Repurposing of Metformin for the prevention and treatment of Tuberculosis

Authors

  • Navya Vyas Prasanna School of Public Health - Department of Health Policy Manipal, Karnataka India
  • Rakhi Punchathidil Department of Health Policy, Prasanna School of Public Health, Manipal Academy of Higher Education, Manipal, Karnataka, India
  • Ansuman Swain Department of Health Policy, Prasanna School of Public Health, Manipal Academy of Higher Education, Manipal, Karnataka, India
  • Irfan Shakeer Department of Health Policy, Prasanna School of Public Health, Manipal Academy of Higher Education, Manipal, Karnataka, India
  • Badikol Shrikar Reddy Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
  • Mohan Kamalanivas Manu Manipal Center for Infectious Diseases, Prasanna School of Public Health, Manipal Academy of Higher Education, Manipal, Karnataka, India
  • Sonal Sekhar Miraj Manipal Center for Infectious Diseases, Prasanna School of Public Health, Manipal Academy of Higher Education, Manipal, Karnataka, India

Keywords:

AMPK activator, Diabetes, Metformin, Tuberculosis

Abstract

The bidirectional relationship between tuberculosis (TB) and diabetes mellitus (DM) is a major concern for medical professionals and epidemiologists as DM affects the severity, progress and outcome of TB and vice versa. Patients affected with TB have a higher rate of morbidity, treatment failure and mortality. Likewise, DM triples the risk of contracting TB and therefore poses a threat to the progress made in the reduction of TB incidence. Hence, it is pivotal to address both the diseases keeping in mind the each other. It is known that adjunct therapy with immunomodulatory drugs can enhance TB immunity among diabetic patients. Metformin, a commonly used anti-diabetic drug with adenosine monophosphate-activated protein kinase (AMPK) activation property, has shown the capacity to reduce the growth of Mycobacterium tuberculosis within the cell. This drug inhibits the mitochondrial complex and possesses anti-inflammatory action. Therefore, Metformin can be considered as an ideal molecule for host-directed or host-targeted therapy for TB.

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References

Alavi SM, Khoshkho MM, Salmanzadeh S, Eghtesad M. Comparison of epidemiological, clinical, laboratory and radiological features of hospitalized diabetic and non-diabetic patients with pulmonary Tuberculosis at Razi hospital in Ahvaz. Jundishapur J Microbiol. 2014;7(9):e12447.

Anjana RM, Ali MK, Pradeepa R, Deepa M, Datta M, Unnikrishnan R, et al The need for obtaining accurate nationwide estimates of diabetes prevalence in India - rationale for a national study on diabetes. Indian J Med Res. 2011;133(4):369-380.

Badowski ME, Perez SE. Clinical utility of dronabinol in the treatment of weight loss associated with HIV and AIDS. HIV AIDS (Auckl). 2016;8:37-45.

Barberis I, Bragazzi NL, Galluzzo L, Martini M. The history of Tuberculosis: From the first historical records to the isolation of Koch’s bacillus. J Prev Med Hyg. 2017;58(1):E9-E12.

Başoğlu OK, Bacakoğlu F, Cok G, Sayiner A, Ateş M. The oral glucose tolerance test in patients with respiratory infections. Monaldi Arch Chest Dis. 1999;54(4):307-310.

Chadha VK. Progress towards millennium development goals for TB control in seven Asian countries. Indian J Tuberc. 2009;56(1):30-43.

Chang JT, Dou HY, Yen CL, Wu YH, Huang RM, Lin HJ, et al Effect of type 2 diabetes mellitus on the clinical severity and treatment outcome in patients with Pulmonary Tuberculosis: A potential role in the emergence of multidrug-resistance. J Formos Med Assoc. 2011;110(6):372-381.

Davies PD. Risk factors for Tuberculosis. Monaldi Arch Chest Dis . 2005;63(1):37-46.

Degner NR, Wang JY, Golub JE, Karakousis PC. Metformin use reverses the increased mortality associated with diabetes mellitus during tuberculosis treatment. Clin Infect Dis. 2018;66(2):198-205.

Deretic V. Autophagy in Tuberculosis. Cold Spring Harb Perspect Med. 2014;4(11):a018481.

