GLP-1 RAs Show Lower CV and Mortality Risk Than SGLT2 Inhibitors among patients with serious mental illness: JAMA
Canada: Researchers have found in a new study that GLP-1 receptor agonist initiation was associated with lower mortality and cardiovascular event rates than SGLT2 inhibitor initiation, with greater absolute benefits among patients with serious mental illness (SMI). Benefits emerged within 1 year, were consistent across SMI subgroups, and were primarily driven by semaglutide and tirzepatide. Prospective randomized trials are needed to confirm these findings.
The study, published in JAMA Psychiatry, was led by Roger S. McIntyre of the Department of Psychiatry at the University of Toronto in Toronto, Ontario, Canada, and colleagues. Researchers evaluated whether starting GLP-1 receptor agonists was associated with better survival and cardiovascular outcomes than initiating sodium-glucose cotransporter-2 (SGLT2) inhibitors among adults with and without SMI.
SMI in the study included major depressive disorder, bipolar disorder, and schizophrenia, conditions associated with substantially increased mortality, particularly from cardiovascular disease. The researchers used a retrospective target trial emulation based on data from the multinational TriNetX Analytics Network. Adults newly prescribed either a GLP-1 receptor agonist or an SGLT2 inhibitor were propensity score matched to enable comparison between the treatment groups.
For the primary 4-year analysis, 1,528,230 adults were included in 764,115 matched pairs, including 195,184 pairs with SMI and 568,931 pairs without SMI.
The following were the key findings:
- Among patients with SMI, 4-year mortality was 4.91% with GLP-1 receptor agonists vs 6.45% with SGLT2 inhibitors, reflecting a 24% lower relative risk of death (HR, 0.76) and an absolute risk reduction of 1.54 percentage points.
- Within 1 year, mortality was 1.46% among GLP-1 receptor agonist users vs 2.84% among SGLT2 inhibitor users, corresponding to a 48% lower relative risk of death (RR, 0.52).
- GLP-1 receptor agonist initiation was associated with lower rates of 3-point and 5-point major adverse cardiovascular events (MACEs), myocardial infarction, stroke, heart failure, and coronary revascularization.
- Among patients with SMI and type 2 diabetes, semaglutide was associated with lower risks of 3-point MACE, as well as myocardial infarction, stroke, heart failure, and coronary artery bypass grafting, compared with SGLT2 inhibitors.
- In 10-year exploratory analyses of patients with type 2 diabetes, semaglutide was associated with lower mortality across all SMI subgroups, with risk reductions seen in major depressive disorder (RR, 0.55), bipolar disorder (RR, 0.57), and schizophrenia (RR, 0.67).
The associations remained consistent across sensitivity analyses. Overall, the findings suggest that GLP-1 receptor agonists, particularly semaglutide and tirzepatide, could potentially help reduce the cardiovascular and mortality burden experienced by people living with SMI. However, the authors emphasized that prospective randomized clinical trials are required to establish causality and confirm these findings.
Reference:
McIntyre RS, Zhang-James Y, Kwan ATH. Glucagon-Like Peptide 1 Receptor Agonists, Mortality, and Cardiovascular Outcomes in Serious Mental Illness. JAMA Psychiatry. Published online August 26, 2026. doi:10.1001/jamapsychiatry.2026.2574
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