Study Suggests GLP-1RAs May Reduce Dementia Risk

Treatment with glucagon-like peptide-1 receptor agonists (GLP-1RAs) may reduce the risk of dementia or cognitive impairment, according to findings from a study published in JAMA Neurology.

To better understand the effect of cardioprotective glucose-lowering therapy on dementia risk, researchers from the University of Galway performed a systematic review and meta-analysis that included 26 randomized clinical trials that reported on dementia or cognitive impairment as a primary or secondary outcome. The studies included 164,531 participants (mean age, 64.4 years; 34.9% female). Among the 23 trials (n=160,191) included in the primary meta-analysis, 12 trials evaluated sodium-glucose cotransporter-2 inhibitors (SGLT2is), 10 evaluated GLP-1RAs, and 1 evaluated pioglitazone. No studies were identified that reported dementia outcomes with metformin.

Findings showed that over a mean follow-up of 31.8 months, glucose-lowering therapy  overall was not significantly associated with a reduction in all-cause dementia or cognitive impairment (odds ratio [OR], 0.83, [95% CI, 0.60-1.14]). Moreover, no significant reduction in risk was noted when evaluating by dementia subtype (eg, vascular dementia, Alzheimer dementia).

Regarding specific drug classes, a statistically significantly lower risk of dementia or cognitive impairment was observed with GLP-1RAs (OR, 0.55 [95% CI, 0.35-0.86]), though not with SGLT2is (OR, 1.20 [95% CI, 0.67-2.17]), when compared with controls (P =.04). “This may be partly explained by differences in populations enrolled, with a higher all-cause dementia event rate noted among the control group of GLP-1RA trials compared with SGLT2i trials (0.14% vs 0.05%), with a resultant increase in statistical power to detect associations,” the authors explained.

Given the limitations of the study, the authors concluded that large randomized clinical trials “dedicated to addressing optimal glucose-lowering therapy in patients with cognitive impairment” are needed. They note several studies currently evaluating GLP-1RAs and SGLT2is in patients with early Alzheimer disease or mild cognitive impairment, including the EVOKE (ClinicalTrials.gov Identifier: NCT04777396) and LIGHT-MCI (ClinicalTrials.gov Identifier: NCT05313529) trials, as well as a study assessing the effects of semaglutide on cognition in healthy participants (OxSENSE; ClinicalTrials.gov Identifier: NCT06363487).