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      Dipeptidyl peptidase-4 inhibitors and the risks of autoimmune diseases in type 2 diabetes mellitus patients in Taiwan: a nationwide population-based cohort study

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          Abstract

          Aims

          Dipeptidyl peptidase-4, a transmembrane glycoprotein expressed in various cell types, serves as a co-stimulator molecule to influence immune response. This study aimed to investigate associations between DPP-4 inhibitors and risk of autoimmune disorders in patients with type 2 diabetes mellitus in Taiwan.

          Methods

          This retrospective cohort study used the nationwide data from the diabetes subsection of Taiwan National Health Insurance Research Database between January 1, 2009, and December 31, 2013. Cox proportional hazards models were developed to compare the risk of autoimmune disorders and the subgroup analyses between the DPP-4i and DPP-4i-naïve groups.

          Results

          A total of 774,198 type 2 diabetic patients were identified. The adjusted HR of the incidence for composite autoimmune disorders in DPP-4i group was 0.56 (95% CI 0.53–0.60; P < 0.001). The subgroup analysis demonstrated that the younger patients (aged 20–40 years: HR 0.47, 95% CI 0.35–0.61; aged 41–60 years: HR 0.50, 95% CI 0.46–0.55; aged 61–80 years: HR 0.63, 95% CI 0.58–0.68, P = 0.0004) and the lesser duration of diabetes diagnosed (0–5 years: HR 0.48, 95% CI 0.44–0.52; 6–10 years: HR 0.48, 95% CI 0.43–0.53; ≧ 10 years: HR 0.86, 95% CI 0.78–0.96, P < 0.0001), the more significant the inverse association of DPP-4 inhibitors with the incidence of composite autoimmune diseases.

          Conclusions

          DPP-4 inhibitors are associated with lower risk of autoimmune disorders in type 2 diabetes mellitus patients in Taiwan, especially for the younger patients and the lesser duration of diabetes diagnosed. The significant difference was found between the four types of DPP-4 inhibitors and the risk of autoimmune diseases. This study provides clinicians with useful information regarding the use of DPP-4 inhibitors for treating diabetic patients.

          Electronic supplementary material

          The online version of this article (10.1007/s00592-020-01533-5) contains supplementary material, which is available to authorized users.

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          Most cited references39

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          Dipeptidyl-peptidase IV from bench to bedside: an update on structural properties, functions, and clinical aspects of the enzyme DPP IV.

          Dipeptidyl-peptidase IV/CD26 (DPP IV) is a cell-surface protease belonging to the prolyloligopeptidase family. It selectively removes the N-terminal dipeptide from peptides with proline or alanine in the second position. Apart from its catalytic activity, it interacts with several proteins, for instance, adenosine deaminase, the HIV gp120 protein, fibronectin, collagen, the chemokine receptor CXCR4, and the tyrosine phosphatase CD45. DPP IV is expressed on a specific set of T lymphocytes, where it is up-regulated after activation. It is also expressed in a variety of tissues, primarily on endothelial and epithelial cells. A soluble form is present in plasma and other body fluids. DPP IV has been proposed as a diagnostic or prognostic marker for various tumors, hematological malignancies, immunological, inflammatory, psychoneuroendocrine disorders, and viral infections. DPP IV truncates many bioactive peptides of medical importance. It plays a role in glucose homeostasis through proteolytic inactivation of the incretins. DPP IV inhibitors improve glucose tolerance and pancreatic islet cell function in animal models of type 2 diabetes and in diabetic patients. The role of DPP IV/ CD26 within the immune system is a combination of its exopeptidase activity and its interactions with different molecules. This enables DPP IV/CD26 to serve as a co-stimulatory molecule to influence T cell activity and to modulate chemotaxis. DPP IV is also implicated in HIV-1 entry, malignant transformation, and tumor invasion.
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            Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis.

