Table 2: Clinical findings of the effectiveness of glucose-lowering medications on AGE-RAGE axis.
| Therapeutic drug | Experimental design | Patient characteristics and treatment groups | Treatment duration | Major findings | Reference |
| Metformin (Biguanides) | Observational | T2DM (n = 57) • Non-metformin (n = 27) • 500-2500 mg metformin (n = 30) |
≥ 3 months | • High-dose (1500-2500 mg) metformin reduced plasma methylglyoxal compared to low-dose (≤ 1000 mg) and non-metformin treatment. • Detoxified methylglyoxal, D-lactate level increased with metformin treatment. |
[60] |
| Metformin | RCT | T2DM (n = 99) • Lifestyle modification (n = 49) • 1000 mg metformin (n = 50) |
3 months | • Metformin reduced AOPP, AGE and increased FRAP. • No difference in LCAT and PON. |
[62] |
| Metformin | Double-blind RCT | T2DM (n = 208) • Placebo (n = 98) • 850-2000 mg metformin (n = 110) |
24 weeks | • Metformin reduced ROS, AGEs and pentosidine, increased total thiol and NO levels, restored CRP, improved ATPase activity without affecting calcium and magnesium levels. | [61] |
| Metformin Pioglitazone (TZD) | RCT | T2DM (n = 129) • No medication (n = 49) • 30 mg pioglitazone (n = 30) • 1000 mg metformin (n = 50) |
3 months | • Metformin increased FRAP. • Pioglitazone significantly restored LCAT and LPL enzymatic activity. • Both metformin and pioglitazone were equally effective at reducing AGE and AOPP. |
[64] |
| Metformin Repaglinide (meglitinide) |
Double-blind crossover study | T2DM (n = 96) • 6 mg repaglinide • 2 g metformin |
4 months for each drug and 1 month washout/td> | • Metformin reduced pro-inflammatory markers like TNF-α, plasminogen activator inhibitor-1 antigen, tissue-type plasminogen activator antigen, von Willebrand factor, soluble intercellular adhesion molecule-1 and soluble E-selectin. • Repaglinide reduced heart rate and Amadori products. • Both drugs had similar effects on IL-6, fibrinogen, VCAM-1, asymmetric dimethylarginine, AGEs and glycaemic level. |
[63] |
| Pioglitazone Rosiglitazone (TZDs) |
RCT | T2DM (n = 60) • Placebo (n = 21) • 30 mg pioglitazone (n = 19) • 4 mg rosiglitazone (n = 20) |
12 weeks | • Pioglitazone increased sRAGE more significantly compared to other treatments. | [69] |
| Rosiglitazone (TZD) Glibenclamide/Gliclazide (sulfonylurea) |
Randomised, parallel group study | T2DM (n = 64) • 5 mg glibenclamide/80 mg gliclazide (n = 32) • 4 mg rosiglitazone (n = 32) |
24 weeks | • Rosiglitazone or sulfonylurea reduced HbA1c, fasting glucose and AGE. • Only rosiglitazone increased sRAGE and esRAGE. |
[68] |
| Pioglitazone (TZD) Glimepiride (sulfonylurea) |
Randomised, parallel group study | T2DM (n = 57) • 15-30 mg pioglitazone (n = 27) • 0.5-2 mg glimepiride (n = 30) |
24 weeks | • Pioglitazone led to higher increase in circulating plasma esRAGE and sRAGE. • Suppression of RAGE expression in mononuclear cells was more significant in pioglitazone-treated groups. |
[75] |
| Alogliptin (DPP4 inhibitor) | Single-arm study | T2DM (n = 61) • 25 mg alogliptin |
12 weeks | • Alogliptin reduced fasting glucose, glycoalbumin, HbA1c, sRAGE and urine albumin-to-creatinine ratio. • AGE level was reduced only in patients with high AGE level. |
[74] |
AGE: Advanced Glycation End Product; AOPP: Advanced Oxidation Protein Products; CRP: C-Reactive Protein; DPP4: Dipeptidyl Peptidase-4; esRAGE: Endogenous Secretory Receptor for Advanced Glycation End Product; FRAP: Ferric Reducing Antioxidant Power; IL-6: Interleukin-6; LCAT: Lecithin-Cholesterol Acyltransferase; LPL: Lipoprotein Lipase; NO: Nitric Oxide; PON: Paraoxonase; RCT: Randomised Controlled Trial; ROS: Reactive Oxygen Species; sRAGE: Soluble Receptor For Advanced Glycation End Product; T2DM: Type 2 Diabetes Mellitus; TNF-α: Tumour Necrosis Factor-α; TZD: Thiazolidinedione; VCAM-1: Vascular Cell Adhesion Molecule-1.