Association Between Dipeptidyl Peptidase-4 Inhibitor Use and Risk of Parkinson's Disease Among Patients with Diabetes Mellitus: a Retrospective Cohort Study

Overview

Journal Aging (Albany NY)

Specialty Geriatrics

Date 2024 Aug 23

PMID 39177655

Authors

Kuang-Hua Huang

Yih Yang

Shuo-Yan Gau

Tung-Han Tsai

Chien-Ying Lee

Affiliations

Soon will be listed here.

Abstract

Background: How a person's Parkinson disease (PD) risk is affected by dipeptidyl peptidase-4 (DPP-4) inhibitors remains unclear. We evaluated the association of PD risk with use of these inhibitors in individuals diagnosed as having diabetes mellitus (DM).

Methods: Individuals diagnosed as having new-onset DM were enrolled into the case group and comparison group, comprising patients who received a DPP-4 inhibitor and a sulfonylurea, respectively. These groups were matched through propensity score matching on the basis of income level, gender, urbanization level, enrollment year, age, and diabetes complications severity index score. The case group was divided into subgroups on the basis of whether they had a cumulative defined daily dose (cDDD) of <75, 75-150, or >150. The DPP-4 inhibitor-PD risk association was evaluated through a Cox proportional hazards model. The Bonferroni adjustment test was employed to adjust -values and reduce the false positive rate.

Results: Compared with those in the comparison group (treatment with a sulfonylurea), patients with a DPP-4 inhibitor cDDD of >150 had a hazard ratio (HR) of 1.30 for PD development (95% confidence interval [CI]: 0.97-1.73; adjusted = .263); the HRs for patients with a cDDD of <75 or 75-150 were 0.95 (95% CI: 0.71-1.27; adjusted = .886) and 1.06 (95% CI: 0.75-1.50; adjusted = .886), respectively. We noted nonsignificant differences regarding the associations between the use of the various DPP-4 inhibitors (linagliptin, saxagliptin, sitagliptin, and vildagliptin) and PD risk after adjustment for any individual inhibitor (adjusted > .05).

Conclusions: DPP-4 inhibitors were discovered in this study to not be associated with increased PD risk. This result was confirmed when the analysis was conducted individually for the 4 investigated DPP-4 inhibitors (sitagliptin, saxagliptin, linagliptin, and vildagliptin).

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References

de Lau L, Breteler M . Epidemiology of Parkinson's disease. Lancet Neurol. 2006; 5(6):525-35. DOI: 10.1016/S1474-4422(06)70471-9. View

Gault V, Lennox R, Flatt P . Sitagliptin, a dipeptidyl peptidase-4 inhibitor, improves recognition memory, oxidative stress and hippocampal neurogenesis and upregulates key genes involved in cognitive decline. Diabetes Obes Metab. 2015; 17(4):403-13. DOI: 10.1111/dom.12432. View

Schernhammer E, Hansen J, Rugbjerg K, Wermuth L, Ritz B . Diabetes and the risk of developing Parkinson's disease in Denmark. Diabetes Care. 2011; 34(5):1102-8. PMC: 3114482. DOI: 10.2337/dc10-1333. View

Yu H, Sun T, Wang Z, Li H, Xu D, An J . Exendin-4 and linagliptin attenuate neuroinflammation in a mouse model of Parkinson's disease. Neural Regen Res. 2023; 18(8):1818-1826. PMC: 10154509. DOI: 10.4103/1673-5374.360242. View

Ascherio A, Schwarzschild M . The epidemiology of Parkinson's disease: risk factors and prevention. Lancet Neurol. 2016; 15(12):1257-1272. DOI: 10.1016/S1474-4422(16)30230-7. View

Brauer R, Wei L, Ma T, Athauda D, Girges C, Vijiaratnam N . Diabetes medications and risk of Parkinson's disease: a cohort study of patients with diabetes. Brain. 2020; 143(10):3067-3076. PMC: 7794498. DOI: 10.1093/brain/awaa262. View

Atiya A, Das Gupta D, Alsayari A, Alrouji M, Alotaibi A, Sharaf S . Linagliptin and Empagliflozin Inhibit Microtubule Affinity Regulatory Kinase 4: Repurposing Anti-Diabetic Drugs in Neurodegenerative Disorders Using In Silico and In Vitro Approaches. ACS Omega. 2023; 8(7):6423-6430. PMC: 9948186. DOI: 10.1021/acsomega.2c06634. View

