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Experts comment on news from Novo Nordisk that semaglutide does not reduce Alzheimer’s Disease progression.
Prof Paresh Malhotra, Group Leader at the UK Dementia Research Institute Care Research & Technology Centre and Head of the Division of Neurology at Imperial College London said:
“These two linked trials show that, unfortunately, semaglutide appears to have no effect on progression in people with established Alzheimer’s disease, including people who have evidence of some damage to brain blood vessels. This is disappointing but it is very important that these trials have been carried out. By using clinically relevant outcome measures the investigators have taken the most robust approach to testing whether semaglutide was effective. It is essential that we continue to explore the most promising treatments, whether newly developed or ‘repurposed’ from other disease areas, and that we do this systematically and efficiently. We must try to give all people affected by Alzheimer’s the opportunity to take part in clinical trials and other research as well as ensuring that we evaluate potential new treatments for every stage of the disease process.”
Prof Sir John Hardy, Group Leader at the UK Dementia Research Institute at UCL, said:
“There is no mechanistic evidence linking Alzheimer’s disease and type 2 diabetes (see Hardy et al 2022) and on that basis, it would be expected that the anti-diabetic GLP-1 agonist would have no beneficial effect in AD. However, when drugs have been shown to be relatively safe, the bar towards testing them even in “long shot” trials is worth it and it is, of course, disappointing that this trial has failed. We do now have drugs (Dononamab and Lecanemab) which show some benefit and one might consider whether these should be the placebo treatments against which new drugs are tested.”
Hardy J, de Strooper B, Escott-Price V. Diabetes and Alzheimer’s disease: shared genetic susceptibility? Lancet Neurol. 2022 Nov;21(11):962-964. doi: 10.1016/S1474-4422(22)00395-7. PMID: 36270305.
Prof Robert Howard, Professor of Old Age Psychiatry, UCL, said:
“While failure of every potential treatment for Alzheimer’s disease is disappointing, this was always something of a hopeful thinking longshot and I’m not completely surprised that the drug has failed to show activity against disease progression.
“But it was important to conduct such a large and carefully managed study so that we can confidently shut this line of enquiry and look elsewhere for progress. Clinical trial outcomes have a definite brutality to them, but this is important if we are to move on and find ultimate treatments that work.”
Dr Riccardo De Giorgi, Clinical Lecturer, University of Oxford Department of Psychiatry, said:
“These early findings from the evoke/evoke+ trials do feel disappointing. They report a lack of clinical benefit on a dementia scale (CDR-SB) but still offer only a partial picture. Full data will be needed to understand adherence, exposure-response patterns, and whether any subgroups may have derived benefit.
“In my opinion, the biomarker improvements remain noteworthy. They suggest that semaglutide engaged relevant biological pathways, even if this did not translate into slower clinical progression. The oral formulation, compared with injectable options, may also have influenced outcomes, as sustained adherence in long Alzheimer’s trials is challenging.
“More broadly, these findings reinforce two possibilities for the field: we may need to re-define the biological processes underlying Alzheimer’s dementia that we target and measure, or we may need to pursue similar agents with stronger brain penetration and more potent metabolic or anti-inflammatory effects.”
Prof Gill Livingston, Professor of Psychiatry of Older people, UCL, said:
“It is very disappointing as it would be great to have something that worked, was well tolerated and could be relatively easily administered. As it failed to slow progression in Parkinson’s disease and reduce neurodegeneration it is not very surprising. The people in the trial were followed up for two years by which time people with Alzheimer’s dementia would be expected to deteriorate but those with Mild Cognitive Impairment might not have. It is difficult to show a difference if people were not getting worse and we do not know if there was a difference in those with dementia or without or what it does to biomarkers. The discontinuation of the follow up suggests that the company is not optimistic.
“There are other promising avenues of research and the recent quasi experimental studies showing a decrease in dementia related to shingles vaccine means this is a promising avenue.”
