Repurposing of Metformin for the prevention and treatment of Tuberculosis

Vyas, Navya; Punchathidil, Rakhi; Swain, Ansuman; Shakeer, Irfan; Reddy, Badikol Shrikar; Manu, Mohan Kamalanivas; Miraj, Sonal Sekhar

doi:10.1590/s2175-97902022e20422

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Article • Braz. J. Pharm. Sci. 58 • 2022 • https://doi.org/10.1590/s2175-97902022e20422 linkcopy

Repurposing of Metformin for the prevention and treatment of Tuberculosis

Authorship SCIMAGO INSTITUTIONS RANKINGS

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.

Keywords:
AMPK activator; Diabetes; Metformin; Tuberculosis

Sl.No.	Author, Year	Study title	Method	Key findings
1.	Zhang M, He JQ, 2020	Impacts of metformin on tuberculosis incidence and clinical outcomes in patients with diabetes: a systematic review and meta-analysis.	Systematic review and meta-analysis of 17 observational studies (n=382,828)	Metformin significantly reduced active TB incidence and mortality in DM patients
2.	Yu et al., 2019	Impact of metformin on the risk and treatment outcomes of tuberculosis in diabetics: a systematic review	Systematic review with 12 observational studies (n=6980 cases)	Metformin significantly reduced TB risk and improved treatment outcomes of TB in DM patients
3.	Park et al., 2019	Metformin and tuberculosis risk in elderly patients with diabetes mellitus	Retrospective cohort study from the National Health Insurance Service-Senior database, South Korea (n=25,164)	Metformin use was associated with a decreased TB risk than sulfonylurea use in elderly DM patients
4.	Lachmandas et al., 2019	Metformin alters human host responses to Mycobacterium tuberculosis in healthy subjects	In vitro and in vivo studies on effects of metformin in Dutch adults (n=11)	Metformin ameliorates the pathological inflammatory responses associated with TB while enhancing antimycobacterial processes such as ROS production and phagocytosis in humans.
5.	Lee et al., 2019	Impact of metformin use among tuberculosis close contacts with diabetes mellitus in a nationwide cohort study	National wide cohort study in Taiwan (n=5846)	Metformin use is associated with a lower risk of active TB among TB close contacts with DM, especially for insulin users
6.	Pan et al., 2018	The risk of TB in patients with type 2 diabetes initiating metformin vs sulfonylurea treatment.	Retrospective cohort study from the Taiwan National Health Insurance Research Database (n= 40,179)	Metformin use in the initial 2 years was associated with a decreased TB risk and metformin users had a reduced risk than sulfonylurea users
7.	Degner et al., 2018	Metformin use reverses the increased mortality associated with diabetes mellitus during tuberculosis treatment	Retrospective cohort study (n= 2416) from National Taiwan University Hospital	Metformin use associated with significantly reduced mortality during TB treatment
8.	Lee et al., 2018	The effect of metformin on culture conversion in tuberculosis patients with diabetes mellitus	Retrospective cohort study (n= 499) from Seoul Metropolitan Government Seoul National University Boramae Medical Center and Seoul National University Hospital, South Korea	Metformin improved the sputum culture conversion rate in patients with cavitary pulmonary TB, who have higher bacterial loads
9.	Lin et al.,2018	Metformin is associated with a lower risk of active tuberculosis in patients with type 2 diabetes	Nationwide population-based cohort study using the Taiwan Longitudinal Health Insurance Database (n= 49,028)	Metformin is associated with a decreased risk of active TB in the DM population
10.	Ma, et al.,2018	Metformin reduces the relapse rate of tuberculosis patients with diabetes mellitus: experiences from 3-year follow-up	Retrospective cohort study (n=58) in China	Metformin use as a combination drug with existing regimen improved the success rate of ATT and reduced the relapse rate in TB patients with DM
11.	Marupuru, et al., 2017	Protective effect of metformin against tuberculosis infections in diabetic patients: an observational study of South Indian tertiary healthcare facility	Case-control study (n=451) IN India	The protective effect of metformin against TB was 3.9-fold than other antidiabetic agents in DM patients
12.	Singhal et al., 2014	Metformin as adjunct antituberculosis therapy	Preclinical study with mouse model and a retrospective cohort study (n=493) in Singapore	Metformin use was associated with improved control of TB infection and decreased disease severity

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Universidade de São Paulo, Faculdade de Ciências Farmacêuticas Av. Prof. Lineu Prestes, n. 580, 05508-000 S. Paulo/SP Brasil, Tel.: (55 11) 3091-3824 - São Paulo - SP - Brazil
E-mail: bjps@usp.br

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[TFN1] ROS:Reactive oxygen species; TB: Tuberculosis

[TFN2] ATT: Anti-tubercular treatment; DM: Diabetes Mellitus;