Di Fusco D, Dinallo V, Monteleone I, Laudisi F, Marafini I, Franzè E, et al Metformin inhibits inflammatory signals in the gut by controlling AMPK and p38 MAP kinase activation. Clin Sci (Lond). 2018;132(11):1155-1168.

Dooley KE, Chaisson RE. Tuberculosis and diabetes mellitus: Convergence of two epidemics. Lancet Infect Dis. 2009;9(12):737-746.

Faurholt-Jepsen D, Range N, Praygod G, Kidola J, Faurholt-Jepsen M, Aabye MG, et al The role of diabetes co-morbidity for tuberculosis treatment outcomes: A prospective cohort study from Mwanza, Tanzania. BMC Infect Dis. 2012;12:165.

Fuller JH, Elford J, Goldblatt P, Adelstein AM. Diabetes mortality: New light on an underestimated public health problem. Diabetologia. 1983;24(5):336-341.

Gebel E. A new shine on an old med. The story of Metformin’s past, present, and possible future. Diabetes Forecast. 2010;63(12):48-51.

Giacco F, Brownlee M. Oxidative stress and diabetic complications. Circ Res. 2010;107(9):1058-1070.

Global Report on Diabetes. World Health Organization. US: World Health Organization 2016; p. 6

Global Tuberculosis Report 2019. World Health Organization. Available from: https://www.who.int/tb/global-report-2019

» https://www.who.int/tb/global-report-2019

Gupta A, Misra A, Deretic V. Targeted pulmonary delivery of inducers of host macrophage autophagy as potential host-directed chemotherapy of Tuberculosis. Adv Drug Deliv Rev. 2016;102:10-20.

Gutierrez MG, Master SS, Singh SB, Taylor GA, Colombo MI, Deretic V. Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages. Cell. 2004;119(6):753-766.

Harries AD, Billo N, Kapur A. Links between diabetes mellitus and Tuberculosis: should we integrate screening and care? Trans R Soc Trop Med Hyg. 2009;103(1):1-2.

International Diabetes Federation. Diabetes Atlas. 9th edition. 2019. Available from: https://www.idf.org/aboutdiabetes/what-is-diabetes/facts-figures.html

» https://www.idf.org/aboutdiabetes/what-is-diabetes/facts-figures.html

IBM Micromedex® Drug interactions | Levofloxacin-Metformin Hydrochloride & Linezolid-Metformin Hydrochloride [Internet]. 2020. Available from: https://www.micromedexsolutions.com/micromedex2/librarian/PFDefaultActionId/evidencexpert.ShowDrugInteractionsResults

» https://www.micromedexsolutions.com/micromedex2/librarian/PFDefaultActionId/evidencexpert.ShowDrugInteractionsResults

Jeon CY, Murray MB. Diabetes mellitus increases the risk of active Tuberculosis: a systematic review of 13 observational studies. PLoS Med. 2008;5(7):e152.

Jick SS, Lieberman ES, Rahman MU, Choi HK. Glucocorticoid use, other associated factors, and the risk of Tuberculosis. Arthritis Rheum. 2006;55(1):19-26.

Joshi N, Caputo GM, Weitekamp MR, Karchmer AW. Infections in patients with diabetes mellitus. N Engl J Med. 1999;341(25):1906-1912.

Kaveeshwar SA, Cornwall J. The current state of diabetes mellitus in India. Australas Med J. 2014;7(1):45-48.

Kibirige D. Endocrine dysfunction among adult patients with Tuberculosis: An African experience. Indian J Endocrinol Metab. 2014;18(3):288-294.

Lachmandas E, Eckold C, Böhme J, Koeken VACM, Marzuki MB, Blok B, et al Metformin Alters Human Host Responses to Mycobacterium tuberculosis in Healthy Subjects. J Infect Dis. 2019;220(1):139-150.

Lawn SD, Zumla AI. Tuberculosis. Lancet. 2011;378(9785):57-72.

Lee MC, Lee CH, Lee MR, Wang JY, Chen SM. Impact of metformin use among Tuberculosis close contacts with diabetes mellitus in a nationwide cohort study. BMC Infect Dis . 2019;19(1):936.