Prof Tara Spires-Jones, Director of the Centre for Discovery Brain Sciences at the University of Edinburgh, Group Leader in the UK Dementia Research Institute, and Past President of the British Neuroscience Association said:
“Novo Nordisk reported that semaglutide failed to slow the progression of Alzheimer’s disease in two well-conducted phase III clinical trials. While these results will be disappointing for people living with dementia, the company reported that treatment did improve Alzheimer’s-related biomarkers leaving open a tiny window of hope that in future this drug might be effective if used earlier as a preventative strategy. Diabetes and obesity are both associated with increased risk of developing Alzheimer’s, and these conditions are effectively treated by GLP-1 drugs including semaglutide. Future trials are needed to confirm whether GLP-1 drugs might be effective in preventing Alzheimer’s disease.”
Dr Ivan Koychev, Clinical Associate Professor in Neuropsychiatry, Imperial College London, said:
“My opinion is that the topline findings from EVOKE and EVOKE+ are not entirely surprising when viewed in the context of the broader evidence base. The pharmacoepidemiological data that originally motivated semaglutide’s evaluation in Alzheimer’s disease consistently pointed toward a preventive signal rather than an effect on symptomatic stages of dementia. In large real-world datasets, people exposed to GLP-1 receptor agonists over many years appear to have a lower risk of ever developing dementia, which suggests an influence on the earliest pathogenic processes rather than on established neurodegeneration.
“In EVOKE, the biomarker changes are encouraging and align with the hypothesis that GLP-1–based therapies may exert a disease-modifying effect biologically. However, by the time individuals have mild cognitive impairment or mild dementia, much of the neuronal loss and circuit disruption is already entrenched. At this point in the disease course, even meaningful shifts in fluid biomarkers may not translate into measurable improvements in cognition or daily functioning over a two-year trial.
“This is a recurring theme in Alzheimer’s disease therapeutics. When pathology is advanced, preventing further biochemical decline is not necessarily enough to restore complex neural networks that have already deteriorated. The EVOKE results reinforce the need to test these agents much earlier, ideally years before symptoms emerge, when neuronal systems are more intact and the potential for clinical benefit is greater.
“So, while semaglutide did not slow progression in established symptomatic Alzheimer’s disease, these findings do not diminish the preventive epidemiological signal. Instead, they point us toward the next logical steps: targeting preclinical stages, leveraging biomarkers to identify those at highest risk, and understanding how metabolic interventions can reshape the trajectory of neurodegeneration before symptoms appear.”
Prof Paul Morgan, Director, UK Dementia Research Institute Cardiff, said:
“The failure of semaglutide therapy to impact disease progression in patients with mild cognitive impairment and mild Alzheimer’s disease (AD) in the EVOKE phase 3 trials is, of course, disappointing but perhaps not surprising. The logic behind these trials was solid – diabetes and obesity are both significant risk factors for AD so a drug that impacts these risk factors might impact AD progression.
“One clear difference between the trials and real-life disease development is time. In the trials, subjects were treated for two years, while the impacts of obesity and diabetes on dementia likely accumulate over many years. As huge numbers of individuals are now taking these types of drugs to control diabetes or for weight loss it will be interesting to evaluate at a population level whether they have any impact on AD risk in the long term.
“Drug trials in AD are, because of the slowly evolving nature of the disease, expensive and time-consuming. This has made pharma reluctant to progress to clinical trials of potential new therapies, a situation improved in recent times with the success, albeit limited, of anti-amyloid drugs in slowing disease progression. I sincerely hope that the failure of semaglutide in a sensible and well-conducted trial does not further discourage future studies. We need new therapeutic approaches above and beyond the anti-amyloid drugs if we are to meaningfully impact AD progression and need to be able to test these when the evidence supports.”
Prof Ian Maidment, Professor of Clinical Pharmacy, Aston University, said:
“Whilst the news is disappointing, at least we now have clear evidence that semaglutide – a GLP-1 agonist – doesn’t appear to slow the progression of Alzheimer’s disease. The previous evidence wasn’t based on controlled studies in this area hence the need for robust clinical trial evidence. There are numerous drugs for Alzheimer’s disease currently under-development. However, we also need to look beyond medication and at life-style. One key message is that what is good for the heart is good for the head.”
