Metabolic and immune interaction between tuberculosis and diabetes mellitus: implications and opportunities for therapies

Abstract

Introduction

Tuberculosis (TB) remains a major infectious threat to global health, while type 2 diabetes mellitus (diabetes) has reached epidemic proportions in many regions of the world. In low-and-middle income countries (LMIC) and among indigenous and minority communities in high-income settings (HIC), these diseases also increasingly overlap posing new clinical and therapeutic challenges.

Areas covered

We searched PUB MED/CINAHL/Web of Science/Scopus, and Google Scholar up to 30 November 2024. While TB and diabetes are different conditions, their bidirectional relationship and immuno-metabolic parallels are underappreciated. Improved understanding of these mechanisms may pave the way for novel therapeutic strategies, for example, using antidiabetic medications as novel adjuvant host-directed therapies (HDT) in active TB. We review the epidemiology of TB, diabetes and their combined comorbidity, their immune and metabolic mechanisms and clinical relevance as well as potential opportunities for general and targeted therapeutic intervention.

Expert opinion

The interaction between diabetes and tuberculosis is bidirectional with diabetes a predisposing factor to tuberculosis and vice-versa. Underlying this interaction are shared inflammatory immunometabolic mechanisms. It follows that treatments for diabetes and its complications may be beneficial in tuberculosis and that the treatment of both active and latent tuberculosis may improve glycaemic control. These interactions are amenable to investigation in experimental models, in human experimental medicine studies and in clinical trials.

Introduction

Tuberculosis (TB) and type 2 diabetes mellitus (diabetes) are two major global health challenges, each causing substantial ill-health, disability and premature death. While different conditions, TB and diabetes are bidirectionally related. A growing body of evidence suggests complex interplay between TB and diabetes, with synergistic adverse impacts on incidence, progression and outcomes of each condition. Driving this bidirectional relationship are similar immune and metabolic derangements. Improved understanding of these interactions and their mechanistic correlates is important to develop needed novel interventions, especially novel therapeutic approaches in TB. Over the past five years, research has shed new light on this complex relationship between diabetes and TB.

Epidemiology

Latent TB is considered to affect 2 billion people worldwide, with 10.1 million incident active TB cases and 1.3 million fatalities annually (WHO, 2025). Diabetes in turn affects 537 million people with 6.7 million deaths per year (IDF, 2021). These diseases increasingly overlap. It is estimated that 15% of patients with active TB globally have prevalent diabetes (Noubiap et al., 2019). This rises to nearly half of all active TB cases in such settings as the Marshall Islands (45.2%) (Nasa et al., 2014), Saudi Arabia (42.2%) (Al-Tawfiq and Saadeh, 2009), Mexico (54.4%) (Munoz-Torrico et al., 2017) and Pakistan (39.6%) (Aftab et al., 2017), (Noubiap et al., 2019). In contrast, the prevalence of TB among patients with diabetes ranges from 0.38% in Taiwan (Lin et al., 2015) to 14% in Pakistan (Amin S, 2011). In sub-Saharan Africa (SSA) where HIV is the main risk factor for TB, the pooled prevalence of diabetes in people with active TB is 8% (Noubiap et al., 2019).

This bidirectional relationship of TB and diabetes is also reflected in increased risks of incident TB. TB is a long-recognized complication of diabetes with the latter increasing the risk of new Mycobacterium tuberculosis (M.tb) infection as well as the risk of progressing to active TB from latent infection (Kamper-Jorgensen et al., 2015; Koesoemadinata et al., 2017). According to prospective observations, people with diabetes are about three-times [relative risk (RR) (95%CI): 3.6 (2.3 - 5.7)] more likely to develop active TB than their non-diabetic counterparts (Al-Rifai et al., 2017; Jeon and Murray, 2008). These prospective studies better establish the temporality of exposure and outcome, a crucial consideration given the bidirectionality of the TB-diabetes relationship.

Conversely, there is growing recognition that diabetes may also be a metabolic sequel of both latent and active infection with M.tb. A study using a UK nationwide cohort of adults enrolled in primary care (mean follow-up 4 years) reported adjusted incidence rate ratios (IRR) for new-onset diabetes of 5.7 following pulmonary TB (PTB) and 4.7 following extrapulmonary TB (EPTB) compared to the general population (Pearson et al., 2019). A US-wide study (median follow-up 3.2 years) found higher diabetes incidence in adults with reactive tuberculin skin testing (TST) and/or interferon-γ release assay (IGRA) than in non-reactive peers [adjusted HR (95%CI): 1.2 (1.2, 1.3)] (Magee et al., 2022). Of note, this study excluded patients with prior active TB and those diagnosed with diabetes within 2 years of TST and IGRA testing. In contrast, a prospective cohort in Oxford, England, did not find evidence that TB increases the risk of incident diabetes [RR (95%CI): 1.1 (0.8, 1.6)] (Young et al., 2012). Diabetes is a multifactorial disease, and it may be that infection with M.tb is a trigger for diabetes to manifest in individuals with predisposing factors. Notwithstanding, these epidemiological links are increasingly corroborated by mechanistic studies of TB in humans and animals showing increased insulin resistance, inflammation within adipose tissue (Agarwal et al., 2014; Ayyappan et al., 2018; Bisht et al., 2023), free fatty acid dysregulation and dysglycaemia (Magodoro et al., 2024), among other characteristics of diabetes.

