Combining SGLT2 inhibitors and GLP-1 drugs in heart failure: promising but unproven

Two of the most celebrated drug classes in modern cardiology and diabetes care—sodium–glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists—are increasingly being prescribed together, yet the evidence supporting that combination in patients with heart failure remains strikingly thin. A new narrative review published in Cardiovascular Diabetology – Endocrinology Reports examines what is actually known about concomitant use of these agents in heart failure, and its authors conclude that while the pairing is biologically plausible and clinically promising, dedicated randomized trials in heart failure populations are still lacking. The review, led by Reza Khademi and Saeed Shoar, was published on 23 July 2026 as an open-access article in the journal’s twelfth volume.

The stakes are considerable. Type 2 diabetes mellitus affects an estimated 462 million people worldwide, and cardiovascular disease is the leading cause of illness and death in this population. Heart failure stands out as a major cardiovascular complication of diabetes: people with the metabolic condition carry an approximately 1.6 to 2-fold higher risk of developing incident heart failure than those without diabetes. Both drug classes in question deliver cardiovascular benefit, but their profiles diverge in ways that matter enormously for treatment decisions, and current guidelines already reflect that divergence.

SGLT2 inhibitors, which include empagliflozin and dapagliflozin, are the undisputed workhorses of heart failure therapy. Across randomized cardiovascular outcome trials and pooled analyses, they consistently reduce hospitalization for heart failure by roughly 30 to 37 percent, corresponding to hazard ratios of 0.63 to 0.70, with benefits observed regardless of whether a patient had prior atherosclerotic cardiovascular disease. These benefits hold across the full ejection fraction spectrum—from heart failure with reduced ejection fraction, defined as a left ventricular ejection fraction of 40 percent or less, to mildly reduced and preserved phenotypes. Pooled analyses of empagliflozin showed clinically meaningful benefit across a broad ejection fraction range, from below 25 percent up to below 65 percent, with attenuation of effect only at very high ejection fraction values of 65 percent or more. The review supports use of these agents as foundational therapy across the heart failure spectrum, with early initiation favored when clinically appropriate.

GLP-1 receptor agonists tell a different story. Meta-analyses suggest these agents reduce hospitalization for incident or new-onset heart failure by approximately 18 percent alongside reductions in major adverse cardiovascular events, but their effect on heart failure hospitalization overall appears more modest, with relative risk reductions of approximately 11 percent, or a hazard ratio of 0.89, in pooled analyses. Their strongest suit is atherosclerotic protection: in the SELECT trial, semaglutide reduced major adverse cardiovascular events in patients with overweight or obesity and established atherosclerotic cardiovascular disease without diabetes. A prespecified analysis of SELECT further suggested reductions in composite heart failure outcomes among participants with and without prior heart failure, though the review’s authors emphasize these were secondary analyses rather than heart failure-dedicated trial endpoints.

The picture darkens considerably in established disease. Evidence in patients with established heart failure with reduced ejection fraction has been less consistent, with small randomized trials reporting neutral or potentially unfavorable findings in some patients with reduced ejection fraction. Meta-analyses indicate that although GLP-1 receptor agonists may reduce the risk of new-onset heart failure, they have not consistently improved outcomes in patients with pre-existing heart failure, and the review notes caution has been suggested in those with a left ventricular ejection fraction below 40 percent. Effects may differ according to phenotype, with potentially greater utility in patients with obesity or preserved ejection fraction, whereas the role in established reduced-ejection-fraction disease remains uncertain and should be individualized pending dedicated outcome trials. Overall, the authors conclude, GLP-1 receptor agonists appear most beneficial for cardiometabolic risk reduction, obesity management, and prevention of atherosclerotic cardiovascular events.

Why might combining the two classes make sense? The mechanistic logic rests on complementarity. SGLT2 inhibitors are thought to work predominantly through hemodynamic and cardiorenal pathways: osmotic diuresis and natriuresis may reduce cardiac preload, modest blood pressure lowering may reduce afterload, and favorable renal hemodynamic effects lessen cardiorenal stress. Additional proposed mechanisms include improved myocardial energetics, reduced inflammation, and attenuation of cardiac remodeling, although the relative contribution of each pathway remains uncertain. GLP-1 receptor agonists, by contrast, exert their cardiovascular benefit through mechanisms more closely tied to metabolic and vascular risk modification—they improve glycemic control, promote weight loss, lower blood pressure, and may reduce systemic inflammation and endothelial dysfunction. These effects are consistent with the class’s established reduction in atherosclerotic events and may be particularly relevant in patients with obesity, insulin resistance, or preserved-ejection-fraction phenotypes.

