GLP-1 RAs outperform SGLT2 inhibitors in mortality risk reduction in patients with serious mental illness

12 hours ago
Kanas Chan
Kanas ChanAssociate Editor; MIMS
Kanas Chan
Kanas Chan Associate Editor; MIMS
GLP-1 RAs outperform SGLT2 inhibitors in mortality risk reduction in patients with serious mental illness
In patients with serious mental illness (SMI), initiation of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) is associated with lower risks of all-cause mortality and major adverse cardiovascular events (MACEs) vs sodium-glucose cotransporter-2 (SGLT2) inhibitors, a large study has shown.

“Bipolar disorder, major depressive disorder, and schizophrenia are associated with substantial excess mortality, principally from cardiovascular disease [CVD],” wrote the researchers. “Identifying strategies to reduce this burden is a critical psychiatric priority.” [JAMA Psychiatry 2026;doi:10.1001/jamapsychiatry.2026.2574]

In a retrospective target trial emulation within the TriNetX Analytics Network, >1.5 million adults initiating either GLP-1 RAs or SGLT2 inhibitors were included. After 1:1 propensity score matching, each group included 764,115 patients, with 195,184 pairs with SMI (GLP-1 RAs: mean age, 60.5 years; female, 57.8 percent; SGLT2 inhibitors: median age, 60.2 years; female, 58.1 percent) and 568,931 pairs without SMI (GLP-1 RAs: mean age, 60.9 years; female, 44.2 percent; SGLT2 inhibitors: median age, 60.6 years; female, 45.8 percent) in each group.

Lower 1- & 4-year mortality with GLP-1 RAs

For the primary outcome, GLP-1 RAs were associated with significantly reduced 4-year all-cause mortality vs SGLT2 inhibitors (4.91 vs 6.45 percent; hazard ratio [HR], 0.76; 95 percent confidence interval [CI], 0.74–0.78; absolute risk difference [ARD], -1.54 percentage points; 95 percent CI, -1.68 to -1.39; p<0.001) in patients with SMI.

“A notable finding was the early separation of mortality curves,” highlighted the researchers. “At 1 year, GLP-1 RA initiation was associated with a 48 percent lower relative risk of death [1-year all-cause mortality: 1.46 vs 2.84 percent with SGLT2 inhibitors; rate ratio, 0.52; 95 percent CI, 0.49–0.54; ARD, -1.38 percentage points; 95 percent CI, -1.47 to -1.29; p<0.001] in the SMI cohort.”

“The rapidity of this divergence exceeds what would be expected from gradual metabolic improvements alone, raising the possibility that GLP-1 RAs exert acute cardioprotective effects that manifest before the full realization of weight loss or glycaemic optimization,” commented the researchers.

Semaglutide reduced CV events and 10-year mortality

Secondary cardiovascular outcomes were assessed among patients with SMI and type 2 diabetes (T2D). Compared with SGLT2 inhibitors, semaglutide was associated with significantly lower risks of:

  •  3-point MACE (HR, 0.77; 95 percent CI, 0.76–0.79; p<0.001);
  • 5-point MACE (HR, 0.76; 95 percent CI, 0.75–0.77; p<0.001);
  • Myocardial infarction (HR, 0.71; 95 percent CI, 0.69–0.73; p<0.001);
  • Stroke (HR, 0.89; 95 percent CI, 0.86–0.92; p<0.001);
  • Heart failure (HR, 0.73; 95 percent CI, 0.72–0.74; p<0.001); and
  • Coronary artery bypass grafting (HR, 0.77; 95 percent CI, 0.70–0.85; p<0.001).

In exploratory analyses among patients with T2D, semaglutide was associated with lower 10-year mortality across SMI subgroups. “The consistency of the mortality benefit across major depressive disorder [relative risk (RR), 0.55; 95 percent CI, 0.53–0.56], bipolar disorder [RR, 0.57; 95 percent CI, 0.51–0.63], and schizophrenia [RR, 0.67; 95 percent CI, 0.59–0.75] demonstrates generalizability across the full SMI diagnostic spectrum [all p<0.001],” the researchers pointed out.

“The findings of this study indicate that GLP-1 RAs, particularly semaglutide, may represent a treatment option to narrow the cardiovascular mortality gap in persons living with SMI,” wrote the researchers.