Next Article in Journal
Current and Future Aspects of Multimodal Imaging, Diagnostic, and Treatment Strategies in Bicuspid Aortic Valve and Associated Aortopathies
Next Article in Special Issue
Link between Diabetes and Alzheimer’s Disease Due to the Shared Amyloid Aggregation and Deposition Involving Both Neurodegenerative Changes and Neurovascular Damages
Previous Article in Journal
Reliability and Validity of the Short-Form 12 Item Version 2 (SF−12v2) Health-Related Quality of Life Survey and Disutilities Associated with Relevant Conditions in the U.S. Older Adult Population
Previous Article in Special Issue
Novel Biochemical Markers of Neurovascular Complications in Type 1 Diabetes Patients
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
JCM
Volume 9
Issue 3
10.3390/jcm9030660
jcm-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Association between the Use of Dipeptidyl Peptidase 4 Inhibitors and the Risk of Dementia among Patients with Type 2 Diabetes in Taiwan

by
Kuan-Chan Chen
1,
Chi-Hsiang Chung
2,
Chieh-Hua Lu
1,
Nian-Sheng Tzeng
3,4,
Chien-Hsing Lee
1,
Sheng-Chiang Su
1,
Feng-Chih Kuo
1,
Jhih-Syuan Liu
1,
Chang-Hsun Hsieh
1,*,† and
Wu-Chien Chien
2,5,6,*,†
1
Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan
2
School of Public Health, National Defense Medical Center, Taipei 11490, Taiwan
3
Department of Psychiatry, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei 114, Taiwan
4
Student Counseling Center, National Defense Medical Center, Taipei 11490, Taiwan
5
Department of Medical Research, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
6
Graduate Institute of Life Science, National Defense Medical Center 11490, Taipei, Taiwan
*
Authors to whom correspondence should be addressed.
†
Equal contribution.
J. Clin. Med. 2020, 9(3), 660; https://doi.org/10.3390/jcm9030660
Submission received: 20 January 2020 / Revised: 22 February 2020 / Accepted: 27 February 2020 / Published: 29 February 2020
(This article belongs to the Special Issue Effects of Diabetes on Neurodegenerative and Neurovascular Changes)
Browse Figures
Versions Notes

Abstract

:
Study Objectives: Diabetes mellitus per se and its related therapy have been frequently associated with an increased risk of developing dementia. However, studies that explored the risk of dementia from the use of the novel oral antidiabetic medication dipeptidyl peptidase 4 inhibitor (DPP-4i) have been limited, especially in Asian populations. The present study aimed to determine the effect of DPP-4i on the subsequent risk of dementia among patients with type 2 diabetes (T2D) in Taiwan. Methods: This study utilized data from the Longitudinal Health Insurance Database between 2008 and 2015. We enrolled 2903 patients aged ≥50 years, who were on DPP-4i for a diagnosis of T2D and had no dementia. A total of 11,612 subjects were included and compared with a propensity score-matched control group who did not use DPP-4i (non-DPP-4i group). Survival analysis was performed to estimate and compare the risk of dementia—including Alzheimer’s disease, vascular dementia, and other dementia types—between the two groups. Results: Both groups had a mean age of 68 years, had a preponderance of women (61.8%), and were followed up for a mean duration of 7 years. The risk of all-cause dementia was significantly lower in the DPP-4i group than in the non-DPP-4i group (hazard ratio (HR) 0.798; 95% confidence interval (CI) 0.681–0.883; p < 0.001), with a class effect. This trend was particularly observed for vascular dementia (HR 0.575; 95% CI 0.404–0.681; p < 0.001), but not in Alzheimer’s disease (HR 0.891; 95% CI 0.712–1.265; p = 0.297). The Kaplan–Meier analysis showed that the preventive effect on dementia was positively correlated with the cumulative dose of DPP-4i. Conclusions: DPP-4i decreased the risk of dementia with a class effect, especially vascular dementia, but not in Alzheimer’s disease. Our results provide important information on the drug choice when managing patients with T2D in clinical practice.

