AHA Scientific Sessions 2026 Abstract · Nov 2, 2026
Efficacy and Safety of Combination Therapy with GLP-1 and SGLT2 Inhibitors versus GLP-1 Monotherapy in Patients with Type 2 Diabetes and Heart Failure with Preserved Ejection Fraction (HFpEF)
By Jaiswal V, Banach M, Jaiswal A et al.
Background: According to the European Society of Cardiology (ESC) guidelines, both GLP-1 receptor agonists and SGLT2 inhibitors have documented cardiovascular benefits in patients with type 2 diabetes mellitus (T2DM), with SGLT2 inhibitors particularly recommended to reduce heart failure hospitalizations. However, real-world data evaluating the efficacy of their concurrent use in patients with both T2DM and HFpEF remain limited. This analysis aimed to assess the impact of combination therapy compared to GLP-1 monotherapy on mortality and cardiovascular complications in this specific patient population. Methods: A retrospective analysis was conducted using the Global Collaborative Network (TriNetX) database. Adult patients with a documented diagnosis of HFpEF and T2DM between January 1, 2015, and May 30, 2025, were included. Following propensity score matching, two balanced cohorts were identified, each comprising 19,589 patients: those receiving concurrent GLP-1 and SGLT2 therapy, and those on GLP-1 monotherapy. The evaluated endpoints were all-cause mortality (ACM), major adverse cardiovascular events (MACE), stroke, heart failure exacerbations, emergency room (ER) visits, and acute kidney injury (AKI). Results: Combination therapy (GLP-1 + SGLT2) was associated with a significant decrease in mortality risk compared to GLP-1 monotherapy (4.35% vs. 5.16%; RR = 0.84; p < 0.001). The incidence of major adverse cardiovascular events (16.57% vs. 16.40%; p = 0.840) and stroke (6.46% vs. 6.63%; p = 0.332) was similar between the two groups. Unexpectedly, the combination therapy cohort had a higher risk of heart failure exacerbations (53.74% vs. 46.31%; RR = 1.16; p = 0.001). The risk of requiring at least one emergency room visit was nearly identical (87.71% vs. 87.73%), although the combination group showed a slightly higher mean number of recurrent visits (p < 0.001). An increased risk of developing AKI was observed in the combination therapy cohort compared to monotherapy (21.15% vs. 18.53%; RR = 1.14; p = 0.006). Conclusions: In patients with T2DM and HFpEF, adding SGLT2 inhibitors to GLP-1 therapy translates to a significant reduction in all-cause mortality (ACM) compared to GLP-1 monotherapy. Conversely, the combination treatment was associated with an unexpected increase in the risk of heart failure exacerbations and acute kidney injury, with no significant differences in MACE or stroke. This divergence highlights the necessity for dedicated prospective studies to evaluate the underlying mechanisms and the overall benefit-risk ratio of the concurrent use of these two drug classes in the HFpEF population.