Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) are associated with a significantly lower risk of dementia and Alzheimer's disease-related dementia (ADRD), findings from two new studies showed.
The results are “consistent with and extend previous observational studies and meta-analyses suggesting a potential protective role of GLP-1RAs and SGLT2is” for reducing the risk of ADRD among patients with diabetes, Huilin Tang, PhD, of the department of pharmaceutical outcomes and policy at the University of Florida College of Pharmacy, and colleagues wrote.
In a retrospective, population-based cohort study, investigators found patients with type 2 diabetes had a significantly lower risk of ADRD when taking GLP-1RAs and SGLT2is compared with other glucose-lowering drugs.
In the second study, which evaluated 23 trials of a broader group of participants, researchers found an association between GLP-Ras — but not SGLT2is — and reduced risk of all-cause dementia.
“While none of the eligible clinical trials included a specific population with cognitive impairment, findings may have implications for choice of glucose-lowering therapy in patients with diabetes and higher risk of dementia,” Allie Seminer, MSc, of the HRB Clinical Research Facility at the University of Galway, Ireland, and colleagues wrote.
Both studies were published online April 7 in JAMA Neurology.
Neuroprotective Effects
Tang and colleagues analyzed the prevalence of ADRD in the electronic health record data of patients with type 2 diabetes, which included evaluating 33,858 patients who received a GLP-1RA or another glucose-lowering drug; 34,185 patients who received a SGLT2i or another glucose-lowering drug; and 24,117 patients who received either a GLP-1RA or SGLT2i drug. The researchers grouped patients into inverse probability of treatment weighted cohorts to limit confounding from other variables.
Compared to individuals who used other glucose-lowering drugs, ADRD was 33% less likely in those who received GLP-1RAs (hazard ratio [HR], 0.67; 95% CI, 0.47-0.96) and 43% less likely in those who received SGLT2is (HR, 0.57; 95% CI, 0.43-0.75). There was no significant difference in ADRD risk between the GLP-1RA and SGLT2i groups.
The second study included a systematic review and meta-analysis of data from 26 randomized controlled trials with an overall cohort of 164,531 adults (median age, 64.4 years; 34.9% female).
Seminer and colleagues examined the association of dementia or cognitive impairment risk and the use of GLP-1RAs, SGLT2is, metformin, and pioglitazone — glucose-lowering therapies that have evidence of cardioprotective properties as recommended by clinical guidelines. They also assessed the impact of these drugs on dementia subtypes and change in cognitive scores as secondary outcomes.
Although there was no association between the use of glucose-lowering therapies in general and reduced risk of cognitive impairment or dementia, GLP-1RA users had a significantly lower risk of all-cause dementia (odds ratio, 0.55; 95% CI, 0.35-0.86) compared with control groups that received placebo, usual care, or no treatment with glucose-lowering drugs. This effect was not seen with SGLT2is.
Researchers found no significant association between glucose-lowering medications and change in cognitive scores or in individual dementia subtypes studied, including vascular dementia, ADRD, or Lewy body dementia.
The authors of both studies called for further research to confirm the findings and evaluate the impact of glucose-lowering therapies on cognitive outcomes.
Mechanism Unclear
Use of GLP-1RAs in clinical practice is only beginning, so “it is crucial to study these newer medications individually rather than grouping them with older drugs in the same class, as their effects may differ significantly,” Diana Thiara, MD, of the division of general internal medicine at the University of California, San Francisco, wrote in a related editorial.
“It is possible that these new drugs, with enhanced mechanisms of action like dual or triple agonism, could have even more potent neuroprotective effects,” she said. “By targeting multiple pathways simultaneously, these next-generation drugs may further enhance brain health, improve vascular integrity, and potentially provide stronger protection against conditions like cognitive impairment, vascular dementia, and ADRD.”
The results from the study by Tang and colleagues raise a number of hopeful questions, David A. Rometo, MD, clinical director of the UPMC Center for Obesity Medicine in Pittsburgh, who was not involved with the research, told Medscape Medical News.
For instance, there may be something potentially harmful about the non-GLP-1 and non-SGLT2i comparator drugs that raise the risk of dementia at baseline. It is also not clear whether the benefit of dementia prevention may also be associated with the “already-known magnitude of weight loss or belly fat loss, the magnitude of glycemic control improvement, the reduction in food intake, improvements in blood pressure and triglycerides from GLP-1 and SGLT2” drugs, he said.