1. Introduction

Diabetes mellitus is one of the major global health problems in an aging society. Driven by aging and aging-related comorbidities, diabetes mellitus continues to increase in prevalence, not only in Taiwan, but also around the world. In Taiwan, the prevalence of type 2 diabetes (T2D) was reported by community studies to be up to 26.9% among those aged over 65 years [1]. In addition, the prevalence of dementia accounted for 2% to 5% of the population aged over 65 years [2], and this has placed a heavy burden on dementia patients, their caregivers and the community [3,4,5].
Alzheimer’s disease (AD) and vascular dementia are the most common types of dementia and share both vascular and neurodegenerative pathophysiological mechanisms [6,7]. Excluding the vascular mechanism, the other postulated mechanisms for the association between AD and T2D include hyperglycemia, inflammation, brain insulin resistance, the reduced degradation of β-amyloid peptides secondary to the formation of advanced glycation end products, and competition for the insulin-degrading enzyme; in fact, AD is being considered as type 3 diabetes [8,9]. A previous study disclosed that diabetes mellitus was associated with a 1.7-fold greater risk of dementia among elderly people [10]. Furthermore, T2D was a significant risk factor for not only AD, but also for vascular dementia [11].
In both nondiabetic and T2D subjects, there are several risk factors for dementia development [12]. T2D-related therapy and its comorbidities were associated with an increasing incidence of dementia [13]. There were a few studies that explored the risk factors and/or validated a practical risk score to predict the future risk of dementia among individuals with T2D [14]. Among these risk factors, antidiabetic medications were extensively evaluated for their potential risks and benefits. However, the results remained controversial for old antidiabetic medications. For example, there were studies that demonstrated a diminished risk of dementia with metformin use [15], but these benefits were found in the age group of <75 years and in patients on high-dose metformin [16,17]. These results for other antidiabetic medications were also inconclusive, including for sulfonylureas and thiazolidinediones [8,18,19].
On the other hand, studies that have explored the role of dipeptidyl peptidase 4 inhibitors (DPP-4i) on dementia development in patients with T2D have been limited. A previous animal study reported that DPP-4i improved the functions of the neuronal insulin receptor and the brain mitochondria, and that it can delay some forms of AD-like pathology [20]. In addition, sitagliptin was reported to have a possible association with the improvement of cognitive function in elderly diabetic patients with and without AD [21]. However, a recent study revealed that therapy with linagliptin did not improve the cognitive performance of patients with T2D and cardiorenal disease [22]. According to present evidence, the effects of DPP-4i on dementia remain inconclusive. In addition, it remains to be clarified whether the association of DPP-4i with dementia is a class effect or is affected by other factors, such as treatment duration.
Therefore, we carried out a study to investigate the association between DPP-4i use and the different types of dementia, as well as the impact of the different types and therapeutic durations of DPP-4i among patients with diabetes. We assessed the incidence of dementia in diabetic patients aged ≥50 years and on DPP-4i use, on the basis of the National Health Insurance Research Database (NHIRD), which was a claims database that was retrieved from the entire population of Taiwan.

2. Materials and Methods

2.1. Data Sources

In this study, we used 7 year data from the NHIRD, based on the two million included in the Longitudinal Health Insurance Database (LHID) in Taiwan (2008 to 2015). The National Health Insurance (NHI) Program was launched in Taiwan in 1995, and as of June 2009, included contracts with 97% of the medical providers, with approximately 23 million beneficiaries, or more than 99% of the entire population [23]. The NHIRD uses the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes to record the diagnoses. All diagnoses of T2D were made by board-certified internists, endocrinologists, or other related specialists, and all diagnoses of dementia were made by board-certified psychiatrists or neurologists. The NHI administration randomly reviews the records of ambulatory care visits and inpatient claims periodically to verify the accuracy of the diagnoses. The NHIRD was therefore considered appropriate for this study on the association between dementia and use of DPP-4i.

2.2. Study Design and Sampled Participants

Sitagliptin was the first DDP-4i approved by the United States Food and Drug Administration on October 16, 2006, and has been marketed in Taiwan since 2008. This study was a retrospective matched-cohort design between January 1, 2008 and December 31, 2015. From the LHID, we identified and selected 5028 patients with diabetes (ICD-9-CM 250.XX) and who used DPP-4i for >90 days. Each enrolled patient was required to have made at least three outpatient visits within the study period. The diabetic patients who were <50 years old, those previously diagnosed with dementia, and those who were on DPP-4i before the index date were excluded. In addition, patients who received GLP-1 agonist before the tracking were excluded.
Data on the use of DPP-4i, including sitagliptin, linagliptin, saxagliptin, vildagliptin, and alogliptin, were collected. This study enrolled 2903 patients on DPP-4i use (DPP-4i group), and 11,612 patients without DPP-4i use (non-DPP-4i group) were matched by 1:4 propensity score matching, using confounding variables including sex, age, comorbidities, medication and index year. (Figure 1).

2.3. Comorbidity

The comorbidities included hypertension, hyperlipidemia, obesity, microvascular or macrovascular complications of diabetes, heart failure, depression, hearing loss, and atrial fibrillation. The microvascular complications included retinopathy, nephropathy, and neuropathy, whereas the macrovascular complications included stroke, coronary artery disease, and peripheral atrial occlusive disease. In addition, the Charlson comorbidity index was used to categorize the comorbidities based on the ICD-9-CM codes; the scores for each comorbidity category were combined into a single comorbidity score. A score of zero indicated that no comorbidities were found, and higher scores indicated a higher comorbidity burden [24].

2.4. Outcome Measurements

All study participants were followed up from the index date until the diagnosis of dementia (ICD 9-CM codes: 290.0, 290.10, 290.11, 290.12, 290.13, 290.20, 290.21, 290.3, 290.41, 290.42, 290.43, 290.8, 290.9, and 331.0), withdrawal from the NHI program, or at the end of 2015. These patients with dementia were grouped as AD (ICD-9-CM331.0), vascular dementia (ICD-9-CM 290.41–290.43), and other dementia (ICD-9-CM 290.0, 290.10–290.13, 290.20–290.21, 290.3, 290.8–290.9).

2.5. Statistical Analysis

All analyses were performed using the SPSS software version 22 (SPSS Inc., Chicago, IL, USA). The χ2 test and Student’s t-test were used to evaluate the distribution of the categorical and continuous variables, respectively. The Fisher’s exact test was used to analyze the differences in categorical variables between the two cohorts. Multivariate Cox proportional hazards regression analysis was used to determine the risk of dementia, and the results were presented as hazard ratios (HR) with 95% confidence intervals (CI). The difference in the risk of dementia between the DPP-4i and the non-DPP-4i groups was estimated using the Kaplan–Meier method with the log-rank test. A two-tailed p value of <0.05 was considered to indicate statistical significance.

