Semaglutide may reduce Alzheimer’s risk in diabetics

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

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

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

Could semaglutide prevent AD?

In 2014, approximately 6.9 million American citizens 65 years of age and older were diagnosed with AD, with the prevalence of this disease predicted to reach 13.8 million by 2060. Although there is no cure for AD, several modifiable risk factors have been identified that can be targeted 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), to treat type 2 diabetes mellitus (T2DM) and obesity.

In addition to these indications, semaglutide can also support the management of various health conditions, including cardiovascular disease, depression, alcohol use, 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 trial was conducted using the TriNetX Analytics platform based on real-world electronic health records (EHRs) of T2DM patients without a history of AD.

Seven target trials were emulated using 1,094,761 eligible patients from a nationwide database of U.S. patients. All study participants, both men and women, were 60 years of age or older.

None of the study participants used any antidiabetic medications within the past six months of the study commencement and were considered ‘new users.’  However, these patients received semaglutide prescriptions due to a history of hypertension, obesity, hypercholesterolemia, heart disease, or stroke.

For every patient population, a specified trial 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-4 inhibitors (DPP-4i) and other GLP-1Ras.

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

Study findings

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

Significant heterogeneity was observed between insulin and semaglutide recipients regarding ethnicity, age, sex, diagnosis of obesity, certain cardiovascular conditions, and AD-related risk factors. However, these groups were balanced after matching their propensity score.

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

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

Similarly, the subpopulation analysis indicated that semaglutide reduced the risk of first-time AD diagnosis as compared to other antidiabetic medication groups. The secondary outcomes analysis also indicated that semaglutide decreased AD-related medication prescriptions as compared to other antidiabetic medications in diabetic patients, with or without obesity.

How does semaglutide protect against AD?

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

Clinical studies have produced similar results, with GLP-1RAs reducing cognitive impairment in patients with T2DM. In fact, one study conducted in Denmark found that patients with T2DM prescribed GLP-1RAs were at a 53% reduced risk of developing all-cause dementia.

Importantly, several other diabetic medications, including SGLT2i, may also reduce the risk of first-time AD diagnoses. SGLT2i, for example, reduces neuroinflammation, oxidative stress, and mitochondrial dysfunction. Nevertheless, the current study reports that semaglutide was significantly more protective against AD than other anti-diabetic medications, including SGLT2i.

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

Study limitations

The current study has several limitations, including the retrospective observational study design that used patient EHRs. This study design may not consider overdiagnoses, underdiagnoses, misdiagnoses, and unmeasured or uncontrolled confounders, which could generate biased results.

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

Patient data was obtained from the TriNetX Analytics platform; therefore, the results require additional validation in analytics platforms. EHRs in TriNetX lack data on medication adherence and cognitive impairment tracking, which may influence study outcomes.

Conclusions

Semaglutide prescription reduced the risk of a first-time AD diagnosis 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 should be investigated.