GLP-1s and SGLT2s More Effective Together in Patients with ASCVD and Heart Failure

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Patients with atherosclerotic cardiovascular disease (ASCVD) and heart failure (HF) who were prescribed a combination of GLP-1 RAs and SGLT2 inhibitors exhibited an overall reduction in 1-year mortality and hospitalization in a recent trial.1

Previous randomized controlled trials have supported the benefit of SGLT2 inhibitors in major adverse cardiovascular events in patients with both ASCVD and HF while GLP-1 RAs have also been noted as potentially beneficial to this cohort.2,3 Despite these results, however, little literature exists examining the effects of combining the 2 therapies in patients with both ASCVD and HF.

“Given the significant overlap between ASCVD and HF in clinical practice, addressing this knowledge gap is essential for optimizing treatment strategies,” wrote Sih-Yao Chen, MD, department of internal medicine, Chi Mei Medical Center, and colleagues.1 “To address this, our study aims to leverage the TriNetX database to compare the outcomes of patients treated with GLP-1 RA in addition to SGLT2i vs. those treated with SGLT2i alone, with a specific focus on hard endpoints such as mortality and HF hospitalizations.”

Chen and colleagues conducted a retrospective observational study analyzing patients with ASCVD and HF from August 2016 to September 2024. To be included, patients had to be ≥18 years old and have been recently prescribed a GLP-1 RA and SGLT2i, or an SGLT2i alone. Patients were then divided into 2 groups based on the treatment they received. Patients in the SGLT2i group who had received GLP-1 RAs prior to investigation were excluded, along with those who had been hospitalized within 1 week of initiating GLP-1 RAs.1

Covariates included age, sex, race, ethnicity, respiratory disease, diabetes mellitus, endocrine or metabolic disease, circulatory disease, nutritional disease, and other conditions. Additionally, patients prescribed medications such as angiotensin-converting enzyme inhibitors, beta blockers, spironolactone, and eplerenone, among others, were excluded.1

A total of 2,797,317 patients were initially selected for review. After screening for exclusion criteria, a remainder of 96,051 were included in the final analysis. Of these, 5548 patients were given both a GLP-1 RA and a SGLT2i, while 90,503 received only the SGLT2i. Propensity score matching resulted in 5272 patients in each group.1

A baseline for comparison was established by using acute cholecystitis, fracture, and gastric ulcer as negative control outcomes. A prespecified subgroup analysis based on HF type, the presence of diabetes mellitus, obesity, and chronic kidney disease was also conducted, aiming to identify potentially influential subgroups. 3 types of GLP-1 RAs – liraglutide, dulaglutide, and semaglutide – were also utilized in testing to determine whether the benefits were consistent across different varieties.1

After the first year, 2162 patients in the combination cohort and 2462 in the SGLT2i cohort experienced hospitalization or mortality. This incidence was substantially lower in the combination group (HR .78; 95% CI, .74-.83; P <.0001). The risk of mortality (HR .72; 95% CI, .62-.84; P <.0001), hospitalization (HR .78; 95% CI, .73-.83; P <.0001), and HFE (HR .77; 95% CI, .72-.83, P <.0001) were all significantly lower in the combination cohort as well. Negative control analysis indicated no significant difference between the cohorts, and results were consistent across all subgroups. The outcome benefits persisted at 2- and 3-year follow-ups, and remained consistent regardless of the variables used in the PSM analysis.1

“In the current era, coronary artery bypass surgery is the only treatment proven to reduce mortality in patients with ischemic cardiomyopathy, while other medical therapies primarily address HF management,” wrote Chen and colleagues. “Our research suggests a potential new therapeutic option to improve prognosis in patients with both ASCVD and HF.”1

References
  1. Chen SY, Wu JY, Liao KM, Lin YM. Prognostic benefit of glucagon-like peptide-1 receptor agonists addition to sodium-glucose cotransporter 2 inhibitors in patients with atherosclerotic cardiovascular disease and heart failure: a cohort study. Eur Heart J Cardiovasc Pharmacother. 2025;11(4):324-333. doi:10.1093/ehjcvp/pvaf014
  2. Cannon CP, Pratley R, Dagogo-Jack S, et al. Cardiovascular Outcomes with Ertugliflozin in Type 2 Diabetes. N Engl J Med. 2020;383(15):1425-1435. doi:10.1056/NEJMoa2004967
  3. Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. N Engl J Med. 2023;389(24):2221-2232. doi:10.1056/NEJMoa2307563

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