Tuberculosis-diabetes comorbidities: Mechanistic insights for clinical considerations and treatment challenges

Abstract

Tuberculosis (TB) remains a leading cause of death among infectious diseases, particularly in poor countries. Viral infections, multidrug-resistant and ex-tensively drug-resistant TB strains, as well as the coexistence of chronic illnesses such as diabetes mellitus (DM) greatly aggravate TB morbidity and mortality. DM [particularly type 2 DM (T2DM)] and TB have converged making their control even more challenging. Two contemporary global epidemics, TB-DM behaves like a syndemic, a synergistic confluence of two highly prevalent diseases. T2DM is a risk factor for developing more severe forms of multi-drug resistant-TB and TB recurrence after preventive treatment. Since a bidirectional relationship exists between TB and DM, it is necessary to concurrently treat both, and promote recommendations for the joint management of both diseases. There are also some drug-drug interactions resulting in adverse treatment outcomes in TB-DM patients including treatment failure, and reinfection. In addition, autophagy may play a role in these comorbidities. Therefore, the TB-DM comorbidities present several health challenges, requiring a focus on multidisciplinary collaboration and integrated strategies, to effectively deal with this double burden. To effectively manage the comorbidity, further screening in affected countries, more suitable drugs, and better treatment strategies are required.

Key Words: Diabetes mellitus, Tuberculosis, Coinfections, Comorbidity, Drug-drug interactions, Autophagy, Treatment challenges

Core Tip: Tuberculosis (TB)-diabetes mellitus (DM) comorbidities are major health problems due to the increasing number of type 2 DM (T2DM) cases in developing countries, where active TB is prevalent. This can negatively affect the outcomes of TB-DM treatments. T2DM is commonly related to obesity and is being increasingly recognized as a risk factor for TB, whereas TB may worsen glycemic control among DM patients. These bidirectional relationships require more effective drugs, better treatment strategies, and the need to adjust dose schedules for controlling hyperglycemia during active TB infection.

INTRODUCTION

Tuberculosis (TB) is caused by Mycobacterium tuberculosis (Mtb), and type 2 diabetes mellitus (T2DM), is a metabolic disorder characterized by hyperglycemia and insulin resistance. The association between TB and diabetes mellitus (DM) was recognized by Avicenna as early as 1000 AD, and Yugimahamuni, a traditional Indian saint described a cluster of symptoms called ‘meganoikal’ for the TB-DM association[1]. T2DM patients mainly suffer from being overweight, excessive thirst and polyuria[1,2]. Juvenile diabetes was linked with a 10-fold higher risk of pulmonary TB[3,4] and tuberculous diabetic clinics were established in the United Kingdom to improve outcomes for patients with TB-DM[4,5]. Several epidemiological studies indicated that DM is a risk factor for TB in the 1990s based on the increasing prevalence of T2DM in low- and middle-income countries (LMICs) where TB remained endemic[4,6]. This relationship was over-shadowed firstly by the emergence of the acquired immune deficiency syndrome epidemic[7], and secondly by the Coronavirus disease 2019 (COVID-19) pandemic[8]. However, several studies have supported the solid link between TB-DM[9,10]. The global TB Union and the WHO developed a collaborative framework for TB-diabetes issued by the “Bali declaration”[11]; and TANDEM (TB and DM) program, through which the TB Union and the World Diabetes Foundation aimed to prevent the convergence of the TB-DM co-epidemic globally[12,13]. In 2021, it was estimated that 537 million people worldwide had DM. More than 80% of T2DM cases are found in LMICs and in areas where TB remains endemic. Moreover, DM is associated with microvascular and macrovascular complications that predominantly result from hyperglycemia[2,14,15].

Bidirectional relationship between TB and DM

TB remains the leading cause of death from a single infectious microorganism, with almost 25% of the human population currently infected with either latent or active TB[16]. DM is an independent risk factor for lower respiratory infections including TB and the two often coexist[1,17,18]. DM-TB comorbidity behaves like a syndemic, in that there is a synergistic confluence of the two conditions[8]. DM is a risk factor for developing severe forms of TB such as active TB (about three fold)[16,19], latent TB infection (LTBI) (approximately two fold)[8], TB recurrence after preventive treatment[16] and worsened TB outcomes after therapeutic treatment[8,16], higher rates of treatment failure, relapse and recurrence of infection and mortality[4,19,20].

Diabetic patients are susceptible to infections and may experience severe illness due to compromised immune system[2]. Various studies have shown that 5%-30% of patients with multi-drug resistant (MDR)-TB also have DM[19]. On the other hand, patients with diabetes have a higher risk of developing MDR-TB, with serious adverse reactions related to the complicated treatment of these diseases[8]. DM may play an important role in the development of resistance to the first-line anti-TB drugs such as rifampin and second-line anti-TB drugs such as linezolid[21-23].

