SGLT2 inhibitors were approved by the FDA as glucose-lowering agents beginning in 2013. The class received its first major cardiovascular signal in the EMPA-REG OUTCOME trial (2015), which showed that empagliflozin dramatically reduced cardiovascular death and HF hospitalization in patients with type 2 diabetes and established cardiovascular disease; an effect that appeared too rapid to be explained by glycemic improvement alone.³ Subsequent dedicated HF trials, DAPA-HF, EMPEROR-Reduced, EMPEROR-Preserved, and DELIVER, established SGLT2 inhibitors as disease-modifying agents in both HFrEF and HFpEF regardless of diabetes status, transforming their role from glucose-lowering adjuncts to core HF therapeutics.¹·²

The mechanism by which SGLT2 inhibitors benefit the failing heart is multifactorial and remains an area of active investigation. Proposed mechanisms include: Osmotic diuresis and natriuresis: SGLT2 inhibitors block the SGLT2 cotransporter in the proximal renal tubule, preventing reabsorption of approximately 60–80 g/day of glucose and 60–70 mEq/day of sodium.¹ The resulting glucosuria and natriuresis reduce intravascular volume, ventricular filling pressures (preload), and plasma volume, producing a mild but sustained osmotic diuresis effect. Unlike loop diuretics, which activate the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system (SNS) as a counter-regulatory response to volume reduction, SGLT2 inhibitor-mediated volume reduction appears to be better tolerated hemodynamically and does not significantly elevate catecholamine or renin levels.¹ Reduction in afterload: Through natriuretic and vasodilatory mechanisms, SGLT2 inhibitors modestly reduce arterial stiffness and systemic vascular resistance, reducing LV afterload. Erythropoiesis and hematocrit: SGLT2 inhibitors increase hematocrit (erythropoiesis-stimulating effect through increased erythropoietin secretion, possibly mediated by tubular hypoxia signaling), improving oxygen-carrying capacity. This effect may improve myocardial and skeletal muscle energetics.¹

Myocardial energetics and metabolic shift: The failing heart preferentially oxidizes glucose but is energetically inefficient due to the relative overuse of glucose metabolism. SGLT2 inhibitors induce a mild metabolic shift toward ketone body production (beta-hydroxybutyrate): a more oxygen-efficient fuel source for the failing myocardium. Increased myocardial ketone utilization may improve energy production per unit oxygen consumed.¹ Anti-inflammatory and anti-fibrotic effects: SGLT2 inhibitors reduce NLR family pyrin domain-containing protein 3 (NLRP3) inflammasome activation, reduce NF-κB-mediated inflammatory cytokine production, and may attenuate myocardial interstitial fibrosis: mechanisms that complement the anti-fibrotic effects of MRAs and RAAS blockers.⁴ Epicardial fat reduction: SGLT2 inhibitors reduce visceral and epicardial adiposity, which in HFpEF is a major driver of systemic inflammation, pericardial constraint, and neurohormonal activation.⁴ Direct cardiomyocyte effects: SGLT2 receptors have been identified in cardiac tissue (though SGLT2 expression in the heart remains controversial), and SGLT2 inhibitors may reduce intracellular sodium and calcium overload through effects on the NHE-1 (sodium-hydrogen exchanger) in the myocardium: potentially reducing cellular calcium overload and improving contractile efficiency.¹

Dapagliflozin (Farxiga): SGLT2 inhibitor with high selectivity for SGLT2 over sodium-glucose cotransporter 1 (SGLT1) (selectivity ratio ~1,200:1). Dose:¹⁰ mg once daily. No dose adjustment required based on renal function for the HF indication. FDA-approved for HFrEF and HFpEF/HFmrEF.¹ Empagliflozin (Jardiance): SGLT2 inhibitor with high selectivity (SGLT2:SGLT1 ratio ~2,500:1). Dose:¹⁰ mg once daily. No dose adjustment required for the HF indication in patients with eGFR ≥20 mL/min/1.73m².² FDA-approved for HFrEF and HFpEF.

