Metformin use is associated with a low risk of tuberculosis among newly diagnosed diabetes mellitus patients with normal renal function: A nationwide cohort study with validated diagnostic criteria

M.-C. Lee, C.-Y. Chiang, C.-H. Lee, C.-M. Ho, C.-H. Chang, J.-Y. Wang, S.-M. Chen

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Abstract

Human studies on the use of metformin as host-directed therapy (HDT) for tuberculosis (TB) are rare. We performed a nationwide cohort study to evaluate the effect of metformin on mitigating the risk of active TB among patients with diabetes mellitus (DM). Among newly diagnosed DM patients identified in the Taiwan National Health Insurance Research Database, metformin users, defined on the basis of >90 cumulative defined daily doses within 1 year, and propensity-score-matched metformin nonusers were selected. The primary outcome was incident TB, identified using diagnostic criteria validated by real patient data at a medical center. Independent predictors were investigated using Cox regression analysis. Similar analysis was performed in a subpopulation without a history of hypertensive nephropathy and renal replacement therapy. A total of 88,866 metformin users and 88,866 propensityscore-matched nonusers were selected. Validation results showed that the TB diagnostic criteria had a sensitivity of 99.13% and specificity of 99.90%. During follow-up, 707 metformin users and 807 nonusers developed active TB. Metformin use was independently associated with a lower risk of incident TB (hazard ratio [HR]: 0.84 [0.74-0.96]). TB risk was lower in high-dose metformin users than in low-dose users (HR: 0.83 [0.72-0.97]). The effect of metformin remained when analysis was restricted in the subpopulation without renal function impairment. Newly diagnosed diabetic patients without contraindication should receive metformin as an anti-diabetic medication, with potential additional benefit against TB. © 2018 Lee et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Original languageEnglish
Article numbere0205807
JournalPLoS One
Volume13
Issue number10
DOIs
Publication statusPublished - Oct 1 2018

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metformin
Metformin
renal function
Medical problems
diabetes mellitus
cohort studies
tuberculosis
Diabetes Mellitus
Tuberculosis
Cohort Studies
Kidney
Hazards
dosage
Health insurance
health insurance
Propensity Score
therapeutics
Renal Replacement Therapy
National Health Programs
Licensure