Direct evidence for the combination is emerging but limited. A recent meta-analysis of randomized controlled trials reported lower risk of heart failure hospitalization with concomitant SGLT2 inhibitor and GLP-1 receptor agonist therapy compared with monotherapy or standard care. However, most available randomized data derive from subgroup, post hoc, or exploratory analyses rather than trials specifically designed to evaluate dual therapy in heart failure populations. Exploratory analyses from the AMPLITUDE-O trial found no statistically significant interaction between efpeglenatide treatment effect and background SGLT2 inhibitor use for cardiovascular or heart failure outcomes. Post hoc analyses of Harmony Outcomes and DECLARE–TIMI 58 suggested preserved benefit with concomitant therapy, but these studies were not powered to establish additive efficacy of the combination.

Observational studies and multinational cohorts have also reported lower risks of heart failure hospitalization, major cardiovascular events, and all-cause mortality with combined therapy compared with either class alone. The review’s authors caution, however, that such studies remain vulnerable to residual confounding, treatment-selection bias, and heterogeneity in patient populations. On safety, available evidence suggests combined therapy is generally well tolerated, with safety profiles largely consistent with each class individually. Studies have reported additive benefits in glycemic control, body weight reduction, and blood pressure lowering without major unexpected safety signals. The most frequently reported adverse events with combination therapy are gastrointestinal symptoms—nausea, vomiting, and diarrhea—primarily attributable to GLP-1 receptor agonists and occurring more often than with SGLT2 inhibitor monotherapy. Gradual dose escalation and patient counseling may improve tolerability.

SGLT2 inhibitor–related adverse effects, including genital mycotic infections, volume depletion, and rarely ketoacidosis, remain clinically relevant when these agents are prescribed as part of combination therapy. Notably, the intrinsic risk of hypoglycemia with the combination is low because neither class directly stimulates insulin secretion in a glucose-independent manner; when hypoglycemia does occur, it is more commonly related to concomitant insulin or sulfonylurea use rather than the combination itself. Current data do not suggest a major increase in serious adverse events with dual therapy, but most studies have been of modest duration and conducted in diabetes populations rather than dedicated heart failure cohorts, so continued pharmacovigilance and longer-term heart failure-specific safety data are needed.

For clinicians, the practical takeaway is clear. In patients with type 2 diabetes and established heart failure, SGLT2 inhibitors currently have the strongest evidence base for improving heart failure outcomes and should be prioritized when not contraindicated, with benefits extending across the ejection fraction spectrum and observed irrespective of diabetes status. GLP-1 receptor agonists may be considered when additional treatment goals include weight reduction, improved glycemic control, chronic kidney disease risk reduction, or lowering atherosclerotic cardiovascular risk, particularly in patients with obesity or established atherosclerotic disease—but they should not be viewed as substitutes for evidence-based heart failure therapies. Combination therapy may be reasonable in selected high-risk patients who would benefit from both heart failure-directed treatment and broader cardiometabolic risk reduction, with decisions individualized according to comorbidity burden, renal function, tolerability, cost, route of administration, and patient preference. At present, routine use of dual therapy specifically to improve heart failure outcomes cannot be recommended, because dedicated randomized heart failure trials are lacking. The review’s limitations mirror those of the field: most data derive from post hoc analyses, subgroup analyses, observational cohorts, or trials designed for glycemic or cardiovascular outcomes rather than dedicated heart failure endpoints; study populations have been heterogeneous with respect to diabetes status, obesity, renal function, baseline cardiovascular disease, and heart failure phenotype; and heart failure-specific outcomes such as functional capacity, quality of life, congestion burden, and recurrent hospitalization have been inconsistently reported. The authors call for adequately powered randomized controlled trials evaluating combined therapy in patients with heart failure, with key objectives including determining long-term safety, identifying patient subgroups most likely to benefit, clarifying effects across heart failure phenotypes, and assessing patient-centered outcomes such as quality of life, functional status, and hospitalization burden. Until such trials arrive, the combination remains a mechanistically appealing hypothesis rather than an established standard of care.

Subject of Research: Concomitant use of SGLT2 inhibitors and GLP-1 receptor agonists in patients with heart failure

Article Title: Concomitant use of SGLT2 inhibitors and GLP-1 receptor agonists in patients with heart failure

Article References: Khademi, R., & Shoar, S. (2026). Concomitant use of SGLT2 inhibitors and GLP-1 receptor agonists in patients with heart failure. Cardiovascular Diabetology – Endocrinology Reports, 12(1), Article 47. https://doi.org/10.1186/s40842-026-00319-y

Image Credits: AI Generated

DOI: 10.1186/s40842-026-00319-y

Keywords: SGLT2 inhibitors, GLP-1 receptor agonists, heart failure, type 2 diabetes, cardiovascular outcomes, combination therapy, empagliflozin, dapagliflozin, semaglutide, HF hospitalization, cardiometabolic risk, randomized trials