The DAPA-HF trial randomized 4,744 patients with HFrEF (left ventricular ejection fraction (LVEF) ≤40%, NYHA class II–IV, on background ACEi/ARB/ARNI and beta-blocker) to dapagliflozin 10 mg daily vs. placebo.¹ Approximately 42% of patients had type 2 diabetes; 58% did not. Primary endpoint (composite of worsening HF or cardiovascular (CV) death): HR 0.74 (95% CI 0.65–0.85; p<0.001): a 26% relative risk reduction. Key findings: benefit was consistent in patients with and without type 2 diabetes (HR 0.75 and 0.73 respectively: no significant interaction). All-cause mortality was reduced by 17%. CV mortality was reduced by 18%. HF hospitalizations reduced by 30%. Symptom burden (Kansas City Cardiomyopathy Questionnaire (KCCQ) score) improved significantly.¹ The benefit was observed on top of background GDMT that included beta-blockers (~96%), RAAS blockers (~93%), and MRAs (~71%): establishing dapagliflozin as additive to the then-existing three pillars of GDMT.

The EMPEROR-Reduced trial randomized 3,730 patients with HFrEF (LVEF <40%, NYHA class II–IV) to empagliflozin 10 mg daily vs. placebo on background GDMT.² Approximately 50% had type 2 diabetes. Primary endpoint (composite of CV death or HF hospitalization): HR 0.75 (95% CI 0.65–0.86; p<0.001): a 25% relative risk reduction. HF hospitalizations were reduced by 31%. A notable finding was that the benefit was consistent across all LVEF subgroups ≤40%, and the trial also enrolled patients with LVEF 40–49% (HFmrEF), showing benefit in this group. Additionally, EMPEROR-Reduced demonstrated a significant slowing of eGFR decline over the trial period: suggesting a renoprotective effect of empagliflozin beyond what would be predicted from its hemodynamic effects alone.² A pre-specified meta-analysis of DAPA-HF and EMPEROR-Reduced (SGLT2 inhibitor HFrEF meta-analysis, 2020) confirmed consistent benefit across both trials: composite endpoint HR 0.74 (95% CI 0.68–0.82), all-cause mortality HR 0.84 (95% CI 0.76–0.93).¹·²

The extension of SGLT2 inhibitor benefit to HFpEF represents a pivotal advance, as HFpEF had resisted all prior pharmacological attempts at mortality reduction. EMPEROR-Preserved (2021): 5,988 patients with HFpEF (LVEF >40%, NYHA class II–IV) randomized to empagliflozin 10 mg vs. placebo.⁴ Primary endpoint (composite of CV death or HF hospitalization): HR 0.79 (95% CI 0.69–0.90; p<0.001): a 21% relative risk reduction. The benefit was driven primarily by a 29% reduction in HF hospitalizations; CV mortality was not significantly reduced. Benefit was consistent regardless of diabetes status. This was the first large-scale randomized trial to show a statistically significant reduction in HF events in HFpEF. DELIVER (2022): 6,263 patients with HFpEF (LVEF >40%, NYHA class II–IV, majority HFpEF plus a proportion of HFmrEF) randomized to dapagliflozin 10 mg vs. placebo.⁵ Primary endpoint (composite of worsening HF or CV death): HR 0.82 (95% CI 0.73–0.92; p<0.001). A pre-specified analysis combining DELIVER and EMPEROR-Preserved (SGLT2i HFpEF pooled analysis) showed consistent and robust benefit across the full LVEF spectrum of HFpEF and HFmrEF. All-cause mortality was not significantly reduced in either individual trial. These trials together form the basis for the 2022 AHA/ACC/HFSA Class IIa recommendation for SGLT2 inhibitors in HFpEF (and a stronger Class I in HFrEF).⁶

Dosing: Dapagliflozin 10 mg once daily or empagliflozin 10 mg once daily. A single fixed dose is used for all HF indications: no titration is required, unlike RAAS blockers and beta-blockers. eGFR considerations: For the glucose-lowering indication, SGLT2 inhibitors require eGFR ≥45 (dapagliflozin) or ≥30 (empagliflozin). For the HF indication specifically, both agents have been approved at lower eGFR thresholds: dapagliflozin for HF regardless of eGFR (including dialysis in some analyses), empagliflozin for HF with eGFR ≥20 mL/min/1.73m².⁶ This distinction is clinically important: patients with advanced CKD who are ineligible for the glucose-lowering benefit may still benefit from SGLT2 inhibitors for HF.