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

@article{4ae197f080ff4d35b1c5e636a4b600fa,
title = "Metformin use is associated with a low risk of tuberculosis among newly diagnosed diabetes mellitus patients with normal renal function: A nationwide cohort study with validated diagnostic criteria",
abstract = "Human studies on the use of metformin as host-directed therapy (HDT) for tuberculosis (TB) are rare. We performed a nationwide cohort study to evaluate the effect of metformin on mitigating the risk of active TB among patients with diabetes mellitus (DM). Among newly diagnosed DM patients identified in the Taiwan National Health Insurance Research Database, metformin users, defined on the basis of >90 cumulative defined daily doses within 1 year, and propensity-score-matched metformin nonusers were selected. The primary outcome was incident TB, identified using diagnostic criteria validated by real patient data at a medical center. Independent predictors were investigated using Cox regression analysis. Similar analysis was performed in a subpopulation without a history of hypertensive nephropathy and renal replacement therapy. A total of 88,866 metformin users and 88,866 propensityscore-matched nonusers were selected. Validation results showed that the TB diagnostic criteria had a sensitivity of 99.13{\%} and specificity of 99.90{\%}. During follow-up, 707 metformin users and 807 nonusers developed active TB. Metformin use was independently associated with a lower risk of incident TB (hazard ratio [HR]: 0.84 [0.74-0.96]). TB risk was lower in high-dose metformin users than in low-dose users (HR: 0.83 [0.72-0.97]). The effect of metformin remained when analysis was restricted in the subpopulation without renal function impairment. Newly diagnosed diabetic patients without contraindication should receive metformin as an anti-diabetic medication, with potential additional benefit against TB. {\circledC} 2018 Lee et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",
author = "M.-C. Lee and C.-Y. Chiang and C.-H. Lee and C.-M. Ho and C.-H. Chang and J.-Y. Wang and S.-M. Chen",
note = "Export Date: 6 November 2018 CODEN: POLNC References: (2016) 20th Edition Geneva, Switzerland: WHO 2015, , http://www.who.int/tb/publications/globalreport/en/, World Health Organization. Global tuberculosis report (Accessed July 17 2017); Restrepo, B.I., Schlesinger, L.S., Host-pathogen interactions in tuberculosis patients with type 2 diabetes mellitus (2013) Tuberculosis (Edinb), 93, pp. S10-S14; Jeon, C.Y., Murray, M.B., Diabetes mellitus increases the risk of active tuberculosis: A systematic review of 13 observational studies (2008) PLOS MED, 5, p. e152. , https://doi.org/10.1371/journal.pmed.0050152; (2015) IDF DIABETES ATLAS-7TH EDITION International Diabetes Federation, , http://www.idf.org/diabetesatlas, Accessed July 17 2017; (2011), http://www.who.int/diabetes/publications/tb_diabetes2011/en/, World Health Organization. Collaborative framework for care and control of tuberculosis and diabetes. Geneva, Switzerland: WHO(Accessed July 17 2017); Zumla, A., Maeurer, M., Rational development of adjunct immune-based therapies for drug-resistant tuberculosis: Hypotheses and experimental designs (2012) J Infect Dis, 205, pp. S335-S339; Yee, D., Valiquette, C., Pelletier, M., Parisien, I., Rocher, I., Menzies, D., Incidence of serious side effects from first-line antituberculosis drugs among patients treated for active tuberculosis (2003) Am J Respir Crit Care Med, 167, pp. 1472-1477. , https://doi.org/10.1164/rccm.200206-626OC; (2015) Taiwan Tuberculosis Control Report, , http://www.cdc.gov.tw/infectionreportinfo.aspx?treeid=075874DC882A5BFD&nowtreeid=91977F9E601D7B75&tid=803486390A4B52C7, Centers for Disease Control, Ministry of Health and Welfare, R.O.C. (Taiwan), Published 2017 Accessed July 17 2017; Raviglione, M.C., Ditiu, L., Setting new targets in the fight against tuberculosis (2013) Nat Med, 19, p. 263. , https://doi.org/10.1038/nm.3129; Singhal, A., Jie, L., Kumar, P., Hong, G.S., Leow, M.K., Paleja, B., Metformin