Effect of adding sitagliptin, a dipeptidyl peptidase-4 inhibitor, to metformin on 24-h glycaemic control and beta-cell function in patients with type 2 diabetes

Diabetes Obes Metab. 2007 Mar;9(2):186-93. doi: 10.1111/j.1463-1326.2006.00691.x.


Aim: The aim of this study was to assess the effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on 24-h glucose control when added to the regimen of patients with type 2 diabetes who had inadequate glycaemic control on metformin therapy.

Methods: In a double-blind, randomized, placebo-controlled, two-period crossover study, patients with type 2 diabetes with inadequate glycaemic control on metformin monotherapy (i.e. on a stable dose of > or = 1500 mg/day for > or = 6 weeks prior to the screening visit and an haemoglobin A(1c) (HbA(1c)) > or = 6.5% and <10% and fasting plasma glucose (FPG) < or = 240 mg/dl) were recruited for participation. A total of 28 patients (baseline HbA(1c) range = 6.5-9.6%) receiving metformin were randomized into one of two treatment sequences: the addition of placebo for 4 weeks followed by the addition of sitagliptin 50 mg twice daily (b.i.d.) for 4 weeks, or vice versa. At the end of each treatment period, patients were domiciled for frequent blood sampling over 24 h. The primary endpoint was 24-h weighted mean glucose (WMG) and secondary endpoints included change in FPG, mean of 7 daily self-blood glucose measurements (MDG) and fructosamine. beta-cell function was assessed from glucose and C-peptide concentrations were measured during the 5-h period after a standard breakfast meal by using the C-peptide minimal model.

Results: Despite a carryover effect from period 1 to period 2, the combined period 1 and period 2 results for glycaemic endpoints were statistically significant for sitagliptin relative to placebo when added to ongoing metformin therapy. To account for the carryover effect, the period 1 results were also compared between the groups. Following period 1, there were significant least-squares (LS) mean reductions in 24-h WMG of 32.8 mg/dl, significant LS mean reduction from baseline in MDG of 28 mg/dl, FPG of 20.3 mg/dl and fructosamine of 33.7 mmol/l in patients treated with sitagliptin relative to placebo (p < 0.05). When added to ongoing metformin therapy, parameters of beta-cell function were significantly improved with sitagliptin compared with placebo. No weight gain or increases in gastrointestinal adverse events or hypoglycaemia events were observed with sitagliptin relative to placebo during this study.

Conclusions: In this study, the addition of sitagliptin 50 mg b.i.d. to ongoing metformin therapy improved 24-h glycaemic control and beta-cell function, and was generally well tolerated in patients with type 2 diabetes.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Blood Glucose / metabolism
  • Cross-Over Studies
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / physiopathology
  • Dipeptidyl Peptidase 4
  • Dipeptidyl-Peptidase IV Inhibitors
  • Female
  • Humans
  • Hypoglycemic Agents / adverse effects
  • Hypoglycemic Agents / therapeutic use*
  • Insulin-Secreting Cells / physiology*
  • Male
  • Metformin / adverse effects
  • Metformin / therapeutic use*
  • Middle Aged
  • Protease Inhibitors / adverse effects
  • Protease Inhibitors / therapeutic use
  • Pyrazines / adverse effects
  • Pyrazines / therapeutic use*
  • Sitagliptin Phosphate
  • Treatment Outcome
  • Triazoles / adverse effects
  • Triazoles / therapeutic use*


  • Blood Glucose
  • Dipeptidyl-Peptidase IV Inhibitors
  • Hypoglycemic Agents
  • Protease Inhibitors
  • Pyrazines
  • Triazoles
  • Metformin
  • DPP4 protein, human
  • Dipeptidyl Peptidase 4
  • Sitagliptin Phosphate