New real-world evidence suggests that while continuing GLP-1 therapy may be important to maintain cardiovascular protection, even short-term discontinuation may reduce long-term benefits in patients with type 2 diabetes.
Study: Glucagon-like peptide 1 receptor agonist discontinuation and risk of major adverse cardiovascular events in adults with type 2 diabetes: Targeted emulation trial. Image credit: Love Employee / Shutterstock
In a recent study published in the journal BMJ MedicineResearchers conducted a targeted trial emulation to assess the association between different scenarios of glucagon-like peptide-1 receptor agonist (GLP-1RA) treatment and the risk of major cardiovascular events (MACE).
GLP-1RA use is associated with health benefits such as weight loss and reduced MACE risk. This pleiotropic efficacy profile has led to increased use of GLP-1RAs, with 12% of U.S. adults reporting ever having used a GLP-1RA. However, GLP-1RAs are also associated with significant adverse events and out-of-pocket costs, which may contribute to discontinuation.
Studies have shown that GLP-1RA discontinuation rates during the first year of treatment range from 36% to 81%. In particular, discontinuation is associated with partial or complete reversal of weight regain and improvements in cardiometabolic risk factors such as inflammatory markers, blood pressure, lipid profile, and blood glucose levels. However, little is known about the impact of discontinuation on MACE risk.
Targeted trial emulation using real-world data
In this study, researchers emulated a targeted trial evaluating the association between different GLP-1RA treatment scenarios and MACE risk. This study used the U.S. Department of Veterans Affairs (VA) electronic health records. VA users with type 2 diabetes (T2D) who used sulfonylureas or GLP-1RAs between 2017 and 2023 were identified, and follow-up was extended until results were available 3 years after treatment initiation or December 31, 2024, whichever came first.
Participants were excluded if they used these drugs in the year prior to enrollment or had a contraindication to them. Participants were followed for 3 years or until results (or administrative censorship at the end of follow-up). After starting GLP-1RA treatment, participants will be considered to have discontinued the drug if they do not receive a refill for at least 90 days after the end of their prescription.
Those who discontinued GLP-1RA use were divided into discontinuation and discontinuation groups. The discontinued group resumed GLP-1RA use some time after discontinuation, but the discontinued group did not. Researchers defined 16 GLP-1RA treatment scenarios for GLP-1RA users by reassigning treatment status every six months conditional on current usage, thereby emulating a dynamic treatment strategy over time.
The main comparisons were made between each of these scenarios and sulfonylurea treatment. A secondary analysis within the GLP-1RA group compared continued use to other scenarios. The primary outcome was MACE, which combines myocardial infarction, stroke, and all-cause mortality. Although we used a marginal structural model to assess the association between GLP-1RA and MACE risk and used inverse probability weighting to account for time-varying confounding, residual confounding cannot be completely excluded.
GLP-1RA usage patterns and discontinuation rates
The study included 201,136 sulfonylurea users and 132,551 GLP-1RA users with a median follow-up of 3 years. Among GLP-1RA users, 26.36% discontinued treatment during follow-up and 22.68% experienced discontinuation.
Continued use of GLP-1RA reduces MACE risk
Incidental use of GLP-1RAs was associated with a decreased risk of MACE compared with incidental use of sulfonylureas. The incidence risk ratio (IRR) was 0.82 for continued GLP-1RA use, 0.88 for discontinued use, and 0.96 for discontinued use compared with sulfonylurea use.
Longer duration of GLP-1RA use was associated with greater risk reduction. The IRR for individuals using GLP-1RAs for 0.5, 1, and 1.5 years was close to 1.0 and there was no significant reduction in MACE risk after 3 years, but these estimates varied depending on the specific treatment strategy defined by the previous period and subsequent exposure pattern.
In contrast, MACE risk was significantly lower in patients who continued GLP-1RA use for 2 and 2.5 years, and lowest in patients who continued treatment for 3 years. Within the GLP-1RA group, discontinuing treatment for even 0.5 years was associated with a higher MACE risk compared with continued use.
Interruption and discontinuation increase cardiovascular risk
Furthermore, longer discontinuation duration was progressively associated with increased MACE risk, with an IRR of 1.14 for 1 year of discontinuation and 1.22 for 2 years. Similarly, discontinuation of use was associated with increased MACE risk, with an IRR of 1.12 for 1 year of discontinuation and 1.16 for 2 years of discontinuation, with effect sizes varying slightly depending on the duration of prior treatment.
Impact on treatment durability and outcome
Overall, discontinuation and discontinuation of GLP-1RA use was common in this cohort, especially during the first year of treatment. Continuous use of GLP-1RAs for 3 years was associated with the greatest reduction in MACE risk compared with sulfonylureas, whereas interruption and discontinuation were associated with progressive attenuation of this protective effect, with risk estimates in some scenarios close to those of the comparator group.
These findings highlight the potential importance of treatment continuity in maximizing the cardioprotective effects of GLP-1RA. However, because this was an observational trial emulation conducted in a predominantly male veteran population, the results support but do not establish a causal relationship and may have limited generalizability to broader populations, particularly women and non-veteran groups.
Reference magazines:
- Xie Y, Choi T, Al-Aly Z (2026). Glucagon-like peptide 1 receptor agonist discontinuation and risk of major adverse cardiovascular events in adults with type 2 diabetes: Goal of trial emulation. BMJ Medicine, 5(1), e002150. DOI: 10.1136/bmjmed-2025-002150, https://bmjmedicine.bmj.com/content/5/1/e002150