TB itself is an identified factor for glucose intolerance[19] and metabolic alterations[24] that can cause tuberculous pancreatitis with pancreatic endocrine hypofunction resulting in hyperglycemia[8]. Importantly, there is a rising incidence of pre-diabetics worldwide, particularly in TB endemic areas[4]. TB-DM patients may have worse symptoms such as weight loss, dyspnea, and prolonged fever[20], which can worsen in case of poor glycemic control[20,25,26].

Pathophysiological mechanisms underlying TB-DM interaction: Since the interactions between TB and DM are multifactorial[1], several mechanisms are shown in Figure 1.

Figure 1 Pathophysiological relationships between tuberculosis and diabetes mellitus and impacts of exogenous and endogenous factors. Both tuberculosis and diabetes mellitus show a bidirectional relationship at various points as depicted, which are affected by exogenous and endogenous factors. GH: Growth hormone; HCV: Hepatitis C virus; ART: Antiretroviral therapy; CTLA-4: Cytotoxic T-lymphocyte associated protein 4; PD-1: Programmed cell death protein 1; PDL-1: Programmed cell death ligand 1; IR: Insulin resistance; TB: Tuberculosis; COVID-19: Coronavirus disease 2019; HIV: Human immunodeficiency virus; MDR: Multi-drug resistant; XDR: Extreme drug resistance; TDR: Total drug-resistance; IL: Interleukin; TNFα: Tumor necrosis factor alpha.

Immune cell alterations in TB-DM

It has been shown that the number and function of immune cells such as macrophages and lymphocytes are significantly compromised by metabolic alterations in TB-DM patients[27,28]. The susceptibility of DM patients to TB infection is mainly due to reduced cellular immunity caused by decreasing numbers and function of T-lymphocytes particularly T-helper 1 (TH1) cells[1]. TH1 cytokines such as interleukin (IL)-1 and IL-6 are reduced in patients with concomitant DM-TB compared to non-diabetic individuals. The impaired function of macrophages in DM patients is associated with oxidative stress products including reactive oxygen species (ROS), dysregulated phagocytosis, and chemotactic action[1,2]. This immune dysfunction in DM may play an important role in the reactivation of TB from endogenous LTBI and increase the susceptibility of hosts to exogenous reinfection[1,29]. Hyperglycemia also impairs the force of the respiratory burst that contributes to expelling Mtb, and this stress response to infection may also be associated with dysglycemia, a situation mediated by the effect of IL-1, IL-6, and tumor necrosis factor alpha[1].

Oxidative stress-mediated alterations in TB-DM

Chronic inflammatory diseases such as TB and DM are linked pathogenetically to oxidative stress[27,28], and in DM, intrinsic predispositions including age, family history, and extrinsic factors such as smoking all enhance oxidative stress[30,31]. Increased expression of efflux pumps may be responsible for the phenotypic tolerance of Mtb persisters to anti-TB drugs such as rifampicin in DM patients[32-34].

Advanced glycation end-products mediated alterations in TB-DM

Oxidative stress in patients with diabetes is linked to the formation of advanced glycation end-products (AGEs), the product of the chemical reactions of proteins with sugars[31,35,36]. An increase in ROS has been positively correlated to enriched AGEs and hyperglycemia, and resveratrol, an antioxidant present in grapes and berries, can ameliorate this effect[31,37]. Excess AGEs in DM patients are involved in the pathophysiology of chronic complications such as diabetic cardiomyopathy via the induced dysfunction of endothelial progenitor cells[38]. AGEs can act in both receptor-dependent and receptor-independent mechanisms. The receptor of AGE (also called RAGE), a Class III MHC protein receptor, has been found on the surface of immune cells, and plays important roles in controlling TB[31]. Macroautophagy (hereafter referred to as autophagy) is a cytoprotective pathway for the clearance of cellular debris upon exposure to various stressors such as oxidative stress. RAGE has been associated with autophagy via its primary ligands, high-mobility group box 1[39,40], and the establishment of neutrophil extracellular traps (NETs)[41]. Mtb has been shown to induce NETs that can activate and trigger the release of pro-inflammatory cytokines by macrophages[31]. Metformin, a prototypical antidiabetic agent, can reduce the impact of AGE production via suppression of soluble RAGE in an AMP-activated protein kinase (AMPK, a key metabolic and energy regulator)-dependent fashion[31,41,42]. The peroxisome proliferator-activated receptor gamma (PPAR) γ agonist rosiglitazone restores AGE-induced dysfunction of endothelial progenitor cells and relieves DM-related vascular complications via activation of the PI3K-AKT-endothelial NO synthase (eNOS) pathway[31,36]. In addition, glucagon-like peptide-1 (GLP-1) and GLP-1 receptor agonists, such as exendin-4, have been proposed as targets for treating diabetes and protecting against diabetic cardiomyopathy[31,43].

