Table 6: Other clinical trials that investigate the inhibitory effect of other pharmacological interventions on AGE-RAGE axis.
| Therapeutic drug | Experimental design | Patient characteristics and treatment groups | Treatment duration | Major findings | Reference |
| Azeliragon (RAGE inhibitor) | Double-blind RCT | ≥ 50-years-old, Alzheimer's disease, dementia (n = 60) • Placebo (n = 10) • Low-dose Azeliragon: 30 mg starting dose; 10 mg maintenance (n = 25) • High-dose Azeliragon: 60 mg starting dose; 20 mg maintenance (n = 25) |
10 weeks | • Low-dose regimen was more tolerable than high-dose regimen. • No significant difference in terms of vital signs, plasma level of amyloid β, proinflammatory cytokines and cognitive performance between groups. |
[152] |
| Azeliragon (RAGE inhibitor) | Double-blind RCT | ≥ 50-years-old, Alzheimer's disease (n = 399) • Placebo (n = 133) • Low-dose Azeliragon: 15 mg starting dose; 5 mg maintenance (n = 131) • High-dose Azeliragon: 60 mg starting dose; 20 mg maintenance (n = 135) |
18 months | • High-dose arm was terminated prematurely due to increased adverse event like confusion, falls and cognitive decline. • Low-dose regimen was well-tolerated and delayed cognitive decline. • No significant difference in CSF levels of amyloid β, total tau protein and phospho-tau-181 between groups. |
[137] |
| Azeliragon (RAGE inhibitor) | Double-blind RCT | ≥ 50-years-old, Alzheimer's disease (n = 399) • Placebo (n = 133) • Low-dose Azeliragon: 15 mg starting dose; 5 mg maintenance (n = 131) • High-dose Azeliragon: 60 mg starting dose; 20 mg maintenance (n = 135) |
18 months | • Low-dose regimen slowed down cognitive decline among the patients with mild Alzheimer's disease. | [138] |
| Epalrestat (Aldose reductase inhibitor) | Observational study | T2DM and nondiabetic (n = 66) • Nondiabetic (n = 12) • Untreated T2DM (n = 38) • 150 mg epalrestat (n = 16) |
≥ 2 months | • Treatment with epalrestat was associated with lower erythrocyte CML, 3-DG, triosephosphates, fructose and sorbitol. | [139] |
| Epalrestat (Aldose reductase inhibitor) | Observational study | T2DM (n = 74) • Untreated T2DM (n = 36) • 150 mg epalrestat (n = 38) |
2 years | • Epalrestat reduced CML and slowed down the deterioration of diabetic peripheral neuropathy. | [140] |
| 1, 25 dihydroxyvitamin D3 (Vitamin D) | Observational study | Vitamin D deficit women w/o PCOS (n = 67) • Untreated (n = 16) • 50000 IU vitamin D3 (n = 51) |
8 weeks | • Vitamin D3 supplementation increased circulating sRAGE in women with PCOS, but not in those without PCOS. | [153] |
| Vitamin E | RCT | Nondiabetic patients on haemolysis (n = 16) • Conventional SMC membrane (n = 8) • Vitamin E-coated dialyzer (n = 8) |
42 weeks | • Dialysis with vitamin E-coated membrane lowered pentosidine and AGEs in the bloodstream. | [154] |
| α-lipoic acid | Single-arm | T1DM (n = 9) • 1200 mg α-lipoic acid plus 600 mg benfotiamine |
28 days | • α-lipoic acid plus benfotiamine normalised angiopoietin-2, monocyte hexosamine-modified proteins, prostacyclin synthase activity and AGE formation. | [126] |
| α-lipoic acid | RCT | Diabetic nephropathy (n = 34) • Placebo (n = 17) • 800 mg α-lipoic acid plus 80 mg pyridoxine (n = 17) |
12 weeks | • α-lipoic acid plus pyridoxine lowered urinary albumin, serum malonyldialdehyde and systolic blood pressure and enhanced circulating nitric oxide compared to placebo. • Supplemented group showed significant decline in pentosidine and CML at the end of the experiment compared to baseline. |
[146] |
3-DG: 3-Deoxyglucosone; AGE: Advanced Glycation End Product; CML: Carboxymethyllysine; CSF: Cerebrospinal Fluid; PCOS: Polycystic Ovarian Syndrome; RAGE: Receptor for Advanced Glycation End Product; RCT: Randomised Controlled Trial; T1DM: Type 1 Diabetes Mellitus; T2DM: Type 2 Diabetes Mellitus; SMC: Synthetic Modified Cellulose Membrane.