65-OR: Effects of Treatment with Metformin and/or Sitagliptin on Beta-Cell Function and Insulin Resistance in Prediabetic Women with Previous Gestational Diabetes

Gestational diabetes (GDM) enhances the risk of type 2 diabetes (T2D) with 20-50% of women progressing to T2D within 10-years after pregnancy. Preventative strategies, including use of pharmacologic agents, are worth considering. We assessed, in a randomized double-blind study, the effect of 16-week therapy with sitagliptin (SITA, 100 mg qd), metformin (MET, 850 mg bid), and SITA+MET (50+850 mg bid) on beta-cell function and insulin sensitivity in women (n=40, age 30-49 y) with recent GDM and impaired glucose regulation (IGR: IFG and/or IGT). A 75gr OGTT and +125 mg/dl hyperglycemic clamp followed by 5 gr i.v. L-arginine were performed at baseline and study-end. Baseline characteristics were comparable in the 3 groups. At week 16, BMI declined in all groups (-1.2±0.2 Kg/m²; p<0.05). First phase_{(2-10 min)} insulin secretion and arginine-stimulated C-peptide response increased with SITA+MET (1.0±0.2 to 1.3±0.3 ng/ml/min and 3.2±0.6 to 4.8±1.0 pmol/min, respectively, both p<0.05) while no changes occurred with MET and SITA. SITA+MET increased OGTT-based glucose sensitivity (55.7±11.3 to 108±56.2 pmol x min^-1m^-2 x mM^-1; p=0.04) but no changes occurred with MET and SITA. No change occurred for rate sensitivity and potentiation factor in any group. SITA+MET increased insulin sensitivity (M/I: 2.2±0.5 to 4.6±1.3 mg/kg/min÷μIU/min/ml; p=0.04; OGIS: 351.9±11.4 to 375.7±9.6 ml x min^-1m^-2; p=0.08) but it was not affected by MET or SITA. Disposition Index increased with SITA+MET (10.8±1.1 to 13.6±1.6 μIU/ml/min÷mg/dl/min) and SITA (8.6±1.0 to 10.6±1.3; both p<0.05). Among SITA+MET women, 33% reverted to NGT compared to 14% with MET and 7% with SITA (p<0.05). This proof of concept study shows that SITA+MET is superior to SITA and MET monotherapy on beta-cell function and insulin sensitivity improvement in IGR women with previous GDM. It may offer a potential pharmacologic intervention to reduce risk of T2D in this high-risk population.