Clinical Manifestations

TB in Diabetes

Concurrent TB and diabetes can pose significant diagnostic challenges (Boadu et al., 2024b; Gil-Santana et al., 2016). For example, diabetes in people with TB has been associated with a considerably longer time (25 days versus 6 days in TB alone) to diagnosis and/or antituberculosis treatment initiation (Chen et al., 2014; Wang et al., 2017). Patients newly diagnosed with PTB in Beijing, China, had a median (IQR) 6 (3-31) days from time of onset of pulmonary symptoms to time of first contact with any formal health facility. Their counterparts with concurrent PTB and diabetes had 25 (5-61) days (Chen et al., 2014). Similarly, Wang et al., found that having hyperglycaemia i.e., either known diabetes, or newly identified diabetes or prediabetes at time of PTB diagnosis, was associated with greater likelihood [odds ratio (OR) (95%CI): 2.1 (1.5, 3.0)] of PTB diagnostic delay (defined as >28 days from symptom onset to first formal healthcare contact) compared to normoglycemic controls (Wang et al., 2017). However, there is also counter evidence suggesting that diabetes does not contribute to TB diagnostic delay, and that it may in fact associate with expedited anti-tuberculosis treatment (ATT) initiation (Xiao et al., 2021).

TB may exhibit greater clinical complexity due to diabetes-related complications such as end-organ damage or failure (Shetty et al., 2024). Commonly, TB in people with diabetes presents either as disseminated, or more infectious and severely cavitating forms of the disease with higher clinical severity scores (Boadu et al., 2024b; Gil-Santana et al., 2016; Huang et al., 2017; Shetty et al., 2024; van Crevel and Critchley, 2021; Zhao et al., 2024). Likewise, PTB patients with poorly controlled diabetes have a more severe clinical picture than peers with PTB and well controlled diabetes. Atypical radiographic features are not uncommon either, and include miliary TB, lower lobe infiltrates, pleural effusions, pulmonary nodules, and cavities involving the middle and lower lung zones (Boadu et al., 2024a; Rottenberg et al., 2017; Shetty et al., 2024; Stubbs et al., 2021; Zhao, 2024).

Diabetes in people with TB

Similarly, the presence of hyperglycaemia at the initial diagnosis of TB disease presents diagnostic and management challenges. This is particularly relevant in patients not previously known to have diabetes (Kubjane et al., 2020; Song et al., 2019). In non-diabetic individuals, hyperglycaemia typically normalizes during the first three months of ATT (Kubjane et al., 2020). Key gaps in knowledge remain about whether this transient hyperglycaemia warrants intervention and whether it affects the long-term risk of diabetes risk. Based on available evidence, guidelines (2010) recommend confirmatory diabetes testing three (3) months after initiation of TB treatment to avoid misclassification of transient hyperglycaemia as diabetes (Ottmani et al., 2010). However, the optimal retesting interval remains to be ascertained.

In contrast, hyperglycaemia may persist despite ATT in people with diabetes who are newly diagnosed with TB (Kubjane et al., 2020). Both TB and ATT can exacerbate existing hyperglycaemia complicating the pharmacological management of diabetes (Boadu et al., 2024a; Song et al., 2019). Furthermore, rising HbA1c levels during and after ATT relate to poor treatment response (Shetty et al., 2024). Importantly, HbA1c values are also influenced by co-existing factors such as anaemia (English et al., 2015) and antiretroviral medications like reverse transcriptase inhibitors (Dave et al., 2011; Kubjane et al., 2020), for example. These factors warrant consideration when interpreting the validity of the HbA1c result (Kubjane et al., 2020).

Impact of diabetes comorbidity on TB treatment efficacy and outcomes

The interaction between TB and diabetes complicates the treatment of each condition with important repercussions for both clinical care and public health programmes (Table 1). For example, the high pill-burden in patients with comorbid diabetes and TB increases the likelihood of missed doses, incorrect drug intake and treatment interruptions (van Crevel and Critchley, 2021). These risks are pronounced with more difficult to control diabetes and/or MDR-TB. The recommended treatment period for the latter is 6 months, and it is not uncommon for it to be extended (Committee, 2014). In addition, people with diabetes have higher risks of developing serious adverse events and reactions to TB medication (Muñoz-Torrico et al., 2017; van Crevel and Critchley, 2021). Nephrotoxicity, hepatoxicity, visual acuity disturbances and hypothyroidism are examples of aggravated TB drugs adverse reactions in people with diabetes while isoniazid can aggravate diabetic neuropathy (Muñoz-Torrico et al., 2017; Syed Suleiman et al., 2012; van Crevel and Critchley, 2021).