Autophagy-mediated alterations in TB-DM: Autophagy occurs during normal development at the basal level, and selectively targets intracellular pathogens (e.g., mycobacteria called xenophagy) under various stresses, including oxidative stress[44,45-47]. Autophagy functions as a protective process in the pathogenesis of most lung diseases by maintaining cellular homeostasis[48]. Accumulating evidence suggests that any dysregulation of autophagy mechanisms or any mutation in autophagy-related genes (ATGs) may contribute to multiple human diseases including TB[49,50] and DM[51,52]. When mycobacteria gain entry to the cytosol, the rupture of mycobacteria-containing phagosomes stimulates autophagy that selectively degrades or inhibits intracellular mycobacteria survival[53,54]. In addition, activation of mycobacterial killing in infected macrophages via phagosome maturation can be assisted by induction of autophagy using metformin[54-56]. Furthermore, autophagy can contribute to the eradication of Mtb by enhancing antimicrobial activity and modulating inflammation[50,52]. However, Mtb can prevent autolysosome formation and degradation in macrophages by secreting different virulence factors[52]. Mtb has also adopted a mechanism that can combat host autophagy of immune cells by interacting with several essential ATGs so that it can survive within host cells (mac-rophages) for an extended period in the dormant LTBI stage[45,52,57,58]. In most cases, LTBI populations act as an important reservoir for disease reactivation and active TB infection in immunocompromised conditions[45]. Thus, given the importance of autophagy in the maintenance of intracellular homeostasis, autophagy modulators offer host-directed therapeutic (HDT) opportunities to control TB infection and represent promising candidates to combat DM. Sodium-glucose co-transporter 2 (SGLT2) inhibitors such as empagliflozin and dapagliflozin play a critical role in glycemic regulation in T2DM[59,60]. In addition, SGLT2 inhibitors have a beneficial impact on many pathophysiological disturbances including kidney disease[61,62] and atherosclerotic cardiovascular events with and without DM[59,63]. Additional cardiorenal protective mechanisms of SGLT2 inhibitors are linked to their antifibrotic effects that correct inflammation and reduce oxidative stress via modulation of mitochondrial function and autophagy[59]. Persistent hyperglycemia increases intracellular stress, including ROS generation and disruption of normal cellular functioning that leads to chronic inflammation, dysregulated energy metabolism, and insulin resistance in DM. As a cleansing mechanism, autophagy can alleviate these imbalances and restore cellular homeostasis. However, the efficiency of autophagy declines with age and overnutrition, and disrupted autophagy has been linked to the pathogenesis of metabolic disorders, including DM[64]. Several nutrient-sensing pathways, such as downstream of Sirtuin1 (SIRT1), which is involved in the regulation of autophagy, have been proposed as therapeutic targets for reducing the progression of type 1 and T2DM[64-68]. SIRT1 activation can dampen Mtb -mediated persistent inflammatory responses and reduce intracellular growth of Mtb via the induction of phagosome-lysosome fusion and autophagy[69]. SIRT1 also antagonizes oxidative stress in the pathogenesis of DM through several important signal mediators, such as AMPK, NADPH oxidase, and eNOS[70]. As a natural SIRT1 activator, resveratrol induces phagolysosome fusion and autophagy, and restricts Mtb growth in vitro and in vivo[71-73]. SIRT1 also cooperates with AMPK and antagonizes oxidative stress in DM[70,74]. Moreover, forkhead TFs, PPARα, and PPARγ co-activator 1 (PGC-1α) are common targets for SIRT1 and AMPK[70,75]. Therefore, activating AMPK and SIRT1 together can reduce oxidative stress in DM by activating these downstream effectors[70] (Figure 2).

Figure 2 Mechanistic insights into the pathophysiologies of tuberculosis and diabetes mellitus interactions. Mtb: Mycobacterium tuberculosis; IFN: Interferon; HDT: Host-directed therapy; Eis: Enhanced intracellular survival; ESAT-6: Early secretory antigenic target; ESX-1: Secretion system-1; vitD3: Vitamin D3; ROS: Reactive oxygen species; LAP: Microtubule-associated protein light-chain 3-associated phagocytosis; VDR: Vitamin D receptor; CAMP: Cathelicidin antimicrobial peptide; iNOS: Inducible nitric oxide synthase; RAAS: Renin–angiotensin–aldosterone system; IR: Insulin resistance; PXR: Rifampicin activates pregnane X receptor; N-CoR: The nuclear receptor corepressor; PPAR: Peroxisome proliferator-activated receptor; RXR: Retinoic acid receptor; ORF: Open reading frame; OATP2: The sinusoidal transporters organic anion transporting protein 2; DDIs: Drug-drug interactions; RIF: Rifampin.

