Dipeptidyl peptidase-4 inhibition in patients with type 2 diabetes treated with saxagliptin, sitagliptin, or vildagliptin

Abstract

Introduction: Saxagliptin, sitagliptin, and vildagliptin are dipeptidyl peptidase-4 (DPP-4) inhibitors widely approved for use in patients with type 2 diabetes. Using a crossover design, the present study compared trough levels of DPP-4 inhibition provided by these agents in a single cohort of patients with type 2 diabetes.

Methods: This was a randomized, placebo-controlled, open-label, five-period crossover study. Eligible patients were 18-65 years of age, either treatment-naïve or off prior antihyperglycemic agent therapy for at least 6 or 12 weeks (depending on the prior therapy), and had glycated hemoglobin (HbA1C) ≥6.5% and ≤10.0%. In separate study periods, patients received 5 mg saxagliptin q.d. (saxa-5), 100 mg sitagliptin q.d. (sita-100), 50 mg vildagliptin q.d. (vilda-50-q.d.), 50 mg vildagliptin b.i.d. (vilda-50-b.i.d.), or placebo for 5 days. The primary endpoint was trough %DPP-4 inhibition, derived by comparing DPP-4 activity 24 h after the Day-5 morning dose with predose activity in the same period and analyzed using a linear mixed-effects model with fixed-effects terms for treatment and period.

Results: Mean (range) baseline HbA1C was 7.4% (6.4-9.0%; N = 22). Least-squares (LS) mean trough %DPP-4 inhibition was 73.5%, 91.7%, 28.9%, 90.6%, and 3.5% after saxa-5, sita-100, vilda-50-q.d., vilda-50-b.i.d., and placebo, respectively. In patients treated with sita-100, the LS-mean difference in trough %DPP-4 inhibition was 18.2% greater than with saxa-5 (p < 0.001), 62.9% greater than with vilda-50-q.d. (p < 0.001), 1.1% greater than with vilda-50-b.i.d. (p = 0.128), and 87.8% greater than with placebo (p < 0.001). Mean %DPP-4 inhibition was nearly maximal at 12 h postdose regardless of active treatment. Thus, these between-group comparisons at trough primarily reflected differences in duration of action. Adverse events reported during the study were transient and mild or moderate in intensity.

Conclusion: Once daily treatment with sitagliptin provided trough DPP-4 inhibition significantly greater than saxagliptin or vildagliptin administered once daily, and similar to that provided by vildagliptin administered twice daily.

Figures

Fig. 1

Mean (±standard error) percent dipeptidyl peptidase-4 (DPP-4) inhibition over time in plasma collected a predose on Days 1–5 of treatment with 5 mg saxagliptin q.d., 100 mg sitagliptin q.d., 50 mg vildagliptin q.d., 50 mg vildagliptin b.i.d., and placebo, and b at the indicated times on Days 5–9. The measurement at 12 h postdose on Day 5 was obtained before the second vildagliptin b.i.d. dose was administered. The dashed horizontal lines indicate 94% inhibition, the maximum level of DPP-4 inhibition that was quantifiable under the assay conditions used in this study. SE standard error