Table 1. Summary of implications of TB and Diabetes comorbidity on treatment strategies for each condition.

TB Treatment in Patients with Diabetes
Implication:	Description:	Selected References:
Increased risk of TB	Increased susceptibility to latent M.tb infection, its progression to active disease, and de novo development of active TB.	(Shetty et al., 2024) (Kamper-Jorgensen et al., 2015; Koesoemadinata et al., 2017)
Delayed TB diagnosis	Longer time to confirmatory diagnosis and anti-TB treatment initiation.	(Chen et al., 2014; Wang et al., 2017)
Severe clinical disease	Disseminated and/or severely cavitating disease at diagnosis with greater clinical complexity if diabetes-related complications.	(Boadu et al., 2024b; Gil-Santana et al., 2016; Huang et al., 2017; Shetty et al., 2024; van Crevel and Critchley, 2021; Zhao et al., 2024)
Poor treatment outcomes	Increased likelihood of death during treatment, TB recurrence or relapse, and extended treatment duration.	(Kornfeld et al., 2023); (Wang et al., 2015); (Yanqiu et al., 2024)
Emergence of MDR-TB	Comparatively poor control of M.tb infection, increased mycobacterial proliferation, and considerably delayed sputum culture conversion to negative. Also, more frequent nosocomial acquisition of drug resistance.	(Zhao et al., 2024); (Abd El-Hamid El-Kady and Abdulrahman Turkistani, 2021; Rehman et al., 2023; van Crevel and Critchley, 2021)
Adverse drug reactions and events	Nephrotoxicity, hepatoxicity, visual acuity disturbances and hypothyroidism, among others, not uncommon due to polypharmacy and extended treatment duration.	(van Crevel and Critchley, 2021); (Muñoz-Torrico et al., 2017; Syed Suleiman et al., 2012; van Crevel and Critchley, 2021)
Post tuberculosis health status	Increased risk of long-term ill-health and disability from tissue destruction with adverse remodelling. Need for tailored treatment, including host directed adjuvants, as well as posttreatment follow up and rehabilitation.	(Restrepo, 2016)
Diabetes Management in Patients with TB
Increased risk of diabetes	M.tb infection may be a novel risk factor for diabetes or a trigger for diabetes to manifest in individuals with predisposing factors.	(Magodoro et al., 2024; Pearson et al., 2019) Magee et al., 2022)
Diagnostic challenges	Difficulty classifying hyperglycaemia seen during active TB in patients of unknown diabetes status. Optimal timing of confirmatory re-testing to avoid misclassification of transient hyperglycaemia as diabetes remains to be established.	(Kubjane et al., 2020; Song et al., 2019)
Poor glycaemic control	Both TB and antituberculosis treatment can worsen blood glucose control in people with diabetes.	(Boadu et al., 2024a; Boadu et al., 2024b; Song et al., 2019)
Worsened glycaemic control	TB can worsen blood sugar control, making diabetes management more challenging.	(Boadu et al., 2024b)
Frequent monitoring and treatment titration	Blood glucose levels need to be monitored more frequently to adjust diabetes medications, including insulin requirements, among people with diabetes. Insulin requirements frequently increased, for example, due to stress and inflammation.	(Niazi and Kalra, 2012)
Integrated Care Approach
Multidisciplinary care	Managing patients with both TB and diabetes often requires a team approach, including infectious disease specialists, endocrinologists, and primary care providers.	(Byashalira et al., 2023)
Patient education	Educating patients about the importance of adherence to both TB and diabetes treatment regimens is crucial for successful outcomes.	(Koesoemadinata et al., 2021)
Extended follow-up	Frequent follow-ups are necessary to monitor the progress of both conditions and make timely adjustments to treatment plans.	(Krishna and Jacob, 2000)
Nutritional support	Proper nutrition is crucial to support the immune system and manage both conditions effectively.	(Girishbhai Patel et al., 2024)

Similarly, diabetes negatively impacts TB treatment outcomes. The risk of death during TB treatment is doubled with comorbid diabetes [OR (95%CI): 1.9 (1.6, 2.2)] (Huangfu et al., 2019). Likewise, the probability of treatment failure is higher in TB patients with diabetes compared to TB alone, as are rates of recurrence or relapse, extended treatment duration, delayed sputum culture conversion and the emergence of MDR-TB (Gautam et al., 2021; Huangfu et al., 2019; Khattak et al., 2024; van Crevel and Critchley, 2021; Zhao et al., 2024). The emergence of MDR-TB is particularly concerning. People with diabetes have comparatively poor control of M.tb infection (Zhao et al., 2024) with resultant increased mycobacterial proliferation, and therefore higher bacterial load (Abd El-Hamid El-Kady and Abdulrahman Turkistani, 2021; van Crevel and Critchley, 2021). Nosocomial acquisition of drug resistance TB is also relatively more common among people with diabetes (Rehman et al., 2023; van Crevel and Critchley, 2021). Overall, these outcomes are worse with poor versus optimal glycemic control among those with comorbid diabetes and TB (Mahishale et al., 2017; Zhao et al., 2024). Curiously, however, TB-related mortality risk [OR (95%CI): 0.6 (0.2, 1.5)] in people with diabetes may not be impacted by glycemic control according to a recent meta-analysis (Zhao et al., 2024).