as adjunct antituberculosis therapy (2014) Sci Transl Med, 6, pp. 263ra159. , https://doi.org/10.1126/scitranslmed.3009885; Wallis, R.S., Maeurer, M., Mwaba, P., Chakaya, J., Rustomjee, R., Migliori, G.B., Tuberculosis-Advances in development of new drugs, treatment regimens, host-directed therapies, and biomarkers (2016) Lancet Infect Dis, 16, pp. e34-e46. , https://doi.org/10.1016/S1473-3099.16.00070-0; Marupuru, S., Senapati, P., Pathadka, S., Miraj, S.S., Unnikrishnan, M.K., Manu, M.K., Protective effect of metformin against tuberculosis infections in diabetic patients: An observational study of south Indian tertiary healthcare facility (2017) Braz J Infect Dis, 13, pp. 30495-30496; Lipska, K.J., Bailey, C.J., Inzucchi, S.E., Use of metformin in the setting of mild-To-moderate renal insufficiency (2011) Diabet Care, 34, pp. 1431-1437; Hussein, M.M., Mooij, J.M., Roujouleh, H., Tuberculosis and chronic renal disease (2003) Semin Dial, 16, pp. 38-44; Al-Efraij, K., Mota, L., Lunny, C., Schachter, M., Cook, V., Johnston, J., Risk of active tuberculosis in chronic kidney disease: A systematic review and meta-Analysis (2015) Int J Tuberc Lung Dis, 19, pp. 1493-1499. , https://doi.org/10.5588/ijtld.15.0081; (2017) WHO Collaborating Centre for Drug Statistics Methodology. Guidelines for ATC Classification and DDD Assignment. 2014th Ed, , https://www.whocc.no/filearchive/publications/2017_guidelines_web.pdf, Accessed July 17 2017; Wang, J.Y., Lee, M.C., Shu, C.C., Lee, C.H., Lee, L.N., Chao, K.M., Optimal duration of anti-TB treatment in patients with diabetes: Nine or six months? (2015) Chest, 147, pp. 520-528. , https://doi.org/10.1378/chest.14-0918; Wang, J.Y., Lee, C.H., Yu, M.C., Lee, M.C., Lee, L.N., Wang, J.T., Fluoroquinolone use delays tuberculosis treatment despite immediate mycobacteriology study (2015) Eur Respir J, 46, pp. 567-570. , https://doi.org/10.1183/09031936.00019915; Marks, G.B., Bai, J., Simpson, S.E., Sullivan, E.A., Stewart, G.J., Incidence of tuberculosis among a cohort of tuberculin-positive refugees in Australia: Reappraising the estimates of risk (2000) Am J Respir Crit Care Med, 162, pp. 1851-1854. , https://doi.org/10.1164/ajrccm.162.5.2004154; Hill, A.B., The environment and disease: Association or causation? (1965) Proc R Soc Med, 58, pp. 295-300; Narasimhan, P., Wood, J., Macintyre, C.R., Mathai, D., Risk factors for tuberculosis (2013) Pulm Med, 2013, p. 828939. , https://doi.org/10.1155/2013/828939; (2017) IDF Consensus Worldwide Definition of the Metabolic Syndrome, , https://www.idf.org/ouractivities/advocacy-Awareness/resources-And-Tools/60:idfconsensus-worldwide-definitionof-Themetabolic-syndrome.html, Accessed July 17; Su, V.Y., Su, W.J., Yen, Y.F., Pan, S.W., Chuang, P.H., Feng, J.Y., Statin use is associated with a lower risk of tuberculosis (2017) Chest, 4, pp. 30813-30819; Meteran, H., Backer, V., Kyvik, K.O., Skytthe, A., Thomsen, S.F., Comorbidity between chronic obstructive pulmonary disease and type 2 diabetes: A nation-wide cohort twin study (2015) Respir Med, 109, pp. 1026-1030. , https://doi.org/10.1016/j.rmed.2015.05.015; Lee, C.H., Lee, M.C., Shu, C.C., Lim, C.S., Wang, J.Y., Lee, L.N., Risk factors for pulmonary tuberculosis in patients with chronic obstructive airway disease in Taiwan: A nationwide cohort study (2013) BMC Infect Dis, 13, p. 194. , https://doi.org/10.1186/1471-2334-13-194; Wu, V.C., Wang, C.Y., Shiao, C.C., Ch, C., Huang, H.Y., Huang, T.M., Increased risk of active tuberculosis following acute kidney injury: A nationwide, population-based study (2013) PLoS One, 8, p. e69556. , https://doi.org/10.1371/journal.pone.0069556; Pan, S.W., Yen, Y.F., Kou, Y.R., Chuang, P.H., Su, V.Y., Feng, J.Y., The risk of tb in patients with type 2 diabetes initiating metformin vs sulfonylurea treatment (2018) Chest, 153, pp. 1347-1357. , https://doi.org/10.1016/j.chest.2017.11.040; Parihar, S.P., Guler, R., Khutlang, R., Lang, D.M., Hurdayal, R., Mhlanga, M.M., Statin therapy reduces the mycobacterium