Ketoconazole enantiomer for the treatment of diabetes mellitus.
The impact of hypercortisolism on multiple metabolic conditions is well recognized; the metabolic manifestations of Cushing's syndrome overlap with those seen in type 2 diabetes and the metabolic syndrome. Ketoconazole (KTZ), a widely used antifungal agent that inhibits various enzymes in adrenal cortisol synthesis, is effective in treating hypercortisolemia, but its use is limited by toxicities. KTZ is a racemic compound of two cis-enantiomers: (2R,4S)-(+)-KTZ and (2S,4R)-(-)-KTZ. The consideration of an enantiomer with selective effect but minimal metabolic toxicity has driven the development of DIO-902 ([2S,4R]-[-]-KTZ) for the treatment of patients with type 2 diabetes and the metabolic syndrome. To evaluate the safety profile and effect of KTZ enantiomer, (2S,4R)-(-)-KTZ, on cortisol production, glycemia, and lipid profiles in patients with type 2 diabetes. Review of multiple published studies and examination of preliminary results from a Phase IIb clinical trial. Twelve weeks of treatment with DIO-902 resulted in reduced levels of HbA1c, FPG, total and LDL cholesterol as well as weight loss and decreased BP. In a previously conducted Phase IIa study, C-reactive protein levels decreased with DIO-902 treatment. Unfortunately, the development of this agent has been terminated due to unacceptable safety profiles.
Arakaki
Richard
R
University of Hawaii-Manoa, John A Burns School of Medicine, Department of Medicine, 677 Ala Moana Blvd, 1024, Honolulu, Hawaii 96813, USA. rfarakak@hawaii.edu
Welles
Bernice
B
D000311:Adrenal Glands / Q000187:drug effects; D017322:Clinical Trials, Phase II as Topic; D003924:Diabetes Mellitus, Type 2 / Q000139:chemically induced / Q000188:drug therapy*; D006801:Humans; D006854:Hydrocortisone / Q000009:adverse effects / Q000096:biosynthesis; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D007654:Ketoconazole / Q000009:adverse effects / Q000627:therapeutic use*; D008111:Liver Function Tests; D013237:Stereoisomerism; D016896:Treatment Outcome
D007004:Hypoglycemic Agents; D007654:Ketoconazole; D006854:Hydrocortisone