2.6. Ethics Approval

This study was conducted in accordance with the Code of Ethics of the World Medical Association (Declaration of Helsinki). The institutional review board of the Tri-Service General Hospital approved this study (IRB No. 2-107-05-026 and IRB No. 1-106-05-169).

3. Results

Table 1 demonstrates the demographics of the study population. There were 2903 patients in the DPP-4i group and 63,430 patients in the non-DPP-4i group. After propensity score matching at a ratio of 1:4, 11,612 pairs remained. Both groups had a mean age of 68 years, had female preponderance (61.8%), and were followed up for a mean duration of 7 years. Of the 14,515 enrollees, dementia developed in 191 (6.5%) of the study subjects and in 913 (7.8%) of the matched controls. Figure 2 demonstrates that the cumulative incidence of dementia was lower in the DPP-4i group than in the non-DPP-4i group (p < 0.001).
Table 2 shows the Cox regression analysis of the association between DPP-4i use and the risk of developing different kinds of dementia. The crude HR of overall dementia was 0.772 (95% CI 0.663–0.856; p < 0.001) and remained significant after adjusting for confounding variables (adjusted HR 0.798; 95% CI 0.681–0.883; p < 0.001). Compared with the non-DPP4i group, the DPP-4i group had associated decreased risks for developing vascular dementia (adjusted HR 0.575; 95% CI 0.404–0.681; p < 0.001) and the other types of dementia (adjusted HR 0.684; 95% CI 0.556–0.749; p < 0.001), but not AD (adjusted HR 0.891; 95% CI 0.712–1.265; p = 0.297). The results were the same, even after the exclusion of individuals who were diagnosed as having dementia within the first year and the first 5 years. The reduction in the risk of dementia development in the DPP-4i group was independent of age, sex, and the presence of microvascular and macrovascular complications (Table 3).
Table 4 shows the comparison of the risk of dementia among the different types of DPP-4i. All types of DPP-4i had significant protective effects against dementia development. Moreover, there was a cumulative protective effect of all of the types of DPP-4i, especially when the duration of therapy was greater than 1 year. The associated decreased risk of dementia with DPP-4i use for less than 1 year was observed only in patients treated with sitagliptin or saxagliptin.

4. Discussion

Our study demonstrated that compared with non-DPP-4i use, DPP-4i use was associated with a 21% lower risk of developing all types of dementia in older patients with T2D. Furthermore, the DPP-4i types seemed to have a class effect that was dose-dependent. This information may be important for physicians when choosing the optimal antidiabetic medications for patients of T2D with or without dementia.
DPP-4 inhibitor, which is one of the incretin-based therapies that increase the concentration of circulating GLP-1, has been frequently used for the treatment of T2D because of its relatively low risk of inducing hypoglycemia [25]. Our results demonstrated that the types of DPP-4i had a class effect on dementia prevention, with a main focus on vascular dementia, but not on AD. These results were not consistent with those of previous human studies [21,22,26]. The discrepancy among the studies may be attributed to the populations and numbers of the study participants, study designs, durations of follow up, and end points of the studies (cognition and dementia definitions and types). The CARMELINA-COG study is the only randomized controlled trial to evaluate the effect of using DPP-4i on cognition function, and the results showed that linagliptin therapy did not modulate cognitive decline in patients with T2D and cardiorenal comorbidities. This study used the Mini-Mental State Examination (MMSE) to evaluate cognitive function, instead of the risk of dementia development, with a mean 2.5 year follow-up [22]. Similarly, Isik et al. demonstrated that sitagliptin therapy improved the cognitive function of elderly patients with T2D, regardless of a prior history of AD. However, the duration of follow up was only 6 months [21]. The latest nested case control study from a cohort of 176,250 patients registered in the Danish National Diabetes Register study showed that the use of DPP-4i in T2D patients significantly decreased the risk of dementia compared to in non-DPP-4i users during a long duration of follow up (7.2 years). However, this study did not reveal the effect of DPP-4i on different types of dementia [26].
GLP 1 receptors are expressed in the neurons of the central nervous system. Stimulation of the GLP-1 receptor could attenuate neuroinflammation and enhance neurogenesis in diabetes-induced dementia, in animal models [27,28]. The concept was supported by a small randomized, controlled study in humans, which showed that liraglutide therapy improved memory function in obese patients with prediabetes or early type 2 diabetes, independently of weight loss and the glycemic lowering effect [29]. Therefore, increased circulating GLP 1 concentrations from DPP-4i therapy may have a neuroprotective role in the treatment of dementia. According to previous animal experimental studies, the neuroprotective effects of DPP-4i were evident in improving learning behavior and memory in AD and/or vascular dementia among the different types of DPP-4i [30,31,32,33,34,35,36]. The mechanisms of DPP-4i on vascular dementia found in animal studies included attenuating endothelial dysfunction, reducing cerebral oxidative stress, and decreasing ischemic brain damage, via a glucose-independent mechanism, likely involving GLP-1 [30,33,34]. Moreover, the complex pathophysiology of AD, which involves vascular and non-vascular mechanisms, is documented and characterized by the accumulation of aggregated amyloid-β (Aβ) protein and hyper-phosphorylated tau protein, neuroinflammation, and a reduction in cerebral glucose consumption [37]. DPP4 might play (a) role(s) in amyloid formation according to an in vitro experiment, and DPP-4i decreased amyloid-β deposition and tau phosphorylation by increasing hippocampal GLP-1 levels [36]. These results implied the beneficial effects of DPP-4i therapy on AD development. Furthermore, not all of the previous animal studies showed neuroprotection with DPP-4i. A previous animal study showed that sitagliptin may increase the risk of dementia by aggravating tau phosphorylation and insulin resistance in the brain [38]. Therefore, the complex pathophysiological mechanism involved in AD development may partly account for the absence of a diminished risk of AD from DPP 4i therapy in the current study.
Thus, although it is generally considered that the use of DPP 4i has a beneficial impact on cognition function, it still remains inconclusive that there is a beneficial effect of DPP 4i therapy on diminishing the risk of different types of dementia development, according to the current experimental and clinical studies. A further, large-scaled, RCT trial should be designed to clarify this issue.
Hypoglycemia is considered to be an independent risk factor for dementia development [39]; the risk of dementia in DPP-4i users should be lower than in users of other, older oral antidiabetic agents. A Korean cohort study showed that compared with sulfonylurea, DPP-4i decreased the risk of dementia in elderly patients with T2D. However, contrary to this present study, that study showed benefits in AD but not in vascular dementia [40]. The results are similar to those from another retrospective longitudinal study of metformin-based therapy, in which adding DPP-4i was shown to better protect against worsening cognitive function than sulfonylureas, in older patients with T2D and mild cognitive impairment [41]. Sulfonylureas have been associated with the risk of hypoglycemia, which had been commonly overused in older patients [42]. In addition, glycemic fluctuations might contribute to poor cognitive outcomes [43]. On the other hand, compared with other oral antidiabetic agents, especially sulfonylureas, DPP-4i provides steady glucose variability [44,45]. Accordingly, our study results demonstrate the independent benefits of DPP-4i use in preserving the cognitive function of patients with diabetes.
In our subgroup analysis, the association between DPP-4i use and the decreased risk of dementia was evident in patients aged ≥50 years, regardless of the presence of diabetes complications. Nevertheless, we found that the benefits of DPP-4i were weaker in those ≥65 years old and in those with macrovascular or microvascular complications of diabetes. The results were similar to those in a recent study that showed that overall, linagliptin did not reduce cognitive decline in patients with T2D and cardiorenal comorbidity [22]. Therefore, the protective effect of DPP-4i against dementia may be greater in younger patients and those without diabetic complications.
There were several limitations of this study. Although these insurance claims data allowed the identification of patients with dementia or diabetes, data on diabetes severity, duration, and impact of control, such as glycated hemoglobin levels, were not available. Owing to the retrospective design, patients with mild cognitive decline may have been underdiagnosed. Other residual confounding factors, such as education, genetics or dietary factors, and body mass index, were not included in the NHIRD. In addition, because this was a population-based study, the actual mechanism for the association between DPP-4i use and dementia in patients with T2D cannot be clarified.
In conclusion, compared with non-DPP-4i use, DPP-4i use was associated with a lower risk of dementia in older Taiwanese patients with T2D. Further study on the neuroprotective effects of DPP-4i, based on a longer follow-up period, may be necessary to validate the risk of dementia with DPP-4i use.