tuberculosis burden in human macrophages and in mice by enhancing autophagy and phagosome maturation (2014) J Infect Dis, 209, pp. 754-763. , https://doi.org/10.1093/infdis/jit550; Lee, M.Y., Lin, K.D., Hsu, W.H., Chang, H.L., Yang, Y.H., Hsiao, P.J., Statin, calcium channel blocker and Beta blocker therapy may decrease the incidence of tuberculosis infection in elderly Taiwanese patients with type 2 diabetes (2015) Int J Mol Sci, 16, pp. 11369-11384. , https://doi.org/10.3390/ijms160511369; Lai, C.C., Lee, M.T., Lee, S.H., Hsu, W.T., Chang, S.S., Chen, S.C., Statin treatment is associated with a decreased risk of active tuberculosis: An analysis of a nationally representative cohort (2016) Thorax, 71, pp. 646-651. , https://doi.org/10.1136/thoraxjnl-2015-207052; Mai, N.T., Dobbs, N., Phu, N.H., Colas, R.A., Thao, L.T., Thuong, N.T., A randomised double blind placebo controlled phase 2 trial of adjunctive aspirin for tuberculous meningitis in HIV-uninfected adults (2018) Elife, 7, p. e33478. , https://doi.org/10.7554/eLife.33478; Marupuru, S., Senapati, P., Pathadka, S., Miraj, S.S., Unnikrishnan, M.K., Manu, M.K., Protective effect of metformin against tuberculosis infections in diabetic patients: An observational study of south Indian tertiary healthcare facility (2017) Braz J Infect Dis, 21, pp. 312-316. , https://doi.org/10.1016/j.bjid.2017.01.001; Pan, S.W., Yen, Y.F., Kou, Y.R., Chuang, P.H., Su, V.Y., Feng, J.Y., The risk of tb in patients with type 2 diabetes initiating metformin vs sulfonylurea treatment (2017) Chest; Dutta, N.K., Pinn, M.L., Karakousis, P.C., Metformin adjunctive therapy does not improve the sterilizing activity of the first-line antitubercular regimen in mice (2017) Antimicrob Agents Chemother, 61, p. e00652. , https://doi.org/10.1128/AAC.00652-17; Inzucchi, S.E., Bergenstal, R.M., Buse, J.B., Diamant, M., Ferrannini, E., Nauck, M., Management of hyperglycemia in type 2 diabetes 2015: A patient-centered approach: Update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes (2015) Diabet Care, 38, pp. 140-149; Martinez, L., Zhu, L., Castellanos, M.E., Liu, Q., Chen, C., Hallowell, B.D., Glycemic control and the prevalence of tuberculosis infection: A population-based observational study (2017) Clin Infect Dis, 65, pp. 2060-2068. , https://doi.org/10.1093/cid/cix632; Wu, C.W., Wu, J.Y., Lee, M.G., Lai, C.C., Wu, I.L., Tsai, Y.W., Risk of incident active tuberculosis disease in patients treated with non-steroidal anti-inflammatory drugs: A population-based study (2017) BMC Pulm Med, 17, p. 82. , https://doi.org/10.1186/s12890-017-0425-3; Kroesen, V.M., Groschel, M.I., Martinson, N., Zumla, A., Maeurer, M., Van Der Werf, T.S., Non-steroidal anti-inflammatory drugs as host-directed therapy for tuberculosis: A systematic review (2017) Front Immunol, 8, p. 772. , https://doi.org/10.3389/fimmu.2017.00772; Selvin, E., Marinopoulos, S., Berkenblit, G., Rami, T., Brancati, F.L., Powe, N.R., Meta-Analysis: Glycosylated hemoglobin and cardiovascular disease in diabetes mellitus (2004) Ann Intern Med, 141, pp. 421-431; Klein, R., Klein, B.E., Moss, S.E., Cruickshanks, K.J., Relationship of hyperglycemia to the long-Term incidence and progression of diabetic retinopathy (1994) Arch Intern Med, 154, pp. 2169-2178; Health, P., And Reducing Disparities in Populations (2017) Diabet Care, 40, pp. S6-S10; Palmer, C.E., Jablon, S., Edwards, P.Q., Tuberculosis morbidity of young men in relation to tuberculin sensitivity and body build (1957) Am Rev Tuberc, 76, pp. 517-539; Edwards, L.B., Livesay, V.T., Acquaviva, F.A., Palmer, C.E., Height, weight, tuberculous infection, and tuberculous disease (1971) Arch Environ Health, 22, pp. 106-112; (2018) DAROC Clinical Practice Guidelines for Diabetes Care-2018, , Taiwan, Diabetes Association of the R O.C",
year = "2018",
month = "10",
day = "1",
doi = "10.1371/journal.pone.0205807",
language = "English",
volume = "13",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
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}

