GLP-1 Agonists and Heart Failure: Decoding the EMPEROR and DAPA-HF Trial Implications

Written by Adam Maggio | Medically reviewed by Dr. James Whitfield, DO, FACOI

While EMPEROR and DAPA-HF trials primarily showcased the profound benefits of SGLT2 inhibitors in heart failure, GLP-1 receptor agonists offer distinct cardiovascular advantages, particularly in stroke prevention and glycemic control, necessitating a nuanced understanding of their roles in comprehensive patient care.

The landscape of cardiovascular disease management has been significantly reshaped by the advent of novel pharmacotherapies, notably glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter 2 (SGLT2) inhibitors. While both classes offer substantial cardiovascular benefits, their primary mechanisms and demonstrated efficacies in specific conditions, such as heart failure, differ. The EMPEROR and DAPA-HF trials, in particular, have provided foundational evidence for the role of SGLT2 inhibitors in heart failure, often leading to questions about where GLP-1 RAs fit into this evolving paradigm.

The Landmark EMPEROR and DAPA-HF Trials

The EMPEROR (EMPagliflozin outcomE tRial in patients with chrOnic heaRt failure) and DAPA-HF (Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure) trials were pivotal studies that unequivocally demonstrated the efficacy of SGLT2 inhibitors, empagliflozin and dapagliflozin respectively, in patients with heart failure. These trials, which included individuals with and without type 2 diabetes, showed significant reductions in heart failure hospitalizations and cardiovascular mortality. For instance, the DAPA-HF trial, published in 2019, reported that dapagliflozin reduced the risk of worsening heart failure or cardiovascular death by 26% compared to placebo [1]. Similarly, the EMPEROR-Reduced trial (a component of the broader EMPEROR program) demonstrated that empagliflozin significantly lowered the composite endpoint of cardiovascular death or hospitalization for heart failure by 25% in patients with heart failure with reduced ejection fraction (HFrEF) [2]. These findings established SGLT2 inhibitors as a cornerstone therapy for heart failure, irrespective of diabetic status.

GLP-1 Receptor Agonists: A Different Cardiovascular Profile

GLP-1 RAs, such as liraglutide, semaglutide, and dulaglutide, have also revolutionized the management of type 2 diabetes and obesity, with compelling evidence for cardiovascular protection. Their mechanisms of action involve enhancing glucose-dependent insulin secretion, suppressing glucagon secretion, slowing gastric emptying, and promoting satiety, leading to improved glycemic control and significant weight loss. Beyond these metabolic effects, GLP-1 RAs have consistently shown reductions in major adverse cardiovascular events (MACE), including non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death, particularly in patients with established atherosclerotic cardiovascular disease [3].

However, the primary cardiovascular benefits of GLP-1 RAs tend to differ from those of SGLT2 inhibitors. While SGLT2 inhibitors directly impact cardiac hemodynamics and renal function, leading to robust heart failure benefits, GLP-1 RAs demonstrate a more pronounced effect on atherosclerotic events and stroke prevention. For example, a meta-analysis of eight cardiovascular outcome trials involving GLP-1 RAs revealed an overall 14% reduction in MACE, with a notable 16% reduction in non-fatal stroke [4]. This distinct profile highlights that while both drug classes are cardioprotective, they achieve this through different pathways and offer complementary benefits.

The Interplay and Clinical Implications

The key takeaway from understanding the EMPEROR and DAPA-HF trials in the context of GLP-1 RAs is that these drug classes are not interchangeable but rather synergistic. The EMPEROR and DAPA-HF trials firmly established SGLT2 inhibitors as essential for heart failure management. GLP-1 RAs, while not the primary focus of these specific heart failure trials, offer critical benefits in other cardiovascular domains, especially stroke prevention and significant weight reduction, which indirectly improve cardiovascular health. The FLOW trial, for instance, has demonstrated that semaglutide (a GLP-1 RA) offers both cardiovascular and renal protection, suggesting an evolving understanding of their broader utility [5].

Clinically, this means that treatment decisions should be individualized, considering a patient's specific comorbidities and risk factors. For a patient with heart failure, an SGLT2 inhibitor is a foundational therapy based on the evidence from EMPEROR and DAPA-HF. If that patient also has type 2 diabetes and a high risk of atherosclerotic events or requires significant weight loss, a GLP-1 RA could be a valuable addition, offering complementary protection. The combination of these agents is increasingly recognized as a powerful strategy for comprehensive cardiovascular and metabolic risk reduction.

Practical Takeaways

SGLT2 Inhibitors are Cornerstone for Heart Failure: The EMPEROR and DAPA-HF trials provide robust evidence for SGLT2 inhibitors in reducing heart failure hospitalizations and cardiovascular death.

GLP-1 RAs Excel in Stroke Prevention and Weight Loss: GLP-1 RAs offer significant benefits in reducing atherosclerotic events, particularly stroke, and achieving substantial weight loss.

Complementary, Not Competitive: These drug classes work through different mechanisms and provide distinct, yet complementary, cardiovascular benefits. They are often used in combination for optimal patient outcomes.

Individualized Treatment: Therapeutic choices should be guided by a patient's specific clinical profile, prioritizing SGLT2 inhibitors for heart failure and considering GLP-1 RAs for additional atherosclerotic risk reduction and weight management.

References

[1] McMurray, J. J. V., et al. (2019). Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. New England Journal of Medicine, 381(20), 1995-2008. [https://www.nejm.org/doi/full/10.1056/NEJMoa1911303]

[2] Packer, M., et al. (2020). Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. New England Journal of Medicine, 383(15), 1413-1424. [https://www.nejm.org/doi/full/10.1056/NEJMoa2022190]

[3] APhA 2025: GLP-1 Receptor Agonists vs SGLT2 Inhibitors Show Varied Benefit for Cardiovascular Outcomes in Patients With Diabetes. Pharmacy Times. [https://www.pharmacytimes.com/view/apha-2025-glp-1-receptor-agonists-vs-sglt2-inhibitors-show-varied-benefit-for-cardiovascular-outcomes-in-patients-with-diabetes]

[4] APhA 2025: GLP-1 Receptor Agonists vs SGLT2 Inhibitors Show Varied Benefit for Cardiovascular Outcomes in Patients With Diabetes. Pharmacy Times. [https://www.pharmacytimes.com/view/apha-2025-glp-1-receptor-agonists-vs-sglt2-inhibitors-show-varied-benefit-for-cardiovascular-outcomes-in-patients-with-diabetes]

[5] APhA 2025: GLP-1 Receptor Agonists vs SGLT2 Inhibitors Show Varied Benefit for Cardiovascular Outcomes in Patients With Diabetes. Pharmacy Times. [https://www.pharmacytimes.com/view/apha-2025-glp-1-receptor-agonists-vs-sglt2-inhibitors-show-varied-benefit-for-cardiovascular-outcomes-in-patients-with-diabetes]