The dilemma of rational co-management of TB-DM comorbidities: Mechanistic insights into drug-drug interactions

Traditionally, standard TB treatment consists of four anti-TB drugs (rifampicin, isoniazid, pyrazinamide, and ethambutol) for an initial intensive phase of 2 months followed by any two drugs for a further 4-month continuation phase[1,18]. The Food and Drug Administration and the American Diabetes Association have approved several oral hypoglycemic drugs including sulfonylureas (glipizide), biguanides (metformin), thiazolidinediones (rosiglitazone), meglitinides (repaglinide), α-glucosidase inhibitors (acarbose), dipeptidyl peptidase (DPP)-IV inhibitors (the gliptins analogues), SGLT2 inhibitors (dapagliflozin), cycloset (bromocriptine) and bile acid sequestrants (colesevelam) for the treatment of T2DM[76,77].

Metformin remains the first line anti-glycemic agent for T2DM because it activates several mechanisms of controlling hyperglycaemia[18,78]. Metformin can be applied as an adjunct to anti-TB drugs like isoniazid, as it can reduce mycobacterial growth by inducing mitochondrial ROS production[20,78] and suppress excessive inflammation and lung tissue injury[79] via inhibition of the nuclear factor κB pathway irrespective of DM status[80,81]. Due to its efficacy in both prevention and treatment outcomes, metformin is a potential candidate for HDT in TB-DM patients[82,83]. In today's world, rifampin (international nonproprietary name, rifampicin) remains one of the most effective and broad-spectrum cornerstone drugs in TB treatment and an active alternative in treating other infections[84]. The combination of isoniazid with rifampicin is used as a TB treatment regime, however sub-therapeutic plasma concentrations of both drugs have been reported, with levels lower by approximately 50% in TB-DM patients[20,34,81,85]. Pyrazinamide is a prodrug that is metabolized by deamidase and xanthine oxidase (XO), a superoxide-generating enzyme to form its active metabolites[117]. Interestingly, the activity of XO increases in liver and plasma of DM patients significantly and is involved in ROS production in type 1 DM[86,87]. Thus, higher doses of pyrazinamide are required for the treatment of TB in patients with uncontrolled DM[20,86,88]. Due to the well-known adverse effect of peripheral- and optic neuropathy, multiple dose regimens of ethambutol should be lowered when treated TB patients with complicated DM[89-91]. Other anti-tuberculous drugs, such as bedaquiline, pretomanid and delamanid, are on the way towards approval, ready to be used in the TB treatment regime. Due to high binding to plasma proteins, co-administration of bedaquiline and delamanid may compete for plasma protein-binding sites, thereby affecting the free drug concentration[20,85] (Figure 2). Importantly, information related to the current management and treatment gaps for comorbidity is required and needs further study.

Metabolizing enzymes, cytochrome P450 and transporter-mediated drug-drug interactions

Drug efficacy results from the interplay of pharmacokinetic parameters such as drug absorption, distribution, metabolism, and excretion. Drug metabolizing enzymes such as cytochrome P450 enzymes (CYP) located intracellularly, and transport proteins located in distinct membrane domains, are important for drug efficacy. Rifampicin induces several drug-metabolizing enzymes, including CYP3A4 in the liver and small intestine, and drug transporter proteins, such as intestinal and hepatic p-glycoprotein[84]. By promoting the expression of CYP3A4 and CYP2C8/9[20,92], rifampicin reduces the plasma concentrations of their substrates[84,93] including most of the oral hypoglycemic agents[93] and thereby leads to hyperglycemia. Hence, monitoring blood glucose levels and adjusting antidiabetic medications such as sulfonylureas in TB-DM is critical to avoid hypoglycemic episodes[20,84]. On the other hand, isoniazid impairs the CYP2C9 metabolism of sulfonylureas, which worsens glycemic control[1]. Isoniazid also interferes with the release and function of insulin resulting in hyperglycemia even in normal subjects. Therefore, dose adjustment of sulfonylureas or insulin is necessary during the therapeutic usage of these drugs[34].