TY - JOUR

T1 - Metformin use is associated with a low risk of tuberculosis among newly diagnosed diabetes mellitus patients with normal renal function: A nationwide cohort study with validated diagnostic criteria

AU - Lee, M.-C.

AU - Chiang, C.-Y.

AU - Lee, C.-H.

AU - Ho, C.-M.

AU - Chang, C.-H.

AU - Wang, J.-Y.

AU - Chen, S.-M.

N1 - Export Date: 6 November 2018 CODEN: POLNC References: (2016) 20th Edition Geneva, Switzerland: WHO 2015, , http://www.who.int/tb/publications/globalreport/en/, World Health Organization. Global tuberculosis report (Accessed July 17 2017); Restrepo, B.I., Schlesinger, L.S., Host-pathogen interactions in tuberculosis patients with type 2 diabetes mellitus (2013) Tuberculosis (Edinb), 93, pp. S10-S14; Jeon, C.Y., Murray, M.B., Diabetes mellitus increases the risk of active tuberculosis: A systematic review of 13 observational studies (2008) PLOS MED, 5, p. e152. , https://doi.org/10.1371/journal.pmed.0050152; (2015) IDF DIABETES ATLAS-7TH EDITION International Diabetes Federation, , http://www.idf.org/diabetesatlas, Accessed July 17 2017; (2011), http://www.who.int/diabetes/publications/tb_diabetes2011/en/, World Health Organization. Collaborative framework for care and control of tuberculosis and diabetes. Geneva, Switzerland: WHO(Accessed July 17 2017); Zumla, A., Maeurer, M., Rational development of adjunct immune-based therapies for drug-resistant tuberculosis: Hypotheses and experimental designs (2012) J Infect Dis, 205, pp. S335-S339; Yee, D., Valiquette, C., Pelletier, M., Parisien, I., Rocher, I., Menzies, D., Incidence of serious side effects from first-line antituberculosis drugs among patients treated for active tuberculosis (2003) Am J Respir Crit Care Med, 167, pp. 1472-1477. , https://doi.org/10.1164/rccm.200206-626OC; (2015) Taiwan Tuberculosis Control Report, , http://www.cdc.gov.tw/infectionreportinfo.aspx?treeid=075874DC882A5BFD&nowtreeid=91977F9E601D7B75&tid=803486390A4B52C7, Centers for Disease Control, Ministry of Health and Welfare, R.O.C. (Taiwan), Published 2017 Accessed July 17 2017; Raviglione, M.C., Ditiu, L., Setting new targets in the fight against tuberculosis (2013) Nat Med, 19, p. 263. , https://doi.org/10.1038/nm.3129; Singhal, A., Jie, L., Kumar, P., Hong, G.S., Leow, M.K., Paleja, B., Metformin as adjunct antituberculosis therapy (2014) Sci Transl Med, 6, pp. 263ra159. , https://doi.org/10.1126/scitranslmed.3009885; Wallis, R.S., Maeurer, M., Mwaba, P., Chakaya, J., Rustomjee, R., Migliori, G.B., Tuberculosis-Advances in development of new drugs, treatment regimens, host-directed therapies, and biomarkers (2016) Lancet Infect Dis, 16, pp. e34-e46. , https://doi.org/10.1016/S1473-3099.16.00070-0; Marupuru, S., Senapati, P., Pathadka, S., Miraj, S.S., Unnikrishnan, M.K., Manu, M.K., Protective effect of metformin against tuberculosis infections in diabetic patients: An observational study of south Indian tertiary healthcare facility (2017) Braz J Infect Dis, 13, pp. 30495-30496; Lipska, K.J., Bailey, C.J., Inzucchi, S.E., Use of metformin in the setting of mild-To-moderate renal insufficiency (2011) Diabet Care, 34, pp. 1431-1437; Hussein, M.M., Mooij, J.M., Roujouleh, H., Tuberculosis and chronic renal disease (2003) Semin Dial, 16, pp. 38-44; Al-Efraij, K., Mota, L., Lunny, C., Schachter, M., Cook, V., Johnston, J., Risk of active tuberculosis in chronic kidney disease: A systematic review and meta-Analysis (2015) Int J Tuberc Lung Dis, 19, pp. 1493-1499. , https://doi.org/10.5588/ijtld.15.0081; (2017) WHO Collaborating Centre for Drug Statistics Methodology. Guidelines for ATC Classification and DDD Assignment. 