Highlight
- GLP-1 receptor agonists and SGLT2 inhibitors are associated with a significantly lower risk of Alzheimer’s disease (AD) compared to DPP-4 inhibitors in patients with diabetes.
- Subgroup analyses indicate the reduced AD risk with GLP-1 receptor agonists is pronounced among women, White individuals, and obese patients, while SGLT2 inhibitors benefit both sexes and overweight/obese subgroups.
- Specific agents, including liraglutide and semaglutide (GLP-1 agonists) and dapagliflozin, canagliflozin, and empagliflozin (SGLT2 inhibitors), show notable associations with reduced AD risk.
- These findings highlight potential repurposing of certain diabetes drugs for AD prevention or treatment, warranting prospective randomized controlled trials.
Study Background and Disease Burden
Alzheimer’s disease (AD) represents a major neurodegenerative disorder marked by progressive cognitive decline and dementia, imposing a heavy personal and societal burden worldwide. Despite extensive research, disease-modifying therapies remain elusive. Observational and experimental studies have suggested a link between metabolic dysfunction, including type 2 diabetes mellitus (T2DM), and elevated AD risk. Given the overlap in pathophysiology involving insulin resistance, oxidative stress, and inflammation, antidiabetic medications have been proposed as potential neuroprotective agents to mitigate AD risk or progression. However, comparative effectiveness of different diabetes drug classes on AD risk remains inadequately characterized, particularly in large, diverse populations. This study addresses this gap by evaluating real-world associations between three major diabetes drug classes—GLP-1 receptor agonists, SGLT2 inhibitors, and DPP-4 inhibitors—and incident AD risk.
Study Design
Researchers conducted a retrospective cohort analysis using two extensive real-world databases: Optum’s de-identified Clinformatics Data Mart (2007–2021) and the Northwestern Medicine Enterprise Data Warehouse (2005–2023). The databases provided longitudinal healthcare data including demographics, enrollment history, diagnostic codes, pharmacy claims, and comprehensive clinical records. The study population comprised adult patients with T2DM initiating therapy with one of three antidiabetic drug classes: GLP-1 receptor agonists (albiglutide, dulaglutide, exenatide, liraglutide, lixisenatide, semaglutide), SGLT2 inhibitors (canagliflozin, dapagliflozin, empagliflozin, ertugliflozin), and DPP-4 inhibitors (alogliptin, linagliptin, saxagliptin, sitagliptin).
Large cohorts were analyzed for comparative AD risk: approximately 64,000 patients on GLP-1 receptor agonists, 59,000 on SGLT2 inhibitors, and 142,000 on DPP-4 inhibitors. Endpoint assessment focused on the incidence of AD diagnosis over the follow-up period. The study employed hazard ratios (HRs) with adjustments for confounders to compare AD risk between drug classes and examined subgroup effects based on sex, race, and body mass index (BMI) categories.
Key Findings
Pooled analyses demonstrated that use of GLP-1 receptor agonists was associated with a 31% reduction in AD risk compared to DPP-4 inhibitors (HR ≤ 0.69; P < .001). Similarly, SGLT2 inhibitors conferred a 33% reduced AD risk compared to DPP-4 inhibitors (HR ≤ 0.67; P < .001). Notably, no statistically significant difference in AD risk was detected between GLP-1 receptor agonists and SGLT2 inhibitors.
Subgroup analyses revealed nuanced benefits:
– GLP-1 receptor agonists significantly lowered AD risk in women (HR ≤ 0.66; P < .0001), White individuals (HR ≤ 0.67; P < .0001), and individuals with obesity (HR ≤ 0.72; P ≤ .002).
– SGLT2 inhibitors were associated with decreased AD risk across both women (HR ≤ 0.76; P ≤ .0002) and men (HR ≤ 0.55; P < .001), White individuals (HR ≤ 0.64; P < .001), as well as individuals categorized as obese (HR ≤ 0.70; P ≤ .008) or overweight (HR ≤ 0.52; P ≤ .02).
Drug-specific analyses indicated that among GLP-1 receptor agonists, liraglutide and semaglutide were linked with reduced AD risk (P ≤ .01). Among SGLT2 inhibitors, dapagliflozin, canagliflozin, and empagliflozin showed similar associations (P ≤ .04).
Safety data and adverse event considerations were not explicitly detailed in this observational assessment. However, the large sample size and real-world nature enhance the robustness of the observed associations.
Expert Commentary
These findings underscore a growing body of evidence suggesting that GLP-1 receptor agonists and SGLT2 inhibitors may extend benefits beyond glycemic control to neuroprotection against AD. The mechanistic rationale includes improved insulin signaling in the central nervous system, reduction of neuroinflammation, enhanced cerebral glucose metabolism, and mitigation of oxidative stress, all implicated in AD pathology.
The study’s real-world data approach adds valuable external validity but is limited by potential confounding factors inherent to observational designs, such as unmeasured lifestyle variables, socioeconomic differences, and absence of standardized AD diagnostic confirmation. Notably, cognitive assessments and neuroimaging were unavailable, and biological confirmation of AD diagnoses could not be assured, which may lead to diagnostic misclassification.
Further, the cohort primarily included insured, treated individuals, limiting generalizability to broader or underinsured populations. Randomized controlled trials (RCTs) remain essential to establish causality and determine efficacy and safety specifically regarding AD prevention or treatment in diverse patient groups.
Conclusion
This large-scale observational study provides compelling evidence that GLP-1 receptor agonists and SGLT2 inhibitors, two prominent diabetes drug classes, are associated with a significantly reduced risk of Alzheimer’s disease compared to DPP-4 inhibitors. The consistency of findings across subpopulations and specific agents supports the potential repurposing of these drugs for AD prevention or therapy. Rigorous RCTs are urgently needed to corroborate these associations, elucidate underlying mechanisms, and inform clinical guidelines. Meanwhile, clinicians should remain attentive to emerging data as these diabetes medications may offer dual benefits for glycemic control and cognitive health in at-risk patients.
References
Zhang P, Mao C, Sun A, Yang Y, Hou Y, Fu Z, Babak T, Leverenz JB, Pieper AA, Luo Y, Cummings J, Cheng F. Real-world observations of GLP-1 receptor agonists and SGLT-2 inhibitors as potential treatments for Alzheimer’s disease. Alzheimers Dement. 2025 Sep;21(9):e70639. doi: 10.1002/alz.70639 IF: 11.1 Q1 . PMID: 40898408 IF: 11.1 Q1 ; PMCID: PMC12404899 IF: 11.1 Q1 .
Additional relevant literature:
1. Hölscher C. Central effects of GLP-1: new opportunities for treatments of neurodegenerative diseases. J Endocrinol. 2014;221(1):T31-T41. doi: 10.1530/JOE-13-0413 .2. McMackin CJ, et al. Sodium–glucose co-transporter 2 inhibitors and cognitive impairment: A systematic review. Diabetes Obes Metab. 2021;23(1): 3-15. doi:10.1111/dom.14168 IF: 5.7 Q1 .3. Craft S. The role of metabolic disorders in Alzheimer disease and vascular dementia: two roads converged. Arch Neurol. 2009;66(3):300-305. doi:10.1001/archneurol.2009.12 .