Cereda E, Barichella M, Cassani E, Caccialanza R, Pezzoli G . Clinical features of Parkinson disease when onset of diabetes came first: A case-control study. Neurology. 2012; 78(19):1507-11. DOI: 10.1212/WNL.0b013e3182553cc9. View

Xu L, Pu J . Alpha-Synuclein in Parkinson's Disease: From Pathogenetic Dysfunction to Potential Clinical Application. Parkinsons Dis. 2016; 2016:1720621. PMC: 5005546. DOI: 10.1155/2016/1720621. View

10.

Li J, Zhang S, Li C, Li M, Ma L . Sitagliptin rescues memory deficits in Parkinsonian rats via upregulating BDNF to prevent neuron and dendritic spine loss. Neurol Res. 2018; 40(9):736-743. DOI: 10.1080/01616412.2018.1474840. View

11.

Ogura J, Yamaguchi H . The Effectiveness of Antidiabetic Drugs in Treating Dementia: A Peek into Pharmacological and Pharmacokinetic Properties. Int J Mol Sci. 2022; 23(12). PMC: 9223777. DOI: 10.3390/ijms23126542. View

12.

Hsu W, Sue S, Liang H, Tseng C, Lin H, Wen W . Dipeptidyl Peptidase 4 Inhibitors Decrease the Risk of Hepatocellular Carcinoma in Patients With Chronic Hepatitis C Infection and Type 2 Diabetes Mellitus: A Nationwide Study in Taiwan. Front Public Health. 2021; 9:711723. PMC: 8484707. DOI: 10.3389/fpubh.2021.711723. View

13.

Lai S, Liao K, Lin C, Lin C, Lin C . Longitudinal data of multimorbidity and polypharmacy in older adults in Taiwan from 2000 to 2013. Biomedicine (Taipei). 2021; 10(2):1-4. PMC: 7608846. DOI: 10.37796/2211-8039.1013. View

14.

Jeong S, Chung S, Yoo H, Hong N, Jung J, Baik K . Beneficial effects of dipeptidyl peptidase-4 inhibitors in diabetic Parkinson's disease. Brain. 2021; 144(4):1127-1137. DOI: 10.1093/brain/awab015. View

15.

Nassar N, Al-Shorbagy M, Arab H, Abdallah D . Saxagliptin: a novel antiparkinsonian approach. Neuropharmacology. 2014; 89:308-17. DOI: 10.1016/j.neuropharm.2014.10.007. View

16.

Yue X, Li H, Yan H, Zhang P, Chang L, Li T . Risk of Parkinson Disease in Diabetes Mellitus: An Updated Meta-Analysis of Population-Based Cohort Studies. Medicine (Baltimore). 2016; 95(18):e3549. PMC: 4863785. DOI: 10.1097/MD.0000000000003549. View

17.

Wills J, Jones J, Haggerty T, Duka V, Joyce J, Sidhu A . Elevated tauopathy and alpha-synuclein pathology in postmortem Parkinson's disease brains with and without dementia. Exp Neurol. 2010; 225(1):210-8. PMC: 2922478. DOI: 10.1016/j.expneurol.2010.06.017. View

18.

Calabresi P, Mechelli A, Natale G, Volpicelli-Daley L, Di Lazzaro G, Ghiglieri V . Alpha-synuclein in Parkinson's disease and other synucleinopathies: from overt neurodegeneration back to early synaptic dysfunction. Cell Death Dis. 2023; 14(3):176. PMC: 9977911. DOI: 10.1038/s41419-023-05672-9. View

19.

Huan Y, Jiang Q, Liu J, Shen Z . Establishment of a dipeptidyl peptidases (DPP) 8/9 expressing cell model for evaluating the selectivity of DPP4 inhibitors. J Pharmacol Toxicol Methods. 2014; 71:8-12. DOI: 10.1016/j.vascn.2014.11.002. View

20.

Hsieh C, Su C, Shao S, Sung S, Lin S, Kao Yang Y . Taiwan's National Health Insurance Research Database: past and future. Clin Epidemiol. 2019; 11:349-358. PMC: 6509937. DOI: 10.2147/CLEP.S196293. View