Randomized Dose Ranging Study of the Reduction of Fasting and Postprandial Glucose in Type 2 Diabetes by Nateglinide (A-4166)

  1. Fiona M. Gribble, MA, BM, BCH, DPHIL1,
  2. Susan E. Manley, PHD2 and
  3. Jonathan C. Levy, BSC, MD2
  1. 1Department of Clinical Biochemistry, Addenbrooke’s Hospital, Cambridge
  2. 2Diabetes Research Laboratories, Radcliffe Infirmary, Oxford, U.K.


    OBJECTIVE—This randomized crossover double-blind placebo-controlled study aimed to assess the efficacy of nateglinide (A-4166), a novel phenylalanine-derived insulin secretagogue, in type 2 diabetic subjects while fasting and 5 min before a standard meal.

    RESEARCH DESIGN AND METHODS—A single dose of nateglinide (60, 120, or 180 mg) or placebo was given to eight diet-treated overnight-fasted type 2 diabetic patients and to seven patients 5 min before a standard breakfast. Plasma glucose, radioimmunoassay insulin, and nateglinide were measured at baseline and for a further 180 min.

    RESULTS—The time-averaged 180-min postdose mean decrease in fasting plasma glucose concentration was greater after nateglinide (1.8 mmol/l; 95% CI 1.5–2.0) than after placebo (0.7 mmol/l; 95% CI 0.3–1.2) (P < 0.001). Hypoglycemia did not develop in any of the subjects. Insulin concentrations increased 1.5-, 1.8-, and 1.9-fold with the 60-, 120-, and 180-mg doses, respectively (P < 0.001), peaking ∼30 min after the dose. Nateglinide concentrations peaked after ∼30 min, decreasing to 21% of peak by 180 min. In the meal test, the mean increase (2.9 mmol/l, 2.3–3.6) in plasma glucose over 180 min after placebo was reduced by 1.8 mmol/l (P < 0.001) with the two higher doses of nateglinide.

    CONCLUSIONS—A single dose of nateglinide administered to diet-treated type 2 diabetic patients with fasting hyperglycemia increased insulin secretion and reduced fasting glucose without hypoglycemia. Administered 5 min before a meal, nateglinide reduced the postprandial glucose excursion by 64%. With its rapid onset and short duration of action, nateglinide is a promising oral prandial therapy in type 2 diabetes.


    • Address correspondence and reprint requests to Dr. Jonathan C. Levy, The Radcliffe Infirmary NHS Trust, Woodstock Road, Oxford OX2 6HE. E-mail: jonathan.levy{at}

      Received for publication 16 January 2001 and accepted in revised form 30 March 2001.

      J.C.L. has received a consulting fee from Novartis for participation in the U.K. West Midlands Advisory Board. Novartis is currently marketing nateglinide in the U.K. under the trade name Starlix.

      A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

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