Advancements in Heart Failure Management: SGLT2 Inhibitors and Beyond

Heart failure (HF) continues to pose a challenge to global health, affecting millions and underscoring the need for more effective treatments. Historically, managing this complex condition has evolved significantly, marked by the introduction of various drug classes that have incrementally improved patient outcomes. Now, the integration of sodium-glucose cotransporter-2 (SGLT2) inhibitors into HF treatment represents a crucial advancement, shifting the focus from purely symptom-focused care to a more comprehensive, evidence-based approach.

SGLT2 inhibitors, initially developed for managing type 2 diabetes, have proven to be successful in reducing significant cardiovascular events and hospitalizations for patients with HF, entirely independent of their diabetic status. Their primary action involves inhibiting the SGLT2 in the kidneys, leading to increased glucose excretion in the urine and improved glycemic control.¹

The mechanisms underlying the cardioprotective effects of SGLT2 inhibitors extend far beyond glucose lowering. Their diuretic and natriuretic properties help reduce volume overload, a common and debilitating symptom of HF, by promoting the excretion of sodium and water. “In my practice, I’ve seen how SGLT2 inhibitors work like tiny doormen in the kidneys, blocking sugar and sodium from being reabsorbed back into the bloodstream,” said Dr. Edward Espinosa, owner, OptumMD. “When I explain this to patients, I often compare it to a bouncer stopping unwanted guests from entering a club—it helps them understand how these medications effectively lower blood sugar and reduce fluid retention.”

Furthermore, SGLT2 inhibitors are believed to improve cardiac energetics and myocardial metabolism, potentially shifting the heart’s fuel source to more efficient substrates.² They also play a role in reducing inflammation and fibrosis, processes that contribute to cardiac remodeling and dysfunction.³ Beyond these effects, their influence on BP and vascular function may also contribute to their overall cardiovascular benefits.⁴

Emerging evidence also points to positive effects on gastrointestinal health. Dr. Bharat Pothuri of Texas-based GastroDoxs, shared that “SGLT2 inhibitors have shown remarkable effects on reducing inflammation throughout the body, which benefits both cardiac and digestive systems. I’ve had several patients with both fatty liver disease and heart failure show significant improvement in both conditions after starting SGLT2 inhibitors. One notable case involved a 62-year-old patient whose liver function tests normalized within 3 months while simultaneously reporting improved exercise tolerance related to their heart condition.”

The transformative impact of SGLT2 inhibitors in HF is strongly supported by evidence from several clinical trials.⁵ Studies such as EMPA-REG OUTCOME,⁶ CANVAS Program, DAPA-HF and  EMPEROR-Reduced,⁷ and EMPEROR-Preserved⁸ have consistently demonstrated significant reductions in hospitalization for HF and cardiovascular death across a broad spectrum of patients. Crucially, these trials have highlighted their broad applicability, proving effective in both HF with reduced ejection fraction (HFrEF) and, remarkably, in HF with preserved ejection fraction (HFpEF), a condition for which treatment options have been limited.

The consistent and compelling results from these trials have solidified the position of SGLT2 inhibitors as foundational therapy in HF management.

Expanding Horizons: Emerging Therapies Beyond SGLT2 Inhibitors

Although SGLT2 inhibitors have fundamentally changed HF treatment, the therapeutic landscape continues to expand with other promising advancements.

Mineralocorticoid Receptor Antagonists: A Newer Generation

Older mineralocorticoid receptor antagonists (MRAs), such as spironolactone and eplerenone, have long been cornerstones of HF management, primarily by blocking the harmful effects of aldosterone on the heart and kidneys. However, a newer, nonsteroidal MRA, finerenone, has emerged, offering a more selective action with a potentially enhanced safety profile, particularly for patients with chronic kidney disease (CKD) alongside HF. Finerenone’s distinct binding characteristics minimize side effects such as hyperkalemia, which can be a concern with older MRAs, especially for patients with renal impairment.⁹ Clinical trials such as FIDELIO-DKD and FIGARO-DKD have demonstrated finerenone’s efficacy in reducing the risk of cardiovascular events and kidney failure progression among patients with type 2 diabetes and CKD, a population often at high risk for HF.¹⁰

Novel Neurohormonal Modulation

Beyond MRAs, other approaches to modulate neurohormonal pathways are gaining traction. Neprilysin inhibition, represented by sacubitril/valsartan, has already established its role in HFrEF by boosting beneficial natriuretic peptides while blocking the action of the renin-angiotensin system.¹¹

Furthermore, selective endothelin receptor antagonists are being investigated. Aprocitentan is showing promise in managing resistant hypertension, a condition often co-occurring with HF and contributing to its progression.¹² By blocking the powerful vasoconstrictor endothelin-1, aprocitentan offers a new possibility for BP control in challenging cases.

Targeting Myocardial Contractility and Function

A more direct approach involves targeting the heart muscle’s ability to contract. Cardiac myosin activators, such as omecamtiv mecarbil, represent a novel class of drugs designed to directly improve myocardial contractility. Unlike traditional inotropes that increase intracellular calcium, omecamtiv mecarbil works by increasing the number of myosin heads that can bind to actin, thereby enhancing the force of contraction without increasing myocardial oxygen consumption.¹³ The GALACTIC-HF trial, a pivotal study for omecamtiv mecarbil, demonstrated an 8% reduction in cardiovascular death or HF events among patients with HFrEF.¹⁴

Emerging Areas of Research

The future of HF therapy extends even further, with exciting research continuing in areas such as gene therapies, which aim to correct underlying genetic defects or introduce beneficial genes to improve cardiac function. A promising new therapy for HF is being tested at the University of Louisville, where cardiologist Dr. Roberto Bolli is leading a groundbreaking clinical trial.¹⁵ This phase II study, known as the CATO trial, is the first in the United States to use IV delivery of umbilical cord–derived stem cells for treatment of chronic HF, specifically targeting ischemic cardiomyopathy. Funded by an $8 million Department of Defense grant, the CATO trial explores the potential of multiple stem cell doses to reduce inflammation, improve heart function, and enhance quality of life. Dr. Bolli stated, “Until now, virtually all stem cell studies have used invasive techniques (transendocardial injections) to deliver cell products, which has effectively limited the treatment to one dose. Compared to these techniques, intravenous delivery of cells is simpler, cheaper, safer, and can be performed almost everywhere in almost all patients with HF, even as an outpatient procedure. Importantly, it is exquisitely suitable for repeated infusions of cells. Thus, intravenous delivery could dramatically expand the impact and application of cell therapy for HF.”

Personalized Approaches and Future Directions

The evolving landscape of HF management increasingly emphasizes personalized approaches. Moving beyond a one-size-fits-all model, clinicians are now considering individual patient characteristics, complex comorbidities, and specific biomarker profiles to tailor treatment strategies. This patient-centric approach allows for the optimization of therapies, maximizing benefits while minimizing adverse effects.

A key area of future progress in HF treatment involves strategically combining innovative therapies—especially integrating SGLT2 inhibitors with emerging options such as next-generation MRAs or cardiac myosin activators. These multi-targeted approaches offer the potential for synergistic benefits by addressing multiple underlying disease mechanisms at once.

Continued investigation into novel therapeutic targets, refining existing drug combinations, and understanding long-term outcomes are crucial to further improve the lives of patients with HF and ultimately conquer this challenging global health burden.