Table 1.
Characteristics of included studies in the systematic review
| Study Authors and Published Year (location) | Study Design | Participants | Exposure | Outcomes | Controls | Case | Result | Adjustment of covariates |
|---|---|---|---|---|---|---|---|---|
| Magee et al. 2018 [8] (U.S.A.) | Cross-sectional study | Patients with diabetes identified by self-report and glycated hemoglobin (n = 4958) | Metformin medication identified by self-report | A diagnosis of LTBI infection identified by QuantiFERON-TB Gold In-tube | Patients without metformin medication | 575 |
Latent TB infection prevalence was non-significantly higher in those without metformin use (prevalence difference, 1.4, 95%CI, −3.7 −6.4%) compared to those self-reporting any metformin use (OR, 1.1, 95%CI, 0.7 to 1.9). |
NA |
| Singhal et al. 2014 [4] (Singapore) | Two retrospective cohort studies |
Cohort 1: Patients suffered from both DM and TB (n = 273) Cohort 2: Patients with DM (n = 220) |
Metformin treatment |
Cohort 1: Pulmonary cavities at diagnosis and mortality during the first year after diagnosis. Cohort 2: A diagnosis of LTBI tested by T-Spot TB array |
Patients using alternative drugs for DM. |
Cohort 1: 273 Cohort 2:62 |
Cohort 1: those receiving metformin had fewer pulmonary cavities (OR, 0.6; 95%CI, 0.36 to 0.97). The Mortality was 3% among patients who received metformin compared to 10% among patients in the non-metformin group (OR, 0.29; 95%CI, 0.14 to 0.95). Cohort 2: metformin therapy was associated with reduced T-SPOT reactivity when compared with controls (OR, 0.44; 95%CI, 0.20 to 0.95). |
NA |
| Marupuru et al. 2017 [19] (India) | Case-control study | Diabetics (≥ 40 years old) identified on the basis of ICD-10 coding for disease classification (E11.9, n = 448) | Metformin usage | The diagnosis of TB following ICD-10 code A15-A19 | Patients without metformin usage | 149 | The protective effect of metformin against TB was 3.9-fold in diabetics (OR = 0.256, 0.16 to 0.40). No difference was found between those on 1000 mg metformin (27.3%), and on 500 mg (25.7%) for development of TB. | NA |
| Lee et al. 2017 [11] (South Korea) | Retrospective cohort study | Culture-proven pulmonary TB in patients diagnosed with DM; follow-up sputum Mtb cultures after 2 months of treatment; completion of World Health Organization-recommended TB treatment (n = 105) | Metformin treatment |
(1) Sputum culture conversion after 2 months of treatment; (2) Recurrence of TB proven by isolation of Mtb or clinical radiological evidence |
Participants without metformin treatment | 105 | The OR of sputum culture conversion at 2 months for patients with metformin use was 2.69 (95%CI, 0.92 to 7.95); A statistical difference in the recurrence rate with the use of metformin (OR, 1.92; 95%CI, 0.42 to 8.76) was observed. Metformin improved the sputum culture conversion rate in patients with cavitary pulmonary TB (OR, 10.8; 95%CI, 1.22 to 95.63) | Sex, statin use, insulin, cancer, AFB smear grade, and drug resistance |
|
Lin et al. 2017 [20] (Tai Wan) |
Retrospective cohort study | Patients aged 20 and older newly diagnosed with diabetes (ICD-9250.XX and A-code A181) and without a past history of pulmonary TB (n = 22,256) | Metformin treatment | Incidence of pulmonary TB identified in follow-up | Patients without metformin treatment | 682 |
Unadjusted crude HR: 0.42 (95%CI, 0.35 to 0.50) Adjusted HR: 0.52 (95%CI, 0.43 to 0.62) |
Sex, age, alcoholism, chronic obstructive pulmonary disease, cirrhosis, alcoholic liver damage, hepatitis C, chronic kidney diseases, and malignancies |
|
Degner et al. 2018 [12] (Tai Wan) |
Retrospective cohort study | Patients aged ≥13 years with culture-confirmed, drug-susceptible pulmonary TB undergoing treatment and diabetes (n = 634) | Metformin medication within 30 days of starting TB treatment | Effect on mortality among patients with DM undergoing TB treatment | Patients without metformin prescriptions | 634 |