Author Contributions

Conceptualization, K.-C.C.; Data curation, C.-H.C. and W.-C.C.; Formal analysis, C.-H.C.; Methodology, W.-C.C.; Project administration, K.-C.C. and Chieh-Hua Lu; Software, C.-H.C.; Supervision, C.-H.L. (Chieh-Hua Lu), N.-S.T., C.-H.L. (Chien-Hsing Lee), S.-C.S., F.-C.K., J.-S.L. and C.-H.H.; Writing—original draft, K.-C.C.; Writing—review & editing, N.-S.T., C.-H.H. and W.-C.C. All authors have read and agreed to the published version of the manuscript.

Funding

The current study was funded by the Tri-Service General Hospital and National Defense Medical Center under grant number (TSGH-B-109010, TSGH-C105-119, TSGH-C106-006-S01, TSGH-C107-006-006-S01, TSGH-C108-005-006-006-S01, MAB-106-112, TSGH-C107-128, TSGH-C108-003), and the sponsor has no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript..

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. DAROC Clinical Practice Guidelines for Diabetes Care- 2018; Diabetes Association of the R.O.C.: Taipei, Taiwan, 2018; p. 19.
  2. Sun, Y.; Lee, H.J.; Yang, S.C.; Chen, T.F.; Lin, K.N.; Lin, C.C.; Wang, P.N.; Tang, L.Y.; Chiu, M.J. A nationwide survey of mild cognitive impairment and dementia, including very mild dementia, in Taiwan. PLoS ONE 2014, 9, e100303. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Tzeng, N.S.; Chang, C.W.; Hsu, J.Y.; Chou, Y.C.; Chang, H.A.; Kao, Y.C. Caregiver Burden for Patients with Dementia with or Without Hiring Foreign Health Aides: A Cross-Sectional Study in a Northern Taiwan Memory Clinic. J. Med. Sci. 2015, 35, 239–247. [Google Scholar] [CrossRef]
  4. Wang, H.Y.; Chen, J.H.; Huang, S.Y.; Yeh, H.W.; Mao, W.C.; Chang, H.A.; Kao, Y.C.; Yeh, C.B.; Chou, Y.C.; Chiang, W.S.; et al. Forensic evaluations for offenders with dementia in Taiwan’s criminal courts. J. Am. Acad. Psychiatry Law 2018, 46, 45–51, in press. [Google Scholar] [PubMed]
  5. Tzeng, N.S.; Chiang, W.S.; Chen, S.Y.; Chou, Y.C.; Lee, K.M.; Huang, S.Y.; Yeh, C.B.; Chen, C.Y.; Chang, H.A.; Kao, Y.C. The Impact of Pharmacological Treatments on Cognitive Function and Severity of Behavioral Symptoms in Geriatric Elder Patients with Dementia. Taiwan. J. Psychiatry (Taipei) 2017, 31, 69–79. [Google Scholar]
  6. Ahtiluoto, S.; Polvikoski, T.; Peltonen, M.; Solomon, A.; Tuomilehto, J.; Winblad, B.; Sulkava, R.; Kivipelto, M. Diabetes, Alzheimer disease, and vascular dementia: A population-based neuropathologic study. Neurology 2010, 75, 1195–1202. [Google Scholar] [CrossRef]
  7. Peila, R.; Rodriguez, B.L.; Launer, L.J. Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies: The Honolulu-Asia Aging Study. Diabetes 2002, 51, 1256–1262. [Google Scholar] [CrossRef] [Green Version]
  8. Cheng, C.; Lin, C.H.; Tsai, Y.W.; Tsai, C.J.; Chou, P.H.; Lan, T.H. Type 2 diabetes and antidiabetic medications in relation to dementia diagnosis. J. Gerontol. A Biol. Sci. Med. Sci. 2014, 69, 1299–1305. [Google Scholar] [CrossRef]
  9. Kandimalla, R.; Thirumala, V.; Reddy, P.H. Is Alzheimer’s disease a Type 3 Diabetes? A critical appraisal. Biochim. Biophys. Acta Mol. Basis. Dis. 2017, 1863, 1078–1089. [Google Scholar] [CrossRef] [PubMed]
  10. Ninomiya, T. Diabetes mellitus and dementia. Curr. Diab. Rep. 2014, 14, 487. [Google Scholar] [CrossRef]
  11. Li, W.; Huang, E. An Update on Type 2 Diabetes Mellitus as a Risk Factor for Dementia. J. Alzheimers Dis. 2016, 53, 393–402. [Google Scholar] [CrossRef] [Green Version]
  12. Livingston, G.; Sommerlad, A.; Orgeta, V.; Costafreda, S.G.; Huntley, J.; Ames, D.; Ballard, C.; Banerjee, S.; Burns, A.; Cohen-Mansfield, J.; et al. Dementia prevention, intervention, and care. Lancet 2017, 390, 2673–2734. [Google Scholar] [CrossRef] [Green Version]
  13. Exalto, L.G.; Biessels, G.J.; Karter, A.J.; Huang, E.S.; Quesenberry, C.P., Jr.; Whitmer, R.A. Severe diabetic retinal disease and dementia risk in type 2 diabetes. J. Alzheimers Dis. 2014, 42, S109–S117. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. Li, C.I.; Li, T.C.; Liu, C.S.; Liao, L.N.; Lin, W.Y.; Lin, C.H.; Yang, S.Y.; Chiang, J.H.; Lin, C.C. Risk score prediction model for dementia in patients with type 2 diabetes. Eur. J. Neurol. 2018, 25, 976–983. [Google Scholar] [CrossRef] [PubMed]
