‑failure hospitalization by 21 % in patients with left‑ventricular ejection fraction > 40 %, independent of diabetes status. 7
The treatment benefit was consistent across the entire spectrum of ejection fractions, supporting use even before any decline in LVEF occurs. Data from the 2025 CCS report and a 2024 Diabetes Care analysis confirm this uniform effect. [7][11]

Empagliflozin produces a modest afterload reduction, lowering systolic blood pressure by an average of ~2 mm Hg, which lessens the workload of a hypertrophied left ventricle. 7
The drug exerts anti‑inflammatory and antifibrotic actions that contribute to reverse cardiac remodeling, including reductions in myocardial fibrosis and left‑ventricular mass. 7
Empagliflozin improves endothelial function and attenuates oxidative stress, addressing vascular contributors to diastolic dysfunction. 7

The most frequent adverse event is genital mycotic infection, occurring in roughly 10–15 % of women (lower in men); these infections are usually managed with topical antifungals without stopping therapy. 10
Volume‑depletion symptoms (e.g., orthostatic dizziness) are generally mild; clinicians should monitor patients, especially those also receiving diuretics or low‑sodium diets. 10
A temporary decline in estimated glomerular filtration rate of up to ~15 % may be observed during the first 1–3 months, typically resolving as a hemodynamic adaptation rather than true kidney injury. 10

Preventive cardiology at the structural‑heart‑disease stage involves initiating disease‑modifying therapy after objective evidence of remodeling (e.g., concentric hypertrophy, grade 1 diastolic dysfunction) but before symptom onset; this approach aligns with the 2025 CCS recommendation for HFnrEF. [7][8]

All statements are derived from cited peer‑reviewed sources and reflect the strength of evidence as reported in the original references.