Evoke (+) trials of semaglutide for early alzheimer's disease: Innovations, lessons, and implications.

The evoke and evoke+ trials for the treatment of early Alzheimer's disease (AD) with semaglutide were founded on the observation that semaglutide reduced the incidence of dementia in patients with type 2 diabetes. Non-clinical investigations support an effect of semaglutide on AD pathology. The evoke and evoke+ trials were large, well conducted, and innovative. These trials were negative, showing no clinical benefit of treatment with 14 milligrams of semaglutide for two years. Semaglutide produced a statistically significant and robust reduction in high sensitivity C-reactive protein consistent with suppression of peripheral inflammation. There was no effect on most plasma measures collected. CSF analyses showed nominally significant effects on biomarkers of the core biology of AD; YKL-40 and glial fibrillary acidic protein in CSF were decreased indicating a reduction in astroglial activation. The magnitude of these changes was small (7%-10%) and there was no correlative effect on AD progression. The discrepancy between observations in real world data and the trial outcomes indicates that treatment of symptomatic AD confirmed with biomarkers differs from treatment of patients with diabetes who were cognitively unimpaired and at risk for all cause cognitive decline. The evoke and evoke+ trials suggest that reduction in peripheral inflammation may be insufficient to produce beneficial clinical effects in AD. The results of the evoke(+) trials do not exclude the possibility that AD populations enriched for elevated levels of markers of peripheral inflammation or use of brain penetrant GLP-1 RAs could produce therapeutic benefit.