M.tb infection impacts glucose metabolism

Adipocytes and adipose tissue may be the mechanistic bridge between M.tb infection and deranged glucose metabolism. M.tb preferentially infect cells of the myeloid lineage, like macrophages, as these are the first innate immune cells to encounter the bacterium upon infection (Chandra et al., 2022; Cliff et al., 2015). M.tb can also infect several non-traditional immune cell types, including adipocytes where they establish latency (Niazi and Kalra, 2012). Aerosolized M.tb initially infects the lungs and disseminates to adipose tissue where it remains latent, In the event of immune system compromise, such as during HIV infection or with diabetes, bacilli could reactivate and disseminate back to the lungs (and other sites). Adipose tissue throughout the body is susceptible and may, therefore, constitute a vast reservoir where M.tb can persist.

Adipose tissue with its triglyceride content is a nutritionally rich niche for the persistence of M.tb. It is also an endocrine organ contributing to metabolic and energy homeostasis. M.tb infection and persistence may have a dynamic effect on this physiology, setting off a cascade within the adipose tissue microenvironment of immune cell infiltration, activation and cytokine release, culminating in disruption of glucose, insulin, and lipid regulation (Das et al., 2024). M.tb-related metabolic disruptions are thought to mirror the inflammatory changes observed in adipose tissue in obesity-related insulin resistance, which often presages the onset of diabetes. Indeed, increased insulin resistance with hyperglycaemia has been demonstrated in both latent and active TB infection.

Although diabetes is primarily a metabolic disorder, its accompanying host immune changes are often deleterious (Figure 1). Diabetes is associated with systemic inflammation, oxidative stress and aberrant cytokine production, among other alterations. These wide-ranging immune effector changes (Figure 1) associate with increased expression of genes associated with innate inflammatory responses, on one hand, and a decrease in those associated with adaptive immunity, on the other. For instance, decreased type I interferon responses in patients with TB and diabetes comorbid conditions, indicating an unexpected separation of the TB transcriptome phenotype, where increased type I responses are detrimental to the host (Eckold et al., 2021). This imbalance is also present in individuals with intermittent hyperglycaemia and TB comorbidity, demonstrating altered immune responses even under acute hyperglycaemic conditions, thus leading to a less effective immune response against TB (Eckold et al., 2021). Here, we discuss how various diabetes therapies further alter the host immune response to M.tb infection (interactions summarized in Figure 1).

Figure 1. An overview of the Innate and Adaptive Immune Responses to M.tb infection and the effect of diabetes therapies thereon.

Hyperglycaemia, a hallmark of type II diabetes, inhibits protective innate immune responses which can be improved with successful diabetes treatment. Diabetes therapies typically inhibit pro-inflammatory immune responses, favouring the upregulation of immunomodulatory responses. M.tb: Mycobacterium tuberculosis; IL: Interleukin; TNFα: Tumor necrosis factor alpha; AGEs: advanced glycation end-products; APC: antigen presenting cell; MHCI: major histocompatibility complex class 1; MHCII: major histocompatibility complex class 2; IFN: interferon; TCR: T cell receptor; NK: natural killer; IDO: Indoleamine 2,3-dioxygenase; TGF: transforming growth factor; Th1: helper T cell subset type 1; Th2: helper T cell subset type 2; Treg: regulatory T cell subset. Created in BioRender. Kotze, L. (2024) https://BioRender.com/l93g049.

Pharmacological considerations

(1). Metformin

Metformin is a widely used oral anti-diabetic drug which, in the last decade, has gained attention as a potential adjuvant host-directed therapy (HDT) in TB (Chung et al., 2024; Salindri et al., 2024; Wang et al., 2022). Recent meta-analyses (Meregildo-Rodriguez et al., 2022a; Yu et al., 2019; Zhang and He, 2020), including only retrospective cohort studies, demonstrate decreased risk of incident active TB with the use of metformin versus none in people with diabetes. Further reports suggest metformin may reduce the risk of incident active TB in people with diabetes to levels seen in persons without diabetes (Pan et al., 2020a). The impact of metformin appears to be dose-dependent, with higher doses associating with greater risk reduction (Heo et al., 2021).

Noteworthy is that available studies are almost exclusively observational. (Padmapriydarsini et al., 2022) randomized 306 adults with newly diagnosed smear positive drug sensitive pulmonary TB to receive standard ATT or standard ATT with additional metformin during the first 8 weeks. People with diabetes were excluded. Participants in the metformin arm had a faster resolution of cavities on chest radiography, i.e., amelioration of lung pathology, and decreased levels of pro-inflammatory cytokines in plasma at 8 weeks of treatment. However, sputum culture conversion rates were similar across study arms. Although the evidence of metformin’s potential as an adjunctive therapy to antituberculosis treatment is growing, it is not unequivocal. In murine TB, for example, metformin use in both diabetic and non-diabetic mice has been associated with augmentation of bacillary load and lung immunopathology (Sathkumara et al., 2020).

