Semaglutide may reduce the risk of Alzheimer’s disease in people with diabetes

Semaglutide is associated with a 40-70% lower risk of first-time Alzheimer’s disease in patients with type 2 diabetes compared with other antidiabetic drugs.

Test: Associations of semaglutide with first-time diagnosis of Alzheimer’s disease in patients with type 2 diabetes: a targeted emulation trial using nationwide real-world data in the US. Photo credit: Marc Bruxelle/Shutterstock.com

A recent Alzheimer’s disease and dementia study used real-world data from the United States to evaluate the protective role of semaglutide in the treatment of Alzheimer’s disease (AD).

Can semaglutide prevent AD?

In 2014, approximately 6.9 million U.S. citizens aged 65 and older were diagnosed with atopic dermatitis, 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 that may be targeted to reduce or delay the onset of both Alzheimer’s disease and dementia.

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

In addition to these indications, semaglutide may also aid in the treatment of a variety of conditions, including cardiovascular disease, depression, alcohol employ, and smoking, all of which are also considered modifiable risk factors for Alzheimer’s disease. Therefore, clinical trials are needed to evaluate whether semaglutide can delay or prevent AD.

About the study

Researchers in the current study hypothesized that semaglutide reduces the risk of developing Alzheimer’s disease in high-risk patients. For this purpose, a target emulation trial was conducted using the TriNetX Analytics platform based on real electronic health records (EHR) of T2DM patients without a history of Alzheimer’s disease.

Seven target studies were emulated with 1,094,761 eligible patients from a nationwide US patient database. All study participants, both men and women, were 60 years of age or older.

None of the study participants had used any antidiabetic medications within the last six months of study entry and were considered “recent users.” However, these patients were prescribed semaglutide due to a history of hypertension, obesity, hypercholesterolemia, heart disease, or stroke.

A specific study was conducted for each patient population to compare semaglutide with other drugs used to treat T2DM, including sodium glucose cotransporter-2 inhibitors (SGLT2i), insulins, metformin, sulfonylureas (SUs), thiazolidinediones (TZDs), dipeptidyl peptidase 4 inhibitors (DPP-4i) and other GLP-1Ras.

Based on EHR data, first-time diagnosis of AD was considered the primary outcome, while prescription of AD-related medications such as donepezil, lekanemab, rivastigmine, aducanumab, memantine, and galantamine were considered secondary outcomes. Each result was analyzed separately.

Research results

The study cohort consisted of 17,104 recent users of semaglutide and 1,077,657 recent users of other antidiabetic medications. The effectiveness of semaglutide was compared with each of the tested antidiabetic drugs.

Considerable heterogeneity was observed between insulin and semaglutide recipients in terms of ethnicity, age, sex, diagnosis of obesity, certain cardiovascular diseases, and risk factors associated with Alzheimer’s disease. However, these groups achieved balance after propensity score matching.

Patients with T2DM who were prescribed semaglutide had a significantly lower risk of being diagnosed with AD at the three-year follow-up visit compared with patients who were prescribed other antidiabetic drugs, regardless of sex, gender, and obesity. The overall risk of being diagnosed with AD for the first time within three years was almost twice as high in the general elderly population.

Three-year cumulative incidence curves comparing semaglutide with each antidiabetic drug showed a divergence in the curve within 30 days that continued to separate thereafter. This finding highlights the role of semaglutide in delaying the progression of Alzheimer’s disease with lasting effects.

Similarly, a subpopulation analysis showed that semaglutide reduced the risk of first-time diagnosis of AD compared with other classes of antidiabetic drugs. Secondary outcomes analysis also showed that semaglutide reduced AD-related drug prescriptions compared with other antidiabetic medications in patients with diabetes, with or without obesity.

How does semaglutide protect against Alzheimer’s disease?

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

Clinical trials have yielded similar results, with GLP-1RAs reducing cognitive impairment in patients with T2DM. In fact, one study from Denmark found that the risk of developing all-cause dementia was 53% reduced in T2DM patients who were prescribed GLP-1RA.

Importantly, several other diabetes medications, including SGLT2i, may also reduce the risk of being diagnosed with Alzheimer’s disease for the first time. For example, SGLT2i reduces neuroinflammation, oxidative stress, and mitochondrial dysfunction. Nevertheless, the current study shows that semaglutide is significantly more effective in protecting against Alzheimer’s disease than other diabetes drugs, including SGLT2i.

Despite these observations, additional research is needed to elucidate the mechanisms by which semaglutide reduces the risk of developing Alzheimer’s disease.

Study limitations

The current study has several limitations, including the retrospective, observational study design that used patient EHRs. This study design cannot account for over-diagnosis, underdiagnosis, misdiagnosis, or unmeasured or uncontrolled confounding factors that could generate biased results.

Moreover, because semaglutide received FDA approval relatively recently, follow-up was constrained to only three years.

Patient data were obtained from the TriNetX Analytics platform; therefore, the results require additional validation on analytical platforms. The EHR in TriNetX lacks data on medication adherence and tracking cognitive impairment, which may impact study results.

Conclusions

Prescribing semaglutide reduced the risk of first-time diagnosis of AD by 40–70% in older populations with T2DM and other comorbidities.

Future studies are needed to test the effectiveness of this drug in other populations. The effects of semaglutide on soft cognitive impairment and other neurodegenerative diseases should be investigated.