  15. Campbell, J.M.; Stephenson, M.D.; de Courten, B.; Chapman, I.; Bellman, S.M.; Aromataris, E. Metformin Use Associated with Reduced Risk of Dementia in Patients with Diabetes: A Systematic Review and Meta-Analysis. J. Alzheimers Dis. 2018, 65, 1225–1236. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  16. Sluggett, J.K.; Koponen, M.; Bell, J.S.; Taipale, H.; Tanskanen, A.; Tiihonen, J.; Uusitupa, M.; Tolppanen, A.M.; Hartikainen, S. Metformin and risk of Alzheimer’s disease among community-dwelling people with diabetes: A national case-control study. J. Clin. Endocrinol. Metab. 2019. [Google Scholar] [CrossRef] [PubMed]
  17. Orkaby, A.R.; Cho, K.; Cormack, J.; Gagnon, D.R.; Driver, J.A. Metformin vs sulfonylurea use and risk of dementia in US veterans aged >/=65 years with diabetes. Neurology 2017, 89, 1877–1885. [Google Scholar] [CrossRef]
  18. Imfeld, P.; Bodmer, M.; Jick, S.S.; Meier, C.R. Metformin, other antidiabetic drugs, and risk of Alzheimer’s disease: A population-based case-control study. J. Am. Geriatr. Soc. 2012, 60, 916–921. [Google Scholar] [CrossRef]
  19. Ye, F.; Luo, Y.J.; Xiao, J.; Yu, N.W.; Yi, G. Impact of Insulin Sensitizers on the Incidence of Dementia: A Meta-Analysis. Dement. Geriatr. Cogn. Disord. 2016, 41, 251–260. [Google Scholar] [CrossRef]
  20. Pipatpiboon, N.; Pintana, H.; Pratchayasakul, W.; Chattipakorn, N.; Chattipakorn, S.C. DPP4-inhibitor improves neuronal insulin receptor function, brain mitochondrial function and cognitive function in rats with insulin resistance induced by high-fat diet consumption. Eur. J. Neurosci. 2013, 37, 839–849. [Google Scholar] [CrossRef]
  21. Isik, A.T.; Soysal, P.; Yay, A.; Usarel, C. The effects of sitagliptin, a DPP-4 inhibitor, on cognitive functions in elderly diabetic patients with or without Alzheimer’s disease. Diabetes Res. Clin. Pract. 2017, 123, 192–198. [Google Scholar] [CrossRef]
  22. Biessels, G.J.; Verhagen, C.; Janssen, J.; van den Berg, E.; Zinman, B.; Rosenstock, J.; George, J.T.; Passera, A.; Schnaidt, S.; Johansen, O.E. Effect of Linagliptin on Cognitive Performance in Patients With Type 2 Diabetes and Cardiorenal Comorbidities: The CARMELINA Randomized Trial. Diabetes care 2019, 42, 1930–1938. [Google Scholar] [CrossRef]
  23. Ho Chan, W.S. Taiwan’s healthcare report 2010. EPMA J. 2010, 1, 563–585. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  24. Charlson, M.E.; Pompei, P.; Ales, K.L.; MacKenzie, C.R. A new method of classifying prognostic comorbidity in longitudinal studies: Development and validation. J. Chronic. Dis. 1987, 40, 373–383. [Google Scholar] [CrossRef]
  25. Karagiannis, T.; Boura, P.; Tsapas, A. Safety of dipeptidyl peptidase 4 inhibitors: A perspective review. Ther. Adv. Drug Saf. 2014, 5, 138–146. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  26. Wium-Andersen, I.K.; Osler, M.; Jorgensen, M.B.; Rungby, J.; Wium-Andersen, M.K.K. Antidiabetic medication and risk of dementia in patients with type 2 diabetes. A nested case-control study. Eur. J. Endocrinol. 2019, 181, 499–507. [Google Scholar] [CrossRef]
  27. Bae, C.S.; Song, J. The Role of Glucagon-Like Peptide 1 (GLP1) in Type 3 Diabetes: GLP-1 Controls Insulin Resistance, Neuroinflammation and Neurogenesis in the Brain. Int. J. Mol. Sci. 2017, 18, 2493. [Google Scholar] [CrossRef] [Green Version]
  28. Harkavyi, A.; Whitton, P.S. Glucagon-like peptide 1 receptor stimulation as a means of neuroprotection. Br. J. Pharmacol. 2010, 159, 495–501. [Google Scholar] [CrossRef] [Green Version]
  29. Vadini, F.; Simeone, P.G.; Boccatonda, A.; Guagnano, M.T.; Liani, R.; Tripaldi, R.; Di Castelnuovo, A.; Cipollone, F.; Consoli, A.; Santilli, F. Liraglutide improves memory in obese patients with prediabetes or early type 2 diabetes: A randomized, controlled study. Int. J. Obes. (Lond.) 2020. [Google Scholar] [CrossRef]
  30. Jain, S.; Sharma, B. Neuroprotective effect of selective DPP-4 inhibitor in experimental vascular dementia. Physiol. Behav. 2015, 152, 182–193. [Google Scholar] [CrossRef]
  31. Kosaraju, J.; Gali, C.C.; Khatwal, R.B.; Dubala, A.; Chinni, S.; Holsinger, R.M.; Madhunapantula, V.S.; Muthureddy Nataraj, S.K.; Basavan, D. Saxagliptin: A dipeptidyl peptidase-4 inhibitor ameliorates streptozotocin induced Alzheimer’s disease. Neuropharmacology 2013, 72, 291–300. [Google Scholar] [CrossRef]
