SGLT2 Inhibitors for Heart Failure: A Breakthrough Regardless of Diabetes Status

What Are SGLT2 Inhibitors and How Do They Help Heart Failure?

Sodium-glucose cotransporter 2 (SGLT2) inhibitors, also called gliflozins, were initially developed as antidiabetic medications. They work by blocking SGLT2 in the proximal tubule of the kidney, which normally reabsorbs approximately 90% of filtered glucose. By inhibiting this transporter, SGLT2 inhibitors cause the excretion of approximately 60–80 grams of glucose per day in urine, lowering blood glucose while also promoting natriuresis (sodium excretion) and osmotic diuresis.

The cardiovascular benefits of SGLT2 inhibitors extend well beyond glucose control and are now understood to involve multiple mechanisms. Natriuresis and osmotic diuresis reduce plasma volume and cardiac preload without activating the neurohormonal compensatory mechanisms (sympathetic nervous system and renin-angiotensin-aldosterone system) that occur with traditional diuretics. SGLT2 inhibitors shift cardiac metabolism from fatty acid oxidation toward more efficient ketone body utilization, improving myocardial energetics. They also reduce inflammation by decreasing NLRP3 inflammasome activation, lower oxidative stress, and may directly improve cardiac fibrosis.

Two SGLT2 inhibitors have received FDA approval specifically for heart failure: dapagliflozin (Farxiga, AstraZeneca) was approved in May 2020 for heart failure with reduced ejection fraction (HFrEF) and expanded to HF regardless of ejection fraction in 2023; empagliflozin (Jardiance, Boehringer Ingelheim/Lilly) was approved for HFrEF in 2022 and for HF regardless of ejection fraction in 2023. These approvals apply to patients with and without type 2 diabetes, reflecting the class's diabetes-independent cardiovascular benefits.

What Did the DAPA-HF and EMPEROR-Reduced Trials Show?

The DAPA-HF trial (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure), published in the New England Journal of Medicine in 2019, enrolled 4,744 patients with heart failure and LVEF ≤40% (NYHA class II–IV) across 20 countries. Patients were randomized to dapagliflozin 10mg daily or placebo, added to standard guideline-directed medical therapy. At a median follow-up of 18.2 months, dapagliflozin reduced the primary composite endpoint of worsening heart failure (hospitalization or urgent visit requiring IV therapy) or cardiovascular death by 26% (HR 0.74, 95% CI 0.65–0.85, p<0.001). Importantly, 55% of participants did not have diabetes, and the benefit was consistent regardless of diabetes status.

The EMPEROR-Reduced trial (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Reduced Ejection Fraction), published in the NEJM in 2020, enrolled 3,730 patients with similar inclusion criteria (LVEF ≤40%, NYHA class II–IV). Empagliflozin 10mg daily reduced the primary composite of cardiovascular death or heart failure hospitalization by 25% (HR 0.75, 95% CI 0.65–0.86, p<0.001). Additionally, empagliflozin significantly slowed the rate of decline in estimated glomerular filtration rate (eGFR), demonstrating a renal protective effect of -0.55 mL/min/1.73m² per year vs. -2.28 in placebo.

A pre-specified meta-analysis combining both trials (published in The Lancet, 2020) confirmed the robustness of the class effect: SGLT2 inhibitors reduced the composite of cardiovascular death or first hospitalization for HF by 26% (HR 0.74, 95% CI 0.68–0.82), all-cause mortality by 13% (HR 0.87, p=0.018), and first HF hospitalization by 31% (HR 0.69). Benefits were consistent across subgroups defined by age, sex, race, diabetes status, baseline ejection fraction, and background medications. The number needed to treat (NNT) to prevent one primary event was approximately 21 over 16 months.

Are SGLT2 Inhibitors Now Standard Heart Failure Treatment?

The 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure elevated SGLT2 inhibitors to a Class I, Level of Evidence A recommendation for patients with HFrEF (LVEF ≤40%), placing them alongside the established three pillars of HF therapy: renin-angiotensin system inhibitors (preferably sacubitril/valsartan), beta-blockers (carvedilol, bisoprolol, or sustained-release metoprolol succinate), and mineralocorticoid receptor antagonists (spironolactone or eplerenone). This "four-pillar" approach is now considered the foundation of HFrEF treatment.

For heart failure with preserved ejection fraction (HFpEF, LVEF >50%), the evidence base has also grown substantially. The EMPEROR-Preserved trial (2021, NEJM) demonstrated that empagliflozin reduced the composite of cardiovascular death or HF hospitalization by 21% (HR 0.79) in HFpEF patients. The DELIVER trial (2022, NEJM) showed dapagliflozin reduced the same composite by 18% (HR 0.82) in patients with LVEF >40%. These results are particularly significant because HFpEF has historically lacked effective pharmacotherapy. The 2022 guidelines provide a Class IIa recommendation for SGLT2 inhibitors in HFpEF.

In clinical practice, SGLT2 inhibitors offer practical advantages including oral once-daily dosing, no need for dose titration, rapid onset of benefit (separation of survival curves begins within weeks), and a favorable side effect profile. The most common adverse effects include genital mycotic infections (occurring in approximately 2–5% of patients), urinary tract infections, and volume depletion. Diabetic ketoacidosis is rare but can occur in patients with type 1 diabetes, which is a contraindication. SGLT2 inhibitors should be used with caution in patients with eGFR below 20 mL/min/1.73m², though recent guidelines have relaxed previous eGFR thresholds as data on renal safety have accumulated.

How Do SGLT2 Inhibitors Compare to Other Heart Failure Treatments?

A comprehensive analysis by Vaduganathan et al. published in The Lancet (2020) estimated that the four-pillar combination (ARNi + beta-blocker + MRA + SGLT2 inhibitor) could provide a 73% reduction in cardiovascular death or HF hospitalization compared to treatment with an ACE inhibitor and beta-blocker alone, the former standard of care. This translates to an estimated additional 8.3 years of event-free survival for a 55-year-old patient with HFrEF. The analysis underscored that each pillar provides independent, additive benefit.

Unlike the other three pillars, SGLT2 inhibitors do not require careful dose titration or monitoring for specific side effects like hyperkalemia (MRA) or bradycardia/hypotension (beta-blockers). This simplicity facilitates rapid initiation and makes them well-suited for starting early in the treatment pathway. Some expert consensus statements now recommend beginning all four pillars simultaneously or in rapid sequence rather than the traditional sequential approach that can delay achieving full guideline-directed medical therapy for months.

The multi-organ protective effects of SGLT2 inhibitors extend beyond the heart. The CREDENCE trial (2019, NEJM) and DAPA-CKD trial (2020, NEJM) demonstrated significant renal protective benefits, reducing the progression of chronic kidney disease by 30–39%. Given the frequent coexistence of heart failure, chronic kidney disease, and diabetes, SGLT2 inhibitors offer a unique advantage in addressing multiple comorbidities with a single well-tolerated medication. This has led to the concept of "cardiorenal metabolic medicine" as an integrated approach, with SGLT2 inhibitors as a central therapeutic agent.