Nateglinide improves glycaemic control when added to metformin monotherapy: results of a randomized trial with type 2 diabetes patients

Diabetes Obes Metab. 2002 May;4(3):177-86. doi: 10.1046/j.1463-1326.2002.00196.x.


Aims/hypothesis: This study evaluated the addition of nateglinide, a d-phenylalanine derivative that restores early phase insulin release, to metformin in type 2 diabetes patients stabilized on high-dose metformin.

Methods: This multicentre, double-blind, parallel group trial included 467 metformin-treated patients with glycosylated haemoglobin (HbA1c) between 6.8% and 11%. Patients were randomized to add nateglinide 60 mg, 120 mg or placebo before three meals to metformin 1000 mg b.i.d. for 24 weeks.

Results: HbA1c was significantly reduced with nateglinide 60 mg and 120 mg plus metformin compared with metformin control (-0.36%, p = 0.003; -0.59%, p < 0.001 respectively). Greater benefits occurred if patients had elevated HbA1c at baseline (-1.38% with nateglinide 120 mg in patients with HbA1c > 9.5%). A modest fasting plasma glucose reduction was observed. Most symptoms suggestive of hypoglycaemia occurred in patients with low HbA1c levels (<or= 8%) at baseline, although no confirmed cases of hypoglycaemia occurred with nateglinide 60 mg in this patient group. Events suggestive of hypoglycaemia were confirmed in 1.1% of cases (plasma glucose <or= 3.3 mmol/l). Weight gain over 24 weeks was 0.9 kg with nateglinide 120 mg vs. metformin alone, and plasma lipids remained unchanged.

Conclusions/interpretation: In patients stabilized on high-dose metformin, the addition of nateglinide improved glycaemic control. The combination of these agents was well tolerated and both doses of nateglinide proved effective. The efficacy of nateglinide 60 mg and the low rate of hypoglycaemia observed at this dose make it suitable for patients close to their therapeutic target on metformin monotherapy.

Publication types

  • Clinical Trial
  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Blood Glucose / metabolism*
  • Body Mass Index
  • Body Weight
  • Cholesterol / blood
  • Continental Population Groups
  • Cyclohexanes / therapeutic use*
  • Diabetes Mellitus, Type 2 / blood*
  • Diabetes Mellitus, Type 2 / drug therapy
  • Double-Blind Method
  • Drug Therapy, Combination
  • Female
  • Glycated Hemoglobin A / metabolism
  • Humans
  • Hypoglycemic Agents / therapeutic use*
  • Male
  • Metformin / therapeutic use*
  • Middle Aged
  • Nateglinide
  • Phenylalanine / analogs & derivatives*
  • Phenylalanine / therapeutic use*
  • Placebos
  • Safety
  • Triglycerides / blood


  • Blood Glucose
  • Cyclohexanes
  • Glycated Hemoglobin A
  • Hypoglycemic Agents
  • Placebos
  • Triglycerides
  • Nateglinide
  • Phenylalanine
  • Metformin
  • Cholesterol