Metformin’s effects on TB may not be related to glycemic control as they are not observed with other anti-diabetic medications (Fu et al., 2021). Metformin is thought to be an immunomodulator acting via immune cells, including autophagy, and various circulating immune mediators. Autophagy, an intracellular self-digestion process, is critical to the elimination of intracellular pathogens and plays an important role in defence against M.tb (Gutierrez et al., 2004). It is regulated by the mammalian target of rapamycin (mTOR) complex and adenosine monophosphate-activated protein kinase (AMPK), which activate the pathway. In vitro studies show that metformin activates AMPK (Singhal et al., 2014), resulting in increased autophagy and subsequently reduced intracellular M.tb growth; as well as inhibition of LPS-induced chemokine expression (Ye et al., 2018).

Another mechanism by which metformin is postulated to exert its effects is inhibition of mycobacterial growth by increasing macrophage viability and activation (Naicker et al., 2023), the production of the antimicrobial peptide β-defensin (Rodriguez-Carlos et al., 2020) and a direct effect on M.tb (Naicker et al., 2023). Metformin use in TB is associated with comparatively low levels of TNF-α, IFN-γ and IL-1β (pro-inflammatory cytokines) (Arai et al., 2010; Gonzalez-Muniz et al., 2024; Naicker et al., 2023; Padmapriydarsini et al., 2022; Roca et al., 2022; Ye et al., 2018) (Kumar et al., 2018; Li et al., 2017), advanced glycation end products (AGE) and soluble receptor for AGE (sRAGE) (Kumar et al., 2019). Moreover, metformin stimulates the differentiation of T-cells into both regulatory (Tregs) and CD8+ memory T cells, shifting the balance away from pro-inflammation. Metformin increases the mitochondrial mass, and oxidative phosphorylation and fatty acid oxidation capacity of CD8+ T cells. This metabolic reprogramming in turn enhances the ability of these cells to contain M.tb (Bohme et al., 2020).

More recently, steroid hormone synthesis has been highlighted as a possible effector of metformin’s antituberculosis actions (Gonzalez-Muniz et al., 2024). Cortisol reduces innate immune responses, while dehydroepiandrosterone (DHEA) is pro-inflammatory. In individuals with both TB and diabetes, these hormones become dysregulated, resulting in an increased cortisol/DHEA ratio. This immuno-endocrine imbalance is thought to impede an effective immune response to M.tb. (Gonzalez-Muniz et al., 2024) have examined ex vivo the impact of metformin on cortisol and DHEA synthesis in adrenal cells and how these hormones affect the expression of proinflammatory cytokines and antimicrobial peptides (AMP) in M.tb-infected macrophages. Metformin enhances DHEA synthesis while maintaining cortisol balance in adrenal cells. In turn, the mycobacterial load was reduced in infected macrophages by the increased production of proinflammatory cytokines (TNF-α, IL-12, IL-1β), the antimicrobial nitric oxide synthase, and AMP (CAMP, DEFB4, DEFB103) (Gonzalez-Muniz et al., 2024).

(2). Other antidiabetic agents

Metformin’s effects on TB appears to be independent of glycemic control as similar effects are not seen with other anti-diabetic medications (Fu et al., 2021). The recent meta-analysis by Meregildo-Rodriguez et al., did not find association between TB risk and the use of other common anti-diabetic drugs like sulfonylureas, meglitinides, thiazolidinediones and alpha-glucosidase inhibitors (Meregildo-Rodriguez et al., 2022a). This further underscores the importance of immunomodulation as a strategy for adjuvant HDT (Sun et al., 2012). Glucagon-like peptide (GLP)-1 receptor agonists stimulate insulin secretion in response to hyperglycaemia. Although the anti-inflammatory effects of these agents have been observed - including decreased C-reactive protein and IL-6 (Prasad-Reddy and Isaacs, 2015), inhibition of macrophage activation and diminished macrophage infiltration into tissues (Nesto, 2004) - their antitubercular benefits, if any, remain to be established.

Similarly, the immunomodulatory properties of dipeptidyl peptidase (DPP)-4 inhibitors are increasingly recognized and include altered T-helper cell responses, decreased pro-inflammatory Th1 and Th17 cells, and increased anti-inflammatory Tregs (Gallwitz, 2019; Kim et al., 2014). The net effect of these appears to be a reduction of pro-inflammatory cytokines IL-6, TNF-α, and MCP-1, which are associated with insulin resistance and chronic inflammation in type 2 diabetes (Agrawal and Kant, 2014). However, DPP-4 inhibitors have not been shown to impact the risk of developing TB (Wang et al., 2023).

