Guru Nanak Institute of Pharmaceutical Science and Technology

Chapter:1
INTRODUCTION

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1. INTRODUCTION:
Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis (TB); a deadly
infectious disease. Most individuals think of tuberculosis (TB) as a disease of respiratory
system. But it may too affect the lymphatic system, genitourinary framework, vascular system,
central nervous system, bones, and joints. Around the world; tuberculosis (TB) is an airborne
ailment that has affected individuals for at least 4,000 years. Genetic research may be moreover
able to identify tuberculosis signs indeed in Egyptian mummies. It may be a exceedingly
infectious respiratory disease; and the host's immunocompetence in conjunction with natural
factors significantly increase the chance of infection. When a individual with tuberculosis
coughs, sniffles, or sings, the disease can spread. This may release minute amounts of the germs
into the air. The microbes can at that point enter the lungs of another person who breathes in the
droplets.

1.1. Different stages & Symptoms:

A tuberculosis (TB) infection occurs when the causative bacteria of the disease survive and
grow in the lungs. A tuberculosis infection can have several phases. Every stage has a
particular set of symptoms.
A. Primary TB:
The initial phase is referred to as the main infection. Immune system cells find and seize
the pathogens. The germs can be completely destroyed by the immune system. However,
a few trapped microbes may proceed to exist and multiply within the body.
A primary infection usually causes no symptoms at all for most individuals. Flu-like
symptoms, such as fatigue, coughing, and low temperature, might strike certain
individuals.
B. Latent TB:
Latent or inactive tuberculosis infection often takes after primary infection. TB germ-
infected lung tissue is encompassed by a wall formed by immune framework cells. In
case the immune system can control the microscopic organisms, they will be incapable
to cause any more damage. In any case, the microbes persevere. When a TB infection is
inactive, there are no indications.
C. Active TB:

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When an infection gets out of control by the immune framework, active tuberculosis
illness comes about. Infections within the lungs or other bodily regions are caused by
germs. Active tuberculosis infection may happen basically after the primary infection.
However, inactive tuberculosis infection for months or a long time is generally the
reason for it.
Symptoms of active tuberculosis within the lungs generally show up continuously and
intensify over numerous weeks. Indications may incorporate coughing up blood or
mucous, Chest Pain, Pain during breathing in or coughing, Fever, chills, night sweats.
Weight Loss Not wanting to eat. Weakness and an in general need of well-being.
D. Active TB disease outside the lungs:
Tuberculosis can spread from the lungs to the other districts of the body. This is often
called as extrapulmonary tuberculosis. Symptoms differ according to where area of the
body is affected. Common indications incorporate fever, chills, night sweats, weight loss,
not wanting to eat, fatigue, Not feeling great in general. Pain within the area of disease.

Figure 1: Image of Evolution of the different clinical stages of

tuberculosis (TB)

1.2.
Historical strategies to prevent TB:
In spite of being mostly treatable, tuberculosis proceeds to be the main cause of death
around the world, due to the critical rise in resistance to anti-mycobacterial drugs. In the
year 2018, the World Wellbeing Organization (WHO) expressed that 10 million people

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contracted active TB. Of them, 558,000 were new cases resistant to rifampicin–a basic
medicine within the current first-line treatment. 82% percent of the rifampicin-resistant
patients developed multi-drug-resistant TB (MDR-TB), which incorporates, at a least,
resistance to the first line treatment isoniazid (World Health Organization, 2018).
Whereas the predominance of treatment resistance is generally 5% of overall TB cases;
17% of TB fatalities were attributed to drug-resistant strains (World Health Organization;
2018).

In 1991; the “World Health Assembly Resolution” described TB as a “major global

health problem,”; and various activities such as the “WHO Directly Observed Treatment;
Short-course (DOTS) strategy” and the “Stop TB strategy” have been launched. Between
2000 and 2015, an approximate 49 million lives were saved, counting a 22cline in TB
fatalities (World Health Organization, 2016a).
In any case, barely one in five people requiring MDR-TB treatment started such
treatment (World Health Organization, 2016a). In May 2014, a new plan and goals for
TB prevention, the End TB plan, were declared. The reason of this strategy is to
terminate the universal TB epidemic, with the taking after targets compared to 2015:
“90% reduction in number of TB deaths, 90% diminishment in TB incidence rate, and
90% lessening in TB influenced families facing unfortunate costs due to TB” by 2035
(World Health Organization, 2016b). The recently proposed End TB approach, whereas
ambitious, can only be satisfied via progressive ways in treating and preventing TB.
1.3. Risk Factors of Tuberculosis:

Tuberculosis spreads readily when individuals gather in masses or where individuals live
in crowded environments. Those with weaker immune systems have a higher chance of
contracting TB than people with average immune systems. The diseases which are the
risk factor of TB include:
a. HIV or AIDS b. Diabetes
c. Serious kidney disease d. Head or neck cancer
e. Low body weight and poor nutrition
f. Cancer treatments such as chemotherapy
g. Medications for organ transplants

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h. Certain drugs to treat rheumatoid arthritis, Crohn’s disease, and psoriasis.

1.4. Pathogenesis of Tuberculosis:
The pathogenic life cycle of M. tb is outlined in the figure below. TB is transmitted
through M. tb-containing aerosol droplet which is propelled by active TB patients when
they cough, sneeze or talk. After the new host breathe in the TB microscopic organisms,
they travel through the respiratory tract and reach the lung. At this point, the host's innate
immune system comes into play to suppress the disease, whereupon the tubercle bacilli
are disguised by alveolar macrophages. When the macrophages fail to inhibit or destroy
the bacilli, the microbes multiply inside their intracellular environment, get released, at
that point phagocytosed by other alveolar macrophages and the cycle proceeds
The immune system reacts by recruiting lymphocytes to the site, initiating a cell-
mediated reaction that points to separate the microbes and it prevent further
multiplication of the bacteria. Amid this stage, the host frequently remains asymptomatic.
A granuloma, an accumulation of immune cells including macrophages, may form to
limit the spread of the microbes. Inside the granuloma, the microscopic organisms can
evade or avoid immune defences, persisting in a dormant state for a long time.

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In case the host's immunity is compromised due to variables like HIV disease,
malnutrition, or other immunosuppressive conditions, the inactive or latent infection can
reactivate. The granuloma's structure may at that point deteriorate, which leads to
necrosis and the formation of a caseous (cheese-like) center. This process can culminate
within the liquification and cavitation of the granuloma, releasing the microbes into the
Figure3: Pathophysiology of pulmonary TB. Taking after the M. tb transmission to the new host, the bacilli enter the lung and
lungs andby macrophages.
get ingested airways, Thenin immune
this cells
manner transitioning
are enrolled to active
to wall off the infected TB,
macrophages, characterized
driving to the formation by
of the granuloma, the trademark of TB. Healthy people stay latently infected, and the contamination is kept at bay at this
symptomatic andto exceedingly
stage, but it is inclined infectious
the risk of reactivation. disease.release
Foamy macrophages Amid thissubstance
their lipid stage,when
thetheymicroscopic
necrotize,
driving to caseation (cheese-like structure). Caseum could be a decay which is manifested at the core of the granuloma that
organisms
compromise itscan moreover
inflexible spreadAsto
or rigid integrity. theother parts
granuloma of the
develops, body,
the bacilli whichtoleads
commence leak outto extensive
of the organ
macrophages
into the caseum layer. When the reactivation happens, M. tb multiplies and the bacterial stack gets to be overwhelmingly tall,
damage.
whereupon Hence, managing
the granuloma TB requires
burst, disseminating notto the
the microbes only tending
airways. to are
The bacilli theat active
that pointdisease but
expectorated as too
infectious aerosol droplets, restarting the cycle, infecting other people.
observing latent infections, especially in immunocompromised people.

1.5. Current Treatment Regimen for Drug-Sensitive (DS) TB:

The current suggested treatment for DS-TB includes a combination of four antibiotics:
isoniazid (INH), rifampicin (RIF), pyrazinamide (PZA) and ethambutol (EMB), which
were all found about 60 years ago. This four medicate cocktail ought to be administered
for at least 6 months under directly observed treatment (Dot) to ensure the high rates of
treatment success and remedy. The treatment includes two stages: 1. the initial stage,
which comprises administering the previously mentioned four drugs for two months, and
2. the continuation stage treatment with INH and RIF for the final four months to kill the
dormant microbes
The four drugs target M. tb through distinctive mechanisms of activity. Briefly, INH is a
prodrug which upon activation inhibits the enoyl-acyl carrier protein or enzyme reductase
(InhA), which could be a key enzyme within the biosynthetic process of MAs. MAs are
the essential mediators of the hydrophobic qualities and lack of permeability of the
mycobacterial external coating. RIF binds to the ꞵ-subunit of the bacterial RNA

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polymerase and applies its bactericidal activity by inhibiting the early steps of gene
transcription. Like INH, PZA is a prodrug that gets activated after diffusing into the TB
granuloma by the pyrazinamidase protein to pyrazinoic acid (POA), which
hence eradicates the M. tb bacillus inside the granuloma

2. Metformin:
Metformin, derivative of biguanide is one of the most frequently utilized drugs in the treatment
of type 2 diabetes (T2D), and it has been utilized for approximately one century in the treatment
of DM 2. Metformin, an antidiabetic drug was approved by the U.S. Food and Drug
Administration (FDA) in 1994 for treating type 2 diabetes; This medicine is used in both
immediate- and extended-release formulations and it is regularly combined with other
antidiabetic drugs. Guanidine, studied to have anti-diabetic qualities in animals in 1918,
shockingly, it was harmful in clinical studies and it pushed researchers to distinguish more
secure substitutions. Within the 1920s, metformin (1,1-dimethyl biguanide hydrochloride) was
synthesized. Since at that point, metformin ought to be the favoured choice to treat T2D due to
its remarkable capacity to lower plasma glucose levels. When patients are analysed with type 2
diabetes, specialists frequently prescribe lifestyle adjustments such as changing their nutrition
and increasing their physical workout. Metformin is frequently taken as a monotherapy or in
conjunction with other drugs when lifestyle treatments, such as changes in diet and work out, are
deficiently in reducing hyperglycaemia. As per the American Diabetes Association (ADA),
metformin remains as the chosen first-line medicate in the treatment of type 2 diabetes in both
adult and paediatric patients 10 or older patients.' Concurring to the Standards of Medical Care in
Diabetes 2018; in case of the patient’s haemoglobin A1C (HbA1c) level less than 9%, metformin
monotherapy is the suggested treatment by doctor. In any case, if the HbA1c level is more than
9%, metformin is prescribed as a part of the combination treatment. Eminently, metformin isn't
endorsed for the treatment of type 1 diabetes.
In later years, a few other unexpected however
valuable uses of metformin were uncovered. The
off-label indications of metformin incorporate

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controlling gestational diabetes, resolving weight gain challenges initiated by antipsychotic

pharmaceutical, avoiding type 2 diabetes, and treating and avoiding polycystic ovary syndrome
(PCOS).