The impact may also be a new effect of these medications on the brain or other circulating factors that are not yet understood, he added.
The studies also have limitations, such as grouping GLP-1RAs together, Rometo noted.
“[W]e know these medications have different magnitude of effect on glucose, diet, and weight, and different effects on GLP-1 receptors in the brain vs. gut vs. pancreas. Each drug is evaluated with prospective randomized control trials to determine their risk reduction for heart attack, stroke,” he said.
“The same needs to be done for dementia, instead of this broad class-effect analysis. But showing the class effect supports the important of investing in trials of the individual medications moving forward,” he added.
For patients and clinicians concerned about preservation of cognitive function, Rometo also suggested looking at affordable and accessible interventions to reduce dementia risk.
It is still unclear how glucose-lowering drugs impact different types of dementias and if the effect on dementia involves more than simply lowering blood glucose, Glen R. Finney, MD, director of the memory of cognition program at Geisinger Health, Wilkes-Barre, Pennsylvania, told Medscape Medical News.
“I think that it is still important for your brain health to keep, through diet and exercise, your blood sugars in the healthy range, and if you do start to have findings of diabetes to work with your primary care providers on what is the best medical management for you,” Finney said. “In the meantime, we need to do more research to know best how to also protect from dementias for those with diabetes.”
Mounting Evidence
Several experts who weren't involved with these studies weighed in on the results in a statement from the independent nonprofit UK Science Media Center.
Both papers have limitations because of their retrospective study’s designs, Ivan Koychev, PhD, MRCPsych, clinical reader in neuropsychiatry and consultant neuropsychiatrist at Imperial College London and Central North West London NHS Foundation Trust, said in a statement.
For instance, the design of the large epidemiological study conducted by Tang and colleagues limits the ability to draw conclusions about causality. In the study by Seminer and colleagues, dementia and cognitive outcomes were not primary endpoints, which, as Koychev noted, could lead to overstating or overlooking potential effects.
However, the results from both “add to a growing and remarkably consistent body of evidence that GLP-1 receptor agonists associate with a reduction in dementia incidence,” he said.
In particular, the finding that GLP-1 RA drugs may perform better than SGLT-2i drugs “suggests that the dementia protection effects are not due to glucose control mechanisms” and that inflammation and cerebrovascular effects may play a role.
Also weighing in was Masud Husain, BMBCh, professor of neurology and cognitive neuroscience at the University of Oxford: “For me, these new retrospective analyses suggest that GLP-1 receptor agonists, particularly semaglutide, might reduce the risk of developing dementia in people with type 2 diabetes,” Husain said. “The wider question of whether such drugs might also be protective against dementia in people who don’t have diabetes is a really intriguing one, and the focus of several ongoing clinical trials.”
The study by Tang and colleagues was supported by the Pharmaceutical Research and Manufacturers of America (PhRMA) Foundation Predoctoral Fellowship, American Foundation for Pharmaceutical Education Predoctoral Fellowship, National Institutes of Health (NIH), National Institutes on Aging, and National Institute of Diabetes and Digestive and Kidney Diseases. Tang and colleagues reported grants, personal and consulting fees, data and safety monitoring board positions, medical advisory board positions, and writing and editorial roles with Acumen Pharmaceuticals, Biogen, Cognition Therapeutics, Eisai, Lilly, Neurotherapeutics, Nido Biosciences, NIH, Novo Nordisk, PhRMA Foundation, Prevail Therapeutics, Takeda Pharmaceuticals, UpToDate, and Vaccinex.
Funding for the study by Seminer and colleagues was not disclosed. Authors reported grants from the Health Research Board, Irish Clinical Academic Training Program, Wellcome Trust, the Health Service Executive National Doctors Training and Planning, and the Health and Social Care Research and Development Division in Northern Ireland.
Thiara reported owning stock in Eli Lilly, Novo Nordisk, and Viking Therapeutics. Koychev reported received speaker fees and grants from Novo Nordisk. Anderson and Husain reported no relevant conflicts of interest. Finney reported no relevant conflicts of interest. Medscape Medical News was unable to confirm Rometo’s financial disclosures at the time of publishing.