Diabetes severity is strongly associated with the risk of active tuberculosis in people with type 2 diabetes: a nationwide cohort study with a 6-year follow-up

Along with the major risk factors for tuberculosis (TB), such as current smoking, heavy alcohol consumption, and malnutrition, diabetes mellitus (DM) is a main contributor to the risk of TB [1‐3]. The recent increase in the incidence of DM at the same time as a slow decline in TB incidence has led to the co-occurrence of DM and TB in an estimated 1 million people worldwide [2]. The percentage of new cases of TB with co-occurrence of DM is expected to increase substantially from 11.4% in 1990 and 21.9% in 2017 to 33.3% in 2050 [3]. By 2050, at least one-third of TB incidence and almost half of TB mortality in Asia–Pacific countries will be attributed to DM [3]. In addition, the COVID-19 pandemic has had adverse effects on TB and DM management [4, 5]. However, it seems difficult to apply preventive policies fully considering the large population of people with DM worldwide and that most people with TB and DM live in insufficient economic countries. It is important to identify subjects requiring targeted screening or therapies for active TB among diabetic patients and to provide a major benchmark for efficient healthcare services.

The clinical manifestations of more severe diabetes are a consequence of diverse and complex pathophysiological processes affecting different organ systems over time, making it difficult for a single severity measure to capture this complexity adequately [6]. Prior studies on diabetes severity used a grading system based on diabetes-related complications and glycemic control measures [6]. In current clinical practice, glycated hemoglobin (HbA1c) level over the preceding 3 months is used as an indicator of glycemic control and may provide a simple proxy measure of disease severity and to guide interventions and management. However, the ability to estimate the severity of DM using HbA1c level recorded at a specific time point is limited because this level tends to fluctuate over time [6]. In the general treatment flow, people with type 2 DM who have difficulty managing glycemic control with one or two oral hypoglycemic agents (OHAs) may require three or more OHAs or insulin initiation. Therefore, the severity of DM is also evaluated in terms of the number of OHAs [7] or insulin treatment [8]. We have devised a diabetes severity score to provide a comprehensive evaluation of DM status. Here, we explored the association between diabetes severity and the development of active TB in nationwide cohort data with a ≥ 6-year follow-up.

Since 2011, the World Health Organization (WHO) and the International Union Against Tuberculosis and Lung Disease have highlighted TB–DM co-epidemic and have recommended bidirectional screening [18]. However, it seems difficult to apply such policies fully in the field considering the large population of people with DM worldwide and that most people with both diseases have a low socioeconomic status. In this context, our findings provide evidence for the feasibility of focusing on TB screening in people with DM and a high diabetes severity score.

Previous studies have investigated the impact of indicators of DM severity or status on the development of TB infection. A prospective study of the Taiwanese population found that people with ≥ 2 diabetes-related complications had a threefold increased risk of incident TB [19]. However, the control group was nondiabetic people and the percentage of those with DM was very small, at only 7–9% of all those included in that study [19]. DM is a chronic heterogeneous metabolic disorder that varies in severity from mild to severe. Assessment of DM severity may be helpful for identifying people requiring targeted and intensive therapies, which may provide a major benchmark for efficient healthcare services [6]. In the current study, we applied five parameters to represent diabetes severity, such as use of insulin and/or multiple OHAs, duration of DM ≥ 5 years, and the presence of CVD or CKD, and we found a significant association between the number of parameters and risk of TB. These parameters are easily obtained in real clinical practice, especially in resources-limited settings, because there is no need for laboratory testing.

The FBG concentration is a fundamental element for achieving good glycemic control and managing DM. Previous studies have shown a J-shaped distribution between all-cause mortality and glycemic control in people with DM and that both high and low FBG levels are associated with a higher risk of all-cause mortality [10]. Similarly, the association between FBG concentration and risk of TB was also found to be J-shaped in our study. A previous study also observed that people with poor glycemic control (FBG > 130 mg/dL) had a higher adjusted HR (2.21) for the risk of TB than those without diabetes but that the risk of TB did not differ significantly between diabetic patients with good glycemic control (≤ 130 mg/dL) and nondiabetic people [20]. In our study, we found that the lowest risk of TB was observed in the FBG range around 130 mg/dL. DM-induced hyperglycemia has been suggested to increase the susceptibility to TB infection [16]. However, we also found that an FBG level ≤ 100 mg/dL was associated with a 37% higher risk for active TB. The increased risk for active TB in people with diabetes and an FBG level ≤ 100 mg/dL is consistent with the U-shaped curve between high mortality rates and hypoglycemia in patients in an intensive care unit [21]. The exact mechanism underlying the association between low FBG level and high risk of active TB among patients with type 2 DM remains unclear. One possibility is that low FBG concentration may be a marker of poor nutritional status, liver dysfunction, or other undetectable illnesses [22].