Figure 2: Image of the structure of metformin

Metformin
is presently the sole ADA-recommended antidiabetic medicate utilized for prediabetes. Besides,
analysts are investigating metformin for its potential anti-inflammatory, antituberculosis,
antiaging, anticancer, and neuroprotective benefits and illustrates affect in liver ailments, and
renal diseases. Sole medication or combination treatment with additional pharmaceuticals has
illustrated to be useful to treat diverse ailments.

3. Host Directed Therapy (HDT):

Host-directed therapy (HDT) may be a novel approach within the field of anti-infectives
for overcoming antimicrobial resistance. HDT points to interfere with host cell components that
are required by a pathogen for replication or persistence, to improve or stimulate host's defensive
immune reactions against a pathogen, to decrease exacerbated inflammation and to adjust
immune reactivity at sites of pathology.
In tuberculosis, HDT points to upgrade the antimicrobial activities of phagocytes through
phagosomal maturation, autophagy and antimicrobial peptides. HDTs moreover reduce
inflammation through obstructions with soluble (such as eicosanoids or cytokines) or cellular
(co-stimulatory particles) variables and modulate granulomas to permit the get to of
antimicrobials or to limit tissue damage.

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Host-directed therapy (HDT) gives a generally unexploited approach as adjunctive anti-

TB treatment. Firstly, HDT may disable Mtb replication and survival by disturbing Mtb
manipulation of macrophage pathways, hence rendering the bacteria more sensitive to host
defenses.

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The current explore for novel therapeutics has centred on the utilize of repurposed drugs pointed
at optimizing the host's response against the mycobacterium. HDT has been proposed as an
adjuvant therapy for TB, to improve the viability of current treatment results. One conceivable
resolution to the challenge of anti-microbial resistance and non-replicating bacterial death is
targeting the host as opposed to the pathogen since it depends not one or the other on bacterial
division nor on the bacterial vulnerability to drugs. HDT for TB makes a difference to shorten
the duration of treatment of drug-sensitive TB and to improve the treatment result in MDR-TB
by protecting the normal lung composition. When combined with tuberculosis (TB) anti-

microbials, HDTs may contribute to improving treatment results, diminishing treatment duration,
and avoiding resistance development.

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Chapter:2
AIM AND OBJECTIVE OF THE WORK

2. AIM OF THE WORK:

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The project topic "Effect of Metformin in the treatment of Tuberculosis" aims to follow the
effect of metformin on tuberculosis. The project's goal is to look into the potential therapeutic
benefits of metformin in the treatment of tuberculosis.

2.1. OBJECTIVE OF THE WORK:

The project's objectives may include the following:
1. Reviewing the current research on metformin impacts on tuberculosis mainly in
patients with Diabetes Mellitus.
2. Identifying the bidirectional relation between tuberculosis and DM.
3. Investigating how metformin affect tuberculosis through Host Directed mechanism
4. In light of potential clinical uses, examining the efficacy of metformin in TB.
5. Describing potential future research directions and areas to look into to understand
the role performed by metformin in the context of tuberculosis.
By aiming on these goals, the project hopes to further scientific understanding of metformin
potential therapeutic advantages in tuberculosis.

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Chapter:3
LITERATURE REVIEW

1. Degner, N. R., Wang, J. Y., Golub, J. E., & Karakousis, P. C. (2018). Metformin Use
Reverses the Increased Mortality Associated with Diabetes Mellitus During
Tuberculosis Treatment. Clinical infectious diseases: an official publication of the

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Infectious Diseases Society of America, 66(2), 198–205.

https://doi.org/10.1093/cid/cix819
In a retrospective cohort study, the effects of type 2 diabetes mellitus on tuberculosis
treatment outcomes, such as mortality and the result of sputum culture conversion, as well as
the benefits of metformin, in 2416 people treated for drug-susceptible pulmonary
tuberculosis, were studied. The study took into account such factors as age, sex, chronic
kidney disease, cancer, hepatitis C, smoking, cavitary disease, and treatment adherence.
Accordingly, it was found that these patients were more at risk: the chances of dying during
treatment for tuberculosis were 1.91 times greater, besides, 1.72 times more often, DM failed
to implement culture conversion after two months. It's fascinating that diabetic patients who
use metformin have shown mortality rates bringing their survival rates closer to those of non-
diabetic individuals. This indicates that metformin could be an addition to host directed
therapy in treating TB for patients with diabetes showcasing its potential impact, beyond
managing blood sugar levels to enhance TB treatment results.

2. Heo, E., Kim, E., Jang, E. J., & Lee, C. H. (2021). The cumulative dose-dependent
effects of metformin on the development of tuberculosis in patients newly diagnosed
with type 2 diabetes mellitus. BMC pulmonary medicine, 21(1), 303.
https://doi.org/10.1186/s12890-021-01667-4
Researchers conducted a retrospective cohort study of the Korean Health Insurance Review
and Assessment Service analyses database to explore the effects of metformin on
tuberculosis prevention in 76,973 newly diagnosed patients with type 2 DM. After removing
10,841 individuals, researchers identified 13,396 subjects who used metformin and 52,736
who did not. The hazard ratios were calculated using 1:1 propensity score matching and Cox
proportional hazard regression models. The study revealed that metformin did not have a
significant effect in preventing TB (Hazard Ratio: 1.17). However, a higher total amount of
metformin seems to be linked to a lower likelihood of TB. For example, people in the highest
quarter of cumulative dose had a 90 percent reduced risk of TB compared to those who did
not use the product. The protective impact decreases as the dosage decreases in smaller
quartiles, indicating that only high doses of metformin are effective in preventing TB
incidence in newly diagnosed DM patients. Metformin could initially impact the immune

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system's capability to combat TB by potentially decreasing the production of certain immune

signaling molecules (TNF-α and IFN-ϒ). This may clarify the short-term increase in TB risk
seen in the Q2 cohort. In the advanced phases of therapy, Metformin may begin to
demonstrate its preventive impact by obstructing the proliferation of TB germs, potentially
by boosting the generation of reactive oxygen species and improving phagocytic activity by
immune cells.

3. Lee, M. C., Lee, C. H., Lee, M. R., Wang, J. Y., & Chen, S. M. (2019). Impact of
metformin use among tuberculosis close contacts with diabetes mellitus in a nationwide
cohort study. BMC infectious diseases, 19(1), 936. https://doi.org/10.1186/s12879-019-
4577-z
The research investigated how metformin protects against active tuberculosis in people with
diabetes who are in close contact with TB patients, using data from Taiwan's National Health
Insurance Research Database. Subjects were divided into three categories: individuals who
had consumed 90 or more defined daily doses of metformin in the year prior to the index
date, individuals not using metformin matched for comparison, and healthy controls matched
based on age and gender. The study's goal was to establish how common TB is among these
specific groups and investigate if there are any possible connections between the use of
metformin and insulin. Examination of 5,846 individuals revealed varying incidence rates per
100,000 person-years among the groups, with healthy contacts having the lowest rate at 526
cases (adjusted hazard ratio (aHR: 0.42), followed by metformin users at 755 cases (aHR:
0.73), and non-users showing the highest rate at 1117 cases. The hazard ratios were altered to
show that healthy individuals had a greatly decreased likelihood of getting TB, while
diabetics taking metformin also experienced a reduced risk of TB, especially when used
alongside insulin. The results indicate that metformin may act as a preventive treatment for
TB in diabetic patients at high risk, but additional studies are needed to confirm these
findings.

4. Lee, Y. J., Han, S. K., Park, J. H., Lee, J. K., Kim, D. K., Chung, H. S., & Heo, E. Y.
(2018). The effect of metformin on culture conversion in tuberculosis patients with

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diabetes mellitus. The Korean journal of internal medicine, 33(5), 933–940.

https://doi.org/10.3904/kjim.2017.249
This retrospective cohort study investigated how metformin affects the treatment results of
tuberculosis in patients who is also diagnosed with diabetes mellitus. Carried out from 2011
to 2012, the research focused on the impact or effect of metformin on the key outcome of
sputum culture conversion following 2 months of TB treatment. 105 out of 499 individuals
with active pulmonary TB tested positive for diabetes mellitus during testing. Around 59.5%
of these people, or a total of 62 patients, were currently receiving metformin therapy. The
research indicated that metformin had no significant impact on the overall rates of sputum
culture conversion (p = 0.60) or recurrence within one-year post-TB treatment (p = 0.39).
Nevertheless, a notable irregularity was noticed in individuals with cavitary pulmonary
tuberculosis - a state marked by high levels of bacteria - in which metformin notably
enhanced sputum culture conversion rates (odds ratio 10.8; 95% confidence interval 1.22 to
95.63). This implies that although not all diabetic patients may find metformin helpful during
TB treatment, it could still be advantageous as an additional treatment for individuals with
cavitary pulmonary TB, potentially enhancing their treatment outcomes.

5. Al-Shaer et al., (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 infectious
diseases, 18(1), 384. https://doi.org/10.1186/s12879-018-3309-0
In a retrospective cohort study conducted across eight hospitals in Qatar, researchers
evaluated the effectiveness of tuberculosis (TB) treatment regimens in diabetic patients
diagnosed with pulmonary TB. The study, spanning from December 2012 to December 2015,
included 103 adult patients who had positive pretreatment sputum smears and were treated
with either fixed dose combination (FDC) or separate tablets (ST) of rifampin, isoniazid,
pyrazinamide, and ethambutol, under directly observed therapy. Patients who had any drug-
resistant Mycobacterium tuberculosis were excluded, and blood glucose levels were strictly
controlled below 180 md/dL using oral hypoglycemic agents or insulin. The primary measure
of treatment effectiveness was the time to confirmed negative sputum smears. Results
indicated that patients on the FDC regimen showed a significantly quicker sputum smear

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conversion compared to those on ST (32 ± 19 days vs. 46 ± 31 days, p = 0.01), especially

among those with a higher initial bacillary load (3+). Additionally, the use of metformin at
doses ≥2000 mg/day notably influenced the outcomes, further reducing the time to smear
conversion in the FDC group compared to the ST group, with the most significant difference
observed in patients with a high bacillary load who were on high-dose metformin (FDC 36 ±
12.1 days vs. ST 92.2 ± 26 days, p = 0.001). This study highlights the potential benefits of
FDC regimens in accelerating sputum smear conversion in diabetic TB patients, particularly
when combined with high-dose metformin.

6. Zhang, M., & He, J. Q. (2020). Impacts of metformin on tuberculosis incidence and
clinical outcomes in patients with diabetes: a systematic review and meta-
analysis. European journal of clinical pharmacology, 76(2), 149–159.
https://doi.org/10.1007/s00228-019-02786-y
A systemic review and meta-analysis were done to explore how metformin impacts the
prevention and treatment of tuberculosis in individuals diagnosed with diabetes. The analysis
examined key databases such as MEDLINE, EMBASE, ISI Web of Science, and Cochrane
CENTRAL until April 15, 2019, to concentrate on research that evaluated the correlation
between metformin utilization and TB results. All studies were assessed for methodological
quality using the Newcastle-Ottawa Scale (NOS) and were determined to have minimal bias.
A total of seventeen observational studies were examined. The meta-analysis showed that
diabetic patients who use metformin have a lower risk of active TB and lower TB-related
death rate. In particular, the combined risk ratio (RR) for developing active TB in diabetic
individuals who take metformin was 0.51 (95% CI, 0.38-0.69, P ≤ 0.001), while the RR for
TB-related deaths in patients with both TB and diabetes was 0.34 (95% CI, 0.20-0.57, P ≤
0.001). These results indicate that metformin assists in managing blood sugar levels and may
also lower the chances and intensity of TB in diabetic individuals. Nevertheless, the findings
from this meta-analysis highlight the importance of conducting future prospective clinical
trials to confirm and delve deeper into these positive connections.

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7. Yu, X., Li, L., Xia, L., Feng, X., Chen, F., Cao, S., & Wei, X. (2019). Impact of
metformin on the risk and treatment outcomes of tuberculosis in diabetics: a systematic
review. BMC infectious diseases, 19(1), 859. https://doi.org/10.1186/s12879-019-4548-4
The goal of the systematic review was to evaluate how metformin impacts the risk and
treatment results of tuberculosis (TB) in patients with diabetes mellitus. Analyzing the
potential advantages of using metformin to manage TB, a review examined data from twelve
observational studies up to March 2019, involving a total of 6980 cases. The results showed
that metformin reduces the likelihood of TB in diabetic individuals by a pooled odds ratio
(OR) of 0.38. Nevertheless, metformin did not demonstrate a notable decrease in the
likelihood of latent TB infection (LTBI), with an odds ratio of 0.73. Significantly, using
metformin alongside anti-TB treatment led to significant enhancements in treatment results,
such as a lower mortality rate (OR, 0.47) and an increased likelihood of achieving sputum
culture conversion by the second month of treatment (OR, 2.72). While the decrease in TB
relapse rates with metformin was not shown to be statistically significant (OR, 0.55), the
overall evidence suggests that metformin can be an advantageous add-on treatment for TB in
diabetic patients, improving both survival and treatment outcomes. These results highlight
metformin's potential to both control diabetes and enhance TB treatment results, indicating
the need for more research in future studies.

8. Park, S., Yang, B. R., Song, H. J., Jang, S. H., Kang, D. Y., & Park, B. J. (2019).
Metformin and tuberculosis risk in elderly patients with diabetes mellitus. The
international journal of tuberculosis and lung disease: the official journal of the
International Union against Tuberculosis and Lung Disease, 23(8), 924–930.
https://doi.org/10.5588/ijtld.18.0687
In an intricate exploration of how metformin impacts tuberculosis (TB) risk among elderly
diabetes mellitus (DM) patients, a retrospective cohort study utilizing the National Health
Insurance Service-Senior database reveals nuanced insights. Focusing on type-2 DM patients
aged 60 years and older from January 2003 to December 2013, researchers identified a
distinct cohort, using propensity score matching to equate metformin users with those on
sulfonylureas. The ensuing analysis, underpinned by a Cox proportional hazards model,
highlighted that metformin users experienced TB at a rate of 280.2 per 100,000 person-years,

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significantly lower than the 394.5 per 100,000 observed among sulfonylurea users. Notably,
the adjusted hazard ratio of 0.74 (95% confidence interval: 0.58-0.95) suggests a robust
protective effect of metformin against TB, with pronounced benefits observed in male
patients. Moreover, a dose-response relationship between metformin usage and reduced TB
incidence further substantiates metformin's potential as a beneficial intervention in this
vulnerable population. These findings provoke contemplation on the dual-benefit treatment
approaches in elderly diabetic patients, potentially guiding future therapeutic strategies
against both chronic and infectious diseases.

9. Pan, S. W., Yen, Y. F., Kou, Y. R., Chuang, P. H., Su, V. Y., Feng, J. Y., Chan, Y. J., & Su,
W. J. (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
Metformin, a frontline antidiabetic agent, not only regulates blood sugar in type 2 diabetes
mellitus (T2DM) patients but also exhibits potential anti-tuberculosis (TB) properties, as
shown in both in vitro and animal studies. A retrospective cohort study leveraging data from
the Taiwan National Health Insurance Research Database, scrutinized the TB risk associated
with metformin compared to sulfonylureas among T2DM patients from 2003 to 2013. This
analysis included 40,179 patients, defining those with a cumulative defined daily dose
(cDDD) of over 60 for metformin and less than 15 for sulfonylureas in the initial two years
as 'metformin majors', and vice versa for 'sulfonylurea majors'. These groups were then
balanced through propensity score matching. Intriguingly, metformin majors displayed a
notably lower TB risk than their sulfonylurea counterparts, with further analyses revealing a
dose-dependent relationship between metformin use and reduced TB risk. For instance,
increasing metformin dosage within the first two years significantly correlated with lower TB
incidence, highlighting metformin's protective effect against TB among T2DM patients. This
comprehensive study underscores metformin's dual benefits, advocating its consideration not
only for glycemic control but also as a preventive strategy against TB.
10. Lin, S. Y., Tu, H. P., Lu, P. L., Chen, T. C., Wang, W. H., Chong, I. W., & Chen, Y. H.
(2018). Metformin is associated with a lower risk of active tuberculosis in patients with

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type 2 diabetes. Respirology (Carlton, Vic.), 23(11), 1063–1073.

https://doi.org/10.1111/resp.13338
Metformin, a staple in the arsenal against type 2 diabetes mellitus (T2DM), not only manages
blood sugar but also appears to wield a protective effect against tuberculosis (TB), as
elucidated in a comprehensive study leveraging Taiwan's expansive Longitudinal Health
Insurance Database. The study meticulously paired 49,028 T2DM patients, predominantly
metformin users, with a smaller cohort of non-users to unearth the incidence of TB between
1998 and 2010. Analysis through Cox proportional hazard models revealed a stark
divergence: T2DM patients generally displayed a doubled risk of developing TB compared to
controls, yet those on metformin showcased a significantly reduced risk—a compelling
adjusted relative risk of 0.24. Intriguingly, this protective mantle of metformin proved dose-
dependent and less effective among the elderly and those suffering from metabolic disorders,
hinting at a complex interplay between metabolic health and therapeutic impact. Thus, while
metformin distinctly reduces TB risk among the broader T2DM population, its efficacy
wanes with age and specific comorbidities, painting a nuanced portrait of its role in clinical
practice.
11. Ma, Y., Pang et al., (2018). Metformin reduces the relapse rate of tuberculosis patients
with diabetes mellitus: experiences from 3-year follow-up. European journal of clinical
microbiology & infectious diseases: official publication of the European Society of
Clinical Microbiology, 37(7), 1259–1263. https://doi.org/10.1007/s10096-018-3242-6
Researchers in China examined the effects of metformin (MET) on diabetic TB patients
receiving standard anti-TB regimens in a groundbreaking retrospective study. There were
Participants from five tuberculosis control and preventive institutions were included in the
study. This study was run from 2009 to 2016 and they were monitored over three years
period. Researchers analyzed clinical outcomes and demographic characteristics between
individuals who received MET and those who did not received metformin. This study was
performed by using different statistical technique such as Fisher's exact test and chi-square
test. Total 58 diabetic TB patients were involved. They were divided into two groups one is
non-metformin group (72.4%, 42/58) and another is Metformin group (27.6%, 16/58).
Interestingly, there was no discernible difference in blood glucose levels between the two
groups (P = 0.494). The results of the treatment, however, showed a different picture: at the

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end of two months, the MET group had a more noticeable rate of culture conversion (87.5%
compared 71.4%) and a noticeably greater treatment success rate (93.8% against 71.4%). In
addition, there was a significant difference in the relapse rates between the MET and non-
MET groups during the follow-up period, with the former experiencing a relapse at a rate of
only 6.3% (1/16) and the latter at a rate of 35.7% (15/42) (P = 0.045). These results describe
the potential of metformin as a helpful adjuvant therapy which can improve the effectiveness
of current anti-TB treatments and reduce the relapse rates of TB patients with diabetes
mellitus. This suggests a promising direction for treatment protocols in this patient
population.

12. Jung, M. K., Lee, S. Y., Ko, J. M., & Im, S. A. (2023). The Effect of Diabetes Control
Status on CT Findings in Pulmonary Tuberculosis: Emphasis on Bronchial Erosive
Changes. Journal of clinical medicine, 12(14), 4725. https://doi.org/10.3390/jcm12144725
Researchers examined the relationship between the radiologic characteristics of pulmonary
tuberculosis (PTB) on CT scans and the control status of diabetes mellitus (DM)-with a
particular focus on medium-sized airway involvement such as bronchial erosion: This study
was a retrospective analysis that took place between January 2017 and March 2020. After
excluding patients with ambiguous hemoglobin A1C values or other pulmonary disorders, the
study's original sample of 426 participants was reduced to 335: Based on analysis, patients
were divided into two groups: non-diabetics and those with managed and uncontrolled DM.
The incidence of bronchial erosive alterations and cavitation varied significantly between the
groups, as the results clearly showed. Specifically, bronchial erosion was seen in 73% of
patients with uncontrolled diabetes, which is significantly more than the 30% of individuals
with managed diabetes and the 44% of patients without diabetes. Comparably, the
uncontrolled diabetes group had an alarmingly greater frequency of cavitation (79%),
compared to 23% for managed diabetics and 43% for non-diabetics. These results strongly
imply that the severity of PTB symptoms on CT scans is significantly influenced by glycemic
management rather than just being a diabetic. Patients with uncontrolled diabetes had
noticeably worse symptoms, most likely as a result of worsening damage to their medium-
sized airways: In order to prevent severe radiologic symptoms in diabetic individuals with
PTB, this research emphasizes the importance of strict glycemic control.

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13. Yoon, Y. S., Jung, J. W., Jeon, E. J., Seo, H., Ryu, Y. J., Yim, J. J., Kim, Y. H., Lee, B. H.,
Park, Y. B., Lee, B. J., Kang, H., & Choi, J. C. (2017). The effect of diabetes control
status on treatment response in pulmonary tuberculosis: a prospective
study. Thorax, 72(3), 263–270. https://doi.org/10.1136/thoraxjnl-2015-207686
In a multicenter prospective study performed from September 2012 to September 2014:
researchers analyzed the effect of diabetes management status on both the clinical symptoms
and treatment outcomes in the patients with Pulmonary tuberculosis (PTB). This study
categorized 661 PTB patients into three unique categories which is based on their glycated
hemoglobin (HbA1C) level. First one, those without diabetes (non-DM), Second one,
patients with managed diabetes (controlled-DM), and the last one those with uncontrolled
diabetes (uncontrolled-DM). Notably, a considerable majority of diabetic patients
approximately 68.8% fell into the uncontrolled-DM category: characterized by a HbA1C
level of 7.0% or above: The results described that individual with uncontrolled diabetes
demonstrated a greater prevalence of severe symptoms, positive sputum smears, and cavity
presence compared to their non-diabetic counterparts. Furthermore, these people were
considerably more likely to retain a positive sputum culture following two months of intense
TB treatment: suggesting a reduced response to medication. The rate of treatment failure or
mortality was similarly raised in the uncontrolled-DM group: placing uncontrolled diabetes
as a powerful independent risk factor for unfavorable outcomes in PTB. Conversely,
individuals with managed diabetes displayed treatment responses comparable to those
reported in non-diabetic patients: underlining the essential role of efficient diabetes
management in fighting PTB. These findings underscore the importance for tight glucose
management among diabetic patients having therapy for PTB, to optimize treatment
effectiveness and improve prognosis outcomes.

14. Yorke, E., Atiase, Y., Akpalu, J., Sarfo-Kantanka, O., Boima, V., & Dey, I. D. (2017). The
Bidirectional Relationship between Tuberculosis and Diabetes. Tuberculosis research
and treatment, 2017, 1702578. https://doi.org/10.1155/2017/1702578
Despite intense attempts to control tuberculosis (TB), particularly in poorer nations, the
burden of this illness remains stubbornly high. Traditional risk factors such as poverty,
malnutrition, overcrowding, and HIV/AIDS are well-known, but accumulating research

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shows that diabetes, with its immunosuppressive effects, is becoming recognized as an

independent risk factor for TB. This bidirectional relationship between the two disorder
mainly complicates the treat outcome and increase the disease severity. Moreover, TB itself,
along with certain anti-TB drugs, can affect glucose metabolism. Mechanistically, the higher
vulnerability of diabetic patients to TB is linked to: 1. Decreased cellular immunity, 2.
Malfunctioning macrophages, and 3. Poor chemotaxis of monocytes. Conversely, the stress
response to the TB infection may promote dysglycemia, mediated by pro-inflammatory
cytokines. Studies have indicated a substantial relationship between TB and impaired glucose
tolerance (IGT) or diabetes, with some individuals showing regression post-treatment.
However, TB can also directly alter glucose metabolism: leading to pancreatitis and
pancreatic endocrine hypofunction. Notably, whereas malnutrition is typically highlighted as
a risk factor for infections and dysglycemia, body mass index does not seem to link with IGT
or diabetes in this setting. This analysis underlines the complicated connection between TB
and diabetes, advising doctors and public health managers to develop screening and
management measures for people with these overlapping illnesses. Further mechanistic
research are necessary to unravel these complicated connections thoroughly.

15. Jeon, C. Y., & Murray, M. B. (2008). Diabetes mellitus increases the risk of active
tuberculosis: a systematic review of 13 observational studies. PLoS medicine, 5(7), e152.
https://doi.org/10.1371/journal.pmed.0050152
Several research investigations show that diabetic mellitus (DM) improves the probability of
getting active tuberculosis (TB), a worry especially noteworthy in locations where both
diseases are widespread. This link might possibly impede TB control efforts if the incidence
of DM grows. To address this, a systematic review and meta-analysis were done, examining
data from 13 observational studies containing approximately 1.7 million people and 17,698
TB cases. The study found that those with DM were almost three times more likely to get TB
compared to those without DM, as demonstrated by the pooled relative risk of 3.11 from
cohort studies. However, case-control studies found considerable range, with odds ratios
ranging from 1.16 to 7.83, suggesting some discrepancies among research. Particularly,
research outside of North America found greater risk estimations. These findings underline
the significance of targeting persons with DM for TB intervention techniques, such as

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proactive case identification and treatment of latent TB. Additionally, increasing the
diagnosis and management of DM might substantially benefit TB reduction efforts
internationally.

16. Singla, R. et al., 2006. Influence of diabetes on manifestations and treatment outcome of
pulmonary TB patients. The international journal of tuberculosis and lung disease: the
official journal of the International Union against Tuberculosis and Lung Disease, 10(1),
74–79.
A retrospective study was conducted at a referral hospital in Saudi Arabia in which the
records of 692 patients with smear positive pulmonary tuberculosis were analyze to assess
and evaluate the impact of diabetes on clinical progression and bacteriological aspects. There
were total 692 consecutive smear-positive PTB patients who were categorized into two
group: comparing 187 individuals with diabetes (PTB-DM group) to 505 without (PTB
group). Results indicated PTB-DM patients had a larger prevalence of many acid-fast bacilli
(AFB) on sputum smear examination (65.2% vs. 54.1%, p = 0.008) and lesser medication
resistance (6.4% vs. 16.0%, p = 0.007) among new cases. Additionally, PTB-DM patients
obtained somewhat better sputum conversion rates after 3 months of therapy (98.9% vs.
94.7%, p = 0.013). However, end treatment results (cured/treatment finished, failure, death,
default) were comparable between groups (p = 0.7005). In conclusion, whereas PTB-DM
patients display larger pre-treatment bacillary loads and better initial treatment responses, the
presence of diabetes does not influence the overall treatment results in PTB patients.
17. Rehman, A. U. et al., 2023. The impact of diabetes mellitus on the emergence of multi-
drug resistant tuberculosis and treatment failure in TB-diabetes comorbid patients: a
systematic review and meta-analysis. Frontiers in public health, 11, 1244450.
https://doi.org/10.3389/fpubh.2023.1244450
A systematic analysis was performed based on thirty publications which was gathered from
the PubMed database up to 3rd April of 2022. It was found the impact of Type 2 Diabetes
Mellitus (DM) on the establishment of multi-drug resistance tuberculosis (MDR-TB) and
treatment outcomes in patients with concomitant tuberculosis (TB) and diabetes. The
research showed: the patients with both Tuberculosis and Diabetes Mellitus are at a greatly
enhanced risk of obtaining MDR-TB (with a hazard ratio (HR) of 0.81 and a confidence

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interval (CI) of 0.60-0.96,): exhibited a larger prevalence compared to TB patients without

diabetes. The variability among the studies was moderate (I2 = 38%). Further, subgroup
analysis by study design validated: these findings (HR 0.81, CI: 0.61-0.96). In terms of
treatment outcomes, diabetic TB patients also faced a greater probability of treatment failure:
with a hazard ratio of 0.46 and a confidence range of 0.27-0.67. These results underline the
crucial need for early screening for MDR-TB, ongoing monitoring, and the creation of
individualized treatment strategies for TB patients with diabetes to decrease the risk of
disease progression and increase treatment effectiveness.
18. Kakisingi, C., Mwamba, C., Kasongo Muteba, M., Kasamba, E., Kabamba, M., Tanon,
A., & Situakibanza, H. (2024). Prevalence and Associated Factors of Diabetes Mellitus
Among Newly Enrolled Tuberculosis Patients in Lubumbashi (DRC). Risk management
and healthcare policy, 17, 171–180. https://doi.org/10.2147/RMHP.S436873
A cross-sectional study was carried out at 11 TB screening and treatment facilities in
Lubumbashi, DRC, from September to December 2022: to analyze the prevalence of diabetes
mellitus among tuberculosis patients and identify relevant variables. 255 adult patients who
tested positive for TB by smear testing was involved in the study. These individuals were also
analyzed and assessed for diabetes mellitus, and demographic data, medical histories:
symptom reports were gathered and analyzed using Microsoft Excel and STATA 16 software.
The data suggested that 11.4% of these TB patients, namely 29 people, were also suffering
from diabetes mellitus. Factors such as a body mass index (BMI) of 18.5 kg/m^2 or lower,
unemployment, polyuria, and severe thirst were strongly related with the incidence of
diabetes in these individuals. This rate of diabetes prevalence is substantially greater than the
rates normally reported in Central Africa, showing to a considerable connection between TB
and diabetes in this demographic, which might identify focused areas for intervention to
address both health concerns successfully.

19. Zhao, L., Gao, F., Zheng, C., & Sun, X. (2024). The Impact of Optimal Glycemic
Control on Tuberculosis Treatment Outcomes in Patients with Diabetes Mellitus:
Systematic Review and Meta-Analysis. JMIR public health and surveillance, 10, e53948.
https://doi.org/10.2196/53948

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This study aims to evaluate the impact of glycemic control on tuberculosis (TB) treatment
outcomes in patients with diabetes mellitus (DM). Utilizing databases such as MEDLINE,
Embase, and the Cochrane Central Register of Controlled Trials, the research focused on
randomized controlled trials that examined the effects of oral glycemic control in TB patients
with DM. Key outcomes assessed included radiological findings, treatment success, sputum
positivity, and mortality, analyzed through risk ratios (RRs) with 95% confidence intervals
(CIs) using a weighted random-effects model. The meta-analysis included data from 6919
patients across seven observational studies, highlighting significant improvements in
treatment outcomes for patients with optimal glycemic control compared to those with poor
control (RR 1.13, 95% CI 1.02-1.25; P=.02; I²=65%). Additionally, optimal control was
associated with a notable reduction in sputum positivity (RR 0.23, 95% CI 0.09-0.61;
P=.003; I²=66%) and fewer cavitary lesions in radiological findings (RR 0.59, 95% CI 0.51-
0.68; P<.001; I²=0%). However, the study found no significant differences in mortality rates
between the two groups (RR 0.57, 95% CI 0.22-1.49; P=.25; I²=0%), and similar findings
were observed in terms of multilobar, upper lobe, and lower lobe involvement in radiological
examinations. The conclusions drawn from the study emphasize the importance of optimal
glycemic control in reducing susceptibility to TB, minimizing complications, and enhancing
treatment outcomes for TB patients with DM. The findings advocate for integrated care and
effective health management strategies to achieve better glycemic control, thereby improving
patient outcomes and reducing the disease burden among this demographic.

20. Feng, Y. Y., Wang, Z., & Pang, H. (2023). Role of metformin in inflammation. Molecular
biology reports, 50(1), 789–798. https://doi.org/10.1007/s11033-022-07954-5
Metformin, which is mostly known for managing type 2 diabetes well without resulting in
hypoglycemia, has drawn interest lately for its advantages, including its anti-inflammatory
effects. It shows anti-inflammatory effect. Its possible uses for treating inflammatory
illnesses are now being investigated more thoroughly. Metformin's anti-inflammatory
processes are highlighted in a thorough evaluation of pertinent material from PubMed; which
may provide novel therapy options for diseases including rheumatoid arthritis and
neuroinflammation. It shows its effect in RA and neuroinflammation. Moreover, as
inflammation is essential to the formation and development of tumors, metformin may

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potentially be helpful in the prevention and treatment of cancer by means of focused anti-
inflammatory therapies. Significant reduction of p65 nuclear translocation is one of the
effects of the medication; yet, compound C, an AMPK inhibitor, or silencing HMGB1, which
is known to suppress NF-κB activation, can offset this effect. Metformin also effects the
mTOR pathway in dendritic cells. It controls FoxO1 via AKT. It also controls the
deacetylation of FoxO by SIRT1 that increases its transcriptional activity. 'These molecular
connections emphasize the intricacy of inflammatory processes and imply that a better
knowledge of these pathways may improve the effectiveness of metformin in the treatment of
inflammatory and cancer-related disorders.

21. Restrepo B. I. (2016). Metformin: Candidate host-directed therapy for tuberculosis

in diabetes and non-diabetes patients. Tuberculosis (Edinburgh, Scotland), 101S, S69–
S72. https://doi.org/10.1016/j.tube.2016.09.008
The bacterium Mycobacterium tuberculosis, which causes tuberculosis, has evolved complex
ways to avoid detection by the human immune system: using various tactics to survive in
host cells and hinder immune responses. It leads to worsen disease symptoms. It also causes
tissue destruction. These changes reduce the efficiency of traditional antibiotic therapies. It
also play a role in the development of multi drug resistant TB strains . Recent developments
in TB treatment have shifted towards host-directed therapies (HDTs) to combat with the
bacteria. Different drugs such as metformin shows host directed effect. These therapeutic
approaches aim to enhance the effectiveness of current antibiotics, possibly shorten the
duration of treatment for all types of TB, encourage the formation of lasting immune memory
to prevent future relapses, and alleviate the harmful immunopathological effects like tissue
damage and fibrosis linked to TB. This overview showcases a number of potentially effective
TB-HDT candidates that have shown clinical importance and may be advanced to reduce the
harmful and enduring impacts on lung performance resulting from the illness. The
information presented here is derived from research results released in 2020 from the
Pathological Society of Great Britain and Ireland and distributed by John Wiley & Sons, Ltd.

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22. Restrepo B. I. (2016). Metformin: Candidate host-directed therapy for tuberculosis

in diabetes and non-diabetes patients. Tuberculosis (Edinburgh, Scotland), 101S, S69–
S72. https://doi.org/10.1016/j.tube.2016.09.008
Although there have been tremendous breakthroughs in the management of tuberculosis
(TB), TB nevertheless remains one of the top causes of mortality globally. Efforts to find
novel medications for both drug-sensitive and drug-resistant forms of TB continue, with the
added research of host-directed therapies (HDTs) to strengthen these endeavors. 'HDTs aim
towards increasing the immune system's capacity to control or eliminate Mycobacterium
tuberculosis (Mtb) by regulating immunological responses and minimizing excessive
inflammation, thereby averting major lung injury and restricting bacterial development.'
Metformin, a routinely recommended medicine for treating type 2 diabetes; has become a
promising choice for these therapies. Initial study shows that metformin may be a crucial
component in treating TB by lowering harmful inflammation associated with immunological
responses and boosting the ability of immune cells to fight off infections. 'This review looks
at the most recent studies on using metformin as a supplemental treatment for TB, points out
areas where we still need more knowledge, and analyzes the benefits and items to think about
when taking metformin for both diabetic and non-diabetic TB patients.' The research implies
that metformin has two advantages: managing blood glucose in diabetic patients and perhaps
boosting TB control through immune system effects, making it an essential element of full
TB care strategies.

23. Cubillos-Angulo et al., (2022). Host-directed therapies in pulmonary tuberculosis:

Updates on anti-inflammatory drugs. Frontiers in medicine, 9, 970408.
https://doi.org/10.3389/fmed.2022.970408
Tuberculosis (TB), one of the deadliest infectious diseases globally, is a major cause of death
and continues to offer considerable problems due to its ability for generating severe
morbidity from continuous inflammation and tissue damage. Standard therapy for pulmonary
TB entails a protracted regimen of numerous medications, lasting ranging from six months
for drug-susceptible strains to up to 20 months for multi-drug resistant variants. These
extended durations, along with the unpleasant side effects of the therapy, typically lead to
poor patient compliance, which in turn contributes to unsatisfactory treatment success rates

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and limits successful TB control efforts. In response to these problems, a novel method
known as host-directed treatment (HDT) is gaining favor. HDT attempts to increase TB
treatment by targeting the host's immunological response to the infection Mycobacterium
tuberculosis; working in concert with standard antimycobacterial medications. This technique
promises to not only cut the treatment period but also enhance overall cure rates and limit
lingering harm to lung tissue. The current analysis dives into the possible advantages and
hurdles involved with the development and deployment of HDTs; emphasizing the progress
of several drugs that have either finished clinical trials or are now undergoing assessment.
This technique represents a promising development in the battle against TB, seeking to
maximize therapeutic results through a more focused and efficient treatment strategy.
24. Cubillos-Angulo et al., (2022). Host-directed therapies in pulmonary tuberculosis:
Updates on anti-inflammatory drugs. Frontiers in medicine, 9, 970408.
https://doi.org/10.3389/fmed.2022.970408
Mycobacterium tuberculosis (Mtb); known to grow rapidly in cholesterol-rich settings; uses
cholesterol from the macrophage membrane for cell entrance and nourishment, 'resulting to
lipid body buildup and the production of foamy cells that enable bacterial growth and
survival. These cells also display traits such as reduced Mtb development, drug resistance,
and delayed phagosome maturation due to elevated IL-10 production. 'In this context, statins,
which are commonly used cholesterol-lowering medicines, show potential for host-directed
treatment (HDT) against tuberculosis (TB). Statins block the enzyme 3-hydroxy-3-
methylglutaryl coenzyme reductase (HMG-CoA) and not only lower cholesterol production
but also contain anti-inflammatory and immunomodulatory activities.' Research shows that
statins can prevent the production of foamy cells, improve phagosome maturation and
autophagy, enhance natural killer T (NKT) cell percentages and co-stimulatory molecule
expression on monocytes; and suppress TGF-β. Notably, animal studies have revealed that
statins can lower Mtb dissemination in the lungs, boost macrophage bactericidal activity, and
perhaps shorten TB treatment duration when paired with traditional anti-TB medicines.
Retrospective studies, particularly in places like Taiwan and South Korea, show that statin
users had a decreased chance of contracting TB, however findings are yet to be substantially
repeated and there are worries about potential confounding variables. Ongoing clinical
research attempt to elucidate the function of statins in TB therapy further. 'Metformin,

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another medicine with promise against TB, is mostly used in treating type 2 diabetes but is
deemed safe for general usage. Its method against TB involves enabling phagosome-
lysosome fusion and activating AMPK, which assists in regulating energy under stress and
may accelerate the formation of reactive oxygen species to kill Mtb; Studies in TB-infected
mice have revealed that metformin can inhibit bacterial growth, boost the efficiency of TB
medicines, and relieve lung damage and inflammation. However, its specific role,
particularly in sterilizing Mtb, remains unclear because to inconsistent results from numerous
research, probably due to different TB medications utilized or the experimental animals.'
Additionally, metformin appears to promote the efficacy of Mtb-specific CD8+ T cell
responses and may enhance the immunogenicity of the BCG vaccination. 'Observational
studies in diabetic patients show that metformin usage during TB therapy is connected with
superior results including quicker sputum conversion, decreased mortality, and reduced TB
recurrence rates compared to other diabetes medications.' Current clinical trials are
evaluating metformin's usefulness as a supplementary medication in TB treatment. Together;
both statins and metformin offer substantial promise as supplementary therapy in TB,
emphasizing a need for future clinical trials to examine and confirm their advantages
completely.

25. Tiwari, D., & Martineau, A. R. (2023). Inflammation-mediated tissue damage in

pulmonary tuberculosis and host-directed therapeutic strategies. Seminars in
immunology, 65, 101672. https://doi.org/10.1016/j.smim.2022.101672
Treatment of tuberculosis (TB) entails the use of anti-mycobacterial medicines for several
months. The advent of drug-resistant strains of Mycobacterium TB (Mtb, the causative agent)
along with increasing disease severity in persons with co-morbidities such as diabetes
mellitus and HIV have impeded attempts to lower case mortality. In severe illness, TB
pathogenesis is mostly attributed to over-exuberant host immune responses aiming at
suppressing bacterial reproduction. Non-resolving inflammation induced by host pro-
inflammatory mediators in response to high bacterial load leads to lung disease including
cavitation and fibrosis. The aim to enhance clinical outcomes and minimize treatment times
has led to a two-pronged strategy combining the development of new antimicrobials as well
as host-directed treatments (HDT) that positively regulate immune responses to Mtb. HDT

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techniques integrate components of immune regulation targeted at downregulating non-

productive inflammatory responses and enhancing antimicrobial effector mechanisms to
reduce lung damage and hasten symptom recovery. HDT in conjunction with current
antimycobacterial medications presents a potentially beneficial technique to enhance the
long-term result for TB patients. In this review, we identify components of the host immune
response that contribute to inflammation and it causes tissue damage in pulmonary TB which
includes cytokines, matrix metalloproteinases, lipid mediators, and neutrophil extracellular
traps. We next proceed to examine HDT directed targeting these routes.

26. Lachmandas et al., (2019). Metformin Alters Human Host Responses to Mycobacterium
tuberculosis in Healthy Subjects. The Journal of infectious diseases, 220(1), 139–150.
https://doi.org/10.1093/infdis/jiz064
Research is being conducted on Metformin, a common diabetes medication, to possibly use it
as an extra treatment for tuberculosis due to its host-targeted traits. Studies utilizing both
controlled experiments in a lab setting and trials involving live animals have demonstrated
that metformin significantly impacts the immune system's reaction to Mycobacterium TB in
humans. During lab experiments, metformin boosted cellular metabolism and blocked mTOR
targets p70S6K and 4EBP1 in PBMCs of healthy people. This resulted in decreased cytokine
secretion and cell proliferation, while enhancing phagocytic function. Similarly, tests
conducted on healthy human volunteers revealed that treatment with metformin resulted in a
reduction in genes associated with oxidative phosphorylation, mTOR signaling, and type I
interferon response pathways after being exposed to M. tuberculosis. Genes responsible for
phagocytosis and the synthesis of reactive oxygen species were observed to be expressed at
higher levels. So, it shows significant effect. Moreover; metformin caused a change in
myeloid cells from classical to nonclassical monocytes. In functional terms; this led to a
reduction in the production of important inflammatory cytokines like tumor necrosis factor α,
interferon γ, and interleukin 1β, along with an increase in phagocytosis and reactive oxygen
species formation. Additionally, these results indicate that metformin has many positive
impacts on both cellular metabolism and the immune response to TB infection.

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27. Sutter, A., Landis, D., & Nugent, K. (2024). Metformin has immunomodulatory effects
which support its potential use as adjunctive therapy in tuberculosis. The Indian
journal of tuberculosis, 71(1), 89–95. https://doi.org/10.1016/j.ijtb.2023.05.011
Metformin, often given for type 2 diabetes mellitus due to its skills in decreasing blood
glucose levels and boosting insulin sensitivity, also has immunomodulatory qualities. It
might be advantageous in controlling numerous autoimmune and infectious disorders;
including TB. This widespread illness continues to be a worldwide health issue, partly
because of Mycobacterium tuberculosis's capacity to escape the immune system. The study
investigates metformin’s possible involvement in modulating both innate and adaptive
immune responses crucial for battling Mycobacterium TB, establishing it as a viable
supplementary medication in tuberculosis treatment. Research analyzed that metformin
facilitates autophagy and phagocytosis and also it enhances the generation of reactive oxygen
species (ROS)in mitochondria, and it caused excessive inflammation and tissue damage.
Additionally; it enhances cellular immune activities by preserving CD8+ T cell metabolic
balance. It also helps in improving immunological memory. Evidence from multiple mouse
models demonstrates that metformin can lessen the severity and tissue damage caused by TB.
Furthermore, two human in vitro investigations have shown that metformin administration
increases immunological responses. Collectively, these data underline the therapeutic
potential of metformin in boosting immunological responses against TB.

28. Sutter, A., Landis, D., & Nugent, K. (2024). Metformin has immunomodulatory effects
which support its potential use as adjunctive therapy in tuberculosis. The Indian
journal of tuberculosis, 71(1), 89–95. https://doi.org/10.1016/j.ijtb.2023.05.011
The development of a quantitative systems pharmacology (QSP) model concentrating on the
host immunological response to Mycobacterium TB marks a significant leap in
understanding and devising host-directed treatments (HDTs). It shows the effect of
metformin in tuberculosis when is used with other anti TB drugs. Specifically, the model
analyzes the ability of metformin to trigger autophagy when taken alongside antibiotics,
presenting a fresh method in treating TB. This QSP model integrates AMPK-mTOR-
autophagy signaling pathways with current pharmacokinetic and pharmacodynamic models
for metformin and antibiotics; thereby offering a complete framework to research their

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combined effects. Validation against experimental data from mice infected with M.
tuberculosis indicated that the model accurately reflects the observed dynamics of bacterial
load following metformin therapy. Further simulations reveal that while metformin’s
involvement in lowering intracellular bacterial load is moderate and dose-dependent, it is
most visible when the total bacterial load is low, particularly towards the end of the antibiotic
treatment course. This pioneering concept not only elucidates the cellular processes behind
the efficiency of metformin as an additional treatment but also offers a vital tool for future
design and development of HDTs targeted at treating TB.

29. Mehta K, Spaink HP, Ottenhoff THM, van der Graaf PH, van Hasselt JGC. Host-
directed therapies for tuberculosis: quantitative systems pharmacology approaches.
Trends Pharmacol Sci. 2022 Apr;43(4):293-304. doi: 10.1016/j.tips.2021.11.016. Epub
2021 Dec 13. PMID: 34916092.
HDTs show potential in addressing Mtb infections by altering host-pathogen interactions.
When combined with traditional tuberculosis (TB) drugs, HDTs have the ability to improve
the effectiveness of treatment, shorten the duration of treatment, and reduce the development
of drug resistance. Yet, translating the intricate host-pathogen interactions targeted by HDTs
into measurable therapeutic advantages proves to be quite difficult. In order to tackle this
challenge, it is crucial to create a quantitative understanding of the complex relationship
between the host and Mtb. Comprehending this is crucial for the logical planning of HDT
strategies. This article presents a summary of important interactions between Mtb and the
host immune system for the development of HDT, along with a discussion on how QSP
models can guide HDT strategies. QSP models are a useful tool for pinpointing and
enhancing treatment goals, aiding in the transition from preclinical research to human trials,
and creating efficient combination treatment plans.

30. Hawn TR, Shah JA, Kalman D. New tricks for old dogs: countering antibiotic
resistance in tuberculosis with host-directed therapeutics. Immunol Rev. 2015
Mar;264(1):344-62. doi: 10.1111/imr.12255. PMID: 25703571; PMCID: PMC4571192.
Despite having treatments available for over 50 years, tuberculosis caused by Mycobacterium
tuberculosis still remains widespread, and the rise of drug-resistant strains emphasizes the

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critical requirement for new treatment approaches. An encouraging strategy involves the
creation of host-directed therapeutics (HDTs) that focus on changing the host's biological
pathways instead of directly attacking the pathogen. These treatments provide possible
advantages like lower chance of resistance, ability to work against strains that are resistant to
drugs, and effectiveness in various stages of TB, even in individuals with HIV co-infection.
HDTs can be classified into two main groups: ones that disrupt Mtb pathogenesis in
macrophages and immunomodulatory HDTs that boost protective immune responses or
reduce harmful ones. HDTs can hinder the bacillus from taking advantage of host cell
processes or boost the body's defense against infection by regulating autophagy, lipid and
sugar metabolism, and inflammatory responses. Even though tuberculosis is complex and
immune responses vary among populations, a thorough understanding of HDT mechanisms,
along with careful dosing and stage-specific treatment selection, could help overcome these
obstacles. Some HDTs have shown encouraging outcomes and safety records, with a few
adapted from existing approved applications. These treatments play a key role in fighting TB
when traditional drugs are ineffective because of resistance, as well as being able to work
together with existing antibiotics. Furthermore, the merging of HDTs with regular antibiotic
therapies may be essential, particularly in cases of multi-drug-resistant (MDR) tuberculosis,
where conventional approaches are ineffective. While certain HDTs are prepared for human
trials, others may need additional animal testing to improve dosing and safety. However, the
distinctive characteristics of HDTs make them feasible additional treatments that could
greatly improve TB treatment and patient results.

31. Sutter, A., Landis, D., & Nugent, K. (2024). Metformin has immunomodulatory effects
which support its potential use as adjunctive therapy in tuberculosis. The Indian
journal of tuberculosis, 71(1), 89–95. https://doi.org/10.1016/j.ijtb.2023.05.011
Mycobacterium tuberculosis infection is still a major global health problem. Even with
attempts to lessen the effects of tuberculosis on human health, advancements have been
limited, emphasizing the requirement for better approaches in diagnosing, preventing, and
treating to successfully reduce the disease's transmission. Current studies are concentrating
on creating ways to stop Mtb infection and spread, detect asymptomatic carriers, and
improve the effectiveness of antimicrobial drugs. Yet, progress is limited by a lack of

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comprehension of the causes of early infection and the elements that impact the host's
vulnerability, immune defense, and the development of the disease. An increasing interest
exists in researching additional treatments that could strengthen the body's reaction to Mtb
infection, thereby improving the effectiveness of current and upcoming drug therapies. This
review explores the current understanding of how hosts respond to Mtb infection in humans
and animal models, focusing on possible treatment targets within the TB granuloma
formation. The goal is to change the balance of granuloma formation to favor protective
outcomes over destructive ones. Granuloma formation, typically seen as a way to contain the
spread of the tubercle bacillus, might also worsen the disease and help spread the infection,
ultimately hindering antimicrobial therapy. Novel treatment strategies can be developed by
understanding how Mtb infection causes irreversible tissue damage, suppresses immune
responses, and slows down tissue repair. Specifically, therapies focused on treating
granulomas offer a chance to use current medications for different illnesses as additional
treatments to improve anti-TB treatments. This review highlights the importance of
conducting more thorough pre-clinical animal studies and clinical trials to investigate host-
directed therapies further, indicating that utilizing approved drugs could greatly improve TB
treatment and prevention efforts.

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Chapter:4
LITERATURE REVIEW

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1. Bidirectional relation between Diabetes and Tuberculosis:

There is a bidirectional relationship between TB and diabetes, and they both impact the
presentation of each other. Diabetes is being increasingly recognized as a risk factor for
TB and may affect its presentation, whilst TB may worsen glycaemic control or lead to
IGT among TB patients.
1.1. Diabetes as a Risk Factor for TB:
Various studies indicate that diabetes raises the risk of tuberculosis by nearly
threefold. Even though type 2 diabetes is more common globally, the likelihood of
developing tuberculosis is significantly increased in individuals with type 1 diabetes,
with a three to five times higher risk attributed to poorer management, lower weight,
and younger age of those impacted. Diabetes raises the likelihood of a negative
outcome, including failure, death, and relapse, in TB patients.
There are multiple variables which increase the risk of TB in individuals with
diabetes, and several possible mechanisms have been given. The decreased amount of
T-lymphocytes lower neutrophil counts and function can hamper the cellular
immunity Diminished cellular immunity. Individuals with diabetes show reduced
levels of T-helper 1 (TH 1) cytokine response, tumor necrosis factor (TNF-alpha and
TNF-beta), interleukin-1, and interleukin-6 production when it is compared to those
without diabetes. In particular, the suppression of TH1 cytokines is effective against
Mycobacterium tuberculosis

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In diabetes, there is a malfunction in macrophages that leads to reduced ability to

produce reactive oxygen species and perform phagocytosis and chemotaxis.
Chemotaxis of monocytes is also dysfunctional in diabetic patients, and this issue
remains unresolved even with insulin treatment. It is believed that hyperglycemia can
also hinder the ability of the respiratory burst to push out pathogens.
1.2. TB as a Risk Factor for Diabetes:
While the bidirectional relationship between diabetes and TB has long been
recognized, dedicated studies to evaluate whether TB increases the risk of diabetes
are few.
The stress response to infection may also play a role in dysglycemia, a situation
mediated by the impact of interleukin1 (IL-1), interleukin-6 (IL-6), and TNF-alpha. It
can increase the insulin resistance and glucose generation. It can too worsen the
glucose control within the patients who are as of now existing with diabetes. TB can
moreover cause to Impaired Glucose Tolerance (IGT) or even new-onset diabetes in
people who did not have diabetes. Moreover, the treatment of TB, especially with
drugs like rifampicin, can associated with diabetes medicine and it can complicate
glycemic control. On the other hand, TB may cause TB pancreatitis as well as
pancreatic endocrine hypofunction which may lead to IGT or new onset diabetes or
worsen its control. TB pancreatitis may gotten to be obvious as it were after the
individual develops diabetes. In conclusion, while malnutrition has been proposed as
a risk factor for infections and dysglycemia, body mass index has not been related
with IGT or diabetes.

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2. Mechanism of Action of Metformin in TB:

Metformin increases both protective and pathogenic immunity and by enhancing TB
host-specific immunity, reducing disease severity and improving treatment results. HDT
for TB serves to decrease the duration of therapy of drug-sensitive TB and to enhance the
treatment result in MDR-TB by retaining the natural lung composition. The mechanisms
of action of antidiabetic medication metformin in the treatment of TB are discussed
below:
2.1. ROS production:
Metformin can limit the development of Mycobacteria through the induction of
mitochondrial generation of reactive oxygen species (ROS) with the help of activated
protein kinase (AMPK) activation. MET was found to modulate the host's innate
immune response including MET-induced increases in whole-blood reactive oxygen
species (ROS) generation and strong upregulation of genes which are responsible for
ROS generation. MET limits bacterial development by increasing the generation of
ROS. ROS are known to promote naive T cell proliferation and play a major
significant role in modulating the development and effector functions of different T
lymphocyte subsets.
2.2. Autophagy:
Metformin helps within the initiation of the method of autophagy of Mtb-infected
macrophages, by any means (physiological, immunological, or pharmacological) may
kill Mtb microscopic organisms. “Autophagy is an immune mechanism of our
body which helps to control inflammation and acts as a cell-autonomous protection
against intracellular organisms, including Mtb”. Metformin has proved to initiate and
promote autophagy in macrophages, phagocytosis, phagolysosome and subsequently
help in the killing of TB bacterium.

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In a few patients, the levels of microtubule-associated Protein 1 light chain 3B

(MAP1LC3B), superoxide dismutase (SOD), and interferon was measured and it was
watched that the levels were increased in a few of the patients with both TB and T2D.
This group observed an increased MAP1LC3B, SOD, and interferon before and after
MET treatment. This is often vital since MAP1LC3B could be a key protein
representing autophagy; SOD is a vital antioxidant that's moreover thought to
improve the bactericidal impacts of isoniazid, and interferon-gamma levels are known
to play a critical part in autophagy.
2.3. Anti-inflammatory effect:
2.4. TB patients who are treated with Metformin have a lesser number of pulmonary
cavities, and they were less likely to die as compared to those patients who were not
treated with Metformin.
Matrix metalloproteases (MMPs), a family of enzymes with proteolytic effcet and
cell recruiting action; contribute to lung tissue damage and disease severity in
tuberculosis.

FIGURE 2 | The effect of metformin on macrophage function and clinical outcomes. Studies labelled A, C, F, G, H, I, and J represent
the effect of metformin on respective clinical outcomes. These include reduced mortality, 2-month culture conversion and toxicity, and
improved glycaemic control. Studies B and L: outcome 1 show the effect of metformin on tumour necrosis factor (TNF)-α and
interferon γ. TNF-α acts together with interferon γ, causing the production of reactive nitrogen intermediates and facilitating the
tuberculostatic function of macrophages and the migration of immune cells to the infection site, contributing to granuloma formation.
Study C shows metformin to increase macrophage reactive oxygen species (ROS) production. Evidence suggests that macrophage-
produced ROS is responsible for increasing macrophage microbicidal activity by directly killing bacteria (Tan et al., 2016). This study
is not part of the inclusion criteria. Study K observes metformin increases superoxide dismutase (SOD) and microtubule-associated
proteins 1A/1B light chain 3B (MAP1LC3B). Mycobacterium tuberculosis (Mtb) binds the pattern recognition receptor (PRR) on the
macrophage which initiates phagocytosis. Superoxide dismutase (SOD) (produced as a by-product of oxygen metabolism within cells)
enables clearance of bacteria and restricts inflammation in response to infection by encouraging bacterial phagocytosis, and
MAP1LC3B is representative of autophagy while SOD induces autophagy. Study L: outcome 2 shows metforminPage: to increase 41
lactateof 48
production within cells. Lactate is formed in large quantities by innate immune cells during inflammatory activation. Lactate
modulates the immune cell metabolism which translates to decreased inflammation and ultimately functions as a negative feedback
signal to avoid unwarranted inflammatory responses. Study L: outcome 3 observed a macrophage-targeting mechanism for the anti-
inflammatory effects of metformin via polarization.
 Guru Nanak Institute of Pharmaceutical Science and Technology