  32. Kosaraju, J.; Murthy, V.; Khatwal, R.B.; Dubala, A.; Chinni, S.; Muthureddy Nataraj, S.K.; Basavan, D. Vildagliptin: An anti-diabetes agent ameliorates cognitive deficits and pathology observed in streptozotocin-induced Alzheimer’s disease. J. Pharm. Pharmacol. 2013, 65, 1773–1784. [Google Scholar] [CrossRef]
  33. Ma, M.; Hasegawa, Y.; Koibuchi, N.; Toyama, K.; Uekawa, K.; Nakagawa, T.; Lin, B.; Kim-Mitsuyama, S. DPP-4 inhibition with linagliptin ameliorates cognitive impairment and brain atrophy induced by transient cerebral ischemia in type 2 diabetic mice. Cardiovasc. Diabetol. 2015, 14, 54. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  34. Darsalia, V.; Ortsäter, H.; Olverling, A.; Darlöf, E.; Wolbert, P.; Nyström, T.; Klein, T.; Sjöholm, Å.; Patrone, C. The DPP-4 inhibitor linagliptin counteracts stroke in the normal and diabetic mouse brain: A comparison with glimepiride. Diabetes 2013, 62, 1289–1296. [Google Scholar] [CrossRef] [Green Version]
  35. Pintana, H.; Apaijai, N.; Chattipakorn, N.; Chattipakorn, S.C. DPP-4 inhibitors improve cognition and brain mitochondrial function of insulin-resistant rats. J. Endocrinol. 2013, 218, 1–11. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  36. Bernstein, H.-G.; Dobrowolny, H.; Keilhoff, G.; Steiner, J. Dipeptidyl peptidase IV, which probably plays important roles in Alzheimer disease (AD) pathology, is upregulated in AD brain neurons and associates with amyloid plaques. Neurochem. Int. 2018, 114, 55–57. [Google Scholar] [CrossRef]
  37. Chatterjee, S.; Mudher, A. Alzheimer’s Disease and Type 2 Diabetes: A Critical Assessment of the Shared Pathological Traits. Front. Neurosci. 2018, 12, 383. [Google Scholar] [CrossRef] [Green Version]
  38. Kim, D.H.; Huh, J.W.; Jang, M.; Suh, J.H.; Kim, T.W.; Park, J.S.; Yoon, S.Y. Sitagliptin increases tau phosphorylation in the hippocampus of rats with type 2 diabetes and in primary neuron cultures. Neurobiol. Dis. 2012, 46, 52–58. [Google Scholar] [CrossRef] [PubMed]
  39. Rhee, S.Y. Hypoglycemia and Dementia. Endocrinol. Metab. (Seoul) 2017, 32, 195–199. [Google Scholar] [CrossRef]
  40. Kim, Y.G.; Jeon, J.Y.; Kim, H.J.; Kim, D.J.; Lee, K.W.; Moon, S.Y.; Han, S.J. Risk of Dementia in Older Patients with Type 2 Diabetes on Dipeptidyl-Peptidase IV Inhibitors Versus Sulfonylureas: A Real-World Population-Based Cohort Study. J. Clin. Med. 2018, 8, 28. [Google Scholar] [CrossRef] [Green Version]
  41. Rizzo, M.R.; Barbieri, M.; Boccardi, V.; Angellotti, E.; Marfella, R.; Paolisso, G. Dipeptidyl peptidase-4 inhibitors have protective effect on cognitive impairment in aged diabetic patients with mild cognitive impairment. J. Gerontol. A Biol. Sci. Med. Sci. 2014, 69, 1122–1131. [Google Scholar] [CrossRef] [Green Version]
  42. Hambling, C.E.; Seidu, S.I.; Davies, M.J.; Khunti, K. Older people with Type 2 diabetes, including those with chronic kidney disease or dementia, are commonly overtreated with sulfonylurea or insulin therapies. Diabet. Med. 2017, 34, 1219–1227. [Google Scholar] [CrossRef] [PubMed]
  43. Sheen, Y.J.; Sheu, W.H. Association between hypoglycemia and dementia in patients with type 2 diabetes. Diabetes Res. Clin. Pract. 2016, 116, 279–287. [Google Scholar] [CrossRef]
  44. Kim, H.S.; Shin, J.A.; Lee, S.H.; Kim, E.S.; Cho, J.H.; Son, H.Y.; Yoon, K.H. A comparative study of the effects of a dipeptidyl peptidase-IV inhibitor and sulfonylurea on glucose variability in patients with type 2 diabetes with inadequate glycemic control on metformin. Diabetes Technol. Ther. 2013, 15, 810–816. [Google Scholar] [CrossRef] [PubMed]
  45. Lee, S.; Lee, H.; Kim, Y.; Kim, E. Effect of DPP-IV Inhibitors on Glycemic Variability in Patients with T2DM: A Systematic Review and Meta-Analysis. Sci. Rep. 2019, 9, 13296. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Jcm 09 00660 g001 550
Figure 1. A flow chart of the sample selection process. DM = diabetes mellitus; DPP-4i = dipeptidyl peptidase 4 inhibitor; GLP-1 agonist = glucagon-like peptide 1 agonist; OHA = Oral Hypoglycemic Agents.
Figure 1. A flow chart of the sample selection process. DM = diabetes mellitus; DPP-4i = dipeptidyl peptidase 4 inhibitor; GLP-1 agonist = glucagon-like peptide 1 agonist; OHA = Oral Hypoglycemic Agents.
Jcm 09 00660 g001
Jcm 09 00660 g002 550
