Skip to main content

Advertisement

SpringerLink
Log in

Impacts of metformin on tuberculosis incidence and clinical outcomes in patients with diabetes: a systematic review and meta-analysis

  • Review
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. World Health Organization (2018) Global tuberculosis report 2018

  2. Narasimhan P, Wood J, Macintyre CR, Mathai D (2013) Risk factors for tuberculosis. Pulm Med 2013: 828939. https://doi.org/10.1155/2013/828939

    Article  Google Scholar 

  3. Jeon CY, Murray MB (2008) Diabetes mellitus increases the risk of active tuberculosis: a systematic review of 13 observational studies. PLoS Med 5(7):e152. https://doi.org/10.1371/journal.pmed.0050152

    Article  PubMed  PubMed Central  Google Scholar 

  4. Dooley KE, Chaisson RE (2009) Tuberculosis and diabetes mellitus: convergence of two epidemics. Lancet Infect Dis 9(12):737–746. https://doi.org/10.1016/S1473-3099(09)70282-8

    Article  PubMed  PubMed Central  Google Scholar 

  5. Baker MA, Harries AD, Jeon CY, Hart JE, Kapur A, Lonnroth K, Ottmani SE, Goonesekera SD, Murray MB (2011) The impact of diabetes on tuberculosis treatment outcomes: a systematic review. BMC Med 9:81. https://doi.org/10.1186/1741-7015-9-81

    Article  PubMed  PubMed Central  Google 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

    Article  Google 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

    Article  PubMed  Google Scholar 

  8. Harries AD, Kumar AM, Satyanarayana S, Lin Y, Zachariah R, Lonnroth K, Kapur A (2015) Diabetes mellitus and tuberculosis: programmatic management issues. Int J Tuberc Lung Dis 19(8):879–886. https://doi.org/10.5588/ijtld.15.0069

    Article  CAS  Google Scholar 

  9. Vashisht R, Brahmachari SK (2015) Metformin as a potential combination therapy with existing front-line antibiotics for tuberculosis. J Transl Med 13:83–83. https://doi.org/10.1186/s12967-015-0443-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Wallis RS, Hafner R (2015) Advancing host-directed therapy for tuberculosis. Nat Rev Immunol 15(4):255–263. https://doi.org/10.1038/nri3813

    Article  CAS  PubMed  Google 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

    Article  CAS  PubMed  Google Scholar 

  12. Pan SW, Yen YF, Kou YR, Chuang PH, Su VYF, Feng JY, Chan YJ, Su WJ (2018) The risk of TB in patients with type 2 diabetes initiating metformin vs sulfonylurea treatment. Chest 153(6):1347–1357. https://doi.org/10.1016/j.chest.2017.11.040

    Article  PubMed  Google 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

    Article  Google 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

    Article  CAS  Google 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

    Article  CAS  PubMed  Google Scholar 

  16. Yew WW, Chang KC, Chan DP, Zhang Y (2019) Metformin as a host-directed therapeutic in tuberculosis: Is there a promise? Tuberculosis (Edinb) 115:76–80. https://doi.org/10.1016/j.tube.2019.02.004

    Article  CAS  Google 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

    Article  PubMed  Google 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

    Article  Google Scholar 

  19. Stang A (2010) Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 25(9):603–605. https://doi.org/10.1007/s10654-010-9491-z

    Article  Google Scholar 

  20. Higgins JP, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21(11):1539–1558. https://doi.org/10.1002/sim.1186

    Article  PubMed  Google Scholar 

  21. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7(3):177–188

    Article  CAS  Google 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):719–748

    CAS  PubMed  Google Scholar 

  23. Begg CB, Mazumdar M (1994) Operating characteristics of a rank correlation test for publication bias. Biometrics 50(4):1088–1101

    Article  CAS  Google Scholar 

  24. Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. Bmj 315(7109):629–634

    Article  CAS  Google Scholar 

  25. Chaimani A, Mavridis D, Salanti G (2014) A hands-on practical tutorial on performing meta-analysis with Stata. Evid Based Ment Health 17(4):111–116. https://doi.org/10.1136/eb-2014-101967

    Article  Google 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

    Article  CAS  Google 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):458–463

    Google 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

    Article  Google 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

    Article  CAS  PubMed  PubMed Central  Google 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

    Article  CAS  PubMed  PubMed Central  Google 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