Metformin is not metabolized by CYP2C to a significant extent[84,89,94], its transport is p-glycoprotein-independent[81] and thus it can be a good alternative for combination with rifampicin, bedaquiline or delamanid due to minimal pharmacokinetic drug-drug interactions (DDIs). However, metformin is a substrate for the solute carrier (SLC) tran-sporters in humans, namely organic cation transporter (OCT1; SLC22 subfamily) and other transporters[89,95], whereas rifampicin increases OCT1 mRNA levels and metformin uptake by the liver, enhancing glucose reduction in healthy subjects[96] and lactic acidosis, the main side effects[89,97]. Rifampicin also alters metformin plasma exposure but not blood glucose levels in DM-TB patients[20,98].

Several anti-TB drugs such as ethambutol are substrates for the SLC transporters in humans namely OCT1/2/3, organic anion transporter (OAT; SLC22 subfamily) families and multidrug and toxin extrusion (MATE), MATE proteins 1 and 2K[22,25,99,100]. These transporters play a major role in the disposition and pharmacology of drugs and thus are important regulators for DDIs[22,25]. Since fluoroquinolones such as moxifloxacin or ciprofloxacin[101] may act as potent inhibitors of OCT1 and MATEs, these agents have shown to reduce the cellular uptake of ethambutol, isoniazid, and metformin in vitro[99], and produce dysglycemia in general[102]. Therefore, additional studies are necessary to focus specific treatment on TB-DM patients[99]. Bedaquiline is metabolized by the CYP3A4 to form N-monodesmethyl metabolite, a major circulating intermediate. Both bedaquiline and its metabolites show bactericidal effects dose dependently and inhibit several transporters, organic anion-transporting polypeptide 1B1 and OCT1/2 essential for the transport of sulfonylureas and SGLT2 inhibitors[85]. Also, concurrent use of bedaquiline and delamanid with hypoglycemic agents including insulin analogues prolong the heart rate and hepatic-related adverse reactions[85]. Further research and post-marketing studies are needed to establish and understand the possible interactions of these new drugs. DPP IV inhibitors (the gliptins) may reduce immunocompetence (immune paresis)[2]; and possibly worsen treatment outcomes of patients with TB[1].

Receptor-mediated DDIs

Vitamin A exists in the form of retinol, retinal and retinoic acid (RA) that act as ligands of nuclear receptors such as RA receptor (RAR) and retinoid X receptor (RXR)[102]. Two significant derivatives; 9-cis-RA and all-trans-RA (ATRA) are related to RA. 9-cis RA, an isomerization product of ATRA is found to be a cognate ligand for RXRs. ATRA acts as an endogenous ligand for nuclear RAR that can act as a ligand-inducible transcription factor[103,104]. On the other hand, RXR molecules forming permissive heterodimers with disparate nuclear receptors comprise pregnane X receptor (PXR, NR1I2), constitutive androstane receptor (CAR or NR113), PPARs, liver X receptors and farnesoid X receptor (FXR)[103-105]. The dihydroxyvitamin D3 receptor (VDR) was found to form a nonpermissive heterodimer, while RARs and thyroid hormone receptors form conditional heterodimers[106]. Thus, RXRs are important molecules for controlling various cellular functions under normal conditions and diseases, including DM and TB[106].

In general, PXR and CAR are located largely in the hepatocyte cell membranes, acting as suppressors of transcription by binding with corepressors[107]. As a dimerization partner binding to PXR or CAR, RXRα produces a transcriptionally active heterodimer, this leads to transcription of target genes[108-110]. Hepatic nuclear factor 4α (HNF4α) is recognized as the key transcription factor for PXR. CYP3A4 has also been identified as a specific cis-acting gene enhancer element, conferring HNF4α binding and promoting PXR- and CAR-mediated hepatic gene activation[93,111]. Additionally, many transcription cofactors have been shown to regulate PXR activity, such as members of the p160 family, including steroid receptor coactivators, as well as the PPAR-α[112,113].

