Diabetes as a risk factor for tuberculosis disease

Background Tuberculosis (TB) is amongst the leading causes of death from an infectious disease, with an estimated 1.3 million deaths from TB in 2022. Approximately 25% of the global population is estimated to be infected with the TB bacterium, giving rise to 10.6 million episodes of TB disease in 2022. The prevalence of diabetes influences TB incidence and TB mortality. It is associated not only with an increased risk of TB disease but also death during TB treatment, TB relapse after treatment completion and multidrug-resistant TB. Since 2011, the World Health Organization (WHO) has recommended collaborative TB and diabetes activities as outlined in the Collaborative Framework for Care and Control of TB and Diabetes. Objectives To determine the prognostic value of diabetes mellitus (DM) in the general population of adults, adolescents and children for predicting tuberculosis disease. Search methods We searched the literature databases MEDLINE (via PubMed) and WHO Global Index Medicus, and the WHO International Clinical Trials Registry Platform (ICTRP) on 3 May 2023 (date of last search for all databases); we placed no restrictions on the language of publication. Selection criteria We included retrospective and prospective cohort studies, irrespective of publication status or language. The target population comprised adults, adolescents and children from diverse settings, encompassing outpatient and inpatient cohorts, with varying comorbidities and risk of exposure to tuberculosis. Data collection and analysis We used standard Cochrane methodology and the Quality In Prognosis Studies (QUIPS) tool. Prognostic factors assessed at enrolment/baseline included diabetes, as defined by the individual studies, encompassing patient-reported status, abstracted from medical records or claims data, or diagnosed by plasma glucose/glycosylated haemoglobin. The primary outcome was the incidence of tuberculosis disease. The secondary outcome was recurrent TB disease. We performed a random-effects meta-analysis for the adjusted hazard ratios, risk ratios, or odds ratios, employing the restricted maximum likelihood estimation. We rated the certainty of the evidence using the GRADE approach. Main results We included 48 cohort studies with over 61 million participants from the six WHO regions. However, the representation was variable as eight population-based studies were from South Korea and 19 from China, with overlapping study periods, and only one from the African region (Ethiopia). All studies included adults, and nine studies also included children and adolescents. Most studies diagnosed DM based on clinical records, including fasting blood glucose levels or glucose-lowering treatments. The studies did not distinguish between type 1 and type 2 DM; only one study focused on type 1 DM. Diagnosis and exclusion of TB were performed using culture or molecular WHO-recommended rapid diagnostic tests (mWRD) in only 12 studies, which could have biassed the effect estimate. The median follow-up time was five years (interquartile range 1.5 to 10, range 1 to 16.9), and the studies primarily reported an adjusted hazard ratio from a multivariable Cox-proportional hazard model. Hazard Ratios (HR) The HR estimates represent the highest certainty of the evidence, explored through sensitivity analyses and excluding studies at high risk of bias. We present 95% confidence intervals (CI) and prediction intervals, which show between-study heterogeneity represented in measuring the variability of effect sizes (i.e. the interval within which the effect size of a new study would fall considering the same population of studies included in the meta-analysis). DM may increase the risk of tuberculosis disease (HR 1.90, 95% CI 1.51 to 2.40; prediction interval 0.83 to 4.39; 10 studies; 11,713,023 participants). The certainty of the evidence is low, due to a moderate risk of bias across studies and inconsistency. Considering a risk without diabetes of 129 cases per 100,000 population, this represents 102 more (59 to 153 more) cases per 100,000. When stratified by follow-up time, the results are more consistent across Authors' conclusions Diabetes probably increases the risk of developing TB disease in the short term ( Funding World Health Organization (203256442) REGISTRATION: PROSPERO registration: CRD42023408807.