    Article  Google Scholar 

  32. Lee YJ, Han SK, Park JH, Lee JK, Kim DK, Chung HS, Heo EY (2018) The effect of metformin on culture conversion in tuberculosis patients with diabetes mellitus. Korean J Intern Med 33(5):933–940. https://doi.org/10.3904/kjim.2017.249

    Article  CAS  Google Scholar 

  33. Lin SY, Tu HP, Lu PL, Chen TC, Wang WH, Chong IW, Chen YH (2018) Metformin is associated with a lower risk of active tuberculosis in patients with type 2 diabetes. Respirology 23(11):1063–1073. https://doi.org/10.1111/resp.13338

    Article  Google Scholar 

  34. Tseng CH (2018) Metformin decreases risk of tuberculosis infection in type 2 diabetes patients. J Clin Med 7(9). DOI https://doi.org/10.3390/jcm7090264

    Article  CAS  Google Scholar 

  35. Magee MJ, Salindri AD, Kornfeld H, Singhal A (2019) Reduced prevalence of latent tuberculosis infection in diabetes patients using metformin and statins. Eur Respir J 53(3). https://doi.org/10.1183/13993003.01695-2018

    Article  Google Scholar 

  36. Novita BD, Ali M, Pranoto A, Soediono EI, Mertaniasih NM (2019) Metformin induced autophagy in diabetes mellitus—tuberculosis co-infection patients: a case study. Indian J Tuberc 66(1):64–69. https://doi.org/10.1016/j.ijtb.2018.04.003

    Article  PubMed  Google Scholar 

  37. Novita BD, Pranoto A, Wuryani, Soediono EI, Mertaniasih NM (2018) A case risk study of lactic acidosis risk by metformin use in type 2 diabetes mellitus tuberculosis coinfection patients. Indian J Tuberc 65(3):252–256. https://doi.org/10.1016/j.ijtb.2017.05.008

    Article  PubMed  Google Scholar 

  38. Kumar Nathella P, Babu S (2017) Influence of diabetes mellitus on immunity to human tuberculosis. Immunology 152(1):13–24. https://doi.org/10.1111/imm.12762

    Article  CAS  PubMed  PubMed Central  Google 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

    Article  Google 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

    Article  CAS  Google 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

    Article  PubMed  Google Scholar 

  42. Lee PH, Fu H, Lai TC, Chiang CY, Chan CC, Lin HH (2016) Glycemic control and the risk of tuberculosis: a cohort study. PLoS Med 13(8):e1002072. https://doi.org/10.1371/journal.pmed.1002072

    Article  CAS  PubMed  PubMed Central  Google 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

    Article  CAS  Google 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

    Article  PubMed  PubMed Central  Google 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

  46. Suh S (2015) Metformin-associated lactic acidosis. Endocrinol Metab (Seoul) 30(1):45–46. https://doi.org/10.3803/EnM.2015.30.1.45

    Article  CAS  Google Scholar 

  47. Su VY, Su WJ, Yen YF, Pan SW, Chuang PH, Feng JY, Chou KT, Yang KY, Lee YC, Chen TJ (2017) Statin use is associated with a lower risk of TB. Chest 152(3):598–606. https://doi.org/10.1016/j.chest.2017.04.170

    Article  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  49. Suissa S, Azoulay L (2012) Metformin and the risk of cancer: time-related biases in observational studies. Diabetes Care 35(12):2665–2673. https://doi.org/10.2337/dc12-0788

    Article  CAS  PubMed  PubMed Central  Google 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

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by the National Natural Science Foundation of China (Grant No. 81870015)

Authors’ contributions

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

Author information

Authors and Affiliations

  1. Department of Respiratory and Critical Care Medicine, West China Hospital of Sichuan University, No. 37,Guo Xue Alley, Chengdu, 610041, China

    Meng Zhang & Jian-qing He

Authors
  1. Meng Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jian-qing He
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jian-qing He.

Ethics declarations

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

ESM 1

(DOCX 29 kb)

Supplementary Table 1

(DOCX 19 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, M., He, Jq. Impacts of metformin on tuberculosis incidence and clinical outcomes in patients with diabetes: a systematic review and meta-analysis. Eur J Clin Pharmacol 76, 149–159 (2020). https://doi.org/10.1007/s00228-019-02786-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-019-02786-y

Keywords

Search

Navigation