CLINICAL TRIALS Repaglinide in Type 2 Diabetes: A 24-Week, Fixed-Dose Efficacy and Safety Study Lois Jovanovic, MD, George Dailey III, MD, Won-Chin Huang, PhD, Poul Strange, MD, PhD, and Barry J. Goldstein, MD, PhD In this 24-week multicenter, double-blind, randomized, fixed-dose trial, 361 patients having type 2 diabetes recL. ved daily preprandial treatment with placebo (n = 75), repa- glinide 1 mg (n = 140), or repaglinide 4 mg (n = 146). By a last-observation carried-forward calculation, repaglinide 1 mg or 4 mg treatment decreased mean fasting plasma glucose (FPG) values (by -47 mg/dL or -49 mg/dL) while the placebo group had increased FPG values (by 19 mg/dL). For the 3 he pathology of glucose intolerance in type 2 dia- betes commonly includes an impairment of insu- lin release by pancreatic islet n-cells in response to elevated plasma glucose levels. It has been postulated that abnormalities in metabolic processing of glucose in f3-cells may impair the increases in ATP levels that normally trigger closing of ATP-sensitive potassium channels in the plasma membrane.' The closure of such channels results in membrane depo- larization, leading to insulin release. Repaglinide, a new oral hypoglycemic agent (OHA), produces an insulinotropic effect by promoting potassium chan- nel closure.23 Repaglinide has distinct features of its mechanism of action when compared to sulfony- lureas since it does not produce a direct stimulation of insulin release by exocytosis.4 The insulin release induced by repaglinide is glucose dependent, with From Sansum Medical Research Institute, Santa Barbara, California (Dr. Jovanovic); Scripps Clinic & Research Foundation, La Jolla, California (Dr. Dailey); Novo Nordisk Pharmaceuticals, Inc., Princeton, New Jersey (Dr. Huang, Dr. Strange), and Thomas Jefferson University, Philadelphia, Penn- sylvania (Dr. Goldstein). This study was supported by Novo Nordisk Phar- maceuticals, Inc., Princeton, New Jersey. Submitted for publication June 7, 1 999; revised version accepted September 21, 1 999. Address for reprints: Dr. Lois Jovanovic, Sansum Medical Research Institute, 221 9 Bath Street, Santa Barbara, CA 93105. J Clin Pharmacol 2000;40:49-57 B9-856 001i0043 repaglinide treatment groups at the end of the study, changes in HbAIC from baseline values ranged from 1.8 to 1.9 percent- age points lower than the placebo group. There were no events of severe hypoglycemia. Nearly all hypoglycemic symptom episodes had blood glucose levels above 45 mg/dL. Repa- glinide was well tolerated in a preprandialfixed-dose regimen of 1 mg or 4 mg, assigned without adjustment for clinical parameters. Journal of Clinical Pharmacology, 2000;40:49-57 ©2000 the American College of Clinical Pharmacology increased response occurring at elevated plasma glu- cose levels.4 Repaglinide has rapid absorption and elimination, resulting in short-term bioavailability in plasma.5 The rapid, nearly complete absorption of repaglinide from the gastrointestinal tract results in correspondingly rapid plasma availability6 and allows administration of repaglinide immediately before a meal. Repaglinide is metabolized in the liver, producing metabolites that are lacking in clinically relevant hypoglycemic activ- ity.7 Repaglinide excretion occurs principally by a bili- ary route, and the absence of significant renal excre- tion (only 8% of the drug) may offer possible treatment advantages in patients with renal impairment. The efficacy and safety of repaglinide were exam- ined in an earlier 18-week, placebo-controlled, dose- adjustment trial in patients with type 2 diabetes.8 The smaller clinical trial (66 repaglinide-treated patients) reported a 1.7% reduction in HbA,(1 values relative to the placebo group. The clinical trial described below was designed to extend those efficacy results and to assess the safety of a longer period of repaglinide treat- ment. This study compared the efficacy and safety of repaglinide to that of placebo during a 24-week treat- ment period. Repaglinide was administered in a ran- domly assigned fixed-dose regimen at preprandial doses of 1 mg or 4 mg. 49