Lee YJ, Han SK, Park JH, Lee JK, Kim DK, Chung HS, et al The effect of Metformin on culture conversion in tuberculosis patients with diabetes mellitus. Korean J Intern Med. 2018;33(5):933-940.

Lin SY, Tu HP, Lu PL, Chen TC, Wang WH, Chong IW, et al Metformin is associated with a lower risk of active Tuberculosis in patients with type 2 diabetes. Respirology. 2018;23(11):1063-1073.

Line DH, Seitanidis B, Morgan JO, Hoffbrand AV. The effects of chemotherapy on iron, folate, and vitamin B12 metabolism in Tuberculosis. Q J Med. 1971;40(159):331-340.

Ma Y, Pang Y, Shu W, Liu YH, Ge QP, Du J, et al Metformin reduces the relapse rate of tuberculosis patients with diabetes mellitus: Experiences from a 3-year follow-up. Eur J Clin Microbiol Infect Dis. 2018;37(7):1259-1263.

Madiraju AK, Erion DM, Rahimi Y, Zhang X-M, Braddock DT, Albright RA, et al Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. >Nature. 2014;510(7506):542-546.

Maniar K, Moideen A, Mittal A, Patil A, Chakrabarti A, Banerjee D. A story of metformin-butyrate synergism to control various pathological conditions as a consequence of gut microbiome modification: Genesis of a wonder drug? Pharmacol Res. 2017;117:103-128.

Marupuru S, Senapati P, Pathadka S, Miraj SS, Unnikrishnan MK, Manu MK. Protective effect of Metformin against tuberculosis infections in diabetic patients: an observational study of south Indian tertiary healthcare facility. Braz J Infect Dis . 2017;21(3):312-316.

Mathieu C, Gysemans C, Giulietti A, Bouillon R. Vitamin D and diabetes. Diabetologia . 2005;48(7):1247-1257

Morrish NJ, Wang SL, Stevens LK, Fuller JH, Keen H. Mortality and causes of death in the WHO Multinational Study of Vascular Disease in Diabetes. Diabetologia . 2001;44 Suppl 2:S14-S21.

Ogbera AO, Kapur A, Abdur-Razzaq H, Harries AD, Ramaiya K, Adeleye O, et al Clinical profile of diabetes mellitus in Tuberculosis. BMJ Open Diabetes Res Care. 2015;3(1):e000112.

Pal R, Ansari MA, Hameed S, Fatima Z. Diabetes Mellitus as Hub for Tuberculosis Infection: A Snapshot. Int J Chronic Dis. 2016;2016:5981574.

Pan SW, Yen YF, Kou YR, Chuang PH, Su VY, Feng JY, et al The risk of TB in patients with type 2 diabetes initiating Metformin vs sulfonylurea treatment. Chest. 2018;153(6):1347-1357.

Park S, Yang BR, Song HJ, Jang SH, Kang DY, Park BJ. Metformin and Tuberculosis risk in elderly patients with diabetes mellitus. Int J Tuberc Lung Dis. 2019;23(8):924-930.

Pearce EL, Walsh MC, Cejas PJ, Harms GM, Shen H, Wang LS, et al Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature . 2009;460(7251):103-107.

Perez-Guzman C, Torres-Cruz A, Villarreal-Velarde H, Vargas MH. Progressive age-related changes in pulmonary tuberculosis images and the effect of diabetes. Am J Respir Crit Care Med. 2000;162(5):1738-1740.

Pickup JC. Inflammation and activated innate immunity in the pathogenesis of type 2 diabetes. Diabetes Care. 2004;27(3):813-823.

Pizzol D, Di Gennaro F, Chhaganlal KD, Fabrizio C, Monno L, Putoto G, et al Tuberculosis and diabetes: Current state and future perspectives. Trop Med Int Health. 2016;21(6):694-702.

Raizada N, Sachdeva KS, Sreenivas A, Kulsange S, Gupta RS, Thakur R, et al Catching the missing million: Experiences in enhancing TB and DR-TB detection by providing upfront Xpert MTB/RIF testing for people living with HIV in India. PLoS One. 2015;10(2):e0116721.

Restrepo BI. Metformin: Candidate host-directed therapy for Tuberculosis in diabetes and non-diabetes patients. Tuberculosis (Edinb). 2016;101S:S69-S72.

