Randomized trial of Metformin with Anti-tuberculosis drugs For Early Sputum Conversion in Adults with Pulmonary Tuberculosis.

BACKGROUND Metformin, by reducing intracellular Mycobacterium tuberculosis growth, can be considered as an adjunctive therapy to anti-tuberculosis treatment (ATT). We evaluated whether metformin with standard ATT reduces time to sputum culture conversion and tissue inflammation in adults with pulmonary tuberculosis (PTB). METHODS In a randomized 8-weeks clinical trial, newly diagnosed, culture positive PTB patients were randomized to standard ATT (HREZ = Control arm) or standard ATT plus daily 1000mg metformin (MET-HREZ = METRIF arm) for 8-weeks, during 2018-2020 at five sites in India. The primary endpoint was time to sputum culture conversion by liquid culture during 8 weeks of ATT. Plasma inflammatory markers were estimated in a subset. Cox proportional hazard model were used to estimate time and predictors of culture conversion. RESULTS Of the 322 patients randomized, 239 (74%) were male, 212 (66%) had bilateral disease on chest radiograph with 54 (18%) showing cavitation. The median time to sputum culture conversion by liquid culture was 42 days in the METRIF arm and 41 days in the Control arm [HR 0.8, 95% CI (0.624 - 1.019)]. After 8-weeks of ATT, cavitary lesions on x-ray [7 (5.3%) vs 18 (12.9%), RR 0.42 (0.18, 0.96), p=0.041] and inflammatory markers were significantly lower in METRIF arm. Higher BMI and lower sputum smear grading were associated with faster sputum culture conversion. CONCLUSION The addition of metformin to standard ATT did not hasten sputum culture conversion, but diminished excess inflammation thus reducing lung tissue damage as seen by faster clearance on x-ray and reduced inflammatory markers.