People with type 2 diabetes who start and then stop using GLP-1 medications may face an increased risk of heart attack, stroke or death than those who keep using them, according to a new international study.
But Australian experts urge caution interpreting the findings, with the study unable to prove causation and no data collected about why people stopped using the drug.
The study, published today in The Lancet Regional Health — Europe journal, followed more than 80,000 Italians with type 2 diabetes and no established cardiovascular disease between 2004 and 2024.
Lead author Antonio Ceriello, head of diabetes research at Italian hospital IRCCS MultiMedica, said the association between stopping GLP-1 receptor agonists and poorer heart health outcomes was "not a complete surprise".
However, Professor Ceriello said the scale of the association found was significant.
About four in 100 people in the study who stopped GLP-1 treatment had a heart attack, stroke or died from any cause; compared to about two in 100 people who kept using the medication.
The risk of adverse outcomes was higher in people with obesity.
Weight gain after stopping use
GLP-1s can help with weight regulation and blood sugar levels in people with type 2 diabetes by mimicking a hormone called glucagon-like peptide-1.
Previous studies showed people who stopped using the drugs commonly experienced weight gain, and an increase in cardiovascular risk factors such as blood pressure.
In this study, Professor Ceriello said there was only a modest increase in weight, blood pressure and blood sugar levels for those who stopped using the medication.
These modest increases were recorded in the group that later had a heart attack, stroke or died as well as the group with no adverse events.
"This suggests that the deterioration of these parameters is not sufficient to fully explain the observed increase in risk," he said.
Professor Ceriello theorised GLP-1 drugs could provide "direct protection" for the cardiovascular system.
But it is not clear from the study whether starting and then stopping GLP-1 medication is riskier than never using the drug in the first place.
Natalie Raffoul, head of clinical strategy at The Heart Foundation who did not contribute to the study, said while the data was "interesting", more research was needed.
"We know that stopping it comes with consequences and perhaps this study is pointing a spotlight on the fact that these negative consequences might actually be quite significant," she said.
This study did not include people who took tirzepatide (brand name Mounjaro), and only a small number of participants used semaglutide (sold under brand names Ozempic and Wegovy).
Most of the participants used liraglutide or dulaglutide.
Why did people stop using the drug?
Clara Chow, academic director of the Westmead Applied Research Centre at the University of Syndey who did not contribute to the study, said the core conclusion "might be misleading" without a deeper understanding of why participants stopped using GLP-1 drugs.
About 60 per cent of the 80,302 total participants stopped using their medication.
"That's a lot of people who are not staying on this medication, despite all the hype," Professor Chow said.
"If you've discontinued medication, is it because you feel sick taking it? Or you've got another illness? Or you've got a problem that interacts with it … there's a lot of reasons why people stop treatment."
Professor Chow said the group who stopped using the medication also had a very high rate of death by any cause, suggesting they could have been sicker than the group who continued with it.
"Discontinuation is a marker of the fact that they're sick as opposed to a cause of their sickness."
Brendon Neuen, associate professor of medicine at Royal North Shore Hospital who did not contribute to the study, agreed.
"They might have stopped for an appropriate [medical] reason, but those patients are typically sicker, and they're going to do worse," he said.
This study did not include the socio-economic status of participants — a known risk factor for cardiovascular disease — although Professor Ceriello noted the Italian health system reimbursed patients who used GLP-1s, which meant cost was unlikely to be a barrier to treatment.
Wean off drugs with a doctor
Despite the study's limitations, Dr Neuen said it contained some important implications for people with type 2 diabetes who used GLP-1 drugs.
"If you do have a chronic health condition for which a GLP-1 drug is helping, it suggests that long-term treatment is important," he said.
Because the study suggested people with type 2 diabetes lost cardiovascular benefits, Dr Neuen said it was important that patients considering stopping the drugs talked to a health professional.
As there was limited information available about the potential long-term impacts and side effects of taking GLP-1s, Professor Chow said people taking them for extended periods must be monitored.
"We need more information about the long-term effects of these medications," she said.
And this would take time, Dr Neuen said.
"There is lots of research going on into how we can effectively use these drugs in the long term," he said.
"Can we reduce the dose? Can we reduce the frequency? What's the impact of stopping versus continuing?
"All of these [questions] continue to be teased out and this is one small piece of the puzzle."