Diabetes status: SGLT2 inhibitors should be used for HFrEF regardless of the presence or absence of type 2 diabetes: this is unambiguously supported by DAPA-HF and EMPEROR-Reduced subgroup analyses showing equivalent benefit regardless of diabetes status.⁶ In patients with diabetes, the glucose-lowering effect is additive; in non-diabetic HF patients, blood glucose does not fall to dangerous levels because SGLT2 inhibitors only prevent reabsorption of filtered glucose and do not stimulate insulin secretion or suppress glucagon. Monitoring: No routine laboratory monitoring is required beyond standard HF follow-up. Checking eGFR and electrolytes at initiation and periodically is reasonable, though SGLT2 inhibitors do not typically cause acute creatinine elevation. Blood glucose monitoring is important in diabetic patients on concurrent insulin or sulfonylureas (small increased hypoglycemia risk from those agents in the context of improved glucose control). Blood pressure should be rechecked; mild BP reduction is common and welcome in most HF patients.

Genital mycotic infections: The most common adverse effect of SGLT2 inhibitors. Glucosuria creates a substrate-rich environment for Candida and other organisms in the genital tract; genital fungal infections occur in approximately 6–8% of women and 3% of men.¹ Most are mild and respond to standard topical antifungal treatment. Uncircumcised men have a higher risk of Fournier gangrene (necrotizing fasciitis of the perineum: a rare but serious adverse effect). Counsel patients on genital hygiene. Urinary tract infections: Modestly increased risk; typically mild. Most patients do not require antibiotic prophylaxis.

Volume depletion/hypotension: The osmotic diuretic effect can cause volume depletion, particularly in patients already on aggressive loop diuretics. Monitor for symptomatic hypotension; diuretic dose may need reduction after SGLT2 inhibitor initiation. Diabetic ketoacidosis (DKA): SGLT2 inhibitor-associated DKA is a recognized risk, typically occurring in patients with diabetes (especially type 1, in whom SGLT2 inhibitors are generally not used). The ketoacidosis may be euglycemic: a particularly dangerous scenario where glucose is not markedly elevated, potentially delaying diagnosis. SGLT2 inhibitors should be held for at least 3–4 days before elective surgery and during prolonged fasting, acute illness, or significant carbohydrate restriction.¹ Lower limb amputation: An increased risk was observed in the CANVAS trial for canagliflozin; this signal has not been consistently replicated with dapagliflozin or empagliflozin and is likely agent-specific or related to the study population. Contraindications: Type 1 diabetes (relative for HF use; limited evidence and DKA risk); SGLT2 inhibitor-associated DKA history; severe renal impairment below the approved eGFR threshold for the specific agent and indication; recurrent severe genital or urinary tract infections.

Hydralazine is a direct arterial vasodilator acting through stimulation of cGMP production and K-channel opening in vascular smooth muscle, producing afterload reduction through mechanisms that are independent of the RAAS.⁶ Isosorbide dinitrate is an organic nitrate that generates NO in vascular smooth muscle, producing venodilation (preload reduction) and mild arterial vasodilation. The combination simultaneously reduces preload and afterload: hemodynamic effects similar to ACEi/ARBs but through RAAS-independent mechanisms. Both drugs also have antioxidant properties. Hydralazine may attenuate nitrate tolerance that develops with sustained nitrate monotherapy.

