Effect of saxagliptin monotherapy in treatment-naïve patients with type 2 diabetes

ABSTRACT

Objective: To evaluate the efficacy and safety of once-daily saxagliptin monotherapy in treatment-naïve patients with type 2 diabetes (T2D) and inadequate glycemic control.

Research design and methods: This study included a main treatment cohort (MTC) with 401 patients (HbA_1c ≥ 7% and ≤10%) randomized and treated with oral saxagliptin 2.5, 5, or 10 mg once daily or placebo for 24 weeks and a separate open-label cohort (OLC) with 66 patients (HbA_1c > 10% and ≤12%) who received saxagliptin 10 mg once daily for 24 weeks. Primary endpoint was HbA_1c change from baseline to week 24. Secondary endpoints included change from baseline to week 24 in fasting plasma glucose (FPG), proportion of patients achieving HbA_1c < 7%, and changes in postprandial glucose area-under-the-curve (PPG-AUC). Efficacy analyses for continuous variables were performed using an ANCOVA model with last-observation-carried-forward methodology.

Results: In the MTC, saxagliptin demonstrated statistically significant decreases in adjusted mean HbA_1c changes from baseline (mean, 7.9%) to week 24 (−0.43%, −0.46%, −0.54%) for saxagliptin 2.5, 5, and 10 mg, respectively, vs. +0.19% for placebo (all p < 0.0001). Adjusted mean FPG was significantly reduced from baseline (−15, −9, −17 mg/dL) for saxagliptin 2.5, 5, and 10 mg, respectively, vs. +6 mg/dL for placebo (p = 0.0002, p = 0.0074, p < 0.0001, respectively). More saxagliptin-treated patients achieved HbA_1c < 7% at week 24 (35% [p = NS], 38% [p = 0.0443], 41% [p = 0.0133]) for saxagliptin 2.5, 5, and 10 mg, respectively, than placebo (24%). PPG-AUC was reduced for saxagliptin 2.5, 5, and 10 mg (−6868, −6896, −8084 mg·min/dL, respectively) vs. placebo (−647 mg·min/dL) with statistical significance demonstrated for saxagliptin 5 mg (p = 0.0002) and 10 mg (p < 0.0001). HbA_1c, FPG, and PPG-AUC reductions were also observed in the OLC at 24 weeks. In the MTC, adverse event frequency was similar across all study arms. No cases of confirmed hypoglycemia (symptoms, with fingerstick glucose ≤50 mg/dL) were observed in either cohort. Saxagliptin was not associated with weight gain. Study limitations included the lack of a control group for the OLC and the use of prespecified rescue criteria, which limited the exposure time during which patients could remain on their originally randomized medication without the introduction of additional antihyperglycemic rescue treatment.

Conclusions: Once-daily saxagliptin monotherapy for 24 weeks was generally well tolerated and demonstrated clinically meaningful reductions in key parameters of glycemic control vs. placebo.

Trial Registration: Clinical Trials NCT00121641

Keywords: :

• Dipeptidyl peptidase-4 inhibitor
• Glycemic control
• Incretin
• Monotherapy
• Saxagliptin
• Type 2 diabetes

Transparency

Declaration of funding

Funding for this study was provided by Bristol-Myers Squibb and AstraZeneca.

Declaration of financial/other relationships

J.R. has disclosed that he has served on advisory boards and received honoraria or consulting fees from Pfizer, Roche, sanofi-aventis, Novo Nordisk and several other pharmaceutical companies. He has also disclosed that he has received research grants from Bristol-Myers Squibb, AstraZeneca and several other pharmaceutical companies. C.A-S. has disclosed that he has served on advisory boards and received honoraria from Bristol-Myers Squibb and Merck Sharp & Dohme, and that he has received grant support from sanofi-aventis. E.K. has disclosed that he has conducted research studies for Bristol-Myers Squibb, AstraZeneca and several other pharmaceutical companies, and has received honoraria for speaking engagements from Bristol-Myers Squibb, Amylin, Merck, and sanofi-aventis. S.N., J.L. and R.C. have disclosed that they are employees of Bristol-Myers Squibb.

All peer reviewers receive honoraria from CMRO for their review work. Peer reviewer 1 has disclosed that he/she has received research support grants from AstraZeneca and several other pharmaceutical companies and from NIH and ADA. He/she also has disclosed that he/she has received honoraria for consulting and lectures from several pharmaceutical companies including GlaxoSmithKline, Novartis, Takeda, and Pfizer. The other peer reviewer has disclosed that he/she has no relevant financial relationships.

Acknowledgment

The authors gratefully acknowledge the study participants and site staff who assisted with this research. The authors also thank Kathleen Langenbacher and Karen May for management of the CV181-011 study protocol. Technical and editorial assistance for this manuscript was provided by Jennifer Ciafullo, MPH, Innovex Medical Communications.

The results of this study were presented in poster form at the 68th Scientific Sessions of the American Diabetes Association, San Francisco, CA, USA, June 6–10, 2008 and at the 13th International Congress of Endocrinology, Rio de Janeiro, Brazil, November 8–12, 2008.