Kidney failure requiring dialysis is recognized as an important risk factor for active TB [23]. Accordingly, the WHO recommends systematic testing and treatment for latent TB infection in this population, a strategy that appears to be safe and effective for reducing the rate of active TB in dialysis patients [24]. Despite a well-established link between dialysis and TB risk, the relationship between CKD before kidney replacement therapy and TB risk requires closer examination. The risk of TB was higher in patients with more severe CKD among patients with CKD stage 2 or higher [25]. Poor immune function in individuals with more profound impairment of kidney function may explain this outcome [25].

TB and atherosclerotic CVD have a close epidemiological and pathogenetic overlap [26]. DM is strongly associated with CVD, and TB infection may increase the risk of CVD further. In one study, TB was associated with an increased risk of acute myocardial infarction (adjusted HR, 1.98; 95% CI, 1.3–3.0) [26]. Another study found that patients with atherosclerotic CVD had higher HR for all-cause and infection-related mortality after initiation of TB treatment [27]. Elevated serum markers of inflammation were found to mediate one-quarter to one-third of this association [27]. There is little evidence that patients with CVD may have an increased risk of active TB. We found that diabetic patients with CVD had a 14% higher risk of active TB compared with those without CVD.

This study has some limitations. First, we may have missed other indicators of DM severity such as diabetic neuropathy or HbA1c level. The clinical manifestations of more severe type 2 DM reflect diverse and complex pathophysiological processes that affect different organ systems over time and make it difficult for a single measure of severity to capture this complexity adequately [6]. We characterized the clinical features indicative of diabetic severity within the range of information we could access. All five parameters in the diabetes severity score in our study showed a significant association with the development of active TB. Second, this was an observational study and, therefore, the association between diabetes severity and active TB may not be causal. To minimize the possible effects of reverse causality, we excluded people with incident TB during the first year of follow-up. Third, this study was restricted to include only the Korean population, where the incidence of TB is 49 cases per 100, 000 people in 2020, relatively high among high-income countries [5], and characteristics associated with DM may differ from those of people of other ethnicities. Fourth, participants in this study were more men than women (60% vs. 40%). Selection of study subjects who participated in health examinations might be a source of bias because men and employee subscribers were more likely to participate in the regular health check-up. Fifth, we were unable to adjust for some unmeasured risk factors, such as contact with a known TB case, which may have mediated the association between DM and TB. Lastly, we did not further analyze the characteristics of TB patients such as a percentage of microbiological diagnosis or severity of TB. According to the National Tuberculosis report of South Korea, pulmonary TB were 79% and extrapulmonary TB were 21% out of the newly diagnosed TB cases. In pulmonary TB, 27.7% cases had positive result for acid-fast stain [28]. This study could not analyze the detailed clinical courses or mortality of subjects with TB. According to a recent study on mortality among TB survivors in Korea, the risk of all-cause mortality was reported to be 1.62 times higher in TB survivors compared to the age- and sex- matched control group [16]. Further studies on the mortality and clinical course of TB in diabetic patients are needed.

In Global TB report 2022, an estimated 0.37 million incident TB cases were attributable to diabetes in 2021 whereas 2.2 million to undernourishment, 0.86 million to HIV infection [29]. As five health-related risk factors for TB such as undernourishment, HIV infection, alcohol use, smoking and diabetes monitored by the WHO have variable impact to TB incidence among the countries or by period, therefore a decision-making and related efforts at a national level are needed that which factors would be prioritized to reduce the TB burden efficiently.

To our knowledge, this is the largest diabetes cohort study over a 6-year follow-up. We ascertained that the diabetes severity score, which included measures of the use of insulin and multiple OHAs, duration of diabetes, and the presence of CKD or CVD, was associated with TB risk in a dose-dependent manner. Of the components included in the diabetes severity score, insulin use was the most significant factor related to the risk of TB, followed by CKD. In addition, in people with type 2 DM, the FBG concentration had a J-shaped relationship with TB occurrence, and the lowest risk of TB was observed in those with an FBG concentration around 130 mg/dL. Both hyperglycemia and hypoglycemia were associated with a higher risk of TB development. These findings suggest that people with a higher diabetes severity score, particularly insulin users or patients with CKD, may be a targeted group for additional active TB screening in clinical practice.