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      Correlation between long-term use of metformin and incidence of NAFLD among patients with type 2 diabetes mellitus: A real-world cohort study

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          Abstract

          Background and aims

          Studies have demonstrated that the short-term use of metformin benefits liver function among patients with type 2 diabetes mellitus (T2DM). However, few studies have reported on the effects of long-term metformin treatment on liver function or liver histology. This study investigated the correlation between metformin use and the incidence of nonalcoholic fatty liver disease (NAFLD) among patients with T2DM.

          Methods

          This population-based study investigated the risk of NAFLD among patients with T2DM who received metformin treatment between 2001-2018. Metformin users and metformin nonusers were enrolled and matched to compare the risk of NAFLD.

          Results

          After 3 years, the patients who received <300 cDDD of metformin and those with metformin use intensity of <10 and 10–25 DDD/month had odds ratios (ORs) of 1.11 (95% confidence interval [CI] = 1.06–1.16), 1.08 (95% CI = 1.02–1.13), and 1.18 (95% CI = 1.11–1.26) for NAFLD, respectively. Moreover, metformin users who scored high on the Diabetes Complications and Severity Index (DCSI) were at high risk of NAFLD. Patients with comorbid hyperlipidemia, hyperuricemia, obesity, and hepatitis C were also at high risk of NAFLD.

          Conclusion

          Patients with T2DM who received metformin of <300 cDDD or used metformin at an intensity of <10 and 10–25 DDD/month were at a high risk of developing NAFLD. The results of this study also indicated that patients with T2DM receiving metformin and with high scores on the DCSI were at a high risk of developing NAFLD.

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          Most cited references55

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          The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases.

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            Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults.

            Non-alcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease, and its worldwide prevalence continues to increase with the growing obesity epidemic. This study assesses the epidemiology of NAFLD in adults based on clinical literature published over the past 30 years. To review epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults based on clinical literature published over the past 30 years. An in-depth search of PubMed (1980-2010) was based on five search terms: 'non-alcoholic fatty liver disease' OR 'non-alcoholic steatohepatitis' OR 'fatty liver' OR 'steatosis' AND 'incidence' [MeSH Terms] OR 'prevalence' [MeSH Terms] OR 'natural history'. Studies of paediatric cohorts were excluded. Articles were categorised by topic and summarised, noting generalisations concerning their content. Four study categories included NAFLD incidence, prevalence, risk factors and natural history. Studies related to NAFLD prevalence and incidence indicate that the diagnosis is heterogeneous and relies on a variety of assessment tools, including liver biopsy, radiological tests such as ultrasonography, and blood testing such as liver enzymes. The prevalence of NAFLD is highest in populations with pre-existing metabolic conditions such as obesity and type II diabetes. Many studies investigating the natural history of NAFLD verify the progression from NASH to advanced fibrosis and hepatocellular carcinoma. Non-alcoholic fatty liver disease is the most common cause of elevated liver enzymes. Within the NAFLD spectrum, only NASH progresses to cirrhosis and hepatocellular carcinoma. With the growing epidemic of obesity, the prevalence and impact of NAFLD continues to increase, making NASH potentially the most common cause of advanced liver disease in coming decades. © 2011 Blackwell Publishing Ltd.
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              Taiwan’s National Health Insurance Research Database: past and future

              Abstract Taiwan’s National Health Insurance Research Database (NHIRD) exemplifies a population-level data source for generating real-world evidence to support clinical decisions and health care policy-making. Like with all claims databases, there have been some validity concerns of studies using the NHIRD, such as the accuracy of diagnosis codes and issues around unmeasured confounders. Endeavors to validate diagnosed codes or to develop methodologic approaches to address unmeasured confounders have largely increased the reliability of NHIRD studies. Recently, Taiwan’s Ministry of Health and Welfare (MOHW) established a Health and Welfare Data Center (HWDC), a data repository site that centralizes the NHIRD and about 70 other health-related databases for data management and analyses. To strengthen the protection of data privacy, investigators are required to conduct on-site analysis at an HWDC through remote connection to MOHW servers. Although the tight regulation of this on-site analysis has led to inconvenience for analysts and has increased time and costs required for research, the HWDC has created opportunities for enriched dimensions of study by linking across the NHIRD and other databases. In the near future, researchers will have greater opportunity to distill knowledge from the NHIRD linked to hospital-based electronic medical records databases containing unstructured patient-level information by using artificial intelligence techniques, including machine learning and natural language processes. We believe that NHIRD with multiple data sources could represent a powerful research engine with enriched dimensions and could serve as a guiding light for real-world evidence-based medicine in Taiwan.
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                Author and article information

                Contributors
                Journal
                Front Endocrinol (Lausanne)
                Front Endocrinol (Lausanne)
                Front. Endocrinol.
                Frontiers in Endocrinology
                Frontiers Media S.A.
                1664-2392
                30 November 2022
                2022
                : 13
                : 1027484
                Affiliations
                [1] 1 Department of Health Services Administration, China Medical University , Taichung, Taiwan
                [2] 2 School of Nursing, Chung Shan Medical University , Taichung, Taiwan
                [3] 3 Department of Nursing, Chung Shan Medical University Hospital , Taichung, Taiwan
                [4] 4 School of Pharmacy, China Medical University , Taichung, Taiwan
                [5] 5 Department of Pharmacy, China Medical University Hospital , Taichung, Taiwan
                [6] 6 School of Medicine, Chung Shan Medical University , Taichung, Taiwan
                [7] 7 Department of Pharmacology, Chung Shan Medical University , Taichung, Taiwan
                [8] 8 Department of Pharmacy, Chung Shan Medical University Hospital , Taichung, Taiwan
                Author notes

                Edited by: Nick Giannoukakis, Allegheny Health Network, United States

                Reviewed by: Anu Grover, Ipca Laboratories, India; Solaleh Emamgholipour, Tehran University of Medical Sciences, Iran

                *Correspondence: Chien-Ying Lee, cshd015@ 123456csmu.edu.tw

                †These authors have contributed equally to this work

                This article was submitted to Diabetes: Molecular Mechanisms, a section of the journal Frontiers in Endocrinology

                Article
                10.3389/fendo.2022.1027484
                9748475
                36531446
                85766773-f870-4a4a-9d98-5bb586ded398
                Copyright © 2022 Huang, Lee, Cheng, Gau, Tsai, Chung and Lee

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 25 August 2022
                : 09 November 2022
                Page count
                Figures: 1, Tables: 3, Equations: 0, References: 55, Pages: 13, Words: 6811
                Categories
                Endocrinology
                Original Research

                Endocrinology & Diabetes
                nonalcoholic fatty liver disease,metformin,type 2 diabetes mellitus,cumulative defined daily dose,nhird

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