EVOKE topline data presented at the CTAD conference

Novo Nordisk presented detailed topline results from its two Phase 3 Alzheimer's trials, EVOKE and EVOKE+, at the Clinical Trials on Alzheimer's Disease (CTAD) meeting in San Diego, held December 1–4 ^[1]. The data confirmed the company's November 24 announcement: oral semaglutide did not slow disease progression, and the treatment and placebo groups tracked each other almost exactly on every cognitive and functional measure shown [1,2].

The two trials screened nearly 10,000 people and enrolled 3,808 adults aged 55 to 85 with mild cognitive impairment or mild dementia due to Alzheimer's, all with confirmed amyloid in the brain — 1,855 in EVOKE and 1,953 in EVOKE+, across 40 countries [1,2]. Participants took a once-daily pill, with the dose stepped up from 3 mg to 7 mg at four weeks and to 14 mg at eight weeks ^[1]. The primary endpoint was change from baseline in the Clinical Dementia Rating–Sum of Boxes (CDR-SB) score at week 104 ^[2]. About 85 percent of participants completed year two before the data were locked; 30 percent had reached the end of year three ^[1].

The results

Jeffrey Cummings of the University of Nevada, Las Vegas presented the efficacy data. Placebo and semaglutide groups declined at the same rate on CDR-SB, and the rate matched what is expected in early Alzheimer's ^[1]. Secondary measures — ADCS-ADL-MCI, MoCA, ADAS-Cog13, MMSE, ADCOMS, and time to progression from MCI to dementia — showed the same flat result ^[1]. Subgroup analyses were not presented. Asked whether any group benefited, Novo Nordisk's Peter Johannsen said, "When you look at the curves, they are exactly on top of each other" ^[1].

A spinal fluid substudy enrolled about 100 people per group at baseline and 60 per group at week 78 ^[1]. Seven biomarkers showed nominally significant reductions of 10 percent or less with semaglutide: p-tau181, p-tau217, np-tau181, np-tau205, the neuroinflammation marker YKL-40, total tau, and neurogranin ^[1]. None of those shifts appeared in blood. Instead, plasma GFAP rose about 4 percent in both trials and plasma NfL rose about 5 percent in EVOKE+ only — a result Cummings said he could not explain ^[1]. Blood high-sensitivity C-reactive protein, an inflammation marker, fell about 30 percent in both trials, suggesting the drug quieted inflammation in the body without producing a cognitive benefit ^[1]. Johannsen noted the roughly 10 percent shift in CSF markers was in the same range seen with other drugs that failed, while approved antibodies lecanemab and donanemab produced larger biomarker changes ^[1].

On safety, Filip Knop of Novo Nordisk reported more total adverse events with semaglutide but no group difference in serious, severe, or fatal events ^[1]. More people on the drug lowered their dose or stopped, mostly for mild to moderate gastrointestinal problems ^[1]. Nearly a quarter reported nausea, 14 percent diarrhea, and 12 percent vomiting ^[1]. Over two years, the semaglutide group lost an average of 5.8 percent of body weight versus a 0.6 percent gain on placebo; participants who started obese lost 8.6 percent, while underweight participants lost 1 percent ^[1].

Why it matters for patients

This result does not change anything about semaglutide's approved uses. Semaglutide is marketed as Ozempic and Rybelsus for type 2 diabetes and Wegovy for chronic weight management, and Novo Nordisk said the existing evidence in those conditions still stands ^[2]. What the trials rule out is using the drug to slow decline in people who already have early, biomarker-confirmed Alzheimer's [1,2].

The open question is prevention. Several observational and registry studies have linked GLP-1 drugs to lower dementia risk, mostly in people with type 2 diabetes ^[1]. EVOKE did not test that question, and whether starting earlier would help is not yet known. The Alzheimer's Drug Discovery Foundation's Howard Fillit called the data "disappointing" but said exploring GLP-1 drugs as a preventive therapy "may still hold promise" ^[3].

What happens next

Novo Nordisk is discontinuing the planned one-year extension of both trials based on the efficacy results ^[2]. Full results are scheduled for the AD/PD conference in Copenhagen in March 2026 [2,3].