Mortality lower with GLP-1 drugs in serious mental illness

Clinical takeaway: Consider GLP-1 receptor agonists as part of cardiometabolic treatment planning for adults with serious mental illness who already meet an indication for therapy. Compared with SGLT2 inhibitors, GLP-1 initiation was associated with lower mortality, with the strongest signals seen for semaglutide and tirzepatide.

Major depressive disorder, bipolar disorder, and schizophrenia are associated with substantial excess mortality, driven largely by cardiovascular disease. A multinational observational study suggests GLP-1 receptor agonists may help reduce that burden.

Researchers used electronic health records to emulate a clinical trial comparing adults who started a GLP-1 receptor agonist with matched adults who started an SGLT2 inhibitor. The four year analysis included more than 1.5 million adults, including 195,184 matched pairs with serious mental illness.

Among adults with serious mental illness, four-year mortality was 4.91% with GLP-1 therapy versus 6.45% with an SGLT2 inhibitor. This represented a 24% lower hazard of death and an absolute difference of 1.54 percentage points.

The difference emerged early. In a separately matched cohort, one-year mortality was 1.46% among GLP-1 users and 2.84% among SGLT2 inhibitor users. The study found greater absolute mortality reductions among adults with serious mental illness than among those without these diagnoses.

Among participants with serious mental illness and type 2 diabetes, semaglutide initiation was also associated with lower risks of major adverse cardiovascular events, myocardial infarction, stroke, heart failure, and coronary artery bypass grafting. Exploratory analyses suggested that semaglutide and tirzepatide accounted for the strongest mortality associations.

The findings support closer coordination of psychiatric and cardiometabolic care when selecting treatment for patients who have an established indication for these medications. The authors noted that prospective randomized trials are needed to confirm the comparative benefits.

Source: McIntyre RS, et al. (2026 Aug 26) JAMA Psychiatry. Glucagon-like peptide 1 receptor agonists, mortality, and cardiovascular outcomes in serious mental illness