Semaglutide may reduce Alzheimer's disease risk in diabetics

Semaglutide is associated with a 40-70% lower risk of being diagnosed with Alzheimer's disease for the first time. Type 2 diabetic patients compared to other diabetes medications.

study: Association of semaglutide with initial diagnosis of Alzheimer's disease in patients with type 2 diabetes: Targeted trial emulation using real-world data from across the United States. Image credit: Marc Bruxelle/Shutterstock.com

A recent Alzheimer's disease and dementia study evaluated the protective role of semaglutide against Alzheimer's disease (AD) using real-world data from the United States.

Can semaglutide prevent Alzheimer's disease?

In 2014, approximately 6.9 million Americans age 65 and older were diagnosed with Alzheimer's disease, and the prevalence of the disease is projected to reach 13.8 million by 2060. Although there is no cure for Alzheimer's disease, several modifiable risk factors have been identified and are intended to reduce or delay the onset of both Alzheimer's disease and dementia.

The U.S. Food and Drug Administration (FDA) has approved semaglutide, a glucagon-like peptide receptor agonist (GLP-1RA), for the treatment of type 2 diabetes mellitus (T2DM) and obesity.

In addition to these indications, semaglutide also supports the management of various health conditions such as cardiovascular disease, depression, alcohol consumption, and smoking. All of these are also considered modifiable risk factors for AD. Therefore, clinical trials are needed to evaluate whether semaglutide can slow or prevent Alzheimer's disease.

About research

Researchers in the current study hypothesized that semaglutide would reduce the risk of developing Alzheimer's disease in high-risk patients. To achieve this objective, an emulation target study was conducted using the TriNetX Analytics platform based on a real electronic health record (EHR) of a T2DM patient without a history of AD.

Seven targeted clinical trials were emulated using 1,094,761 eligible patients from the US national patient database. All study participants, both men and women, were over 60 years old.

None of the study participants had used antidiabetic drugs within the past 6 months from the start of the study and were therefore considered “new users.” However, these patients were prescribed semaglutide due to a history of hypertension, obesity, hypercholesterolemia, heart disease, or stroke.

For all patient populations, semaglutide and other drugs used to treat T2DM, including sodium-glucose cotransporter-2 inhibitors (SGLT2i), insulin, metformin, sulfonylureas (SUs), thiazolidinediones (TZDs), and dipeptidyl peptidases, Specific trials have been conducted to compare it with other drugs. Four inhibitors (DPP-4i) and other GLP-1Ra.

Based on EHR data, initial diagnosis of AD was considered the primary outcome, while prescription of AD-related drugs, such as donepezil, lecanemab, rivastigmine, aducanumab, memantine, and galantamine, was considered a secondary outcome. Each result was analyzed separately.

Research results

The study cohort consisted of 17,104 new users of semaglutide and 1,077,657 new users of other antidiabetic agents. The efficacy of semaglutide was compared with each antidiabetic drug studied.

Significant heterogeneity was observed between insulin and semaglutide recipients with respect to ethnicity, age, gender, obesity diagnosis, specific cardiovascular diseases, and Alzheimer's disease-related risk factors. However, these groups were balanced after propensity score matching.

T2DM patients prescribed semaglutide were significantly more likely to be diagnosed with AD during 3-year follow-up compared to patients prescribed other antidiabetic agents, regardless of sex, sex, or obesity. It was low. The overall three-year risk of being diagnosed with Alzheimer's disease for the first time was nearly twice as high in the general elderly population.

The 3-year cumulative incidence curves comparing semaglutide with each antidiabetic drug showed a divergence of the curves within 30 days and continued to separate thereafter. This finding highlights the role of semaglutide in delaying the onset of Alzheimer's disease with long-lasting effects.

Similarly, subpopulation analysis showed that semaglutide reduced the risk of being diagnosed with Alzheimer's disease for the first time compared to other antidiabetic drug groups. A secondary outcome analysis also showed that semaglutide reduced prescriptions for Alzheimer's disease-related drugs compared to other antidiabetic drugs in patients with diabetes, regardless of obesity.

How does semaglutide prevent Alzheimer's disease?

Existing evidence suggests that GLP-1RAs like semaglutide may protect cognitive function by increasing orthophagy and brain glucose uptake. Preclinical studies have also demonstrated that semaglutide can reduce neurotoxicity by preventing the growth of amyloid-β (Aβ) plaques and tau tangles.

Similar results have been obtained in clinical studies, where GLP-1RAs reduce cognitive impairment in T2DM patients. In fact, one study conducted in Denmark found that T2DM patients prescribed GLP-1RA had a 53% reduced risk of developing all-cause dementia.

Importantly, several other antidiabetic drugs, including SGLT2i, may also reduce the risk of initial diagnosis of AD. For example, SGLT2i reduces neuroinflammation, oxidative stress, and mitochondrial dysfunction. Nevertheless, the current study reports that semaglutide had a significantly greater protective effect against Alzheimer's disease than other antidiabetic drugs, including SGLT2i.

Despite these observations, additional studies are needed to elucidate the mechanism by which semaglutide reduces the risk of developing Alzheimer's disease.

Research limitations

The current study has several limitations, including its retrospective observational study design using patients' EHRs. This study design may not account for overdiagnosis, underdiagnosis, misdiagnosis, and unmeasured or uncontrolled confounders, potentially resulting in biased results.

Furthermore, because semaglutide received FDA approval relatively recently, the follow-up period was limited to only 3 years.

Patient data were obtained from the TriNetX Analytics platform. Therefore, the results require additional validation on an analytical platform. TriNetX's EHR lacks data regarding medication adherence and cognitive impairment tracking, which could impact study results.

conclusion

Prescription of semaglutide reduced the risk of first diagnosis of AD by 40-70% in an elderly population with T2DM and other comorbidities.

Future studies are needed to investigate the efficacy of this drug in other populations. The effects of semaglutide in mild cognitive impairment and other neurodegenerative diseases should be investigated.