GLP-1s May Stave Off Dementia, EHR-Based Study Shows

More data, this time from a large observational study, are bolstering the idea that glucagon-like peptide-1 (GLP-1) receptor agonists offer neuroprotective and cerebrovascular benefits beyond what can be attributed to glycemic control.

Among adults with type 2 diabetes and obesity, researchers led by Huan-Tang Lin, MD, PhD (Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan), found that the use of semaglutide (Novo Nordisk) and tirzepatide (Eli Lilly) is associated with lower risks of dementia, stroke, and all-cause mortality. The findings were published recently in JAMA Network Open.

Importantly, the 2024 Lancet Commission on dementia specified diabetes and obesity as modifiable factors that raise the risk of disease by approximately 70% and 30%, respectively, Lin and colleagues point out. “Patients with both conditions face an elevated risk of neurodegenerative and cerebrovascular diseases, including dementia, Parkinson’s disease, and stroke.”

While GLP-1s have shown positive signs in this area, the researchers say, large-scale studies have been limited thus far. For this report, they leveraged electronic health records (EHR) from more than 60,000 patients to fill that gap.

Ziyad Al-Aly, MD (VA St. Louis Health Care System and Washington University School of Medicine, MO), commenting on the results for TCTMD, said they are in line with earlier reports, including one of his own, suggesting neuroprotection may be among the pleotropic effects of GLP-1 receptor agonists.

“This is yet another study, on top of all this prior evidence, again pointing in the same direction,” he said. This consistency in the data “raises the likelihood that this is actually a real thing.” The EVOKE and EVOKE Plus randomized trials of semaglutide in patients with early Alzheimer’s disease are currently underway, said Al-Aly, and will hopefully shed some light on this potential.

“We don’t know,” as of now, whether the GLP-1s are directly impacting brain health, Al-Aly specified. It may be that the drivers are weight loss and better glycemic control, though other possibilities include the decreases in inflammation and LDL cholesterol seen with the drugs. That said, “we know there are GLP-1 receptors in the brain, and . . .  a lot of people suggest that the GLP-1s’ effect on appetite is mediated by [their] effect on impulse control and reward signaling in the brain,” he added.

Less Dementia, Stroke, and Death

Lin et al analyzed more than 6 years of data from the EHR of 60,860 US patients age 40 or older in the TriNetX research platform, using propensity-score matching to account for baseline differences. All had type 2 diabetes and obesity, and none had prior neurodegenerative or cerebrovascular disease.

Half of the patients were new users of GLP-1 drugs (mean age 57.9 years; 50.2% female) and half were new users of other antidiabetic drugs (mean age 58 years; 51.4% female), a category that included biguanides, sulfonylureas, dipeptidyl peptidase 4 inhibitors, sodium-glucose cotransporter 2 inhibitors, thiazolidinediones, and alpha-glucosidase inhibitors.

For patients who started on GLP-1s compared with other antidiabetic medications, Cox proportional hazard models showed lower 7-year risks of dementia (HR 0.63; 95% CI 0.50-0.81), stroke (HR 0.81; 95% CI 0.70-0.93), and all-cause mortality (HR 0.70; 95% CI 0.63-0.78). No differences were seen between the two groups in the risks of Parkinson’s disease and intracerebral hemorrhage.

The advantages of GLP-1 drugs were greater in patients age 60 and older (versus younger), women (versus men), white patients (versus Black), and those with a body mass index of 30-40 kg/m₂ (versus higher).

Dementia risk was reduced with semaglutide, whereas stroke risk was reduced with tirzepatide. Tirzepatide, in addition to its GLP-1 agonism, also works as a glucose-dependent insulinotropic polypeptide receptor agonist. This dual mechanism “may further enhance incretin responses and insulin secretion, potentially leading to a substantially lower risk of cerebral infarction than semaglutide,” the investigators explain, noting that tirzepatide results in greater weight loss, as well.

On the whole, the new “findings suggest that semaglutide and tirzepatide may offer neuroprotective and cerebrovascular benefits beyond glycemic control, potentially improving long-term cognitive and survival outcomes in adults with type 2 diabetes and obesity,” Lin and colleagues conclude, stressing that future studies should be done to clarify differences in mechanism and benefit between the two drugs.

It’s important to initiate strategies for dementia prevention in midlife, they say, and include multifactorial interventions that promote physical activity and smoking cessation as well as address diabetes and obesity, potentially through GLP-1 therapy.

Al-Aly, however, offered a note of caution given that older adults are the individuals most likely to suffer from Alzheimer’s disease and dementia—a different population than the middle-aged and younger patients with diabetes and/or obesity who are currently the main demographic taking GLP-1s.

The drugs, in addition to their positive qualities, “also result in profound loss of bone mass and muscle mass,” he said. Older adults, as opposed to younger, are more vulnerable to conditions like osteoporosis and frailty, said Al-Aly. “[If] they stumble and they fall and they break a hip, that is really bad in older adults.”

So, the excitement for the therapeutic potential of GLP-1 medications in Alzheimer’s disease and dementia is understandable, Al-Aly agreed,  ”but it also has to be balanced against the risk.”