Semaglutide may reduce Alzheimer’s risk in diabetics

Semaglutide linked to 40-70% lower risk of first diagnosis of Alzheimer’s disease in type 2 diabetes patients compared to other antidiabetic drugs.

Study: Associations of semaglutide with first diagnosis of Alzheimer’s disease in patients with type 2 diabetes: target study emulation using real-world nationwide data in the US.. Image credits: Marc Bruxelle/Shutterstock.com

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

Can semaglutide prevent AD?

In 2014, approximately 6.9 million US citizens aged 65 years and older were diagnosed with AD, with the prevalence of this disease expected to reach 13.8 million by 2060. Although there is no cure for AD, several modifiable risk factors have been identified that may do so. aim to reduce or delay the onset of both AD 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 may also support the treatment of several health conditions, including cardiovascular disease, depression, alcohol consumption and smoking, all of which are also considered modifiable risk factors for AD. Thus, clinical trials are needed to assess whether semaglutide can delay or prevent AD.

About the study

The researchers of the current study hypothesized that semaglutide reduces the risk of developing AD in high-risk patients. To this end, an emulation target study was conducted using the TriNetX Analytics platform, based on real electronic health records (EHRs) of T2DM patients without a history of AD.

Seven target studies were simulated using 1,094,761 eligible patients from a nationwide database of US patients. All participants in the study, both men and women, were 60 years or older.

None of the study participants had used antidiabetic medications in the past six months after the start of the study and were considered ‘new users’. However, these patients received semaglutide prescriptions because of a history of hypertension, obesity, hypercholesterolemia, heart disease, or stroke.

For each patient population, a specific study was conducted 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 inhibitors. 4 inhibitors (DPP-4i) and other GLP-1Ras.

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

Findings of the study

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

Significant heterogeneity was observed between insulin and semaglutide recipients with regard to ethnicity, age, gender, diagnosis of obesity, certain cardiovascular conditions and AD-related risk factors. However, these groups were balanced after propenity score matching.

T2DM patients prescribed semaglutide were significantly less likely to be diagnosed with AD at a three-year follow-up visit compared with those prescribed other antidiabetic medications, regardless of sex, gender, and obesity. The overall three-year risk of a first diagnosis of AD was almost twice as high in the general older population.

The three-year cumulative incidence curves comparing semaglutide with each antidiabetic agent indicated a divergence in the curve within 30 days, which continued to separate thereafter. This finding highlights the role of semaglutide in delaying the development of AD with persistent effects.

Similarly, the subpopulation analysis indicated that semaglutide reduced the risk of a first diagnosis of Alzheimer’s compared to other groups of antidiabetic agents. The secondary outcome analysis also indicated that semaglutide reduced the number of AD-related medication prescriptions compared to other antidiabetic agents in diabetic patients, with or without obesity.

How does semaglutide protect against AD?

Existing evidence suggests that GLP-1RAs such as semaglutide may protect cognitive function by increasing autophagy and glucose uptake in the brain. 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 shown similar results, with GLP-1RAs reducing cognitive impairment in patients with T2DM. In fact, a study conducted in Denmark found that patients with T2DM prescribed GLP-1RAs had a 53% lower risk of developing all-cause dementia.

Importantly, several other diabetes medications, including SGLT2i, may also reduce the risk of an initial diagnosis of AD. For example, SGLT2i reduces neuroinflammation, oxidative stress and mitochondrial dysfunction. Nevertheless, the current study reports that semaglutide provided significantly more protection against AD than other antidiabetic agents, including SGLT2i.

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

Limitations of the study

The current study has several limitations, including its retrospective observational study design using patient EHRs. This study design may not account for overdiagnoses, underdiagnoses, misdiagnoses, and unmeasured or uncontrolled confounders, which could produce biased results.

Furthermore, the follow-up period was limited to only three years, as semaglutide was approved by the FDA relatively recently.

Patient data were obtained from the TriNetX Analytics platform; therefore, the results require additional validation on analysis platforms. EHRs in TriNetX lack data on medication adherence and cognitive impairment tracking, which could impact study results.

Conclusions

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

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