Figure 2. Kaplan–Meier curves for the cumulative risk of dementia in diabetic patients with or without dipeptidyl peptidase 4 inhibitor use.
Figure 2. Kaplan–Meier curves for the cumulative risk of dementia in diabetic patients with or without dipeptidyl peptidase 4 inhibitor use.
Jcm 09 00660 g002
Table
Table 1. Baseline characteristics of the matched pairs.
Table 1. Baseline characteristics of the matched pairs.
With DPP-4i useWithout DPP-4i usep
N2,90311,612
Number of men (percentage)1,109 (38.20%)4,436 (38.20%)0.999
Age (years)68.05 ± 8.7568.01 ± 8.690.808
Age group (years) 0.999
50–641,247 (42.96%)4,988 (42.96%)
≥651,656 (57.04%)6,624 (57.04%)
Hypertension 28.2828.120.861
Hyperlipidemia11.85 12.030.789
Obesity 0.070.070.999
Macrovascular complications of DM20.4320.760.690
Microvascular complications of DM22.9422.500.613
Heart failure 2.002.020.953
Chronic kidney disease 17.4317.280.852
Depression4.063.910.701
Hearing loss4.103.95 0.718
Atrial fibrillation 1.24 1.63 0.131
Obstructive sleep apnea4.27 4.31 0.919
CCI_R1.24 ± 1.741.26 ± 1.800.558
Medication used
Metformin98.00 98.16 0.582
Sulfonylureas89.46 88.52 0.153
Glinide78.50 77.39 0.199
Thiazolidinedione54.53 53.21 0.203
AGi19.70 19.98 0.740
SGLT-2i18.9818.320.410
Insulin73.03 73.17 0.881
Categorical variables were compared using Chi-square or Fisher’s exact test. Continuous variables were compared using Student’s t-test. DM = diabetes mellitus; CCI_R = Charlson comorbidity index without dementia; DPP-4i = dipeptidyl peptidase 4 inhibitor; AGi=α-glucosidase inhibitor; SGLT-2i=Sodium–glucose co-transporter 2 inhibitor.
Table
Table 2. The risk for dementia according to the use of DPP-4i.
Table 2. The risk for dementia according to the use of DPP-4i.
All Dementia CasesDementia in the First Year ExcludedDementia in the First 5 Years Excluded
Dementia SubgroupAdjusted HR (CI)pAdjusted HR (CI)pAdjusted HR (CI)p
Overall dementia0.798 (0.681–0.883)<0.0010.811 (0.682–0.901)<0.0010.849 (0.700–0.927)0.005
Alzheimer’s disease0.891 (0.712–1.265)0.2970.986 (0.789–1.303)0.2971.265 (0.886–1.986)0.596
Vascular dementia0.575 (0.404–0.681)<0.0010.612 (0.423–0.705)<0.0010.631 (0.497–0.786)<0.001
Other dementia0.684 (0.556–0.749)<0.0010.756 (0.589–0.834)<0.0010.793 (0.643–0.912)0.001
HR was adjusted according to the variables listed in the baseline. DPP-4i = dipeptidyl peptidase 4 inhibitor; HR = hazard ratio, CI = confidence interval.
Table
Table 3. Subgroup analyses on the use of DPP-4i according to sex, age, and microvascular and macrovascular complications of DM.
Table 3. Subgroup analyses on the use of DPP-4i according to sex, age, and microvascular and macrovascular complications of DM.
DPP-4iWithWithoutWith vs. without
GroupEventsRateEventsRateAdjusted HRp
Total191 10.42 913 13.74 0.798 (0.681–0.883)<0.001
Sex
Male66 10.14 326 14.11 0.756 (0.643–0.836)<0.001
Female125 10.58 587 13.54 0.822 (0.701–0.909)<0.001
Age group (years)
50–6418 8.71 96 12.38 0.742 (0.601–0.801)<0.001
≥65173 10.64 817 13.92 0.895 (0.727–0.976)0.026
Macrovascular complications of DM
Without124 9.43 575 12.36 0.713 (0.512–0.808)<0.001
With67 12.97 338 16.97 0.804 (0.695–0.937)0.005
Microvascular complications of DM
Without176 12.72 861 16.13 0.706 (0.511–0.806)<0.001
With15 3.34 52 3.98 0.835 (0.718–0.962)0.013
The rate was calculated per 1000 person-years. HR was adjusted according to the variables listed in the baseline characteristics DM = diabetes mellitus; DPP-4i = dipeptidyl peptidase 4 inhibitor; HR = hazard ratio; CI = confidence interval.
Table
Table 4. Comparison of the risk for dementia according to the use of DDP-4i.
Table 4. Comparison of the risk for dementia according to the use of DDP-4i.
Adjusted HRLower CIHigher CIp
All DDP4i0.798 0.681 0.883 <0.001
All DDP4i (90–364 days)0.874 0.746 0.967 0.027
 Sitagliptin0.749 0.672 0.928 0.013
 Linagliptin0.861 0.768 1.002 0.051
 Saxagliptin0.769 0.683 0.927 0.009
 Vildagliptin 0.901 0.801 1.397 0.244
 Alogliptin0.984 0.870 1.495 0.395
All DDP4i (≧365 days)0.780 0.665 0.864 <0.001
 Sitagliptin0.669 0.599 0.788 <0.001
 Linagliptin0.772 0.685 0.894 <0.001
 Saxagliptin0.687 0.610 0.828 <0.001
 Vildagliptin 0.805 0.712 0.915 0.006
 Alogliptin0.879 0.778 0.971 0.031
HR was adjusted according to the variables listed in the baseline characteristics. DDP-4i = dipeptidyl peptidase 4; HR = hazard ratio; CI = 95% confidence interval.

