The GLP1 receptor agonists (GLP1RAs) are a class of medications originally developed to treat type 2 diabetes. As time goes on since the first GLP1RA approval in 2005, these medications are proving to be beneficial to many other organ systems and health conditions. Dementia is one of the health conditions in which GLP1RAs are showing promise.
The first data to suggest that GLP1RAs may be of benefit in preventing dementia came from studies of people with type 2 diabetes. For some background, people with type 2 diabetes have a faster rate of cognitive decline, and a 60% higher risk of developing dementia, than people without T2DM. The cardiovascular outcome trials of several GLP1RAs have shown a reduction in the risk of stroke in people with type 2 diabetes. When a stroke is diagnosed, it is typically a clear-cut event with obvious symptoms. However, what often goes undetected is microvascular (think microscopic) stroke events, which don’t have obvious symptoms at the time they occur because they are too small to be obvious. But with time, and repeated microvascular events, vascular dementia can set in, and worsen insidiously over time. This may be ‘written off’ by the patient’s family or health care team as part of the aging process. Often, vascular dementia doesn’t come to clinical attention until a family member or friend brings the patient in for assessment because their cognitive (brain) function seems to be going down hill over the years.
Turning back to the cardiovascular outcome trials, the data suggest that GLP1RAs may reduce the risk of cognitive impairment/dementia:
- A pooled post hoc analysis of the cardiovascular outcome trials of liraglutide (Victoza) and semaglutide (Ozempic) suggested a 53% decreased risk of development of dementia over a median 3.6 years, though it’s important to note that the number of people where new onset dementia was documented was extremely low (15 in GLP1RA treated patients vs 32 with placebo).
- In the cardiovascular outcome trial of dulaglutide (Trulicity) in people with type 2 diabetes, an exploratory analysis showed that the hazard of substantive cognitive impairment was reduced by 14% vs placebo over a median follow up of 5.4 years.
- In a Danish nationwide registry-based cohort of over 120,000 people with type 2 diabetes, demetia rate was 11% lower with yearly increased exposure to GLP1RAs, compared to other second-line diabetes treatments.
We know that GLP1RAs have anti atherosclerotic effects (protecting the lining of blood vessels), which is one of the mechanisms by which some GLP1RAs reduce stroke, and possibly vascular dementia. In addition, GLP1 RAs improve risk factors associated with dementia, including blood sugars, blood pressure, and weight. GLP1RAs also have anti-inflammatory effects, which is another likely mechanism by which they could be beneficial. As cognitive impairment has an insidious and slow progress over time and is not a clear-cut event, dementia may well be underreported in these studies; formal clinical trials need to be done to really understand the potential impact of GLP1RAs on vascular dementia.
Also, it turns out that it may not be just vascular dementia for which GLP1RAs may be of benefit. Of great interest, early stage research has suggested potential benefit of GLP1RAs in people with Alzheimer’s dementia, and in people with Parkinson’s disease. Postulated mechanism of benefit include anti-inflammatory, neurotropic and neuroprotective effects, and reduction in insulin resistance. Preliminary data with dual and triagonists of GLP1/GIP/glucagon are promising as well. The only medication in this group currently approved (for type 2 diabetes) is tirzepatide, a dual GIP/GLP1 agonist – preclinical data on dual GIP/GLP1 agonism in Parkinson’s disease and Alzheimer’s disease can be found here.
I’m excited to see this field evolve as ongoing and future studies bring us more information!
Disclaimer: I am/have been an investigator in clinical trials of tirzepatide (Eli Lilly), semaglutide, and liraglutide (Novo Nordisk). I receive honoraria as a continuing medical education speaker and consultant from the makers of semaglutide and liraglutide (Novo Nordisk) and tirzepatide (Eli Lilly).
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