Thanks to metformin, a drug that is commonly prescribed for type 2 diabetes patients, treating TB — both the drug-sensitive and drug-resistant types — may become far more effective if clinical trials in humans produce the same results as laboratory and animal studies.

According to a study published today (November 20) in the journal Science Translational Medicine, metformin was found to “inhibit intracellular growth of TB bacteria, restrict disease immunopathology and enhance the efficacy of anti-TB drugs.”

“These data suggest that metformin could be used as an adjuvant therapy to treat TB infection,” says the note from the journal Editor.

Besides the higher effectiveness, the biggest advantage is that metformin offers little chance for the TB bacilli to develop resistance against the drug.

The reason: unlike the age-old practice of developing new drugs that directly target the TB bacteria, the focus now is to choose drugs that are already being used in humans and investigate their ability to ramp up the body’s responses to the pathogen’s ravaging attack in several ways.

Besides the ease with which the pathogen can be eradicated and the disease cured, the novel route has other advantages. As the drug does not directly target the TB bacteria, the chances of the bacteria developing drug resistance are slim. Currently, drug resistance is one of the biggest problems in TB treatment. Since the drugs being investigated are already in use by humans, there is less likelihood of them being dumped on safety grounds when used for treating TB.

Test results

Of the 13 drugs tested using human monocytic cell lines, the team of researchers led by Amit Singhal of the Singapore Immunology Network Agency for Science, Technology and Research, Singapore, chose metformin for detailed studies. They found that the diabetes drug was capable of inhibiting the growth of intracellular BCG within one day and also “restricted” the replication of multi-drug resistant TB strains (MDR-TB).

The growth inhibition of TB bacteria was achieved by prompting the body’s innate immune response to produce reactive oxygen species. If TB bacteria have an inherent mechanism of suppressing the synthesis of reactive oxygen species, the drug not only overcame this but also enhanced ROS production. This turned out to be the critical factor by which the drug was able to control the intracellular growth of the bacteria.

Animal studies

After testing the drug on cell lines, the scientists studied the effects of 500 mg per kg metformin in mice that had both acute and chronic drug-sensitive TB. The drug reduced the bacterial load in the lungs and spleen.

This was through a reduction in lung tissue damage of mice. When given along with isoniazid (INH) or ethionamide, the tissue damage reduction was even better compared to mice treated with only anti-TB drugs.

They also found that the drug had superior ability to reduce the disease-induced chronic inflammation. The reason: 45 of the 48 gene pathways affected by TB infection became normal after metformin treatment.

Although the researchers conducted studies in cell lines and in mice, the potential benefit of metformin in humans was evaluated through retrospective analysis of human data.

In humans

To do this, they chose diabetics who had TB and used metformin drug. They compared 106 diabetics who were on metformin with 164 patients who were on other anti-TB drugs. Chest X-rays revealed that those on metformin had fewer pulmonary cavities than those who were on other anti-TB drugs.

Besides improving the health parameters, the drug was found to have other beneficial effects. It was found to apparently lower the mortality risk. Also, diabetics who were on metformin and did not have TB were found to be less likely to get infected with TB. This protective effect was due to the drug’s ability to enhance the TB-specific T cell immune response.

Published in the Hindu on November 20, 2014