Eli Lilly’s recent market rally has been fueled largely by investor confidence in its Alzheimer’s disease portfolio, especially its monoclonal antibodies that target amyloid pathology. These therapies have positioned Lilly as a leading contender in the emerging neurodegenerative drug market. However, Novo Nordisk, traditionally dominant in the metabolic-disease space, may pose an unexpected competitive threat if its data on GLP-1 receptor agonists in Alzheimer’s disease continue to strengthen. Although originally developed for type 2 diabetes and obesity, GLP-1 agonists have shown intriguing neuroprotective properties that could reshape therapeutic strategy in Alzheimer’s disease.
The biological rationale for GLP-1 agonists in neurodegeneration is increasingly robust. Beyond glucose-lowering effects, GLP-1 signalling influences neuronal insulin sensitivity, mitochondrial function, and neuroinflammatory pathways that play crucial roles in the pathophysiology of Alzheimer’s disease.
Preclinical studies have demonstrated reductions in neuroinflammation, decreased tau phosphorylation, and improvements in synaptic integrity following GLP-1 agonist exposure. These mechanistic insights have encouraged clinical evaluation, leading to early-phase and mid-stage human studies assessing GLP-1 analogues like liraglutide and semaglutide in patients with mild cognitive impairment or early Alzheimer’s disease.
One of the most notable clinical findings comes from a Phase II randomised controlled trial assessing liraglutide in mild Alzheimer’s disease. Although the primary endpoint, changes in cerebral glucose uptake measured by FDG-PET, did not reach statistical significance, key secondary analyses suggested meaningful neuroprotective effects. Patients treated with liraglutide exhibited roughly half the degree of brain-volume loss seen in the placebo group, particularly in cortical regions associated with memory consolidation, executive function, and complex learning.
Brain-volume preservation in these areas is considered clinically relevant, as structural degeneration in Alzheimer’s disease often precedes measurable cognitive decline. The study also demonstrated an approximate 18% slowing of cognitive deterioration in the liraglutide group, offering early evidence that GLP-1 agonist–mediated neuroprotection may translate to observable functional benefit.
Supportive real-world evidence further strengthens Novo’s case. Large observational datasets, including national health registries and insurance claims analyses, have repeatedly found lower incidence rates of dementia among long-term GLP-1 users compared with patients on other glucose-lowering therapies. These findings, while not proving causality, provide population-level reinforcement for the hypothesis that chronic GLP-1 exposure could slow or modify neurodegenerative processes. Such real-world trends are especially compelling given the extended duration of GLP-1 use in metabolic cohorts, offering insights into long-term safety and effect size that controlled studies may not capture within their limited timelines.
These signals have motivated Novo Nordisk to initiate two large Phase III trials—EVOKE and EVOKE+—using oral semaglutide in early Alzheimer’s disease. These studies aim to determine whether GLP-1 receptor activation can meaningfully slow cognitive and functional decline, reduce neurodegeneration, or modify biomarkers such as tau, amyloid load, or neuroinflammatory markers.
Positive outcomes would dramatically shift the therapeutic landscape. Unlike monoclonal antibodies requiring infusion and carrying risks such as amyloid-related imaging abnormalities (ARIA), an oral GLP-1 therapy would represent a more accessible, potentially safer, and highly scalable option. This could substantially broaden the treatment-eligible population and alter payer dynamics.
For Eli Lilly, the advancement of GLP-1 therapies into Alzheimer’s disease introduces a non-amyloid, mechanistically orthogonal competitor with strong commercial momentum. Lilly’s programs rely heavily on antibody therapies that, while effective in amyloid reduction, involve cost, logistical complexity, and safety risks that may limit widespread adoption. Should Novo demonstrate meaningful disease-modifying efficacy with semaglutide, investor enthusiasm concentrated around Lilly’s Alzheimer’s franchise could soften.
The GLP-1 approach might attract patients earlier in disease progression, those unable or unwilling to receive infusions, or those with contraindications to antibody therapy. Moreover, a metabolism-driven mechanism of action could suggest additive or synergistic potential with amyloid-targeting treatments, raising the possibility of combination strategies that could further diversify the competitive field.
Despite these promising developments, several uncertainties remain. MRI-based indications of slowed brain atrophy, while encouraging, do not always correlate directly with sustained cognitive benefit. Regulatory bodies will require robust evidence of clinical function, not just biomarker improvement. GLP-1 agonists, although widely used, can pose tolerability challenges, particularly gastrointestinal adverse effects, which may be amplified in frail elderly populations typical of Alzheimer’s trials.
Long-term neurological safety in non-diabetic patients also warrants evaluation. Furthermore, even if semaglutide proves effective, cost considerations and payer pressure may influence adoption, given the already substantial financial burden associated with GLP-1 therapies in obesity and diabetes.
Overall, Novo Nordisk’s expanding Alzheimer’s research program introduces a compelling alternative to traditional amyloid-centric strategies and may ultimately contest the investor narrative currently favouring Eli Lilly. Should Phase III results validate the neuroprotective benefits suggested by earlier studies and real-world evidence, GLP-1 agonists could emerge as a transformative class in Alzheimer’s disease therapeutics, redefining expectations for disease modification, improving patient accessibility, and reshaping competitive dynamics in one of the pharmaceutical industry’s most consequential markets.
Source
https://seekingalpha.com/news/4525149-can-novo-hurt-lilly-rally-alzheimers-data-glp-1