Adjusted HR: 0.56 (95%CI, 0.39 to 0.82) Unadjusted HR: 0.50 (95%CI, 0.35 to 0.72) |
Age, sex, chronic kidney disease, cancer, cavitary diseases, TB treatment adherence |
|
Lee et al. 2018 [9] (Tai Wan) |
Retrospective cohort study | Patients had at least one hospital admission or at least three outpatient visits with a DM diagnostic code (ICD-9) within 365 calendar days (n = 177,732) | With total prescriptions of metformin for > 90 cumulative defined daily doses within 1 year after the onset of DM treatment | A newly diagnosed TB (ICD-9-CM code: 010–018) after the index date. | Diabetics do not satisfy the exposure criteria | 1514 |
Adjusted HR: 0.84 (95%CI, 0.74 to 0.96) TB risk was lower in high-dose metformin users than in low-dose users (HR, 0.83; 95%CI, 0.72 to 0.97) |
Sex, type 1 diabetes mellitus, age, low income, chronic obstructive pulmonary disease, liver cirrhosis, pulmonary cancer, extra-pulmonary cancer, bronchiectasis, and so on |
|
Lin et al. 2018 [10] (Tai Wan) |
Retrospective cohort study | Patients who were 20–100 years old and who were newly diagnosed with type 2 DM (ICD-9-CM, 250.X0 and 250.X2) (n = 10,052) | Metformin usage | A diagnosis of active TB (ICD-9-CM, 010–018) during the follow-up period and the prescription of more than two anti-TB medications for more than 90 days. | Participants without metformin usage | 329 |
Adjusted RR: 0.24 (95%CI, 0.18 to 0.32) Unadjusted RR: 0.37 (95%CI, 0.29 to 0.47) |
The duration of DM diagnosis, comorbidities (chronic pulmonary disease/ renal disease), oral anti-diabetic therapy, and insulin injection therapy |
|
Ma et al. 2018 [21] (China) |
Retrospective cohort study |
Culture-positive retreatment pulmonary TB patients with type 2 DM Multidrug-resistant TB, extensively drug-resistant TB, and extra-pulmonary TB were excluded.(n = 58) |
Metformin treatment in regimens for diabetes |
(1) Success treatment of TB (2) Sputum culture conversion by the end of 2 months (3) Relapse rates of patients |
Patients without metformin medication | 58 | There were a higher proportion of treatment success (OR, 6.00; 95%CI, 0.71 to 50.59) and sputum culture conversions by the end of 2 months (OR, 2.80; 95%CI, 0.55 to 14.23) among metformin group. The relapse rates of patients in the metformin and non-metformin group were 6.3 and 35.7% (OR, 0.12; 95%CI, 0.01 to 1.20). | NA |
|
Pan et al. 2018 [13] (Taiwan) |
Retrospective cohort study |
Patients with a diagnosis of type 2 DM (ICD-9250 × 0, 250 × 2). Patients aged < 20 years or had a diagnosis of TB were excluded.(n = 9475) |
Participants received ≥60 cumulative defined daily dose of metformin and < 15 cumulative defined daily dose of sulfonylurea |
TB occurrence (ICD-9, 010–018) |
Participants received ≥60 cumulative defined daily dose of sulfonylurea and < 15 cumulative defined daily dose of metformin | 263 |
Adjusted RR: 0.337 (95%CI, 0.169 to 0.673) Unadjusted RR: 0.477 (95%CI, 0.268 to 0.850) |
Age, sex, adapted diabetes complication severity index score, index year, income level, and comorbidities |
|
Tseng et al. 2018 [7] (Taiwan) |
Retrospective cohort study |
Newly diagnosed diabetes patients (ICD-9) who had been followed up in the outpatient clinics with a prescription of antidiabetic drugs for two or more times (n = 164,267) |
Patients had been prescribed metformin as the first antidiabetic drug | Incidence density of TB infection | Patients without metformin prescriptions | 2336 |
Adjusted HR: 0.552 (95%CI, 0.493–0.617) Unadjusted HR: NA |
Age, diabetes duration, sex, occupation, living region, hypertension, dyslipidemia, obesity, diabetes-related complications, antidiabetic drugs and so on |
Abbreviations: TB Tuberculosis, LTBI Latent tuberculosis infection, DM Diabetes mellitus, Mtb Mycobacterium tuberculosis, HR Hazard ratio, OR Odds ratio, RR Relative ratio, CI Confidence interval, ICD International classification of diseases, AFB Acid-fast bacilli, NA Not available