Clinical Drug Investigation

, Volume 33, Issue 10, pp 707–717

Saxagliptin Add-on Therapy to Insulin With or Without Metformin for Type 2 Diabetes Mellitus: 52-Week Safety and Efficacy

  • Anthony H. Barnett
  • Bernard Charbonnel
  • Jia Li
  • Mark Donovan
  • Douglas Fleming
  • Nayyar Iqbal
Original Research Article

Abstract

Background

Achievement of glycemic control is an important objective in the management of type 2 diabetes mellitus (T2DM).

Objective

The objective of this study was to evaluate the safety and efficacy of the dipeptidyl peptidase-4 inhibitor saxagliptin versus placebo as add-on therapy in patients with T2DM inadequately controlled with insulin alone or insulin plus metformin.

Methods

This was a long-term (28-week) extension of a short-term (24-week), randomized, double-blind, parallel-group trial of saxagliptin 5 mg once daily versus placebo as add-on therapy to open-label insulin or insulin plus metformin therapy totaling 52 weeks of treatment. In contrast with the goal of maintaining a stable insulin dosage during the short-term phase, during the extension phase the insulin dosage was flexible and adjusted as deemed appropriate by the investigator. The study was conducted in a clinical practice setting, including family practice and hospital sites. Patients with T2DM aged 18–78 years with glycated hemoglobin (HbA1c) 7.5–11 % on a stable insulin regimen (30–150 U/day with or without metformin) for ≥8 weeks at screening were included in the study. Patients were stratified by metformin use and randomly assigned 2:1 to oral saxagliptin 5 mg (n = 304) or placebo (n = 151) once daily. All patients who completed the initial 24 weeks of treatment were eligible to participate in the 28-week extension, regardless of whether they had required rescue treatment. The main outcome measure was change in HbA1c from baseline to week 52.

Results

In general, the outcomes achieved at week 24 were sustained to week 52. Adjusted mean change from baseline HbA1c at week 52 was greater with saxagliptin (−0.75 %) versus placebo (−0.38 %); the adjusted between-group difference was −0.37 % (95 % CI −0.55 to −0.19); between-group differences were similar in patients treated with metformin (−0.37 % [95 % CI −0.59 to −0.15]) and without metformin (−0.37 % [95 % CI −0.69 to −0.04]). At week 52, a greater proportion of patients receiving saxagliptin achieved HbA1c <7 % than those receiving placebo (21.3 vs. 8.7 %; between-group difference 12.6 % [95 % CI 6.1–19.1]). The increase from baseline in mean total daily insulin dose at week 52 was numerically smaller with saxagliptin (5.67 vs 6.67 U with placebo; difference, −1.01 U [95 % CI −3.24 to 1.22]). During the 52-week study period, the proportion of patients reporting ≥1 adverse event (AE) was 66.4 % with saxagliptin and 71.5 % with placebo, the majority being mild or moderate in intensity. The most common AEs (≥5 % with saxagliptin or placebo) were urinary tract infection, nasopharyngitis, upper respiratory tract infection, headache, influenza, and pain in extremity; the incidence of each AE was similar between treatment groups. In the saxagliptin and placebo groups, the incidence of reported hypoglycemia was 22.7 and 26.5 %, respectively; the incidence of confirmed hypoglycemia (fingerstick glucose ≤50 mg/dL [≤2.77 mmol/L] with characteristic symptoms) was 7.6 and 6.6 %, respectively. Adjusted mean change from baseline body weight was +0.8 kg with saxagliptin and +0.5 kg with placebo.

Conclusion

Saxagliptin 5 mg once daily as add-on to insulin, with or without concomitant metformin, produced a durable improvement in glycemic control and was well tolerated over 52 weeks of treatment.

Supplementary material

40261_2013_107_MOESM1_ESM.doc (45 kb)
Supplementary material 1 (DOC 45 kb)