Riza AL, Pearson F, Ugarte-Gil C, Alisjahbana B, van de Vijver S, Panduru NM, et al Clinical management of concurrent diabetes and Tuberculosis and the implications for patient services. Lancet Diabetes Endocrinol. 2014;2(9):740-753.

Roglic G, Unwin N, Bennett PH, Mathers C, Tuomilehto J, Nag S, et al The burden of mortality attributable to diabetes: Realistic estimates for the year 2000. Diabetes Care . 2005;28(9):2130-2135.

Sachan M, Srivastava A, Ranjan R, Gupta A, Pandya S, Misra A. Opportunities and challenges for host-directed therapies in tuberculosis. Curr Pharm Des. 2016;22(17):2599-2604.

Sachdeva KS, Kumar A, Dewan P, Kumar A, Satyanarayana S. New vision for Revised National Tuberculosis Control Programme (RNTCP): Universal access - “reaching the unreached”. Indian J Med Res . 2012;135(5):690-694.

Sendi P, Friedl A, Graber P, Zimmerli W. Reactivation of dormant microorganisms following a trauma. Pneumonia, sternal abscess and calcaneus osteomyelitis due to Mycobacterium tuberculosis. Neth J Med. 2008;66(8):363-364.

Singhal A, Jie L, Kumar P, Hong GS, Leow MK-S, Paleja B, et al Metformin as adjunct anti tuberculosis therapy. Sci Transl Med. 2014;6(263):263ra159.

Smith I. Mycobacterium tuberculosis pathogenesis and molecular determinants of virulence. Clin Microbiol Rev. 2003;16(3):463-496.

Sullivan T, Ben Amor Y. The co-management of Tuberculosis and diabetes: Challenges and opportunities in the developing world. PLoS Med . 2012;9(7):e1001269.

Tatar D, Senol G, Alptekin S, Karakurum C, Aydin M, Coskunol I. Tuberculosis in diabetics: Features in an endemic area. Jpn J Infect Dis . 2009;62(6):423-427.

USAID. Tuberculosis in India [Internet]; United States Agency for International Development. 2017 Nov. Available from: https://www.usaid.gov/what-we-do/global-health/ tuberculosis/technical-areas/tuberculosis-india

» https://www.usaid.gov/what-we-do/global-health/ tuberculosis/technical-areas/tuberculosis-india

Uplekar M, Pathania V, Raviglione M. Private practitioners and public health: Weak links in tuberculosis control. Lancet . 2001;358(9285):912-916.

Vashisht R, Brahmachari SK. Metformin as a potential combination therapy with existing front-line antibiotics for Tuberculosis. J Transl Med. 2015;13:83.

Yin Y, Choi SC, Xu Z, Perry DJ, Seay H, Croker BP, et al Normalization of CD4+ T cell metabolism reverses lupus. Sci Transl Med . 2015;7(274):274ra18.

Yu X, Li L, Xia L, Feng X, Chen F, Cao S, et al Impact of Metformin on the risk and treatment outcomes of Tuberculosis in diabetics: A systematic review. BMC Infect Dis . 2019;19(1):859.

Zaman K. Tuberculosis: A global health problem. J Health Popul Nutr. 2010;28(2):111-113.

Zhan Y, Jiang L. Status of vitamin D, antimicrobial peptide cathelicidin and T helper-associated cytokines in patients with diabetes mellitus and pulmonary Tuberculosis. Exp Ther Med. 2015;9(1):11-16.

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. 2020;76(2):149-159.

Ziskind B, Halioua B. La tuberculose en ancienne Egypte [Tuberculosis in ancient Egypt]. Rev Mal Respir. 2007;24(10):1277-1283.

Zumla A, Nahid P, Cole ST. Advances in the development of new tuberculosis drugs and treatment regimens. Nat Rev Drug Discov. 2013;12(5):388-404.

Zumla A, Raviglione M, Hafner R, von Reyn CF. Tuberculosis. N Engl J Med . 2013;368(8):745-755.

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Published

2022-11-25

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Review

How to Cite

Repurposing of Metformin for the prevention and treatment of Tuberculosis. (2022). Brazilian Journal of Pharmaceutical Sciences, 59, e20422. https://www.journals.usp.br/bjps/article/view/215529