Randomized Trial of Metformin With Anti-Tuberculosis Drugs for Early Sputum Conversion in Adults With Pulmonary Tuberculosis

Abstract

Background: Metformin, by reducing intracellular Mycobacterium tuberculosis growth, can be considered an adjunctive therapy to anti-tuberculosis treatment (ATT). We determined 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-week, clinical trial, newly diagnosed, culture-positive PTB patients were randomized to standard ATT (HREZ = control arm) or standard ATT plus daily 1000 mg metformin (MET-HREZ = Metformin with Rifampicin [METRIF] arm) for 8 weeks during 2018-2020 at 5 sites in India. The primary end point was time to sputum culture conversion by liquid culture during 8 weeks of ATT. Plasma inflammatory markers were estimated in a subset. A Cox proportional hazard model was used to estimate time and predictors of culture conversion.

Results: Of the 322 patients randomized, 239 (74%) were male, and 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 (hazard ratio, 0.8; 95% confidence interval [CI], .624-1.019). After 8 weeks of ATT, cavitary lesions on X-ray (7, 5.3% vs 18, 12.9%; relative risk, 0.42; 95% CI, .18-.96; P = .041) and inflammatory markers were significantly lower in the METRIF arm. Higher body mass index and lower sputum smear grading were associated with faster sputum culture conversion.

Conclusions: 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.

Clinical trials registration: Clinical Trial Registry of India (CTRI/2018/01/011176).

Keywords: host-directed therapy; immunomodulation; metformin; pharmacokinetics; tuberculosis.

Figure 1.

Study diagram of the METRIF clinical trial. Abbreviations: AE, adverse events; CBC, complete blood count; CBNAAT, cartridge based nucleic acid amplification test; DOTS, directly observed treatment short course; DST, drug susceptibility test; HbA1C, glycosylated heamoglobin; HRE, isoniazid, rifampicin, ethambutol; HRZE, isoniazid, rifampicin, pyrazinamide, ethambutol; LJ, Lownstein Jensen; LFT, liver function test; MGIT, Mycobacteria Growth Indicator tube; MET, metformin; METRIF, metformin with rifampicin; NTEP, National Tuberculosis Elimination Programme; OD, once daily; PG, pharmacogenomics; PK, pharmacokinetic; RBS, random blood sugar; RFT, renal function test; R/M, routine and microscopy.

Figure 2.

Enrollment and end point at 8 weeks: profile of trial participants. Abbreviations: ATT, anti-tuberculosis treatment; BL, baseline; HCV, hepatitis C virus; INH, isoniazid; METRIF, metformin with rifampicin; POS, positive; TB, tuberculosis.

Figure 3.

Time to MGIT stable culture conversion in the METRIF arm and control arm (with 95% confidence interval). Abbreviations: METRIF, metformin with rifampicin; MGIT, Mycobacteria Growth Indicator tube.

Figure 4.

(A) Baseline (pretreatment) and 8 weeks of anti-tuberculosis treatment (ATT) plasma levels of acute phase proteins in pulmonary tuberculosis (PTB) patients in the METRIF arm and control non-metformin arm (n = 44). (B) Baseline and 8 weeks of ATT plasma levels of proinflammatory cytokines in PTB patients in the METRIF arm (n = 82) and non-metformin arm (n = 81). The data are represented as scatter plots with each circle representing a single individual. Abbreviations: ATT, anti-tuberculosis treatment; CRP, C-reactive protein; IFN, interferon; IL, interleukin; Met, metformin; METRIF, metformin with rifampicin; TNF, tumor necrosis factor.