Study: Adding GLP1RA to T2D Therapy Linked With Lower MACE In Older Patients Without CVD


Study authors said the findings could inform clinicians when selecting therapies for patients with type 2 diabetes (T2D). However, an editorial found the follow-up period too short and differences between the study arms too small to be meaningful.

Glucagon-like peptide-1 receptor agonists (GLP1RAs) are linked with fewer major adverse cardiovascular events (MACE) in older veterans with type 2 diabetes (T2D) and no prior heart disease, compared with dipeptidyl peptidase-4 inhibitors (DPP4i), a new retrospective cohort study has found.

The research was published today in Annals of Internal Medicine,1 and, according to authors, the findings can help clinicians choose an appropriate diabetes drug regimen for older adults.

“We believe this study is an important contribution to patient care and adds to what we as clinicians know about treating diabetes and heart disease prevention,” said author Christianne Roumie, MD, MPH, of Vanderbilt University Medical Center, in a release.

Diabetes raises this risk of cardiovascular disease, which remains the leading cause of death for US adults.

Because many newer diabetes medications were tested versus a placebo, less is known about how the drugs compare with each other. In addition, clinical trials of the medications were often carried out among patients who already had cardiovascular disease.

To determine if MACE incidence was lower with the addition of GLP1RA or SGLT2i compared with DPP4i, researchers carried out a retrospective cohort study from 2001 to 2019. Veterans aged 18 or older who received care from the Veterans Health Administration were included in the analysis. Authors linked data with Medicare, Medicaid, and the National Death Index.

All participants added GLP1RA, SGLT2i, or DPP4i onto metformin, a sulfonylurea, or insulin treatment alone or in combination. MACE included incidences of acute myocardial infarction, stroke, or cardiovascular death. Researchers also assessed heart failure hospitalization.

Median patient age was 67 years and patients had a median diabetes duration of 8.5 years. A total of 28,759 GLP1RA versus 28,628 DPP4i weighted pairs and 21,200 SGLT2i versus 21,170 DPP4i weighted pairs were included.

Data showed:

  • GLP1RA were associated with lower MACE and HF versus DPP4i (adjusted hazard ratio [aHR], 0.82 [95% CI, 0.72 to 0.94]), yielding an adjusted risk difference (aRD) of 3.2 events (95% CI, 1.1 to 5.0) per 1000 person-years
  • SGLT2i were not associated with MACE and heart failure (HF) (aHR, 0.91 [95% CI, 0.78 to 1.08]; aRD, 1.28 [-1.12 to 3.32]) compared with DPP4i

In other words, the addition of a GLP1RA was linked with about a 20% reduction in MACE risk and heart failure hospitalization compared with treatment of a DPP4i, suggesting “GLP1RA may have a role in [cardiovascular disease] prevention, which pertain to all users regardless of [cardiovascular disease] history.”

Notably, the study did not assess use of any of the 3 medications as first-line therapies T2D treatment. Most of the patients included were also white men, marking a limitation to the analysis. The lack of association between SGLT2i and MACE and HF primary prevention could have been due to a short follow-up, authors added.



In an accompanying editorial,2 Steven E. Nissen, MD, of the Cleveland Clinic, noted the comparison of GLP1RA with DPP4i had a median follow-up of 7 months, while the SGLT2i follow-up was 5 months.

“These drugs are long-term therapies, not short-term interventions, and comparing their effects over a few months is not clinically relevant,” Nissen wrote. He also cites incomplete capture of outcome data, along with missing data on ejection fraction at patient index date as limitations.

“The observed differences in HRs (0.82 vs. 0.91) comparing GLP1RA and SGLT2i with DPP4i are too small to derive reliable conclusions,” in light of these concerns and additional limitations, Nissen wrote.

“In the current study, although [randomized controlled trials] have not been done in a pure primary prevention population, we do not have a biological reason for why effects should be different.”

GLP1RA include exenatide, liraglutide, semaglutide, among others, while SGLT2 inhibitors include empagliflozin, dapagliflozin and canagliflozin. Alogliptin, linagliptin, saxagliptin and sitagliptin are examples of DPP4i.


  1. Richardson TL, Halvorson AE, Hackstadt AJ, et al. Primary occurrence of cardiovascular events after adding sodium-glucose contransporter-2 inhibitors or glucagon-like peptidase-4 inhibitors: a cohort study in veterans with diabetes. Ann Intern Med. Published online May 8, 2023. doi: 10.7326/M22-2751
  2. Nissen SE. Comparative effectiveness of diabetes drugs: the use and misuse of observational research. Ann Intern Med. Published online May 8, 2023. doi:10.7326/M23-0958
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