Study shows GLP-1 drugs reduce mortality and cardiovascular problems in people with mental illness

GLP-1 diabetes and weight-management medications may improve cardiovascular health and lower the risk of all-cause mortality among adults with serious mental illness by 25 per cent, suggests a new study led by researchers at University of Toronto’s Temerty Faculty of Medicine and SUNY Upstate Medical University.

Published in JAMA Psychiatry, the study found that starting a glucagon-like peptide-1 receptor agonist (GLP-1 RA) was associated with lower mortality and fewer major adverse cardiovascular events compared with another commonly prescribed class of medications called sodium-glucose cotransporter-2 (SGLT2) inhibitors.

The findings address an important health disparity. Research cited in the paper estimates that people living with SMI have a life expectancy approximately 10 to 25 years shorter than the general population, with cardiovascular disease accounting for most of that difference.

“For patients and their families, those figures represent lost time, relationships, and opportunities,” says Angela Kwan, co-author on the study and internal medicine resident at Temerty Medicine. “Understanding that gap requires looking at both clinical risks, including the metabolic effects of some psychiatric medications, and the difficulties people may face in accessing preventive and ongoing medical care.”

“Reducing excess mortality in persons with serious mental illness is the strategic imperative in psychiatry across high-, middle-, and low-income countries,” adds lead author Roger McIntyre, a professor of psychiatry, and pharmacology and toxicology, at U of T and a faculty member at SUNY Upstate Medical University.

Kwan became involved in the research through her collaboration with McIntyre, who is also head of the mood disorders psychopharmacology unit at University Health Network’s Toronto Western Hospital, and Professor Yanli Zhang-Jamesat SUNY Upstate Medical University. The team shared a common interest in addressing the burden of cardiovascular disease and premature mortality among marginalized populations, particularly people living with serious mental illness.

That interest led them to investigate whether advances in cardiometabolic treatment could help improve outcomes for this patient population and provide evidence to support clinical decision-making.

The researchers focused on a question physicians may face in practice: How do outcomes compare between adults who start a GLP-1 RA and those who start a SGLT2 inhibitor were chosen as a comparison because they are known to provide cardiovascular and kidney benefits.

To answer that question, they used a method called target trial emulation, which uses observational data to mimic a hypothetical randomized controlled trial. The analysis included more than 1.5 million deidentified TriNetX health records from adults with and without serious mental illness. This is the largest known sample of well-characterized individuals with serious mental illness evaluated to date in a target trial emulation study.

While large datasets can reveal meaningful patterns, they cannot capture every factor that influences health outcomes. For example, electronic health records may not fully reflect psychiatric illness severity, medication adherence, or barriers that affect a person's ability to access care.

“Another concern was whose experiences the data represented,” says Kwan. “People with limited or interrupted access to healthcare may remain underrepresented even in a dataset this large, so findings among those who receive treatment may not fully apply to those who struggle to obtain it.”

As senior author, Kwan co-developed the study's concept and design with McIntyre and worked closely with Zhang-James on the methodology and analysis. She also co-drafted the manuscript with McIntyre, contributed to its revision, and helped coordinate the work required to complete the study.

“I particularly valued bringing internal medicine and psychiatry together, which helped us consider both patients’ clinical needs and the barriers they may face in receiving care,” says Kwan. “Connecting a specific treatment question with these broader concerns about unequal health outcomes made the work especially meaningful to me. It reflects the kind of research I hope to continue leading – work that evaluates promising treatments while asking whether people facing the greatest barriers to care have an opportunity to benefit from them.”

Kwan hopes this research will encourage clinicians to view cardiovascular health as a central component of care for people living with serious mental illness, and that her experience can encourage other residents to see the opportunities trainees have to contribute to research on a global scale.

“Early in my training, it has been meaningful to investigate a question where clinical medicine and health equity are so closely connected,” says Kwan. “I’m also grateful for the mentorship from McIntyre that helped me take on these responsibilities as senior author.”

Looking ahead, Kwan believes future research on this topic should include prospective randomized studies that directly evaluate cardiovascular outcomes and mortality in people living with serious mental illness. She also hopes researchers will explore how effective treatments can be made more accessible and sustainable in everyday care.

Importantly, she says that people with lived experience should help shape future studies by identifying which outcomes matter most, what participation should involve, and what supports would make involvement feasible. Their perspectives can help guide practical decisions about communication, follow-up, and care delivery.

“I hope the study contributes to collaboration among patients, clinicians, researchers, and policymakers, with a shared commitment to preventing avoidable illness and premature death,” says Kwan. “A psychiatric diagnosis should never diminish the seriousness with which we protect someone’s physical health or the value we place on their future. We believe these findings could be transformative for people living with serious mental illness and have the potential to save lives among those affected by these challenging disorders.