Interestingly, activation of PXR and CAR can be regulated by many ligands, inducing the expression of several target genes, including CYP3A4, CYP2C9, and CYP1A2, which are highly expressed in hepatocytes[114]. Accordingly, the accelerated blood clearance activity of PXR and CAR affects the pharmacokinetics (PK) of hepatic enzyme substrates, resulting in increased substrate elimination[115,116]. The human PXR is activated by several molecules including antibiotics, and bile acids, and PXR activation regulates several of xenobiotic-inducible genes including CYP3A4, glutathione S-transferases, sulfotransferases, UDP-glucuronosyltransferases (UGTs) and p-glycoprotein resulting in undesirable effects clinically including harmful DDIs in patients on combination therapy[84,117]. Therefore, detecting PXR activity using various assays can help in the development of safer prescription drugs. In mice, PXR also regulates the expression of the drug transporter genes such as OATP2, MDR protein 1 (MDR1) and MDR-associated proteins 2 and 3[117]. Rifampicin is also involved in DDI by inducing gut (enterocytic) CYP3A4 as well as its own metabolism (autoinduction)[93]. Roscovitine, a cyclin-dependent kinase inhibitor enhances the expressions of UGT1A1, CYP2B6 or CYP3A4, and activates PXR in a ligand-independent manner in HepG2 cells in comparison with the CAR and aryl hydrocarbon receptor[118,119]. UGT1A catalyses the glucuronidation of a wide range of xenobiotics and endogenous substrates. It can be induced by rifampicin through both PXR- and CAR -mediated expression[93,113]. P-glycoprotein is a plasma membrane-bound drug efflux (MDR pump) belonging to the ATP binding cassette superfamily of transport proteins, which are encoded by the MDR genes. Rifampicin induces p-glycoprotein in addition to PXR that induces CYP3A4 and reduction of the intracellular concentration of drug substrates by transmembrane efflux[93]. In addition, rifampicin was found to activate PXR- mediated MDR1 gene expression for the efflux of several drugs and drug conjugates[120]. Furthermore, PXR is involved in the regulation of OATP2, an uptake transporter that uptakes of drugs from blood into the hepatocytes[84]. It is also found that OCT1 (SLC22A1) expression is also upregulated by PXR agonists in chronic myeloid leukemia cells[121]. Another receptor, CAR, is also involved in CYP3A4 transcriptional regulation by binding to PXR, which affects CYP3A4 expression[93]. The liver is the main metabolic organ for glucose homeostasis and the accumulation of bile acids can induce hepatotoxicity. Thus, the activation of multiple bile acid receptors such as CAR, FXR, PXR, VDR is preventive against this toxicity by downregulating the bile acid efflux transporters such as OATP1A1, OATP1A4 and MRP3[82,92].

Clinical considerations and recommendations

Due to these multidrug regimens of anti-TB and anti-DM therapies, DDIs, unwanted PK/pharmacodynamics (PD) effects and adverse events including nephrotoxicity, ocular toxicity, neurotoxicity, liver injury and teratogenicity have been reported in the literature[101]. Thus, rational management of combined TB-DM is important but challenging for several reasons: (1) Both DM and active TB may affect the PK and pharmacodynamic parameters of drugs, resulting in lower efficacy and increased toxicity[81,122,123]; (2) compared with nondiabetics, DM reduces the immune responses needed to control TB infection, resulting in a higher rate of therapy failure, death, and recurrence of TB in patients with DM[81,124]; (3) anti-TB drugs such as inhibitors (isoniazid) or inducers (rifampicin) of the CYP enzymes, which are regularly used for TB patients can alter plasma concentrations of hypoglycemic and other anti-TB drugs[81]; and (4) although several anti-TB drugs such as bedaquiline, delamanid, clofazimine, linezolid and carbapenems are concurrently used for the treatment of MDR-TB and extreme drug resistance-TB cases, these drugs cannot show efficacy in DM patients with and active TB[18,125,126]. For properly managing patients with concurrent TB-DM, some key clinical considerations, and recommendations[4,13,89] are included here, as shown below.

Patient education and counselling: Informing patients with TB and DM about the nature of the disease, the duration of treatment, adverse effects of drugs, and disease complications[1]. Intense counselling for promotion of healthy lifestyle choices, dealing with medication adherence and starting insulin therapy as necessary in TB-DM patients.

Consciousness of DDIs: Rifampicin increases metabolism of the major anti-diabetes drugs, and COVID-19/human immunodeficiency virus (HIV) treatment is likely to incur additional DDIs. In these cases, more studies are needed on DDIs between co-administered drugs and between new and existing drugs during the development of new anti-TB drugs and combination regimens[127]. This can help avoid DDIs to ensure therapeutic success and reduce the curve of TB-related mortality.

Therapeutic drug-monitoring: Proper understanding of possible DDIs before designing an anti-TB regimen is mandatory to improve the quality of patient life. Updated knowledge of anti-TB drugs and PK/PD parameters coupled with therapeutic drug-monitoring (TDM)[85] are important for guiding physicians towards effective treatments. For example, chronic hyperglycemia mitigates the efficiency of the anti-TB treatment and affects the elimination of Mtb for optimal immune surveillance. Moreover, a low plasma level of anti-TB drugs in DM patients has been observed compared to non-DM patients. Thus, TDM intervention may establish effective dosing, specifically in uncontrolled DM patients[93,128,129].