V-HeFT I (1986): The first randomized trial to demonstrate that any drug combination improved survival in HFrEF: H/ISDN reduced all-cause mortality by 38% compared to placebo over 2 years in a predominantly male HF population.⁸ V-HeFT II subsequently showed that enalapril produced a more sustained mortality reduction than H/ISDN, establishing ACEi as the superior agent in this comparison and relegating H/ISDN to an alternative role. A-HeFT (2004): 1,050 patients of self-identified Black race with HFrEF (NYHA class III–IV) randomized to H/ISDN (fixed-dose combination: hydralazine 37.5 mg / isosorbide dinitrate 20 mg, three times daily) vs. placebo, all on background ACEi/ARB, beta-blocker, and diuretics.⁹ The trial was stopped early due to a significant reduction in all-cause mortality (HR 0.57; 43% relative risk reduction; p=0.01) and HF hospitalization (33% reduction) with H/ISDN. This trial formed the basis for a specific Class I guideline recommendation for H/ISDN as add-on therapy in patients of self-identified Black race with HFrEF remaining symptomatic despite ACEi/ARB and beta-blocker.⁶

Primary indication: Patients of self-identified Black race with HFrEF (LVEF ≤35%, NYHA class III–IV) remaining symptomatic on maximally tolerated ACEi/ARB/ARNI + beta-blocker, per A-HeFT evidence.⁶ A-HeFT used the fixed-dose combination product (BiDil); equivalent doses can be prescribed as separate agents. Secondary indication: ACEi/ARB/ARNI-intolerant patients (due to angioedema, severe renal impairment, pregnancy) where RAAS blockade is not possible. In these patients, H/ISDN provides vasodilator therapy with demonstrated survival benefit (V-HeFT I): though evidence for equivalence to RAAS blockade is not established.⁶

Dosing: Start hydralazine 25 mg + isosorbide dinitrate 10 mg three times daily (or the fixed-dose combination 37.5/20 mg TID); titrate to hydralazine 75 mg + ISDN 40 mg TID (or fixed combination 75/40 mg TID) as tolerated. Adverse effects: Headache (very common, especially with nitrate component, often improves after 2 weeks), tachycardia (from reflex SNS activation in response to vasodilation, particularly with hydralazine), hypotension, drug-induced lupus-like syndrome with high-dose hydralazin (anti-histone antibodies; rare at HF doses), GI intolerance. Adherence to TID dosing can be challenging. Nitrate tolerance: Continuous nitrate use causes tolerance through depletion of sulfhydryl groups required for nitrate bioactivation. A nitrate-free interval of 8–12 hours daily (typically overnight) should be maintained where possible; the TID dosing protocol provides some natural tolerance-free interval.

The practical implication of DAPA-HF, EMPEROR-Reduced, EMPEROR-Preserved, and DELIVER is that dapagliflozin 10 mg or empagliflozin 10 mg once daily should be initiated in essentially all HF patients (HFrEF, HFmrEF, and HFpEF) as part of routine GDMT, regardless of diabetes status, unless specific contraindications exist.⁶ The ease of use (single fixed dose, no titration, no laboratory monitoring requirement) and the breadth of the evidence base make SGLT2 inhibitors particularly accessible compared to the other GDMT pillars.

Vericiguat: Consider in patients with recent worsening HF event (hospitalization or IV diuresis) despite optimized four-pillar GDMT: particularly in patients with high NT-proBNP and persistent NYHA class III–IV symptoms.⁶ Ivabradine: Consider in patients with stable HFrEF, LVEF ≤35%, NYHA class II–III, sinus rhythm, resting HR ≥70 bpm despite maximally tolerated beta-blocker. Ivabradine should not be initiated in patients with AF or when beta-blocker up-titration is still possible.⁶ H/ISDN: (1) Add-on therapy in patients of self-identified Black race with HFrEF who remain symptomatic despite optimized four-pillar GDMT (Class I); (2) Vasodilator substitute for RAAS blockade in patients with true ACEi/ARB/ARNI intolerance (Class I).⁶