SGLT2 inhibitors exhibit anti-inflammatory properties by decreasing the levels of pro-inflammatory cytokines like IL-6 and TNF-α. The effects have been studied in the context of cardiovascular benefit; this has been seen through mitigating systemic inflammation and enhancing endothelial function, particularly in patients with diabetes (Ahlstrom and Lamberg-Allardt, 1999; Esaki et al., 1998; Kurosaki and Ogasawara, 2013). Their impact, if any, on TB infection risk in people with diabetes is unknown.

(3). Statins

Like metformin, statins are widely used drugs which inhibit 3-hydroxy-3-methyl glutaryl (HMG)-CoA reductase, and thereby cholesterol biosynthesis (Istvan and Deisenhofer, 2001). Guidelines recommend statins for primary and secondary prevention of cardiovascular events in patients with diabetes (Marx et al., 2023). More recently, statins have been associated with beneficial effects in various infectious diseases (Ray et al., 2010; Vuorio and Kovanen, 2020), including TB. Three recent meta-analyses (Duan et al., 2020; Li et al., 2020; Meregildo-Rodriguez et al., 2022b) of retrospective cohorts, including than 2 million patients, found that the use of statins reduces the risk of incident active TB in people with (RR (95%CI): 0.78 (0.63, 0.95)) and without (RR (95%CI): 0.60 (0.50, 0.71)) diabetes (Duan et al., 2020).

Several mechanisms are thought to mediate these effects of statins. Improved phagosome maturation in murine macrophages with statins has been demonstrated (Parihar et al., 2014), as has decreased intracellular viability of M.tb in the presence of statins (Bruiners et al., 2020; Guerra-De-Blas et al., 2019; Lobato et al., 2014; Parihar et al., 2014). Some of these effects are dose-dependent. Statins modulate lymphocyte, including T helper 1 (T_H1) and T_H2 cells, and macrophage responses including their capacity to produce chemokines and cytokines (Guerra-De-Blas et al., 2019; Matsumoto et al., 2004; Montero-Vega et al., 2024), and autophagy (Guerra-De-Blas et al., 2019; Parihar et al., 2014).

M.tb uses cholesterol in the host macrophage membrane to bind and enter the macrophage (Gatfield and Pieters, 2000). It also accumulates host cholesterol in its own cell wall, thereby decreasing its permeability torifampicin. A reduction in cholesterol by statins may impair the entry of M.tb inside macrophages but improve the entry of rifampicin (Brzostek et al., 2009). Decreasing cholesterol levels also impacts the AMPK-mTORC1-TFEB axis leading to increased autophagy (Bruiners et al., 2020). Contradicting the latter, however, is the fact TB risk reduction has not been demonstrated with non-statin lipid lowering drugs (Pan et al., 2020b). Further, population-based studies suggest lower cholesterol levels may be associated with a higher risk of incident active TB (Jo et al., 2021). Thus, statin-mediated effects are likely driven by cholesterol-independent effects as well as the hydrophilic or lipophilic nature of these drugs (Bruiners et al., 2020; Brzostek et al., 2009; Davuluri et al., 2023; Dutta et al., 2016; Dutta et al., 2020; Gatfield and Pieters, 2000; Guerra-De-Blas et al., 2019; Lobato et al., 2014; Matsumoto et al., 2004; Montero-Vega et al., 2024; Parihar et al., 2014).

Studies assessing the effect of statins on TB treatment outcomes are less frequent and have varied results. In mice and guinea pigs (Figure 2), statin use was associated with reduced mycobacterial burden in the lungs. This was observed in animals dosed with statins before TB infection and where statins were added as adjunct to TB treatment (Davuluri et al., 2023; Dutta et al., 2016; Dutta et al., 2020; Parihar et al., 2014). One retrospective cohort study including patients with comorbid TB and cardiovascular disease showed a lower overall mortality but no apparent improvement in infection-related mortality with statin use (Chidambaram et al., 2021). A study assessing patients with TB and diabetes found a beneficial effect of statins on TB treatment outcomes independent of glucose regulation (Meng et al., 2024). Statin use was also associated with a lower incidence of drug-induced liver injuries during TB treatment (Huang et al., 2024).

Figure 2. An overview of the influence of metformin and statins on the systemic and immune effects of M.tb infection in animal models, primarily those in mice and Guinea pigs.

AMPK: adenosine monophosphate-activated protein kinase; mTORC1: mammalian target of rapamycin complex 1; TFEB: transcription factor EB; Th2: helper T cell subset type 2. Created in BioRender. Kotze, L. (2024) https://BioRender.com/l93g049.

Two RCT have tested the effect of standard ATT versus standard ATT plus adjunctive statins on sputum culture conversion at 8 weeks in humans with PTB. (Cross et al., 2023) included 137 participants from the Philippines, Vietnam and Uganda, and found rosuvastatin had no effect on time to culture conversion. In contrast, (Adewole et al., 2023) found higher frequency (97% vs. 85%; p=0.02) of sputum culture conversion at 8 weeks and a greater reduction in chest radiograph severity scores with atorvastatin among patients with PTB in Nigeria. Both trials found statin use was not associated with an overall increase in adverse events.