References

  1. 1.
    DeFronzo RA. Pathogenesis of type 2 diabetes mellitus. Med Clin North Am. 2004;88(4):787–835, ix.Google Scholar
  2. 2.
    UK Prospective Diabetes Study Group. U.K. prospective diabetes study 16. Overview of 6 years’ therapy of type II diabetes: a progressive disease. Diabetes. 1995;44(11):1249–58.CrossRefGoogle Scholar
  3. 3.
    Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012;35(6):1364–79.PubMedCrossRefGoogle Scholar
  4. 4.
    Rodbard HW, Jellinger PS, Davidson JA, et al. Statement by an American Association of Clinical Endocrinologists/American College of Endocrinology consensus panel on type 2 diabetes mellitus: an algorithm for glycemic control. Endocr Pract. 2009;15(6):540–59.PubMedCrossRefGoogle Scholar
  5. 5.
    Pradhan AD, Everett BM, Cook NR, et al. Effects of initiating insulin and metformin on glycemic control and inflammatory biomarkers among patients with type 2 diabetes: the LANCET randomized trial. JAMA. 2009;302(11):1186–94.PubMedCrossRefGoogle Scholar
  6. 6.
    Barnett AH, Cradock S, Fisher M, et al. Key considerations around the risks and consequences of hypoglycaemia in people with type 2 diabetes. Int J Clin Pract. 2010;64(8):1121–9.PubMedCrossRefGoogle Scholar
  7. 7.
    Charbonnel B, Cariou B. Pharmacological management of type 2 diabetes: the potential of incretin-based therapies. Diabetes Obes Metab. 2011;13(2):99–117.PubMedCrossRefGoogle Scholar
  8. 8.
    Holman RR, Thorne KI, Farmer AJ, et al. Addition of biphasic, prandial, or basal insulin to oral therapy in type 2 diabetes. N Engl J Med. 2007;357(17):1716–30.PubMedCrossRefGoogle Scholar
  9. 9.
    Gordon J, Pockett RD, Tetlow AP, et al. A comparison of intermediate and long-acting insulins in people with type 2 diabetes starting insulin: an observational database study. Int J Clin Pract. 2010;64(12):1609–18.PubMedCrossRefGoogle Scholar
  10. 10.
    Freeman JS. Managing hyperglycemia in patients with type 2 diabetes mellitus: rationale for the use of dipeptidyl peptidase-4 inhibitors in combination with other oral antidiabetic drugs. J Am Osteopath Assoc. 2010;110(9):528–37.PubMedGoogle Scholar
  11. 11.
    Freeman JS. A physiologic and pharmacological basis for implementation of incretin hormones in the treatment of type 2 diabetes mellitus. Mayo Clin Proc. 2010;85(12 suppl):S5–14.PubMedCrossRefGoogle Scholar
  12. 12.
    ONGLYZA (saxagliptin). Full prescribing information. Princeton, NJ: Bristol-Myers Squibb; 2011.Google Scholar
  13. 13.
    Barnett AH, Charbonnel B, Donovan M, et al. Effect of saxagliptin as add-on therapy in patients with poorly controlled type 2 diabetes on insulin alone or insulin combined with metformin. Curr Med Res Opin. 2012;28(4):513–23.PubMedCrossRefGoogle Scholar
  14. 14.
    Fonseca V, Schweizer A, Albrecht D, et al. Addition of vildagliptin to insulin improves glycaemic control in type 2 diabetes. Diabetologia. 2007;50(6):1148–55.PubMedCrossRefGoogle Scholar
  15. 15.
    Rosenstock J, Rendell MS, Gross JL, et al. Alogliptin added to insulin therapy in patients with type 2 diabetes reduces HbA(1C) without causing weight gain or increased hypoglycaemia. Diabetes Obes Metab. 2009;11(12):1145–52.PubMedCrossRefGoogle Scholar
  16. 16.
    Vilsboll T, Rosenstock J, Yki-Jarvinen H, et al. Efficacy and safety of sitagliptin when added to insulin therapy in patients with type 2 diabetes. Diabetes Obes Metab. 2010;12(2):167–77.PubMedCrossRefGoogle Scholar
  17. 17.
    Ratner R, Wynne A, Nakhle S, et al. Influence of preprandial vs. postprandial insulin glulisine on weight and glycaemic control in patients initiating basal-bolus regimen for type 2 diabetes: a multicenter, randomized, parallel, open-label study (NCT00135096). Diabetes Obes Metab. 2011;13(12):1142–8.PubMedCrossRefGoogle Scholar
  18. 18.
    Neumiller JJ, Campbell RK. Saxagliptin: a dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes mellitus. Am J Health Syst Pharm. 2010;67(18):1515–25.PubMedCrossRefGoogle Scholar
  19. 19.
    Richter B, Bandeira-Echtler E, Bergerhoff K, et al. Emerging role of dipeptidyl peptidase-4 inhibitors in the management of type 2 diabetes. Vasc Health Risk Manag. 2008;4(4):753–68.PubMedGoogle Scholar
  20. 20.
    Amori RE, Lau J, Pittas AG. Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis. JAMA. 2007;298(2):194–206.PubMedCrossRefGoogle Scholar
  21. 21.
    Jabbour S, Ziring B. Advantages of extended-release metformin in patients with type 2 diabetes mellitus. Postgrad Med. 2011;123(1):15–23.PubMedCrossRefGoogle Scholar
  22. 22.
    Fonseca V, Baron M, Shao Q, et al. Sustained efficacy and reduced hypoglycemia during one year of treatment with vildagliptin added to insulin in patients with type 2 diabetes mellitus. Horm Metab Res. 2008;40(6):427–30.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2013

Authors and Affiliations

  • Anthony H. Barnett
    • 1
  • Bernard Charbonnel
    • 2
  • Jia Li
    • 3
  • Mark Donovan
    • 3
  • Douglas Fleming
    • 3
  • Nayyar Iqbal
    • 3
    • 4
  1. 1.Diabetes CentreHeart of England National Health Service Foundation Trust and University of BirminghamBirminghamUK
  2. 2.Centre HospitalierUniversitaire de NantesNantesFrance
  3. 3.Bristol-Myers SquibbPrincetonUSA
  4. 4.GCR-MetabolicsPrincetonUSA

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