Treatment adherence: Perfect adherence to prescribed regimens is a cornerstone for individuals infected with MDR Mtb strains as the therapy typically lasts for around 2 years and involves multiple doses, which can increase the risk of drug-related adverse events. Improper intake of medication by the patient or abandonment of treatment can be for multiple reasons, e.g., quiescent disease symptoms, prior perception of high pill burden[89,98] or adverse effects from the combination of TB and DM drugs[20]. Up to 30% TB-DM patients experience a higher incidence of gastrointestinal adverse effects (nausea and vomiting) when treated with metformin and rifampicin[18] that possibly lead to non-adherence and poor treatment outcome[98]. Thus, TB-DM patients should complete the entire course of TB treatment, while also controlling their DM with diet, lifestyle modifications and specific drugs to avoid possible DDIs[20,130].

Simultaneous TB-DM screening: Although recommendations have been made for screening and diagnosis of combined TB-DM, there is little evidence regarding the efficacy of specific TB testing in individuals with DM and specific DM tests for patients with TB. Because comorbidity represents a risk factor for dangerous TB outcomes, TB clinics provide specific care for this type of illness[18,89,131]. Therefore, further studies are needed to improve the screening of TB patients for diabetes and TB screening in diabetics from a public health perspective, particularly in developing countries where the double burden of TB and diabetes is high. Screening and diagnosing combined TB-DM morbidities according to WHO/IDF recommendations could be a valuable tool.

It is important to pay close attention when constructing the care cascade process for every individual case[132]. Wherever necessary, these patients should be assessed by interdisciplinary specialists, including endocrinologists to confirm the DM diagnosis[20,58], pharmacologists to confirm overlapping toxicities with different types of drugs[72,103], and medical specialists to confirm the risk of coinfection (HIV, COVID-19) or comorbidities (cardiovascular or other diseases)[133]. This is because TB-DM patients vary in terms of frequency of complications such as heart disease, liver and renal problems and other diseases associated with comorbidities[4]. Table 1 summarizes the interactions between anti-TB drugs with anti-DM drugs[134-145].

Table 1 Interactions between anti-tuberculosis drugs with anti- diabetes mellitus drugs.

