GLP-1 receptor agonists show varied mental health risks compared to SGLT2, but not DPP4 inhibitors
Background
Patients with Type 2 Diabetes (T2D) often experience co-morbid mental health disorders, including depression and anxiety, which can complicate disease management and reduce quality of life. Glucagon-like peptide-1 receptor agonists (GLP1RAs) are effective T2D treatments that also offer cardiovascular and renal benefits. However, their psychiatric safety profile, particularly in comparison to other widely used anti-diabetic drugs like dipeptidyl peptidase-4 (DPP-4) inhibitors and sodium-glucose cotransporter-2 (SGLT2) inhibitors, requires robust real-world evidence. Understanding these comparative risks is crucial for informed clinical decision-making and patient counseling.
Study Design
Researchers conducted a nationwide, active-comparator new-user cohort study utilizing the Korean claims database spanning from 2012 to 2022. The study included patients aged ≥18 years who initiated GLP1RAs, SGLT2 inhibitors, or DPP4 inhibitors for Type 2 Diabetes. They compared the hazard ratios (HRs) and 95% confidence intervals (CIs) for depression, anxiety, sleep disorders, and suicide using Cox proportional hazards models after propensity score matching to balance baseline characteristics between the treatment groups. The primary endpoint was the incidence of new mental health disorder diagnoses.
Results
The study matched 18,825 GLP1RA users with 623,750 SGLT2 inhibitor users, and 5,762 GLP1RA users with 874,902 DPP4 inhibitor users. Compared with DPP4 inhibitors, GLP1RAs were not associated with increased risks of depression (HR 1.00 [95% CI, 0.83-1.20]), anxiety (0.92 [0.77-1.08]), or sleep disorder (1.14 [0.97-1.33]). In contrast, when compared with SGLT2 inhibitors, GLP1RA use was associated with higher risks of depression and anxiety.
Specifically,
GLP1RAuse showed a 1.20-fold higher risk of depression (HR 1.20 [95% CI, 1.09-1.31]) and a 1.09-fold higher risk of anxiety (HR 1.09 [1.00-1.19]) compared toSGLT2 inhibitors.
Suicidality events were rare and not observed among GLP1RA users in this cohort. These findings highlight that psychiatric safety signals can vary significantly depending on the active comparator drug.
Key Findings
- GLP1RA use was not associated with increased risks of depression (HR 1.00), anxiety (HR 0.92), or sleep disorder (HR 1.14) compared to DPP4 inhibitors.
- GLP1RA use was associated with a 20% higher risk of depression (HR 1.20 [95% CI, 1.09-1.31]) compared to SGLT2 inhibitors.
- GLP1RA use was associated with a 9% higher risk of anxiety (HR 1.09 [95% CI, 1.00-1.19]) compared to SGLT2 inhibitors.
- Suicidality events were rare and not observed among GLP1RA users in this cohort.
- Psychiatric safety signals for GLP1RAs vary significantly depending on the active comparator drug.
Why It Matters
This study provides crucial real-world evidence suggesting that psychiatric safety signals for GLP-1RAs are not uniform across different comparator anti-diabetic drugs. For clinicians and patients, this means that while GLP1RAs appear safe regarding mental health when compared to DPP4 inhibitors, a different risk profile emerges when compared to SGLT2 inhibitors. This doesn't necessarily mean GLP1RAs cause mental health issues, but rather that their relative safety profile shifts depending on the alternative treatment considered. Future protocols may need to account for these comparative risks, especially when prescribing GLP1RAs to individuals with pre-existing mental health concerns or when choosing between GLP1RAs and SGLT2 inhibitors. This data emphasizes the need for personalized treatment decisions and careful monitoring.
glp-1ra
type-2-diabetes
mental-health
depression
anxiety
dpp4-inhibitor