(4). Antihypertensives and other drug classes

Various classes of antihypertensive drugs have immunomodulatory actions. These include angiotensin-converting enzyme inhibitors (ACEI), angiotensin II receptor blockers (ARB), and calcium channel blockers (CCB). Variously these actions include dampening of the inflammatory response via lowering pro-inflammatory cytokines like TNF-α, IL-6, and IL-1β, and/or enhancing anti-inflammatory cell responses (Ambrosioni et al., 2001; Brown and Ellis, 1969; Hagiwara et al., 2009; Tuite, 1992); (Benicky et al., 2009; Crowley, 2014; Gurlek et al., 2001; Kasal and Schiffrin, 2012; Sierra and de la Sierra, 2005; Silveira et al., 2013). The latter entails, for example, moving away from a pro-inflammatory Th1 profile and towards a more anti-inflammatory Th2 and T-regulatory cell profile (Arbues et al., 2020; Cardona and Cardona, 2019; Chatterjee et al., 2021; Cooper and Khader, 2008; Pahari et al., 2018; Shakya et al., 2012; Shi et al., 2019), or inducing macrophage polarisation towards the anti-inflammatory M2 phenotype (Carson et al., 2001; Dhande et al., 2015; Schmieder, 2005). There are additional actions like mitigating oxidative stress by ACEI via inhibition of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. This in turn potentially limits tissue damage (Ambrosioni et al., 2001; Brown and Ellis, 1969; Hagiwara et al., 2009; Tuite, 1992).

Whether these immunomodulatory effects can modulate TB risk, and/or improve treatment is a matter of ongoing investigation. One nested case–control analysis using a Taiwanese nationally-representative longitudinally followed cohort (772,000 person-years) found current use of ACEI to be associated with a decreased risk of incident active TB, particularly with chronic use (>90 days), showing a duration-response effect (Wu et al., 2016). Chronic ACEI use was associated with a 26% decrease in TB risk compared to non-users (RR (95%CI): 0.74 (0.66, 0.83)). The decrease in TB risk was also consistent across all age, sex and cardiovascular comorbidity patient subgroups. Meregildo-Rodriguez et al., have recently shown in a meta-analysis including 4 million participants that CCB reduce the risk of developing active TB by 29% (RR (95%CI): 0.71 (0.67, 0.75)) with and without diabetes mellitus (Meregildo-Rodriguez et al., 2024). These protective effects of CCB were independent of the class of CCB used.

Drug interactions and pharmacokinetic implications

Diabetes may impact antitubercular drug pharmacokinetics. Altered body composition in diabetes impacts the distribution of lipophilic drugs like rifampicin and pyrazinamide, potentially leading to subtherapeutic concentrations (McIlleron et al., 2006; Weiner et al., 2004). Hepatic metabolism of isoniazid, rifampicin, and pyrazinamide may be impaired by non-alcoholic fatty liver disease, common in diabetes, increasing risks of toxicity or reduced efficacy (Ruslami et al., 2010). Chronic kidney disease, frequently observed with diabetes, can also reduce clearance of drugs like ethambutol and streptomycin, heightening toxicity risks, notably ethambutol-induced optic neuropathy (Cevik et al., 2024; Ruslami et al., 2010; Sekaggya-Wiltshire and Dooley, 2019).

Concomitant medications for diabetes management also impact tuberculosis treatment. Rifampicin increases metformin exposure without altering its glucose-lowering effects, while metformin reduces exposure to and accelerates clearance of rifampicin, isoniazid, and pyrazinamide (Padmapriydarsini et al., 2022; Te Brake et al., 2019). In vitro, metformin enhances rifampicin and isoniazid activity but hinders ethambutol’s (Trivedi and Chaturvedi, 2023). Rifampicin also reduces simvastatin plasma concentrations (Dutta et al., 2016; Skerry et al., 2014; Kyrklund et al., 2000), necessitating alternative statins like pravastatin or rosuvastatin during tuberculosis treatment. Clinicians should be aware of potential myopathy risk with combined isoniazid and simvastatin therapy (Alffenaar et al., 2016). Therefore, careful consideration of body composition, organ function, and drug-drug interactions is crucial when treating tuberculosis in patients with diabetes. Dose adjustments or therapeutic drug monitoring may be necessary to optimize outcomes and minimize adverse events. Lastly, corticosteroids are regularly prescribed as adjunctive therapy in the treatment of TB, especially in meningeal or pericardial TB or for the treatment or prevention of paradoxical TB immune reconstitution inflammatory syndrome. Their use can lead to hyperglycaemia or dysregulation of existing DM, also in patients with TB (Schutz et al., 2018).

