Real-World Data Suggest Two Antidiabetic Drug Classes May Curb Alzheimer’s Risk

Observational data drawn from two large U.S. patient databases indicate that initiation of glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter-2 (SGLT-2) inhibitors is associated with a significantly reduced risk of Alzheimer’s disease (AD) compared with starting dipeptidyl peptidase-4 (DPP-4) inhibitors.

The data — from a pharmacoepidemiologic study co-led by Cleveland Clinic researchers and published in Alzheimer’s & Dementia (2025;21[9]:e70639) — offer compelling real-world evidence in support of ongoing randomized clinical trials investigating the therapeutic potential of these antidiabetic drug classes for neurodegenerative conditions.

“Clinicians prescribing these antidiabetes agents, particularly for patients with coexisting cardiac or renal risk factors, may have an additional consideration — a potential neuroprotective effect against Alzheimer’s disease,” says Feixiong Cheng, PhD, Director of Cleveland Clinic’s Genome Center and one of the study’s corresponding authors.

A metabolism/neuroinflammation link

The connection between Type 2 diabetes mellitus (T2DM) and neuroinflammation is well established in the pathophysiology of both AD and Parkinson’s disease (PD). GLP-1 receptor agonists, SGLT-2 inhibitors and DPP-4 inhibitors are commonly used second-line treatments for T2DM, with the first two classes also finding increased use for weight loss.

While all three classes have shown promise in preclinical models by potentially reducing neuroinflammation, amyloid-beta accumulation and tau hyperphosphorylation, GLP-1 receptor agonists and SGLT-2 inhibitors also possess properties that may enhance their central nervous system effects. Specifically, these agents are hypothesized to cross the blood-brain barrier more effectively than DPP-4 inhibitors. Moreover, GLP-1 receptor agonists and SGLT-2 inhibitors might improve cognition by reducing neuronal loss and vascular damage, as well as mitigating dysregulations in autophagy and mitophagy, processes linked to AD.

Clinically, GLP-1 receptor agonists and SGLT-2 inhibitors generally offer greater effects on weight reduction and blood glucose lowering compared with DPP-4 inhibitors. Standard recommendations already favor GLP-1 receptor agonists for T2DM patients with prior atherosclerotic cardiovascular disease and SGLT-2 inhibitors for those with chronic kidney disease or heart failure.

“Different antidiabetic drug classes work through different biological pathways,” Dr. Cheng explains. “We wanted to evaluate whether some of these medications could also target mechanisms directly linked to the brain and neurodegeneration.”

Study design at a glance

The new study was an analysis of two extensive U.S. real-world patient databases over nearly two decades — the Optum Clinformatics^® Data Mart (from 2007 to 2021) and electronic health record data from the Northwestern Medicine Enterprise Data Warehouse (from 2005 to 2023). The researchers identified all individuals aged 60 years or older who initiated one or more of the three drug classes, for a total sample comprising more than 430,000 patients.

The methodology involved fitting covariate-adjusted Cox models to estimate the hazard ratios (HRs) for AD risk and PD risk. The primary comparisons evaluated were:

• Initiators of GLP-1 receptor agonists initiators versus DPP-4 inhibitors
• Initiators of SGLT-2 inhibitors versus DPP-4 inhibitors

DPP-4 inhibitors served as the reference group because, while sharing a common indication (T2DM), they are thought to have lesser neuroprotective effects than the other two classes. The analysis adjusted for numerous baseline covariates, including age, sex, race, weight-related factors (e.g., obesity) and key comorbidities such as renal disease, cerebrovascular disease and congestive heart failure.

In total, the analysis constructed 12 cohorts across the two data sources for both AD outcomes and PD outcomes.

Risk of the neurodegenerative conditions was assessed based on medical claims in the databases related to codes associated with AD and PD.

Key findings for AD risk

GLP-1 receptor agonists vs. DPP-4 inhibitors

In overall analyses, initiation of GLP-1 receptor agonists was associated with a statistically significant reduced risk of AD (HR ≤ 0.69 and P < .001). Drug-specific sensitivity analyses confirmed this benefit, showing reduced risks for liraglutide and semaglutide initiation compared with DPP-4 inhibitor initiation.

SGLT-2 inhibitors vs. DPP-4 inhibitors

In overall analyses, initiation of SGLT-2 inhibitors was also significantly associated with a reduced risk of AD (HR ≤ 0.67 and P < .001). Specific drugs associated with reduced AD risk included dapagliflozin, canagliflozin and empagliflozin.

Subgroup consistency

The lowered risk of AD observed with both GLP-1 receptor agonists and SGLT-2 inhibitors versus DPP-4 inhibitors was maintained in subgroup analyses focused on female patients, white patients and patients with obesity.

GLP-1s vs. SGLT-2s

No consistent difference in AD risk was identified when directly comparing GLP-1 receptor agonist initiation with SGLT-2 inhibitor initiation.

The study did not observe consistent differences in the risk of PD across any comparisons among the three drug classes.

Conclusions, caveats and future directions

The significant association between starting GLP-1 receptor agonists or SGLT-2 inhibitors and a lower risk of AD supports previous real-world data and strengthens the mechanistic rationale for these drug classes’ potential neuroprotective benefits.

At the same time, the researchers emphasize that their findings are observational and cannot establish causality. They note that their results may be subject to unmeasured confounding effects, such as genetics (e.g., apolipoprotein E genotype), socioeconomic status, diabetes severity or differences in healthcare-seeking behaviors.

The results provide preliminary evidence for further studies to validate the neuroprotective benefits of GLP-1 RAs and SGLT-2 inhibitors and, after validation, to untangle the mechanisms of how they may help protect the brain.

“It’s crucial to investigate whether GLP-1 receptor agonists and SGLT-2 inhibitors could serve as disease-modifying therapies for Alzheimer’s disease in humans by targeting the disease’s biology directly, beyond these drugs’ known antidiabetic effects,” Dr. Cheng says. “Clinical trials testing these medications are also underway, but we hope our findings will help shape more targeted clinical trials in the future.”