Metformin Use Reverses the Increased Mortality Associated With Diabetes Mellitus During Tuberculosis Treatment

Abstract

Background: The global type 2 diabetes mellitus (DM) epidemic threatens progress made in reducing tuberculosis (TB)-related mortality worldwide. Previous clinical studies have not fully evaluated potential confounding variables in addressing the impact of DM on TB treatment outcomes. The antidiabetic agent metformin regulates autophagy and may play a role as a host-directed therapeutic adjuvant to antitubercular treatment.

Methods: We conducted a retrospective cohort study comprising patients aged ≥13 years undergoing treatment for culture-confirmed, drug-susceptible pulmonary TB. We assessed the effect of DM on mortality during TB treatment and 2-month TB sputum-culture conversion. We also evaluated the effect of metformin use on survival during TB treatment.

Results: Among 2416 patients undergoing TB treatment, after adjusting for age, sex, chronic kidney disease, cancer, hepatitis C, tobacco use, cavitary disease, and treatment adherence, patients with DM had 1.91 times higher odds (95% confidence interval [CI], 1.51-2.40) of death during TB treatment than patients without DM, and 1.72 (95% CI, 1.25-2.38) times higher odds of remaining culture-positive at 2 months. Metformin use in patients with DM was significantly associated with decreased mortality during TB treatment (hazard ratio, 0.56 [95% CI, .39-.82]), and metformin users had similar mortality as patients without DM.

Conclusions: This study suggests that despite multiple potential confounding variables, DM poses an increased risk of adverse TB treatment outcomes. There was a significant association between metformin use and decreased mortality during TB treatment, suggesting a potential role for this agent as adjunctive, host-directed therapy.

Keywords: diabetes mellitus; host-directed therapy; metformin; treatment outcomes; tuberculosis.

© The Author(s) 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Figures

Figure 1.

Kaplan-Meier estimates of time to mortality among diabetic patients during tuberculosis treatment according to metformin use (n = 634). Patients with chronic kidney disease stage 3b or higher were excluded due to concerns for confounding. A, Intention-to-treat analysis. If a person was on metformin within 30 days of starting tuberculosis treatment, they were classified as using metformin throughout tuberculosis treatment. B, Documented metformin use for 80% of tuberculosis treatment. Only those patients with prescription data showing metformin use during equal to or more than 80% of tuberculosis treatment were classified as metformin users.

Figure 2.

Kaplan-Meier estimates of time to mortality during tuberculosis treatment, comparing diabetic patients on metformin to nondiabetic patients (n = 1894). Patients with chronic kidney disease stage 3b or higher were excluded due to concerns for confounding. Abbreviation: DM, type 2 diabetes mellitus.