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

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.