2014th Ed, , https://www.whocc.no/filearchive/publications/2017_guidelines_web.pdf, Accessed July 17 2017; Wang, J.Y., Lee, M.C., Shu, C.C., Lee, C.H., Lee, L.N., Chao, K.M., Optimal duration of anti-TB treatment in patients with diabetes: Nine or six months? (2015) Chest, 147, pp. 520-528. , https://doi.org/10.1378/chest.14-0918; Wang, J.Y., Lee, C.H., Yu, M.C., Lee, M.C., Lee, L.N., Wang, J.T., Fluoroquinolone use delays tuberculosis treatment despite immediate mycobacteriology study (2015) Eur Respir J, 46, pp. 567-570. , https://doi.org/10.1183/09031936.00019915; Marks, G.B., Bai, J., Simpson, S.E., Sullivan, E.A., Stewart, G.J., Incidence of tuberculosis among a cohort of tuberculin-positive refugees in Australia: Reappraising the estimates of risk (2000) Am J Respir Crit Care Med, 162, pp. 1851-1854. , https://doi.org/10.1164/ajrccm.162.5.2004154; Hill, A.B., The environment and disease: Association or causation? (1965) Proc R Soc Med, 58, pp. 295-300; Narasimhan, P., Wood, J., Macintyre, C.R., Mathai, D., Risk factors for tuberculosis (2013) Pulm Med, 2013, p. 828939. , https://doi.org/10.1155/2013/828939; (2017) IDF Consensus Worldwide Definition of the Metabolic Syndrome, , https://www.idf.org/ouractivities/advocacy-Awareness/resources-And-Tools/60:idfconsensus-worldwide-definitionof-Themetabolic-syndrome.html, Accessed July 17; Su, V.Y., Su, W.J., Yen, Y.F., Pan, S.W., Chuang, P.H., Feng, J.Y., Statin use is associated with a lower risk of tuberculosis (2017) Chest, 4, pp. 30813-30819; Meteran, H., Backer, V., Kyvik, K.O., Skytthe, A., Thomsen, S.F., Comorbidity between chronic obstructive pulmonary disease and type 2 diabetes: A nation-wide cohort twin study (2015) Respir Med, 109, pp. 1026-1030. , https://doi.org/10.1016/j.rmed.2015.05.015; Lee, C.H., Lee, M.C., Shu, C.C., Lim, C.S., Wang, J.Y., Lee, L.N., Risk factors for pulmonary tuberculosis in patients with chronic obstructive airway disease in Taiwan: A nationwide cohort study (2013) BMC Infect Dis, 13, p. 194. , https://doi.org/10.1186/1471-2334-13-194; Wu, V.C., Wang, C.Y., Shiao, C.C., Ch, C., Huang, H.Y., Huang, T.M., Increased risk of active tuberculosis following acute kidney injury: A nationwide, population-based study (2013) PLoS One, 8, p. e69556. , https://doi.org/10.1371/journal.pone.0069556; Pan, S.W., Yen, Y.F., Kou, Y.R., Chuang, P.H., Su, V.Y., Feng, J.Y., The risk of tb in patients with type 2 diabetes initiating metformin vs sulfonylurea treatment (2018) Chest, 153, pp. 1347-1357. , https://doi.org/10.1016/j.chest.2017.11.040; Parihar, S.P., Guler, R., Khutlang, R., Lang, D.M., Hurdayal, R., Mhlanga, M.M., Statin therapy reduces the mycobacterium tuberculosis burden in human macrophages and in mice by enhancing autophagy and phagosome maturation (2014) J Infect Dis, 209, pp. 754-763. , https://doi.org/10.1093/infdis/jit550; Lee, M.Y., Lin, K.D., Hsu, W.H., Chang, H.L., Yang, Y.H., Hsiao, P.J., Statin, calcium channel blocker and Beta blocker therapy may decrease the incidence of tuberculosis infection in elderly Taiwanese patients with type 2 diabetes (2015) Int J Mol Sci, 16, pp. 