Dr Susan Kohlhaas, Executive Director of Research and Partnerships at Alzheimer’s Research UK says:
“Today’s disappointing results on semaglutide will come as a blow for people affected by Alzheimer’s.
“These trial results are another reminder that Alzheimer’s is driven by several different biological processes. No single approach is likely to be enough. The field now needs to focus on understanding those processes in much greater detail and developing treatments that can be used together to tackle the disease from multiple angles.
“That means widening the range of therapeutic targets, investing in research that uncovers new mechanisms, and building the evidence needed to translate those discoveries into medicines. This is the approach that will ultimately lead to combination treatments.
“However, the growing use of GLP-1 medicines through private prescriptions, largely for weight loss or other health conditions rather than cognitive decline, offers an opportunity to gather better real-world data on their longer-term effects. Making full use of that information will help shape future research and strengthen the evidence base the field relies on.”
“We look forward to seeing further data next week so the research community can understand what this trial tells us and how it should shape future studies. People with Alzheimer’s urgently need better options, and this setback reinforces the need to invest in the science that can drive real progress towards a cure.”
Fiona Carragher, Chief Policy and Research Officer at Alzheimer’s Society, said:
“It’s very disappointing that these eagerly awaited results are not what we hoped for. Semaglutide does not appear successful in slowing the progression of Alzheimer’s disease.
“However, no trial is wasted. Every investigation helps us develop better drugs and design better trials in the future. Research is hope and there are currently over 130 Alzheimer’s drugs in clinical trials of which around 30 are in late-stage trials, the final step before they are considered by regulators.
“Despite these results, there is a critical window of opportunity to prepare for other disease-modifying treatments coming down the track. The Government must invest in getting more people diagnosed at an earlier stage, as one in three people with dementia don’t currently have a diagnosis. We must avoid a situation where regulators approve treatments but too many people don’t receive them because they don’t have an early and accurate diagnosis.”
Novo Nordisk A/S: Evoke phase 3 trials did not demonstrate a statistically significant reduction in Alzheimer’s disease progression
Declared interests
Prof Paresh Malhotra: I receive research funding from NIHR, MRC, Dementia Platforms UK, Alzheimer’s Research UK, the Football Association, British Heart Foundation and Alzheimer’s Society. I am a Trustee for Alzheimer’s Society, Group leader of the UK Dementia Research Institute, and am the National Specialty Lead for Dementia and Neurodegeneration in the NIHR Research Delivery Network. I have sat on two NHS England policy working groups looking at diagnostic pathways and delivery issues relating to lecanemab treatment for Alzheimer’s Disease. I practise clinically at Imperial College Healthcare NHS Trust and also carry out a fortnightly private clinic at Cleveland Clinic London.
Prof Sir John Hardy: I have consulted for Eisai and Eli Lilly
Prof Robert Howard: No conflicts
Dr Riccardo De Giorgi: RDG reports no conflict of interest.
Prof Gill Livingston: I have no conflicts of interest
Prof Tara Spires-Jones: I have no conflicts with this study but have received payments for consulting, scientific talks, or collaborative research over the past 10 years from AbbVie, Sanofi, Merck, Scottish Brain Sciences, Jay Therapeutics, Cognition Therapeutics, Ono, and Eisai, and direct a company Spires-Jones Neuroscience, Ltd to act as a consultant. I am also Charity trustee for the British Neuroscience Association and the Guarantors of Brain and serve as scientific advisor to several charities and non-profit institutions.
Dr Ivan Koychev: I am in receipt of an investigator-initiated grant by Novo Nordisk to study semaglutide in people at-risk for dementia.
Prof Paul Morgan: No conflicts
Prof Ian Maidment: No conflicts of interest
Fiona Carragher: No conflicts
For all other experts, no reply to our request for DOIs was received.