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We know that some GLP1 receptor agonists reduce the risk of cardiovascular events in people with type 2 diabetes [including (as blogged previously) liraglutide (Victoza), dulaglutide (Trulicity), and semaglutide (Ozempic)]. We also know that in people with cardiovascular disease and obesity, without diabetes, semaglutide 2.4mg (Wegovy) reduces cardiovascular risk. GLP1 receptor agonists have many possible mechanisms by which they could reduce cardiovascular events. But what happens to risk of cardiovascular events if GLP1 receptor agonist treatment is stopped?
A real world data analysis was conducted in people with type 2 diabetes in Italy, which looked at this question. The study was small, comprising 550 people, 395 of whom had no known CV disease (the ‘primary prevention’ group), and 155 who had known CV disease (the ‘secondary prevention’ group). Data was retrospectively assessed, looking at people who had started GLP1 receptor agonist treatment between 2009 and 2019 (about 61% were taking liraglutide (Victoza), about 37% dulaglutide (Trulicity), about 1% exenatide (Byetta/Bydureon), and less than 1% semaglutide (Ozempic). The median duration of GLP1 treatment was 3.2 years in the primary prevention group, and 2.5 years in the secondary prevention group. During a median follow-up of 5 years in the primary prevention group, 8.6% had a cardiovascular event. During a median follow up of 3.6 years in the secondary prevention group, 20.7% of people had a cardiovascular event.
While there are several interesting findings in this study, what I want to focus on today is two points:
- A longer duration of GLP1 treatment was associated with a lower rate of cardiovascular events, both in people who had prior known cardiovascular disease and in those who did not.
- Stopping GLP1 strongly and independently increased the risk of a cardiovascular event in both groups. [The numbers: GLP1 cessation by time increased cardiovascular event (MACE) risk in the primary prevention group (HR 3.40) and in the secondary prevention group (HR 2.71).]
While this study is small and subject to many limitations (retrospective, no control group, self-reported treatment adherence, single center study, real world data), the findings are intriguing nonetheless, suggesting that the cardiovascular protection of GLP1 medications is better with a longer duration of treatment, and that treatment needs to continue for the cardiovascular benefits to continue.
In a world where there is reluctance on the part of government and insurance companies to pay for GLP1 receptor agonists with moves to even ‘tighten up’ access to the point where some people who had coverage have subsequenty lost it, we urgently need larger and more robust studies to evaluate the long-term benefits of these medications, beyond the duration that can realistically be expected of formal randomized controlled clinical trials.
We also need to ask these same questions in populations of people without diabetes, who are taking GLP1 medications as a treatment for obesity: is there a greater CV benefit with longer duration of treatment, and does treatment need to be continued in order for those benefits to continue? I suspect the answer to be yes on both counts, but as always, we need data to inform us.
BOTTOM LINE: In a small real-world study of people with type 2 diabetes, longer GLP1 receptor agonist treatment duration was associated with a lower rate of cardiovascular events, and stopping GLP1 receptor agonist treatment was associated with a higher risk of cardiovascular (CV) events, both in people with and without a prior history of CV events. While more data is needed to confirm this finding, and while evaluation is also needed in people taking GLP1 medication as an obesity treatment without diabetes, this finding points towards the importance of continuing GLP1 receptor agonists long term for long term cardiovascular benefits.
Disclaimer: I receive honoraria as a continuing medical education speaker and consultant from the maker of liraglutide and semaglutide (Novo Nordisk), dulaglutide (Eli Lilly), and exenatide (Astra Zeneca). I am/have been an investigator in clinical trials of liraglutide, dulaglutide, and semaglutide.
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