11369-11384. , https://doi.org/10.3390/ijms160511369; Lai, C.C., Lee, M.T., Lee, S.H., Hsu, W.T., Chang, S.S., Chen, S.C., Statin treatment is associated with a decreased risk of active tuberculosis: An analysis of a nationally representative cohort (2016) Thorax, 71, pp. 646-651. , https://doi.org/10.1136/thoraxjnl-2015-207052; Mai, N.T., Dobbs, N., Phu, N.H., Colas, R.A., Thao, L.T., Thuong, N.T., A randomised double blind placebo controlled phase 2 trial of adjunctive aspirin for tuberculous meningitis in HIV-uninfected adults (2018) Elife, 7, p. e33478. , https://doi.org/10.7554/eLife.33478; Marupuru, S., Senapati, P., Pathadka, S., Miraj, S.S., Unnikrishnan, M.K., Manu, M.K., Protective effect of metformin against tuberculosis infections in diabetic patients: An observational study of south Indian tertiary healthcare facility (2017) Braz J Infect Dis, 21, pp. 312-316. , https://doi.org/10.1016/j.bjid.2017.01.001; Pan, S.W., Yen, Y.F., Kou, Y.R., Chuang, P.H., Su, V.Y., Feng, J.Y., The risk of tb in patients with type 2 diabetes initiating metformin vs sulfonylurea treatment (2017) Chest; Dutta, N.K., Pinn, M.L., Karakousis, P.C., Metformin adjunctive therapy does not improve the sterilizing activity of the first-line antitubercular regimen in mice (2017) Antimicrob Agents Chemother, 61, p. e00652. , https://doi.org/10.1128/AAC.00652-17; Inzucchi, S.E., Bergenstal, R.M., Buse, J.B., Diamant, M., Ferrannini, E., Nauck, M., Management of hyperglycemia in type 2 diabetes 2015: A patient-centered approach: Update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes (2015) Diabet Care, 38, pp. 140-149; Martinez, L., Zhu, L., Castellanos, M.E., Liu, Q., Chen, C., Hallowell, B.D., Glycemic control and the prevalence of tuberculosis infection: A population-based observational study (2017) Clin Infect Dis, 65, pp. 2060-2068. , https://doi.org/10.1093/cid/cix632; Wu, C.W., Wu, J.Y., Lee, M.G., Lai, C.C., Wu, I.L., Tsai, Y.W., Risk of incident active tuberculosis disease in patients treated with non-steroidal anti-inflammatory drugs: A population-based study (2017) BMC Pulm Med, 17, p. 82. , https://doi.org/10.1186/s12890-017-0425-3; Kroesen, V.M., Groschel, M.I., Martinson, N., Zumla, A., Maeurer, M., Van Der Werf, T.S., Non-steroidal anti-inflammatory drugs as host-directed therapy for tuberculosis: A systematic review (2017) Front Immunol, 8, p. 772. , https://doi.org/10.3389/fimmu.2017.00772; Selvin, E., Marinopoulos, S., Berkenblit, G., Rami, T., Brancati, F.L., Powe, N.R., Meta-Analysis: Glycosylated hemoglobin and cardiovascular disease in diabetes mellitus (2004) Ann Intern Med, 141, pp. 421-431; Klein, R., Klein, B.E., Moss, S.E., Cruickshanks, K.J., Relationship of hyperglycemia to the long-Term incidence and progression of diabetic retinopathy (1994) Arch Intern Med, 154, pp. 2169-2178; Health, P., And Reducing Disparities in Populations (2017) Diabet Care, 40, pp. S6-S10; Palmer, C.E., Jablon, S., Edwards, P.Q., Tuberculosis morbidity of young men in relation to tuberculin sensitivity and body build (1957) Am Rev Tuberc, 76, pp. 517-539; Edwards, L.B., Livesay, V.T., Acquaviva, F.A., Palmer, C.E., Height, weight, tuberculous infection, and tuberculous disease (1971) Arch Environ Health, 22, pp. 106-112; (2018) DAROC Clinical Practice Guidelines for Diabetes Care-2018, , Taiwan, Diabetes Association of the R O.C

