SGLT2 Inhibitors in Heart Failure Regardless of Diabetes Status

SGLT2 inhibitors reduce heart failure hospitalizations and cardiovascular death across HFrEF and HFpEF populations, independent of diabetes status. Benefits extend to functional capacity and quality of life, with a consistent class effect and favorable safety profile when monitored appropriately ^[1], ^[2], ^[3], ^[4], ^[5], ^[6].

Clinical question

Do SGLT2 inhibitors improve outcomes in heart failure patients irrespective of diabetes, and what are the practical considerations for use?

Heart FailureSGLT2 inhibitorsHFrEFHFpEFCardiometabolicGuideline-directed therapy

Key points

Class Effect Across EF and Diabetes Status

SGLT2 inhibitors consistently reduce HF events regardless of diabetes, EF category, or cardiometabolic comorbidities, supporting a broad HF indication ^[1], ^[3], ^[6].

Meaningful Patient-Centered Outcomes

Meta-analyses show improved functional capacity and quality of life across subgroups, reinforcing day-to-day benefits beyond hard outcomes ^[2].

Therapeutic Backbone

In HFrEF, SGLT2 inhibitors join RASi/ARNI, beta-blockers, and MRAs as foundational therapy; combinations yield large absolute risk reductions ^[4].

Non-Diabetic HF Patients Benefit

Evidence in non-diabetic HF shows significant reductions in HF hospitalization and improved outcomes, aligning with class-wide findings ^[5].

Safety and Monitoring

Adverse effects are generally manageable; volume depletion and genital mycotic infections warrant monitoring—ketoacidosis is rare in non-diabetics but educate patients on sick-day rules ^[4].

Evidence highlights

~29% relative reduction in first HF hospitalization in HF cohorts ^[1].

HF Hospitalization

~14% reduction in CV death in HF populations; similar benefit in T2D and CKD cohorts ^[7], ^[3].

Cardiovascular Death

Improved KCCQ and 6MWD regardless of sex, diabetes status, or EF ^[2].

QoL / Functional Gains

Implementation

How to Initiate SGLT2 Inhibitors in HF Regardless of Diabetes

Integrate early, alongside other guideline-directed therapies, with attention to renal function and volume status.

Select the Agent and Dose

Use dapagliflozin 10 mg daily or empagliflozin 10 mg daily for HF, irrespective of diabetes. No routine uptitration required; start at the target dose ^[4].

Assess Eligibility and Baseline

Check eGFR, volume status, blood pressure, and concomitant diuretics. Most benefits persist down to low eGFR, but expect an initial transient eGFR dip ^[4].

Start Early and Combine

Add to background ARNI/ACEi/ARB, beta-blocker, and MRA in HFrEF; in HFpEF, add to diuretic and comorbidity management. Benefits accrue rapidly (weeks) ^[4].

Monitor Safety

Reassess volume status, creatinine/eGFR, and electrolytes in 1–2 weeks if frail or on high diuretic doses. Counsel on genital hygiene, sick-day rules, and perioperative holds ^[4].

Evidence Synthesis

Key Outcomes and Certainty of Evidence

Randomized trial syntheses and meta-analyses underpin consistent benefits across HF phenotypes and diabetes strata.

Hard Outcomes

HF hospitalization reduction ~29% in HF cohorts ^[1].

CV death reduction ~14% in HF; similar 11–15% across T2D/CKD ^[7], ^[3].

Benefits observed regardless of diabetes and HF type ^[3], ^[6].

Functional Capacity and QoL

Improved KCCQ scores and 6-minute walk distance with SGLT2i, independent of diabetes status and EF ^[2].

Effects consistent across sex and HF phenotypes ^[2].

Mechanistic Plausibility

Hemodynamic unloading, natriuresis, improved energetics, anti-inflammatory and renal-cardiac crosstalk mechanisms support benefits in non-diabetics ^[8], ^[9].

Position in Therapy

Part of foundational HFrEF therapy with ARNI/ACEi/ARB, beta-blocker, MRA; combinations yield HR ~0.36–0.39 for major outcomes ^[4].

Broad cardiometabolic benefits across HF, T2D, CKD, ASCVD populations ^[3].

Safety Signals

Genital mycotic infections (mild–moderate; counsel and treat).

Potential volume depletion/hypotension; adjust loop diuretic if needed.

Rare euglycemic ketoacidosis; higher risk with prolonged fasting/illness—use sick-day holds ^[4].

References

Source material

Primary literature that informs this article.