SGLT2 Inhibitors in Acute Heart Failure: Early Initiation After Stabilization Gains Guideline Support, Though Key Questions Remain
Key Insights
SGLT2 (search) inhibitors have evolved from glucose-lowering agents to cornerstone therapy for chronic heart failure, with application now expanding into acute heart failure (search) (AHF) management.
The EMPULSE trial demonstrated that empagliflozin initiated after clinical stabilization significantly improved a hierarchical composite outcome of death, heart failure events, and symptom score at 90 days.
The 2025 JCS/JHFS Guidelines now assign a class I, level A recommendation for SGLT2 (search) inhibitors in AHF, supporting initiation after hemodynamic stability is achieved.
The role of sodium-glucose cotransporter 2 (SGLT2 (search)) inhibitors has undergone a remarkable transformation—from glucose-lowering agents for type 2 diabetes (search) to foundational therapy for chronic heart failure—and now evidence is mounting for their use in the acute heart failure (search) (AHF) setting. A comprehensive narrative review published in the International Journal of General Medicine synthesizes the latest clinical evidence, guideline updates, and remaining uncertainties surrounding SGLT2 inhibitor initiation during or shortly after hospitalization for AHF.
Acute heart failure (search) remains a leading cause of hospital admission, with 30-day mortality rates of 15–25% and a 1-year readmission rate exceeding 40%. Two-year mortality has been reported as high as 52.8%. While conventional in-hospital therapy—loop diuretics, vasodilators, and inotropes—provides rapid symptomatic relief, these measures do not improve long-term prognosis and may activate neurohormonal systems such as the renin-angiotensin-aldosterone axis (RAAS).
Randomized Evidence Supporting In-Hospital Initiation
Several randomized controlled trials have evaluated the efficacy and safety of initiating SGLT2 (search) inhibitors during hospitalization or around discharge. The EMPAG-HF trial randomized 60 patients with acute decompensated heart failure to empagliflozin 25 mg or placebo within 12 hours of admission. Over 5 days, empagliflozin increased cumulative urine output and improved loop diuretic efficiency without adversely affecting renal function.
The larger EMPULSE trial provided pivotal evidence, randomizing 530 patients with de novo or decompensated chronic heart failure to empagliflozin 10 mg or placebo after clinical stabilization (median time to randomization: approximately 3 days after admission). Empagliflozin significantly improved the primary hierarchical composite outcome of all-cause death, heart failure events, and change in Kansas City Cardiomyopathy Questionnaire total symptom score at 90 days, with fewer serious adverse events than placebo.
For sotagliflozin, a dual SGLT1 (search)/2 inhibitor, the SOLOIST-WHF trial enrolled 1,222 patients with type 2 diabetes (search) and recent worsening heart failure. Initiated either before discharge or within 3 days after discharge, sotagliflozin significantly reduced the total number of cardiovascular deaths, hospitalizations for heart failure, and urgent visits for heart failure over a median follow-up of 9 months.
Dapagliflozin has also been studied extensively. The DICTATE-AHF trial showed that dapagliflozin initiated within 24 hours of admission reduced loop diuretic requirements, improved natriuresis, and facilitated earlier discharge. However, the DAPA ACT HF-TIMI 68 trial—the largest to date with 2,401 patients—did not reach statistical significance for its primary composite endpoint of cardiovascular death or worsening heart failure at 2 months, though dapagliflozin was well tolerated.
A prespecified meta-analysis incorporating DAPA ACT HF-TIMI 68, EMPULSE, and SOLOIST-WHF (3,527 patients total) suggested that in-hospital or peri-discharge initiation of SGLT2 (search) inhibitors reduced the early risk of cardiovascular death or worsening heart failure and all-cause mortality.
Guideline Recommendations Strengthen
Guideline recommendations have evolved rapidly. The 2021 ESC Guidelines incorporated SGLT2 (search) inhibitors as part of foundational therapy for heart failure with reduced ejection fraction. The 2023 ESC focused update further emphasized early guideline-directed medical therapy optimization. Most notably, the 2025 JCS/JHFS Guidelines assigned a class I, level A recommendation to SGLT2 inhibitors in AHF, recommending initiation after hemodynamic stability is achieved. The 2025 HFA/HFAI Scientific Statement similarly recommended dapagliflozin or empagliflozin and supported early initiation after stabilization in patients hospitalized with acute decompensation.
Mechanisms of Benefit in the Acute Setting
The review outlines multiple mechanisms by which SGLT2 (search) inhibitors may confer benefit in AHF. Through osmotic diuresis—blocking glucose and sodium reabsorption in the proximal tubule—these agents promote fluid excretion without relying on renal medullary blood flow, potentially remaining effective even when renal perfusion is reduced. Unlike loop diuretics, SGLT2 inhibitors appear to remove fluid more efficiently from the interstitial compartment relative to intravascular volume.
Additional mechanisms include improved myocardial energy metabolism through a shift toward ketone body oxidation, relief of congestion through complementary pathways to loop diuretics, and anti-inflammatory and antioxidant effects. In the AHF context, these mechanisms exhibit rapid onset: osmotic diuretic effects can relieve pulmonary congestion within hours, while metabolic and anti-inflammatory effects may provide myocardial protection over days to weeks.
Unresolved Questions and Safety Considerations
Despite growing evidence, several clinically important questions remain. The optimal timing of initiation has not been standardized—studies have used windows ranging from within 12 hours of admission (EMPAG-HF) to after clinical stabilization at a median of 3.6 days (DAPA ACT HF-TIMI 68). The definition of hemodynamic stabilization itself varies across studies and guidelines.
Safety data remain limited in high-risk populations excluded or underrepresented in trials, including patients with cardiogenic shock, severe renal impairment, persistent hypotension, active infection, or ongoing requirement for vasoactive agents. While the overall safety profile in trials has been reassuring—with no significant excess of hypotension, severe renal adverse events, or hyperkalemia in DAPA ACT HF-TIMI 68—clinicians are advised to defer initiation in patients with persistent hemodynamic instability, severe volume depletion, or rapidly progressive renal dysfunction.
Real-world evidence, including the AGING-HF study in very elderly patients (mean age approximately 90 years), suggests feasibility in carefully selected older adults, with low discontinuation rates. However, observational studies also indicate that only a minority of AHF patients in routine practice would meet clinical trial eligibility criteria, and eligible patients tend to have better outcomes than ineligible patients.
The review concludes that SGLT2 (search) inhibitors should be considered early after hemodynamic stabilization in eligible patients with AHF, while emphasizing that future large-scale randomized trials and well-designed real-world studies are needed to define the optimal initiation window, standardize clinical stabilization criteria, and systematically evaluate the risk-benefit profile in high-risk populations.