PY - 2018/10/1

Y1 - 2018/10/1

N2 - Human studies on the use of metformin as host-directed therapy (HDT) for tuberculosis (TB) are rare. We performed a nationwide cohort study to evaluate the effect of metformin on mitigating the risk of active TB among patients with diabetes mellitus (DM). Among newly diagnosed DM patients identified in the Taiwan National Health Insurance Research Database, metformin users, defined on the basis of >90 cumulative defined daily doses within 1 year, and propensity-score-matched metformin nonusers were selected. The primary outcome was incident TB, identified using diagnostic criteria validated by real patient data at a medical center. Independent predictors were investigated using Cox regression analysis. Similar analysis was performed in a subpopulation without a history of hypertensive nephropathy and renal replacement therapy. A total of 88,866 metformin users and 88,866 propensityscore-matched nonusers were selected. Validation results showed that the TB diagnostic criteria had a sensitivity of 99.13% and specificity of 99.90%. During follow-up, 707 metformin users and 807 nonusers developed active TB. Metformin use was independently associated with a lower risk of incident TB (hazard ratio [HR]: 0.84 [0.74-0.96]). TB risk was lower in high-dose metformin users than in low-dose users (HR: 0.83 [0.72-0.97]). The effect of metformin remained when analysis was restricted in the subpopulation without renal function impairment. Newly diagnosed diabetic patients without contraindication should receive metformin as an anti-diabetic medication, with potential additional benefit against TB. © 2018 Lee et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

AB - Human studies on the use of metformin as host-directed therapy (HDT) for tuberculosis (TB) are rare. We performed a nationwide cohort study to evaluate the effect of metformin on mitigating the risk of active TB among patients with diabetes mellitus (DM). Among newly diagnosed DM patients identified in the Taiwan National Health Insurance Research Database, metformin users, defined on the basis of >90 cumulative defined daily doses within 1 year, and propensity-score-matched metformin nonusers were selected. The primary outcome was incident TB, identified using diagnostic criteria validated by real patient data at a medical center. Independent predictors were investigated using Cox regression analysis. Similar analysis was performed in a subpopulation without a history of hypertensive nephropathy and renal replacement therapy. A total of 88,866 metformin users and 88,866 propensityscore-matched nonusers were selected. Validation results showed that the TB diagnostic criteria had a sensitivity of 99.13% and specificity of 99.90%. During follow-up, 707 metformin users and 807 nonusers developed active TB. Metformin use was independently associated with a lower risk of incident TB (hazard ratio [HR]: 0.84 [0.74-0.96]). TB risk was lower in high-dose metformin users than in low-dose users (HR: 0.83 [0.72-0.97]). The effect of metformin remained when analysis was restricted in the subpopulation without renal function impairment. Newly diagnosed diabetic patients without contraindication should receive metformin as an anti-diabetic medication, with potential additional benefit against TB. © 2018 Lee et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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U2 - 10.1371/journal.pone.0205807

DO - 10.1371/journal.pone.0205807

M3 - Article

VL - 13

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 10

M1 - e0205807

ER -