Impacts of metformin on tuberculosis incidence and clinical outcomes in patients with diabetes: a systematic review and meta-analysis
Accumulating evidence suggested that the use of metformin had more benefits for both prevention and treatment of tuberculosis (TB) than non-metformin use in patients with diabetes mellitus (DM); however, it remains to be fully elucidated on this topic. Thus, we conducted a systematic review and meta-analysis of published studies to determine the association between metformin use and TB in patients with diabetes.
The MEDLINE, EMBASE, Information Sciences Institute (ISI) Web of Science, and Cochrane CENTRAL databases were searched from their inception to 15 April 2019. Studies that evaluated the use of metformin and TB disease were included. The quality of each study was evaluated through the Newcastle-Ottawa Scale (NOS). For pooled data, the relative risk (RR) and 95% confidence intervals (CIs) were calculated; otherwise, a systematic review.
Seventeen observational studies were included, all of which indicated a low risk of bias according to the NOS. The pooled analysis showed that metformin use was associated with a significantly lower active TB incidence and mortality among individuals with DM (RR = 0.51; 95% CI, 0.38–0.69, P ⩽ 0.001) and with TB-DM (RR = 0.34; 95% CI, 0.20–0.57, P ⩽ 0.001), respectively.
This meta-analysis indicated metformin use is related to benefits in both prevention and treatment outcomes of tuberculosis among patients with diabetes. Prospective clinical trials are needed to confirm these associations.
KeywordsMetformin Tuberculosis Diabetes mellitus Meta-analysis Systematic review
This work was supported by the National Natural Science Foundation of China (Grant No. 81870015)
ZM and HJQ both searched databases, selected studies, extracted data, analyzed data. ZM wrote the manuscript. All authors read and approved the final manuscript.
Availability of data and material
All data generated or analyzed during this study are included in this published article
Compliance with ethical standards
The authors declare that they have no competing interests.
- 1.World Health Organization (2018) Global tuberculosis report 2018Google Scholar
- 6.Salindri AD, Kipiani M, Kempker RR, Gandhi NR, Darchia L, Tukvadze N, Blumberg HM, Magee MJ (2016) Diabetes reduces the rate of sputum culture conversion in patients with newly diagnosed multidrug-resistant tuberculosis. Open Forum Infect Dis 3(3):ofw126. https://doi.org/10.1093/ofid/ofw126 CrossRefGoogle Scholar
- 7.Jimenez-Corona ME, Cruz-Hervert LP, Garcia-Garcia L, Ferreyra-Reyes L, Delgado-Sanchez G, Bobadilla-Del-Valle M, Canizales-Quintero S, Ferreira-Guerrero E, Baez-Saldana R, Tellez-Vazquez N, Montero-Campos R, Mongua-Rodriguez N, Martinez-Gamboa RA, Sifuentes-Osornio J, Ponce-de-Leon A (2013) Association of diabetes and tuberculosis: impact on treatment and post-treatment outcomes. Thorax 68(3):214–220. https://doi.org/10.1136/thoraxjnl-2012-201756 CrossRefPubMedGoogle Scholar
- 11.Singhal A, Jie L, Kumar P, Hong GS, Leow MK, Paleja B, Tsenova L, Kurepina N, Chen J, Zolezzi F, Kreiswirth B, Poidinger M, Chee C, Kaplan G, Wang YT, De Libero G (2014) Metformin as adjunct antituberculosis therapy. Sci Transl Med 6(263):263ra159. https://doi.org/10.1126/scitranslmed.3009885 CrossRefPubMedGoogle Scholar
- 13.Degner NR, Wang JY, Golub JE, Karakousis PC (2018) Metformin use reverses the increased mortality associated with diabetes mellitus during tuberculosis treatment. Clin Infect Dis: an Official Publication of the Infectious Diseases Society of America 66(2):198–205. https://doi.org/10.1093/cid/cix819 CrossRefGoogle Scholar
- 14.Ma Y, Pang Y, Shu W, Liu YH, Ge QP, Du J, Li L, Gao WW (2018) Metformin reduces the relapse rate of tuberculosis patients with diabetes mellitus: experiences from 3-year follow-up. Eur J Clin Microbiol Infect Dis: Official Publication of the European Society of Clinical Microbiology 37(7):1259–1263. https://doi.org/10.1007/s10096-018-3242-6 CrossRefGoogle Scholar
- 15.Kumar NP, Moideen K, Bhootra Y, Nancy A, Viswanathan V, Shruthi BS, Sivakumar S, Natarajan M, Kornfeld H, Babu S (2019) Elevated circulating levels of monocyte activation markers among tuberculosis patients with diabetes co-morbidity. Immunology 156(3):249–258. https://doi.org/10.1111/imm.13023 CrossRefPubMedGoogle Scholar
- 17.Tiberi S, du Plessis N, Walzl G, Vjecha MJ, Rao M, Ntoumi F, Mfinanga S, Kapata N, Mwaba P, McHugh TD, Ippolito G, Migliori GB, Maeurer MJ, Zumla A (2018) Tuberculosis: progress and advances in development of new drugs, treatment regimens, and host-directed therapies. Lancet Infect Dis 18(7):e183–e198. https://doi.org/10.1016/s1473-3099(18)30110-5 CrossRefPubMedGoogle Scholar
- 18.Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, Clarke M, Devereaux PJ, Kleijnen J, Moher D (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol 62(10): e1–34. DOI https://doi.org/10.1016/j.jclinepi.2009.06.006 CrossRefGoogle Scholar