Share and Cite

MDPI and ACS Style

Chen, K.-C.; Chung, C.-H.; Lu, C.-H.; Tzeng, N.-S.; Lee, C.-H.; Su, S.-C.; Kuo, F.-C.; Liu, J.-S.; Hsieh, C.-H.; Chien, W.-C. Association between the Use of Dipeptidyl Peptidase 4 Inhibitors and the Risk of Dementia among Patients with Type 2 Diabetes in Taiwan. J. Clin. Med. 2020, 9, 660. https://doi.org/10.3390/jcm9030660

AMA Style

Chen K-C, Chung C-H, Lu C-H, Tzeng N-S, Lee C-H, Su S-C, Kuo F-C, Liu J-S, Hsieh C-H, Chien W-C. Association between the Use of Dipeptidyl Peptidase 4 Inhibitors and the Risk of Dementia among Patients with Type 2 Diabetes in Taiwan. Journal of Clinical Medicine. 2020; 9(3):660. https://doi.org/10.3390/jcm9030660

Chicago/Turabian Style

Chen, Kuan-Chan, Chi-Hsiang Chung, Chieh-Hua Lu, Nian-Sheng Tzeng, Chien-Hsing Lee, Sheng-Chiang Su, Feng-Chih Kuo, Jhih-Syuan Liu, Chang-Hsun Hsieh, and Wu-Chien Chien. 2020. "Association between the Use of Dipeptidyl Peptidase 4 Inhibitors and the Risk of Dementia among Patients with Type 2 Diabetes in Taiwan" Journal of Clinical Medicine 9, no. 3: 660. https://doi.org/10.3390/jcm9030660

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop