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
contracted active TB. Of them, 558,000 were new cases resistant to rifampicin–a basic

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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
h. Certain drugs to treat rheumatoid arthritis, Crohn’s disease, and psoriasis.
1.4. Pathogenesis of Tuberculosis:

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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.

Figure3: Pathophysiology of pulmonary TB. Taking after the M. tb transmission to the new host, the bacilli enter the lung and
get ingested by macrophages. Then immune cells are enrolled to wall off the infected macrophages, driving to the formation of
the granuloma, the trademark of TB. Healthy people stay latently infected, and the contamination is kept at bay at this stage,
but it is inclined to the risk of reactivation. Foamy macrophages release their lipid substance when they necrotize, driving to
caseation (cheese-like structure). Caseum could be a decay which is manifested at the core of the granuloma that compromise
its inflexible or rigid integrity. As the granuloma develops, the bacilli commence to leak out of the macrophages into the caseum
layer. When the reactivation happens, M. tb multiplies and the bacterial stack gets to be overwhelmingly tall, whereupon the
granuloma burst, disseminating the microbes to the airways. The bacilli are at that point expectorated as infectious aerosol
droplets, restarting the cycle, infecting other people.

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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 lungs and
airways, in this manner transitioning to active TB, characterized by symptomatic and
exceedingly infectious disease. Amid this stage, the microscopic organisms can moreover
spread to other parts of the body, which leads to extensive organ damage. Hence, managing
TB requires not only tending to the active disease but too 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
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

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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.

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In later years, a few other unexpected however valuable uses of metformin were uncovered. The
off-label indications of metformin incorporate 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.

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,

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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

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2. AIM OF THE WORK:

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

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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 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,

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indicating that only high doses of metformin are effective in preventing TB incidence in newly
diagnosed DM patients. Metformin could initially impact the immune 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
diabetes mellitus. The Korean journal of internal medicine, 33(5), 933–940.
https://doi.org/10.3904/kjim.2017.249

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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 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

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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.

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

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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, 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

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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
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

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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 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

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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.
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

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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 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

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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 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.

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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 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.

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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
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

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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 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.

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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.

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

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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 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.

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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, 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

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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 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.

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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.

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

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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 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.

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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
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,

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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 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

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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
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.

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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.

Figure 1: Image of pathophysiological mechanisms

underlying TB–diabetes interaction

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

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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.
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.

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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 metformin to increase lactate 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.

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

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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:
Antibiotics or antimicrobial agents targets and hinders mycolic acid biosynthesis which
is the key component of bacterial cell wall synthesis. Systems-level changes attribute

Figure 2: Image of rerouting of metabolic pathway of bacteria

to the diminished flux carrying capacity of glycolysis as well as the citric acid cycle.

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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.
❖ Metformin has an anti-folate impact and this makes a difference to inhibit the folate
cycle of microscopic organisms.

Figure 2: Image of overall MOA of Metformin in TB

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❖ 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-T
❖ 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 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:
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

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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.

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.

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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.
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

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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) 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

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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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