GLP-1 Therapy Interruption Increases Cardiovascular Risk in Type 2 Diabetes: Study
A target trial emulation study has found that a 6-month break in GLP-1 drug therapy in patients with type 2 diabetes was associated with a higher risk of major adverse cardiovascular events compared to those who continued treatment, emphasizing the importance of consistent therapy adherence. The study was published in BMJ Medicine by Yan Xie and colleagues.
In order to draw such findings, the investigators relied on a "target trial emulation" study design, wherein the data were examined between 1 January 2017 and 31 December 2023. The sample size was huge, involving 132,551 new users of GLP-1RAs and 201,136 new users of sulfonylureas, all of whom had type 2 diabetes mellitus. In order to qualify for inclusion into the study, the participants had to make at least two visits to the VA healthcare facility and use the VA pharmacy at least once during the past year before taking the medications under study. The participants were then tracked for three years, and their medication status was switched every six months, creating 16 distinct medication regimens.
Key findings:
There is a clear relationship between the use of GLP-1 receptor agonists and the reduction in the cumulative risk of major adverse cardiovascular events (MACEs), including myocardial infarction, stroke, or all-cause mortality within a period of three years.
Comparing the sulfonylurea reference group to patients using GLP-1RAs, there was no statistically significant decrease in cardiovascular risk when using GLP-1RAs for 0.5, 1, or 1.5 years, where the incidence risk ratios (IRRs) were nearly equal to 1.0. Nevertheless, a reduction in the risk was observed when the GLP-1RAs were used for two years at an IRR of 0.93 (95% CI 0.88 to 0.98), but a slightly greater reduction occurred with the use of these drugs for 2.5 years (IRR 0.85; 95% CI 0).
The largest reduction in the risk was recorded among the users who continued to use GLP-1RAs for the full three years, obtaining a statistically significant IRR of 0.82 (95% CI 0.78 to 0.85).
In contrast to continued users, discontinuers with 0.5 years of interruption had a higher risk of developing MACE, which had an IRR of 1.04 (95% CI 1.01 to 1.08).
Discontinuing use of GLP-1RA drugs for longer periods, however, increased the MACE risk even more rapidly; specifically, one-year and two-year interruptions increased the risks by IRRs of 1.14 (1.09 to 1.18) and 1.22 (1.16 to 1.27), respectively.
Short interruptions were also harmful, since a 0.5-year interruption increased risks, while one-year and two-year interruptions yielded IRRs of 1.12 (95% CI 1.06 to 1.19) and 1.16 (1.11 to 1.22), respectively.
From these data, it is evident that although the protective effect of GLP-1RAs forms a shield against MACEs, this protection is temporary since discontinuation starts to erode it instantly.
In conclusion, the benefits of GLP-1RAs when it comes to cardiovascular protection are difficult to achieve yet easy to lose. The findings of the three-year trial have shown that, whereas consistent use provides for a 18% decrease in the occurrence of major adverse cardiovascular events in comparison to patients on sulfonylureas, this achievement is fragile indeed. Any deviation from the regime can result in loss of these hard-gained benefits and increase the chances of having a myocardial infarction, stroke, or even mortality. Medical practitioners need to understand that GLP-1RAs should not be used cyclically but on a consistent basis.
Reference:
Xie Y, Choi T, Al-Aly Z. Glucagon-like peptide 1 receptor agonist discontinuation and risks of major adverse cardiovascular events in adults with type 2 diabetes: target trial emulation. BMJ Medicine. 2026;5:e002150. https://doi.org/10.1136/bmjmed-2025-002150
