Effect of the Dipeptidyl Peptidase-4 Inhibitor Sitagliptin as Monotherapy on Glycemic Control in Patients With Type 2 Diabetes

Aschner P, Kipnes MS, Luncenford JK, Sanchez M, Mickel C, William-Herman DE; Sitagliptin Study 021 Group. Diabetes Care. 2006;29:2632-2637.

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are released by the intestine in response to caloric intake. They stimulate the release of insulin while suppressing release of glucagon in a glucose-dependent manner, and these incretins delay gastric emptying and increase satiety among patients with type 2 diabetes (T2DM). GLP-1 and GIP are rapidly degraded by the enzyme dipeptidyl peptidase-4 (DPP-4), inhibitors of which are a novel class of oral antihyperglycemic agents (OHAs). The slowing of incretin degradation provided by DPP-4 inhibitors can enhance active GLP-1 and GIP levels stimulated by meal intake by 2- to 3-fold.

A multinational, randomized, double-blind, placebo-controlled study was designed to examine the efficacy and safety of once-daily oral sitagliptin (SITA) monotherapy among patients with T2DM (n = 741). Different run-in periods were instituted depending upon patients“ hemoglobin A_1c (A1C) level and prior OHA therapy. Patients who had an A1C between 7% and 10% without having received OHAs for ≥8 weeks were able to directly enter a 2-week single-blind placebo run-in period. Patients that had A1C >10% that were not receiving an OHA entered a run-in period ≤6 weeks. Patients who had an A1C from 6% to 10% while receiving an OHA discontinued the agent and entered a 6- to 10-week wash-out period (8 to 12 weeks for those on a thiazolidinedione [TZD]) followed by a 2-week placebo run-in when their A1C was 7% to 10%. Patients with adequate medication adherence during the placebo run-in period (≥75%) were randomized to SITA 100, SITA 200 mg, or placebo in a 1:1:1 ratio for 24 weeks. Patients were administered rescue therapy with metformin (MET) that was continued until the end of the study if they exceeded the following fasting plasma glucose (FPG) limits: >15.0 mmol/L (270 mg/dL) from baseline through week 6, >13.3 mmol/L (240 mg/dL) from weeks 7 through 12, and >11.1 mmol/L (200 mg/dL) from weeks 13 to 24.

A greater percentage of patients who received placebo (20.6%) than SITA 100 mg (8.8%) or SITA 200 mg (4.8%) required rescue therapy (P <.001 for SITA vs placebo), and the time to rescue therapy was longer in each SITA group than in the placebo group. At the end of the study, both SITA groups had significantly reduced A1C (compared to placebo, SITA 100 mg: -0.79% [95% CI, -0.96 to -0.62], SITA 200 mg: -0.94% [95% CI, -1.11 to -0.77]; both P ≤.001). While only 17% of the placebo group attained A1C <7%, it was achieved by 41% of the 100-mg and 45% of the 200-mg SITA group (P <.001). Among patients with baseline A1C ≥9% the differences in decreases were -1.52% and -1.50% for the 100- and 200-mg groups, respectively, after accounting for the placebo-subtracted reductions. SITA 100-mg and 200-mg groups had significant between-group differences versus placebo in FPG change from baseline of -1.0 mmol/L (-17.1 mg/dL) and -1.2 mmol/L (-21.3 mg/dL), respectively, and those effects were maintained over the entire 24 weeks. Other significant improvements observed in the SITA groups at Week 24 included increased proinsulin-to-insulin ratio (P ≤.01), increased homeostasis model assessment of β-cell function (HOMA-β) (P ≤.01), reduction in 2-hour postprandial glucose (PPG) (100 mg: -2.7 mmol/L [-48.9 mg/dL], 200 mg: -3.1 mmol/L [-56.3 mg/dL], placebo: -0.1 mmol/L [-2.2 mg/dL]; both P <.001), glucose total area under the curve (AUC) (P <.001), insulin total AUC (P <.05), C-peptide total AUC (P <.05), and ratio of insulin AUC to glucose AUC (P <.05). There were no significant differences observed for fasting C-peptide, insulin, proinsulin, homeostasis model assessment of insulin resistance (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), or fasting lipids.

The between-group incidence of overall clinical adverse experiences did not differ, and there were no differences in experiences classified as serious, drug-related, or leading to discontinuation. No adverse experiences resulted in discontinuation of treatment. Hypoglycemia incidence was similar among the groups, and no episodes exhibited marked severity. At the end of the trial SITA 100-mg and 200-mg doses had no significant effects on body weight relative to baseline (-0.2 ± 0.2 kg and -0.1 ± 0.2 kg, respectively), while the change in the placebo group (-1.1 ± 0.2 kg) was significantly different from the others (P <.01).

This study showed that SITA can improve glycemic control and β-cell function for patients with T2DM. These benefits were demonstrated by clinically meaningful reductions in A1C, FPG, and 2-h PPG, and the improvements in A1C and FPG persisted over the entire 24 weeks of this trial. In addition, patients that received SITA had improvements in 2-h PPG and glucose AUC after a standard meal. Along with the benefits in FPG, these results demonstrate that SITA can provide clinically important glucose lowering in both the fasting and postprandial states. SITA also enabled a larger proportion of patients to achieve A1C <7%, and further resulted in fewer patients requiring glycemic rescue therapy with MET and increased the amount of time before patients required such therapy. The authors concluded that these results demonstrate that once-daily SITA monotherapy can provide effective glycemic control for patients with T2DM, and it was generally well-tolerated with rates of hypoglycemia similar to placebo while causing no significant changes in body weight.