'ozempic in a pill' not effective for Alzheimer's disease

As blogged previously, there has been interest to investigate whether GLP1-based medications, which are medications originally developed for diabetes and obesity, could benefit Alzheimer’s disease. Some of the thinking here is that GLP1s reduce insulin resistance and related inflammation, and neuroinflammation is part of Alzheimer’s disease. Obesity is a risk factor for Alzheimer’s, so for some people with Alzheimer’s and obesity, weight loss may be beneficial.

However, the topline results of two studies of oral semaglutide (Rybelsus) revealed no benefit to delay progression of Alzheimer’s disease. The evoke and evoke+ trials enrolled over 3,800 people age 55-85 with mild cognitive impairment or mild dementia due to Alzheimer’s, and randomized them to receive oral semaglutide 14mg daily vs placebo. The 2 year primary analysis did not show a benefit with semaglutide to reduce progression of Alzheimer’s, as measured by a clinical dementia rating score (Sum of Boxes CDR-SB). There was an improvement in Alzheimer’s-related biomarkers (data are not yet available on exactly which biomarkers or how much), but this did not translate to delayed disease progression.

The topline results also share that semaglutide demonstrated a similar safety profile as in other semaglutide trials. Earlier this year, I co-authored a pooled analysis of people age 65+ in diabetes/obesity (Ozempic/Wegovy) semaglutide trials, where we found that a similar proportion of people over 65 overall had gastrointestinal side effects, though discontinuation rates due to adverse events were a little higher in age 65+, compared to the overall trial populations. We don’t know whether this reflected a lower threshold to stop medication due to side effects in older people, or whether older people are perhaps more susceptible to excessive weight loss and thus medication was more commonly stopped, or other factors. (As per our Obesity Canada Pharmacotherapy 2025 Clinical Practice Guidelines, we should titrate these medications as needed, as tolerated, and as appropriate to each person – remembering that many people may achieve their treatment goals on less than maximum dose of medication.)

So why didn’t oral semaglutide delay progression of Alzheimer’s disease? It may be because semaglutide can’t access the regions of the brain involved in cognitive function and memory. Maybe there wasn’t enough reduction in systemic inflammation to have a benefit. Perhaps the dose of semaglutide wasn’t high enough [injectable semaglutide – Ozempic (diabetes) and Wegovy (weight management) can achieve higher levels in the body than the 14mg oral semaglutide tested in these trials]. I look forward to the publication of these data to understand the results in more detail.

We do know that some GLP1-based medications, including semaglutide, reduce cardiovascular events including stroke. I would be keen to see studies of GLP1-based medications looking specifically at people with vascular dementia (caused by large or small vessel cerebrovascular disease, ie stroke or ‘mini-strokes’) to see if there is benefit to this type of dementia.

BOTTOM LINE: Oral semaglutide did not show benefit to delay progression of Alzheimer’s disease.

Disclaimer: I am/have been an investigator in clinical trials of semaglutide. I receive honoraria as a continuing medical education speaker and consultant from the makers of semaglutide (Novo Nordisk).

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