Anti-DM drug	Anti-TB drug	Interaction effects	Expected clinical effects
Biguanides
Metformin	Rifampin (RIF, INN, rifampicin)	RIF induces upregulation of metformin effects	Promotes glucose-lowering effect of metformin[98]
Sulfonylurea group
Tolbutamide	Rifampin (INN, rifampicin)	RIF promotes the CYP2C9 and reduces in tolbutamide plasma conc	Hyperglycemia and diminished anti-TB efficacy over time[18,84]
Glyburide (INN, glibenclamide)	Rifampin (INN, rifampicin)	RIF promotes the CYP2C9 and reduces 39% glyburide conc	Hyperglycemia and diminished anti-TB efficacy over time[134]
Glyburide (INN, glibenclamide)	Rifapentine	Rifapentine induces CYP3A4 and CYP2C8/9 expressions and reduces glyburide plasma conc	Hyperglycemia[81,135]
Glyburide (INN, glibenclamide)	Bedaquiline	Glyburide inhibits CYP3A4 in liver	[85,136]
Glyburide (INN, glibenclamide)	Delamanid	Glyburide inhibits CYP3A4 in liver	[85,136]
Gliclazide	Rifampin (INN, rifampicin)	RIF decreases plasma conc. of gliclazide by 70% by inducing CYP2C9	Hyperglycemia and diminished anti-TB efficacy over time[18,137]
Gliclazide	Rifapentine	Rifapentine induces CYP3A4 and CYP2C8/9 and decreases gliclazide	Hyperglycemia[81]
Gliclazide	Bedaquiline	M2 of bedaquiline inhibits effects on CYP3A4 and CYP2C8	Hypoglycemic episodes[85]
Gliclazide	Delamanid	No crossing interaction	[85]
Glimepiride	Rifampin (INN, rifampicin)	RIF promotes the expression of CYP2C9 reducing in 34% of glimepiride conc	Hyperglycemia and diminished anti-TB efficacy over time[138]
Glipizide	Rifampin (INN, rifampicin)	RIF promotes CYP2C9 and reduces 22% of glipizide conc	Hyperglycemia and diminished anti-TB efficacy over time[134]
Gliquidone	Rifapentine	Rifapentine induces CYP3A4 and CYP2C8/9 and decreases gliquidone	Hyperglycemia[81]
Gliquidone	Bedaquiline	M2 of bedaquiline inhibits CYP3A4 effects	Hypoglycemic episodes[85]
Gliquidone	Delamanid	Delamanid induces CYP3A4 and decreases gliquidone level	[85]
Meglitinide analogues
Repaglinide	Rifampin (INN, rifampicin)	RIF promotes CYP3A4 and reduces repaglinide conc. 57%	Hyperglycemia and diminished anti-TB efficacy over time[18,138-140]
Repaglinide	Rifapentine	Rifapentine induces CYP3A4 and CYP2C8 and decreases repaglinide level	Hyperglycemia[81]
Repaglinide	Bedaquiline	Interindividual variability	Variable hypoglycemic episodes[85,141]
Repaglinide	Delamanid	Interindividual variability	Variable hypoglycemic episodes[85,141]
Nateglinide	Rifampin (INN, rifampicin)	RIF promotes CYP3A4 and CYP2C9 and reduces nateglinide conc by 24%.	Hyperglycemia and diminished anti-TB efficacy over time[84]
Nateglinide	Rifapentine	Rifapentine induces CYP3A4 and CYP2C9 and decreases nateglinide level	Hyperglycemia[81]
Nateglinide	Bedaquiline	M2 of bedaquiline inhibits effects on CYP3A4	Hypoglycemic episodes[85]
Nateglinide	Delamanid	Coadministration of delamanid with nateglinide reduces exposure to delamanid	TB reactivation[85,142]
Thiazolidinediones
Rosiglitazone	Rifampin (INN, rifampicin)	RIF promotes CYP2C8 and reduces of rosiglitazone conc by 65%	Hyperglycemia and diminished anti-TB efficacy over time[18,92]
Rosiglitazone	Rifapentine	Rifapentine induces CYP3A4 and CYP2C9 and decreases rosiglitazone level	Hyperglycemia[81]
Rosiglitazone	Bedaquiline	M2 of bedaquiline inhibits effects on CYP2A8	Hypoglycemic episodes[85]
Rosiglitazone	Delamanid	No crossing	[116]
Pioglitazone	Rifampin (INN, rifampicin)	RIF promotes CYP2C8 and reduces pioglitazone conc by 65%	Hyperglycemia and diminished anti-TB efficacy over time[20,62,143]
Pioglitazone	Rifapentine	Rifapentine induces CYP3A4 and CYP2C8 and decreases pioglitazone level	Hyperglycemia[81]
Pioglitazone	Bedaquiline	In combination with bedaquiline, pioglitazone may cause severe acute rhabdomyolysis	Dose-independent myalgia[85,144]
Pioglitazone	Delamanid	Inhibitory effects on CYP3A4	Hypoglycemic episodes[85]
Dipeptidyl peptidase IV inhibitors
Sitagliptin	Rifapentine	Rifapentine induces CYP3A4 and CYP2C8 and decreases sitagliptin level	Hyperglycemia[81]
Sitagliptin	Bedaquiline	M2 of bedaquiline inhibits effects on CYP3A4 and CYP2A8	Hypoglycemic episodes[85]
Sitagliptin	Delamanid	Inhibitory effects on CYP3A4	Hypoglycemic episodes[85]
Saxagliptin	Rifapentine	Rifapentine induces CYP3A4 and decreases saxagliptin level	Hyperglycemia[81]
Saxagliptin	Bedaquiline	M2 of bedaquiline inhibits effects on CYP3A4	Hypoglycemic episodes[85]
Saxagliptin	Delamanid	Inhibitory effects on CYP3A4	Hypoglycemic episodes[85]
Insulin		No effect anticipated	No studies published[85]
Isoniazid	In DM patients	Isoniazid in combination with rifampicin causes hepatotoxicity TB-DM patients (50%)	Low Anti-TB efficacy[34,84,128,129]
Isoniazid	HIV-positive patient with type 2 DM	Prophylaxis of TB	Hyperglycaemia induced by isoniazid[20,145]
Pyrazinamide	In DM patients	DM patients with higher levels of xanthine oxidase causes low therapeutic targets for pyrazinamide	TB resistance[20,86,88]
Ethambutol	In DM patients	Neuritis optica in patients with complicated diabetes. Reduced kidney function in TB-DM patients	Enhances side effects[20,89]

CYP: Cytochrome P450; DM: Diabetes mellitus; TB: Tuberculosis; INN: International nonproprietary name; RIF: Rifampin.

CONCLUSION

DM and TB have a bidirectional relationship with epidemiological implications since T2DM is becoming more prevalent in TB-endemic settings. The alarming increase in DM (particularly T2DM) cases in developing countries where active TB is prevalent will negatively influence the outcomes of TB-DM treatments shortly. DM associated with higher age and body weight is considered a risk factor for TB, potentially affecting its presentation, while TB may negatively affect glycemic control in patients with DM. This bidirectional relationship demands more suitable drugs, better treatment strategies, and the need to properly adjust dose schedules for diabetic patients' therapy during active TB infection.