Efficacy and Safety of Vildagliptin as an Add-on to Insulin with or without Metformin in Japanese Patients with Type 2 Diabetes Mellitus: A 12-week, Double-Blind, Randomized Study

Abstract

Introduction: To assess the efficacy and safety of vildagliptin as add-on therapy in Japanese patients with type 2 diabetes mellitus (T2DM), inadequately controlled on stable long-acting, intermediate-acting, or pre-mixed insulin, with or without concomitant metformin.

Methods: In this 12-week placebo-controlled study, patients were randomized to receive either vildagliptin 50 mg twice daily (bid) or placebo treatment in a 1:1 ratio. The primary endpoint was change in glycated hemoglobin A1c (HbA1c) from baseline to 12-week endpoint. Secondary endpoints included proportion of patients achieving pre-defined HbA1c targets of ≤6.5%, <7.0%, and HbA1c <7.0% in patients with baseline HbA1c ≤8.0% and change in fasting plasma glucose (FPG) after 12 weeks of treatment. Regular monitoring was performed to record any treatment-emergent adverse events (AEs) and serious adverse events or hypoglycemic episodes.

Results: Of the 156 patients randomized, 96.8% completed the study (vildagliptin, n = 76; placebo, n = 75). Patient demographics and clinical characteristics were comparable between the groups at baseline. Addition of vildagliptin resulted in statistically significant reductions in HbA1c after 12 weeks (-1.01 ± 0.06%), with a between-treatment difference of -0.91 ± 0.09% (p < 0.001). FPG levels reduced from baseline to 12 weeks in the vildagliptin group (-1.2 ± 0.2 mmol/L), with a between-treatment difference of -1.2 ± 0.3 mmol/L which was significant (p < 0.001). The proportion of patients achieving HbA1c targets was higher with vildagliptin treatment for all pre-defined responder rate categories. The overall incidence of AEs was comparable between groups (vildagliptin, 46.2% vs. placebo, 43.6%). The overall incidence of hypoglycemic events was low and all events were self-treatable without using drug therapy. No severe hypoglycemic events were reported.

Conclusion: Treatment with vildagliptin 50 mg bid as add-on to insulin with or without metformin resulted in statistically significant reductions in HbA1c in Japanese patients with T2DM. Overall, vildagliptin was well tolerated with a safety profile similar to that of placebo in this patient population. ClinicalTrials.gov Identifier, NCT02002221 FUNDING: Novartis Pharma K.K.

Keywords: Hypoglycemia; Insulin; Japanese; Type 2 diabetes mellitus; Vildagliptin.

Figures

Fig. 1

Study design. *Patients continued on a stable dose of long-acting or intermediate-acting or pre-mixed insulin, and metformin if applicable, throughout the study. BL€ Baseline, the first day of blinded study medication. **Each patient was instructed to visit the study site within 13 weeks from baseline. bid twice daily

Fig. 2

Patient disposition

Fig. 3

a Mean HbA1c (%) by treatment and visit. Unadjusted means and standard errors (verticalbars) are presented. Study endpoint is defined as the final available post-randomization assessment obtained at any visit (scheduled or unscheduled), prior to the start of major changes in insulin background therapy, up to the final scheduled visit including week 12. bid twice daily, BL baseline, EP endpoint, HbA1c glycated hemoglobin. b Change in HbA1c (%) from baseline to study endpoint. *p < 0.001. Study endpoint is defined as the final available post-randomization assessment obtained at any visit (scheduled or unscheduled), prior to the start of major changes in insulin background therapy, up to the final scheduled visit including week 12. bid twice daily, BL baseline, HbA1c glycated hemoglobin, SE standard error

Fig. 4

a Mean FPG (mmol/L) by treatment and visit. Unadjusted means and standard errors (verticalbars) are presented. bid twice daily, BL baseline, EP endpoint, FPG fasting plasma glucose. b Change in FPG (mmol/L) from baseline to endpoint by treatment. *p < 0.001. Baseline is measurement obtained on day 1, or the sample obtained on an earlier visit (scheduled or unscheduled) which was closest to day 1, if day 1 measurement is missing. Study endpoint is defined as the final available post-randomization assessment obtained at any visit (scheduled or unscheduled), prior to the start of major changes in insulin background therapy, up to the final scheduled visit including week 12. bid twice daily, BL baseline, FPG fasting plasma glucose, SE standard error