Prevention of TB in people with diabetes

The increased risk of TB and its associated morbidity and mortality underscores the need for targeted interventions to prevent TB. Treatment of TB infection, also known as TB preventive treatment (TPT), is globally recommended for populations at increased risk of TB, such as people living with HIV and individuals who are household contacts of persons with active TB. However, the global recommendation on TPT in people with diabetes does not exist currently unless they belong to risk groups that are eligible for TPT (WHO, 2024). There is a lack of robust evidence from RCTs to definitively inform the benefit-risk profile of TPT in people with diabetes and thus shape practice. In addition, in the absence of trial evidence, there are several factors that necessitates the careful consideration of the benefit and risk of TPT in this group.

First, the risk of TB in individuals with diabetes appears moderate (e.g., 1.5–3.5 fold)(Al-Rifai et al., 2017) compared to other high-risk groups (e.g. 10-fold increase in people living with HIV). Second, people with diabetes tend to be older and thus at higher risk for hepatotoxicity associated with TPT, particularly with the 6–9 months of daily isoniazid, which was until recently the only option for TPT. Third, there is a perceived burden on the health system; 366 million people in low- and middle-income countries where TB burden is high have diabetes, compared to only 30 million living with HIV. This would result in a vast number of individuals needing to be tested for TB infection and initiated on and followed up for TPT, potentially straining health systems. Further, isoniazid may adversely impact glycaemic control antagonizing the effects of sulphonylureas, and impairing insulin metabolism (Boadu et al., 2024a).

Two RCT are currently underway to evaluate the effectiveness of TPT in people with diabetes. The PROTID trial will assess the effectiveness and safety of a 3-month weekly rifapentine plus isoniazid regimen to prevent TB in people with diabetes in a placebo-controlled trial in Uganda and Tanzania (Ntinginya et al., 2022). The BALANCE trial is an open-label RCT evaluating the effectiveness and safety of a 1-month daily rifapentine plus isoniazid regimen compared to standard diabetes care in the Philippines and South Africa. Rifapentine-containing regimens are less hepatotoxic than daily isoniazid regimens and, together with their shorter durations, may alter the benefit-risk balance of TPT in favour of its use (Swindells et al., 2019).

An alternative, if not complementary, strategy to mitigate the risk of TB may be to target host factors. Studies suggest a significant association between poorly controlled diabetes and an increased risk of TB. For example, a cohort study reported that a 10 mg/dL increase in fasting plasma glucose was associated with a 6% increase in TB risk (Lee et al., 2016). Some immunological studies suggest that diabetes treatment restores impaired immune function, which may reverse the increased risk of TB. Metformin might also reduce the TB risk, independent of glycemic effects. A trial to clarify the TB preventive efficacy of metformin would be ideal but given that it is already the first-line treatment for people with diabetes, such a trial may not be feasible, unless tested in people without diabetes. Nevertheless, the ongoing RCT will help determine whether TPT offers additional benefits beyond standard diabetes treatment, including metformin use.

Expert Opinion

The increasing prevalence of type 2 diabetes mellitus in areas of high tuberculosis incidence has created a syndemic. It is now well-recognized that diabetes predisposes to tuberculosis that is more severe, more difficult to treat and more likely to lead to complications. Quantitively more cases of tuberculosis associate with diabetes than with the best−recognized risk factor, HIV-1 co-infection. It is less well recognized that active tuberculosis associates with dysglycaemia which may progress to established diabetes. There is evidence that latent tuberculosis may also associate with impaired glucose tolerance. Underlying this bidirectional relationship are commonalities in immuno-metabolic dysregulation that may therefore represent important therapeutic opportunities. There is some evidence that drugs used to treat diabetes or its complications (e.g. metformin and statins) may have beneficial effects in resolving tuberculosis-induced immunopathology: these effects are not mediated via improved glycaemic control. Other compounds used in the treatment of diabetes such as calcium channel or angiotensin receptor blockers may also exert potential therapeutic benefit in tuberculosis. Conversely the use of corticosteroid therapy in some forms of tuberculosis will tend to exacerbate diabetes. There is a need to more precisely and quantitatively study the effects of tuberculosis and its treatment on glucose metabolism. Immunometabolic dysregulation can be investigated in controlled experimental laboratory models. Similarly, ongoing trials of tuberculosis prevention in people with diabetes should assess the effects of such therapy on glycaemic control and inflammatory markers. Randomized controlled trials of adjunctive therapies in tuberculosis have hitherto shown modest effects: standardized international case registries and experimental medicine studies of outcome in people with diabetes undergoing tuberculosis treatment with very accurate ascertainment, or experimental use, of concomitant medications may offer an alternative to conventional trials of adjunctive therapy which otherwise need to be large and therefore expensive to demonstrate clinically important results.

Article highlights.

• There is a syndemic of diabetes mellitus and Mycobacterium tuberculosis infection.

• Insulin resistance, hyperglycemia, pro-inflammatory cytokine release, aberrant NLRP3 inflammasome activation and oxidative stress occur in both TB and diabetes.

• The hypoglycemic and immunomodulatory effects of antidiabetic medications might deserve consideration as adjuvant host directed therapies in active TB.

• Opportunities for risk stratification and more precise adjuvant host directed therapies in active TB may exist.