In people with type 2 diabetes, starting a GLP-1 receptor agonist was associated with lower new-onset neurodegeneration risk than starting DPP4 inhibitors or basal insulin.
Evidence
This retrospective TriNetX cohort study propensity-score matched 214,442 people with type 2 diabetes and found a lower 4.0-year neurodegeneration incidence with GLP-1 RAs versus (2.2% versus 2.9%; hazard ratio 0.81, 95% CI 0.77 to 0.86), with similar direction versus basal insulin.
Caveat
Because this was an EHR-based observational comparison, it cannot prove causation, and the Parkinson's disease result was null versus DPP4i (hazard ratio 1.04, 95% CI 0.93 to 1.17).
Simplified
BACKGROUND: Type 2 diabetes (T2D), affecting approximately 12% of the global population and over 30% of older adults, is among the most prevalent and fast-growing risk factors for . Evidence is lacking on whether specific glucose-lowering agents may reduce the risk of neurodegeneration onset in people living with T2D.
METHODS: In this retrospective cohort study, we utilized the TriNetX platform, which contains electronic health records of over 170 million people worldwide. We propensity-score matched (1:1) people with T2D lacking evidence of neurodegeneration who initiated glucagon-like peptide-1 receptor agonists (GLP-1 RAs) or (DPP4i) (2010-2021). In a separate analytical cohort, we compared individuals initiating GLP-1 RA with those initiating basal insulin. Follow-up continued for ≤ 5 years. We used Cox proportional-hazard regression models to assess the risk of the composite outcome of developing new neurodegenerative conditions, including Alzheimer's disease, Parkinson's disease, dementia subtypes, and other synucleinopathies. We also assessed each component individually. Analyses were repeated among subgroups defined by sex, age, and the specific GLP-1 RA initiated.
RESULTS: Overall, 214,442 matched individuals initiated GLP-1 RAs or DPP4i (109,731 women, mean age 58.6 years [SD 12], and mean HbA1c 7.7% [1.4]). During a 4.0-year mean follow-up, neurodegenerative disorder onset occurred in 2,393 (2.2%) and 3,062 (2.9%) people initiating GLP-1 RAs and DPP4i, respectively (hazard ratio of 0.81 [95% CI 0.77 to 0.86]; absolute risk difference - 0.6% [- 0.8 to - 0.5]). The associations were separately observed among women (0.78 [0.72 to 0.84]) and men (0.90 [0.83 to 0.98]), individuals aged ≥ 65 years old (0.82 [0.78 to 0.87]) or < 65 years old (0.84 [0.70 to 1.00]), and in those initiating semaglutide (0.75 [0.67 to 0.84]), liraglutide (0.77 [0.70 to 0.84]), or dulaglutide (0.82 [0.77 to 0.88]). The hazard ratios for dementia, Alzheimer's disease, vascular dementia, and Parkinson's disease onset were 0.76 [0.72 to 0.81], 0.77 [0.68 to 0.87], 0.75 [0.67 to 0.85], and 1.04 [0.93 to 1.17] with GLP-1 RAs versus DPP4i, respectively. The results were in the same direction when comparing individuals initiating GLP-1 RAs with those initiating basal insulin.
CONCLUSIONS: In a real-world cohort of people living with T2D with a multinational representation, the initiation of GLP-1 RAs, compared to DPP4i or basal insulin, was associated with a lower risk of new-onset neurodegeneration. These data support the rationale for dedicated clinical trials to assess the potential neuroprotective properties of GLP-1 RAs in this population.
Key numbers
19%
Relative Risk Reduction
Relative risk reduction of with GLP-1 RAs vs. .
-0.6%
Absolute Risk Difference
Absolute risk difference of new-onset .
0.77
for Alzheimer's Disease
for new-onset Alzheimer's disease with GLP-1 RAs vs. .
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Declarations. Conflict of interest: MS reports travel support from Novo Nordisk and AstraZeneca through Hadassah Medical Center, and lecturing fees from AstraZeneca (2022). AF and DRSS report no conflict of interest. OM reports Advisory Board membership for Novo Nordisk, Eli Lilly, Sanofi, Merck Sharp & Dohme, Boehringer Ingelheim, AstraZeneca and BOL Pharma, research grant support through Hadassah Hebrew University Hospital from Novo Nordisk and AstraZeneca, and Speaker's Bureau participation for AstraZeneca, Novo Nordisk, Eli Lilly, Sanofi, Merck Sharp & Dohme, and Boehringer Ingelheim. From May 1st, 2023, OM has been an employee of Regeneron Pharmaceuticals Inc. This work was not funded by Regeneron Pharmaceuticals, Inc.; it was not part of OM’s job responsibilities; and the company had no role in conception, data acquisition, analysis, interpretation, or manuscript preparation. TCY reports receiving research support from Medtronic, Regeneron, Novo Nordisk, and Merck Sharp & Dohme. Honorarium for lecture/advisory board from Medtronic, Sanofi, Novo Nordisk, Boehringer Ingelheim, AstraZeneca, and Amgen. GL reports participation in previous Advisory Boards: Novo Nordisk, Eli Lilly, Sanofi, Merck Sharp & Dohme, Boehringer Ingelheim, AstraZeneca and Medtronic. He reports travel support from Novo Nordisk, Boehringer Ingelheim and AstraZeneca through Hadassah Medical Center. Speaker's Bureau: AstraZeneca, Novo Nordisk, Eli Lilly, Boehringer Ingelheim. GAH reported previous Advisory Board: Sanofi and Eli Lilly. She is a current PI in several RCTs conducted by Novo Nordisk, Eli Lilly, Sanofi, AstraZeneca and Bayer including the CONFIDENCE study, through Hadassah Medical Center. GAH reports travel support from Novo Nordisk and Medetronic through Hadassah Medical Center and AstraZeneca through Sheba medical center. Speaker's Bureau: AstraZeneca, Novo Nordisk, Eli Lilly and Sanofi.