- 22.Mantel N, Haenszel W (1959) Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 22(4):719–748Google Scholar
- 26.Leow MK, Dalan R, Chee CB, Earnest A, Chew DE, Tan AW, Kon WY, Jong M, Barkham T, Wang YT (2014) Latent tuberculosis in patients with diabetes mellitus: prevalence, progression and public health implications. Exp Clin Endocrinol Diabetes: Official Journal, German Society of Endocrinology and German Diabetes Association 122(9):528–532. https://doi.org/10.1055/s-0034-1377044 CrossRefGoogle Scholar
- 27.Lin HF, Lai SW, Chang CM, Tsai PY, Chen PC, Sung FC (2016) Anti-diabetic medication reduces risk of pulmonary tuberculosis in diabetic patients: a population-based cohort study in Taiwan. Intern Med J 23(5):458–463Google Scholar
- 28.Marupuru S, Senapati P, Pathadka S, Miraj SS, Unnikrishnan MK, Manu MK (2017) Protective effect of metformin against tuberculosis infections in diabetic patients: an observational study of south Indian tertiary healthcare facility. Braz J Infect Dis: an Official Publication of the Brazilian Society of Infectious Diseases 21(3):312–316. https://doi.org/10.1016/j.bjid.2017.01.001 CrossRefGoogle Scholar
- 29.Al-Shaer MH, Elewa H, Alkabab Y, Nazer LH, Heysell SK (2018) Fixed-dose combination associated with faster time to smear conversion compared to separate tablets of anti-tuberculosis drugs in patients with poorly controlled diabetes and pulmonary tuberculosis in Qatar. BMC Infect Dis 18(1):384. https://doi.org/10.1186/s12879-018-3309-0 CrossRefPubMedPubMedCentralGoogle Scholar
- 30.Kumar NP, Moideen K, Viswanathan V, Shruthi BS, Sivakumar S, Menon PA, Kornfeld H, Babu S (2018) Elevated levels of matrix metalloproteinases reflect severity and extent of disease in tuberculosis-diabetes co-morbidity and are predominantly reversed following standard anti-tuberculosis or metformin treatment. BMC Infect Dis 18(1):345. https://doi.org/10.1186/s12879-018-3246-y CrossRefPubMedPubMedCentralGoogle Scholar
- 31.Lee MC, Chiang CY, Lee CH, Ho CM, Chang CH, Wang JY, Chen SM (2018) 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. PLoS One 13(10). DOI https://doi.org/10.1371/journal.pone.0205807 CrossRefGoogle Scholar
- 39.Stalenhoef JE, Alisjahbana B, Nelwan EJ, van der Ven-Jongekrijg J, Ottenhoff TH, van der Meer JW, Nelwan RH, Netea MG, van Crevel R (2008) The role of interferon-gamma in the increased tuberculosis risk in type 2 diabetes mellitus. Eur J Clin Microbiol Infect Dis: Official Publication of the European Society of Clinical Microbiology 27(2):97–103. https://doi.org/10.1007/s10096-007-0395-0 CrossRefGoogle Scholar
- 40.Hensel RL, Kempker RR, Tapia J, Oladele A, Blumberg HM, Magee MJ (2016) Increased risk of latent tuberculous infection among persons with pre-diabetes and diabetes mellitus. Int J Tuberc Lung Dis: the Official Journal of the International Union Against Tuberculosis and Lung Disease 20(1):71–78. https://doi.org/10.5588/ijtld.15.0457 CrossRefGoogle Scholar
- 41.Barron MM, Shaw KM, Bullard KM, Ali MK, Magee MJ (2018) Diabetes is associated with increased prevalence of latent tuberculosis infection: findings from the National Health and Nutrition Examination Survey, 2011–2012. Diabetes Res Clin Pract 139:366–379. https://doi.org/10.1016/j.diabres.2018.03.022 CrossRefPubMedGoogle Scholar
- 43.Restrepo BI, Fisher-Hoch SP, Pino PA, Salinas A, Rahbar MH, Mora F, Cortes-Penfield N, McCormick JB (2008) Tuberculosis in poorly controlled type 2 diabetes: altered cytokine expression in peripheral white blood cells. Clin Infect Dis: an Official Publication of the Infectious Diseases Society of America 47(5):634–641. https://doi.org/10.1086/590565 CrossRefGoogle Scholar
- 44.Palaci M, Dietze R, Hadad DJ, Ribeiro FK, Peres RL, Vinhas SA, Maciel EL, do Valle Dettoni V, Horter L, Boom WH, Johnson JL, Eisenach KD (2007) Cavitary disease and quantitative sputum bacillary load in cases of pulmonary tuberculosis. J Clin Microbiol 45(12):4064–4066. https://doi.org/10.1128/jcm.01780-07 CrossRefPubMedPubMedCentralGoogle Scholar
- 45.Salpeter S, Greyber E, Pasternak G, Salpeter E (2006) Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev (1): Cd002967. https://doi.org/10.1002/14651858.CD002967.pub2
- 48.Parihar SP, Guler R, Khutlang R, Lang DM, Hurdayal R, Mhlanga MM, Suzuki H, Marais AD, Brombacher F (2014) Statin therapy reduces the mycobacterium tuberculosis burden in human macrophages and in mice by enhancing autophagy and phagosome maturation. J Infect Dis 209(5):754–763. https://doi.org/10.1093/infdis/jit550 CrossRefPubMedGoogle Scholar
- 50.Padmapriyadarsini C, Bhavani PK, Natrajan M, Ponnuraja C, Kumar H, Gomathy SN, Guleria R, Jawahar SM, Singh M, Balganesh T, Swaminathan S (2019) Evaluation of metformin in combination with rifampicin containing antituberculosis therapy in patients with new, smear-positive pulmonary tuberculosis (METRIF): study protocol for a randomised clinical trial. BMJ Open 9(3):e024363. https://doi.org/10.1136/bmjopen-2018-024363 CrossRefPubMedPubMedCentralGoogle Scholar