            Pharmacotherapies that augment the incretin pathway have recently become available, but their role in the management of type 2 diabetes is not well defined. To assess the efficacy and safety of incretin-based therapy in adults with type 2 diabetes based on randomized controlled trials published in peer-reviewed journals or as abstracts. We searched MEDLINE (1966-May 20, 2007) and the Cochrane Central Register of Controlled Trials (second quarter, 2007) for English-language randomized controlled trials involving an incretin mimetic (glucagonlike peptide 1 [GLP-1] analogue) or enhancer (dipeptidyl peptidase 4 [DPP4] inhibitor). We also searched prescribing information, relevant Web sites, reference lists and citation sections of recovered articles, and abstracts presented at recent conferences. Randomized controlled trials were selected if they were at least 12 weeks in duration, compared incretin therapy with placebo or other diabetes medication, and reported hemoglobin A(1c) data in nonpregnant adults with type 2 diabetes. Two reviewers independently assessed trials for inclusion and extracted data. Differences were resolved by consensus. Meta-analyses were conducted for several efficacy and safety outcomes. Of 355 potentially relevant articles identified, 51 were retrieved for detailed evaluation and 29 met the inclusion criteria. Incretins lowered hemoglobin A(1c) compared with placebo (weighted mean difference, -0.97% [95% confidence interval {CI}, -1.13% to -0.81%] for GLP-1 analogues and -0.74% [95% CI, -0.85% to -0.62%] for DPP4 inhibitors) and were noninferior to other hypoglycemic agents. Glucagonlike peptide 1 analogues resulted in weight loss (1.4 kg and 4.8 kg vs placebo and insulin, respectively) while DPP4 inhibitors were weight neutral. Glucagonlike peptide 1 analogues had more gastrointestinal side effects (risk ratio, 2.9 [95% CI, 2.0-4.2] for nausea and 3.2 [95% CI, 2.5-4.4] for vomiting). Dipeptidyl peptidase 4 inhibitors had an increased risk of infection (risk ratio, 1.2 [95% CI, 1.0-1.4] for nasopharyngitis and 1.5 [95% CI, 1.0-2.2] for urinary tract infection) and headache (risk ratio, 1.4 [95% CI, 1.1-1.7]). All but 3 trials had a 30-week or shorter duration; thus, long-term efficacy and safety could not be evaluated. Incretin therapy offers an alternative option to currently available hypoglycemic agents for nonpregnant adults with type 2 diabetes, with modest efficacy and a favorable weight-change profile. Careful postmarketing surveillance for adverse effects, especially among the DPP4 inhibitors, and continued evaluation in longer-term studies and in clinical practice are required to determine the role of this new class among current pharmacotherapies for type 2 diabetes.
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              Taiwan's New National Health Insurance Program: Genesis And Experience So Far

              In 1995, after a planning effort of about half a decade, the Republic of China (Taiwan) replaced a previous patchwork of separate social health insurance funds with one single-payer, national health insurance scheme that is administered by an agency of the central government's Department of Health. Within a year this bold legislative act brought the health care utilization rates of the 41 percent of Taiwan's hitherto uninsured population up to par with those of the previously insured population. This paper describes the achievements of this policy initiative so far, along with the growing pains it has encountered, and seeks to extract lessons from the experience for health policymakers in other countries.
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                Author and article information

                Contributors
                tsaiyiwen@gmail.com
                Journal
                Acta Diabetol
                Acta Diabetol
                Acta Diabetologica
                Springer Milan (Milan )
                0940-5429
                1432-5233
                21 April 2020
                : 1-12
                Affiliations
                [1 ]Department of Family Medicine, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan
                [2 ]GRID grid.454209.e, ISNI 0000 0004 0639 2551, Division of Cardiology, Department of Internal Medicine, , Chang Gung Memorial Hospital, ; Keelung, Taiwan
                [3 ]GRID grid.145695.a, College of Medicine, , Chang Gung University, ; Taoyuan, Taiwan
                [4 ]GRID grid.454209.e, ISNI 0000 0004 0639 2551, Department of Ophthalmology, , Chang Gung Memorial Hospital, ; Keelung, Taiwan
                [5 ]GRID grid.145695.a, Department of Chinese Medicine, , Chang Gung University, ; Taoyuan, Taiwan
                [6 ]GRID grid.412897.1, ISNI 0000 0004 0639 0994, Department of Family Medicine, , Taipei Medical University Hospital, ; Taipei City, Taiwan
                [7 ]GRID grid.145695.a, Graduate Institute of Clinical Medical Sciences, College of Medicine, , Chang Gung University, ; Taoyuan, Taiwan
                [8 ]GRID grid.454209.e, ISNI 0000 0004 0639 2551, Department of Family Medicine, , Chang Gung Memorial Hospital, ; Keelung Branch, No. 222, Maijin Road, Keelung, Taiwan
                [9 ]GRID grid.260565.2, ISNI 0000 0004 0634 0356, Graduate Institute of Medical Sciences, , National Defense Medical Center, ; Taipei, Taiwan
                Author notes

                Managed by Massimo Porta.

                Article
                1533
                10.1007/s00592-020-01533-5
                7173685
                59f58eff-de08-44ea-b220-3bfb4ae8712f
                © Springer-Verlag Italia S.r.l., part of Springer Nature 2020

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

                History
                : 7 December 2019
                : 1 April 2020
                Categories
                Original Article

                Endocrinology & Diabetes
                dpp-4 inhibitors,rheumatoid arthritis,autoimmune disease,diabetes mellitus

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