MMPs may contribute to pulmonary cavitation in tuberculosis, which is

mainly related with a increased bacillary burden, delayed sputum culture conversion,
and the occurance of drug resistance in case of TB. Metformin treatment brings down
systemic MMP-1, -2, -3, -7, -9 and -12 levels in diabetic patients with tuberculosis
and might possibly diminish MMP-mediated tissue damage in tuberculous patients
without DM (24). Moreover, patients with diabetes and tuberculosis have higher
levels of systemic monocyte activation markers, including soluble cluster of
differentiation 14 (sCD14), soluble CD163 (sCD163), soluble tissue figure (sTF), and
C-reactive protein (CRP), demonstrating expanded inflammatory reactions of
monocytes and macrophages contributing to tissue damage and development of
pulmonary disease A few studies which shows that sCD14 and sCD163 levels were
higher in diabetic patients with bilateral versus unilateral disease and cavitary versus
non-cavitary disease and thus are related with expanded disease severity and bacterial
burden. In diabetic patients on metformin treatment, the levels of sCD14, sCD163,
and CRP were essentially diminished compared to those not on metformin. By
balancing monocyte activation, metformin has an anti-inflammatory impact that may
help diminish disease severity in these patients. These propose that Metformin can be
recognized as an successful drug to treat active TB in conjunction with the standard
line of anti-microbial drugs.
2.5. Inhibition of mycolic acid synthesis:

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Anti-microbial targets and hinders mycolic acid biosynthesis which is the key
component of bacterial cell wall synthesis. Systems-level changes attribute to the
diminished flux carrying capacity of glycolysis as well as the citric acid cycle.
Metformin targets NDH-I and promotes the rerouting of metabolic fluxes via the de
novo NAD biosynthesis pathway and electron transport.
Above figure shows the effect of Metformin while using along with anti-TB drugs.
Metformin targets NDH-I and advances the rerouting of metabolic fluxes through the
de novo NAD biosynthesis pathway and electron transport. Above figure
demonstrates the impact of Metformin whereas using alongside anti-TB drugs.
Metformin, through nicotinamide adenine dinucleotide (NAD) de novo biosynthesis
pathway, reroute metabolic flux. Thus, it reduces the method of glycolysis and citric
acid cycle within the pathogens. Other than this, systems-level changes and resulting
hindrance of mycolic acid synthesis by mycobacterium happens. basically, anti-TB
drugs target mycolic acid biosynthesis and the combination of Metformin with these
drugs favors this mechanism.
2.6. Other mechanisms:
 Metformin moreover inhibits mitochondrial complex 1 which leads to the
inhibition of energy generation, which is required for the development of microscopic
organisms.

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 Metformin has an anti-folate impact and this makes a difference to inhibit the folate
cycle of microscopic organisms.
 Metformin helps in the development of Mtb-specific IFN secreting CD8+ T cells
which demonstrated that Metformin has an effect on the immune cells of the lungs.
Cytotoxic T cells and CD4+ cells in human control MDR-TB
 It is identified that there was a lessening within the number of acid-fast bacilli (AFB)
and increased lymphocyte infiltration towards infected sites among Metformin treated
mice. This evidence describes that Metformin seem decrease the pathological changes
in Mtb infected tissues.
 It is additionally detailed that t the DM patients with latent TB taking Metformin had
a

more
Figure 2: Image of overall MOA of Metformin in TB

prominent number of IFN-gamma emitting cells against Mtb as compared to the

others who are not on Metformin treatment. Another study reported that Metformin
intensified the resistance against Mtb by upgrading the development of memory T-cell
responses and in this manner made a difference to decrease the incidence of latent TB.
3. Synergistic effect of metformin with Anti TB drugs:

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The benefits of Metformin to utilize as adjuvant treatment against TB diseases have a

extraordinary scope; however, these need advance investigation. Metformin treatment
improved the effectiveness of first-line anti-TB medication Isoniazid (INH) and there was
a diminished bacterial load in mice treated with both Metformin with INH compared to
the mice treated with INH alone. When tried with a combination of Metformin with
second-line anti-TB medicate Ethionamide (ETH), the it too appeared the diminished
bacillary load within the lungs and spleen compared to those mice received ETH alone.
To progress the viability of TB treatment, antiMtb drugs should promote tissue resolution
in expansion to speeding up bacterial clearance. The involvement of pathogenic changes
within the lungs and spleen of TB infected mice those are treated with Metformin was
little as compared to the mice which are not treated with Metformin.
Approximately 90% of the recently analysed sputum-positive patients are sensitive to
isoniazid and rifampicin, including the drug metformin would have a useful impact
within the early killing of intracellular microbes by affecting the host immunity.
3.1. Possible mechanism in synergistic effect:
Mycolic acid is the essential component of the cell wall of Mycobacterium
tuberculosis. Antibiotic targets and inhibits mycolic acid biosynthesis. Systems-level
changes attribute to the decreased flux carrying ability of glycolysis as well as the
citric acid cycle. Metformin targets NDH-I and promotes the rerouting of metabolic
fluxes via the de novo NAD biosynthesis pathway and electron transport. Following
figure shows the effect of Metformin while using along with anti-TB drugs.
Metformin, via nicotinamide adenine dinucleotide (NAD) de novo biosynthesis
pathway, reroute metabolic flux.

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Figure 2: Image of possible mechanism of synergistic effect of metformin & antibiotic in

TBa) Antibiotic targeting mycolic acid biosynthesis; b) systems-level changes resulting
into the reduction of flux carrying capacity of glycolysis and citric acid cycle c) resulting
re-routing of metabolic fluxes through de novo NAD biosynthesis pathway and electron
transport through NDH-I d) possibility of targeting NDH-I with metformin.

Consequently, it reduces the process of glycolysis and citric acid cycle in the
pathogens. Besides this, systems-level changes and consequent inhibition of mycolic
acid synthesis by mycobacterium occurs. So, lesser the amount of key component of
cell wall causes weaker cell wall formation of the bacteria. So, the cell wall will be
easily disrupted and the bacteria will be killed by the antibiotic. Usually, anti-TB
drugs target mycolic acid biosynthesis and the combination of Metformin with these
drugs favours this mechanism.

4. Effect of Metformin:
4.1. Reduce lung tissue damage:
In case the early host defences fail to kill or essentially slow the growth of Mtb,
macrophages contribute to the complicated and dynamic cytokine- and chemokine-
mediated recruitment of extra inflammatory cells, which form the early infectious
injury. Formation of granuloma, the clusters of immune cells that forms around the
microscopic organisms is the critical feature of TB. This granuloma may be a source
of lung pathology in active TB disease. Excessive pro-inflammatory reactions are
unfavorable within the early stages of infection since they result in extensive tissue
damage earlier to the advancement of Mtb particular adaptive immunity.
Metformin can activate AMP-activated protein kinase (AMPK) in macrophages. It
can improve the capacity to eradicate the microscopic organisms additionally regulate
their inflammatory reaction. By modulating the immune reaction, metformin can
diminish the generation of pro-inflammatory cytokines such as INFy, TNFα etc. So,
lower the inflammation helps to diminish the lung tissue harm in case of TB.

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Patients with optical glycemic control had a lower risk of cavitary injuries than those
with poor glycemic control.
4.2. Decrease relapse rate of TB:
Relapse rate implies the percentage of patients who experience a recurrence of the
active TB after the initial TB treatment is done and the patient is being declared
cured. Several studies propose that the relapse rates in case of anti TB treatment with
metformin is 6.3% though, the relapse rates in case of anti TB treatment without
metformin is 35.7%.
The number of T cells producing IFN-γ, as well as promoting the Th1 mediated
immune reaction, vital for protecting against TB can be effectively seen by
administering with metformin. This reality is that wherever the microscopic
organisms might come into the lymph nodes from distinctive angles, it'll be stopped
as this tissue is preventive from the deposition of this place where the qualified
macrophages are produced. The increase in IFN-gamma secreting cells among DM
patients with latent TB on metformin treatment proposes that metformin enhances the
Th1 immune response. IFN-gamma may be a critical cytokine within the defense
against TB, promoting the activation of macrophages and the eradicating of
intracellular microbes. This increased immune reaction can help clear Mtb more
proficiently, possibly reducing the pool of latent bacteria that might cause relapse due
to inefficient treatment. The development of memory T-cell reactions is especially
significant for long-term immunity. Memory T cells can "recognise" the pathogen,
enabling a quicker and more successful reaction upon re-exposure to Mtb. This
memory response is crucial for avoiding relapse, because it permits the immune
system to rapidly contain and suppress Mtb in case it reactivates.
4.3. Smear Conversion:
FDC dosing was related with a essentially quicker time to negative sputum smears
and a more prominent extent with negative smears after 2 months of anti-TB
treatment compared to ST dosing in hospitalized patients with pulmonary TB and
ineffectively controlled diabetes. Such impact was more evident in patients who had
3+ bacillary load and received metformin ≥2000 mg/day. One of the factors which
will contribute to this result is the lower pill burden of FDC (normal of 4 tablets/day)

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compared to ST regimen (normal 10 tablets/day), and how it may further disable the
absorption of the anti-TB medications in diabetic patients.
There's no such impact of metformin on smear conversion rate. But in case of those
patients with cavity pulmonary TB, metformin appears significant impact on smear
conversion rate.
5. Dose-dependent effect of Metformin in TB:
A higher total amount of metformin seems to be linked to a lower likelihood of TB
towards a reduction in the development of TB among patients taking a higher cumulative
dose of metformin. For example, people in the highest quarter of cumulative dose had a
90 percent reduced risk of TB compared to those who did not use the product. The
protective impact decreases as the dosage decreases in smaller quartiles Patients who
were in the highest quartile (Q4) of cumulative metformin dose had only a 10% risk of
developing TB compared to metformin non-users. In contrast, during the early phases of
metformin treatment, patients in the second quartile (Q2) of cumulative metformin use
had a higher risk of developing TB than patients in the first quartile (Q1) because
Metformin could initially impact the immune system's capability to combat TB by
potentially decreasing the production of certain immune signalling molecules (TNF-α and
IFN-ϒ). This may clarify the short-term increase in TB risk seen in the Q2. But in many
cases, after the course of Q4 the risk of TB become under the 10%.

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