Efficacy and safety of insulin degludec/insulin aspart versus biphasic insulin aspart 30 in Chinese adults with type 2 diabetes: A phase III, open-label, 2:1 randomized, treat-to-target trial

Wenying Yang, Jianhua Ma, Tianpei Hong, Ming Liu, Heng Miao, Yongde Peng, Changjiang Wang, Xiangjin Xu, Tao Yang, Anne M Nielsen, Lili Pan, Weihong Liu, Weigang Zhao, Wenying Yang, Jianhua Ma, Tianpei Hong, Ming Liu, Heng Miao, Yongde Peng, Changjiang Wang, Xiangjin Xu, Tao Yang, Anne M Nielsen, Lili Pan, Weihong Liu, Weigang Zhao

Abstract

Aims: To assess the efficacy and safety of twice-daily insulin degludec/insulin aspart (IDegAsp) versus biphasic insulin aspart 30 (BIAsp 30) twice daily, both ± metformin, in Chinese adults (N = 543) with type 2 diabetes (T2D) inadequately controlled on premixed/self-mixed or basal insulin ± metformin.

Materials and methods: We conducted a 26-week, phase III, open-label, treat-to-target, 2:1 randomized trial. Hierarchical testing was used with non-inferiority of glycated haemoglobin (HbA1c) change from baseline to week 26 as the primary endpoint and superiority for the confirmatory secondary endpoints which were as follows: change from baseline in fasting plasma glucose (FPG); nocturnal confirmed hypoglycaemic episodes (12:01-5:59 am, inclusive); total confirmed hypoglycaemic episodes (severe or plasma glucose <3.1 mmol/L with/without symptoms); body weight; and percentage of responders (HbA1c <53 mmol/mol [<7.0%]) without confirmed hypoglycaemic episodes.

Results: Non-inferiority for change from baseline to week 26 in HbA1c and superiority of IDegAsp twice daily versus BIAsp 30 twice daily for change in FPG, nocturnal confirmed and total confirmed hypoglycaemic episodes, was demonstrated. Estimated rates of nocturnal confirmed and total confirmed hypoglycaemic episodes were 47% and 43% lower, respectively, with IDegAsp twice daily versus BIAsp 30 twice daily. Superiority for change in body weight was not confirmed. Participants were more likely to reach the HbA1c goal of <53 mmol/mol (<7.0%) without confirmed hypoglycaemia with IDegAsp twice daily versus BIAsp 30 twice daily by trial end. No new safety signals were identified.

Conclusions: The efficacy and safety of IDegAsp in Chinese patients with T2D was demonstrated, confirming results from international trials.

Keywords: biphasic insulin aspart; insulin aspart; insulin degludec; insulin treatment; intensive insulin therapy; type 2 diabetes.

Conflict of interest statement

A.M.N. is an employee and a stock/shareholder of Novo Nordisk A/S. W.L. and L.P. are employees of Novo Nordisk (China) Pharmaceuticals Co. Ltd. T.H. is on an advisory panel and is a speakers' bureau member for Novo Nordisk, Sanofi, AstraZeneca and Merck Serono, is on an advisory panel for Merck Sharp & Dohme, and is a speakers' bureau member for Eli Lilly and Bayer. W.Y., J.M., M.L., H.M., Y.P., C.W., X.X., T.Y. and Z.W. have no conflicts of interest to declare. No other potential conflicts of interest relevant to this article are reported.

© 2019 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Figures

Figure 1
Figure 1
Participant disposition. Three participants who were previously treated with bolus insulin were randomized in error: two participants in the IDegAsp group who had been treated with bolus insulin with metformin and one participant in the BIAsp 30 group who was categorized as receiving “premixed/self‐mixed insulin” but had previously received basal plus bolus medication. BIAsp 30, biphasic insulin aspart 30; IDegAsp, insulin degludec/insulin aspart; n, number of participants; N, total number of participants
Figure 2
Figure 2
Confirmed endpoints between baseline and week 26: A, glycated haemoglobin (HbA1c); B, fasting plasma glucose (FPG) levels; C, nocturnal confirmed hypoglycaemic episodes; and D, confirmed hypoglycaemic episodes. HbA1c (A) and FPG (B) data are shown for all randomized participants; hypoglycaemia data (C and D) are shown for participants who were exposed to treatment. Data at week 26 are last observed values. BIAsp 30, biphasic insulin aspart 30; IDegAsp, insulin degludec/insulin aspart; n, number of patients

References

    1. International Diabetes Federation . IDF Diabetes Atlas, 8th ed. 2017. . Accessed November 8, 2018.
    1. Wang L, Gao P, Zhang M, et al. Prevalence and ethnic pattern of diabetes and prediabetes in China in 2013. JAMA. 2017;317:2515‐2523.
    1. . Population China 2013: Increases in Chinese population. 2013. . Accessed November 8, 2018.
    1. Federation ID . IDF Diabetes Atlas, 8th ed. (China report). 2017. . Accessed November 8, 2018.
    1. American Diabetes Association . 4. Lifestyle management: Standards of medical care in diabetes‐2018. Diabetes Care. 2018;41:S38‐S50.
    1. American Diabetes Association . 8. Pharmacologic approaches to glycemic treatment: Standards of medical care in diabetes‐2018. Diabetes Care. 2018;41:S73‐S85.
    1. Weng J, Ji L, Jia W, et al. Standards of care for type 2 diabetes in China. Diabetes Metab Res Rev. 2016;32:442‐458.
    1. Chinese Diabetes Society . China's type 2 diabetes prevention and control guide: 2017 edition. 2017. . Accessed November 8, 2018.
    1. Mosenzon O, Raz I. Intensification of insulin therapy for type 2 diabetic patients in primary care: Basal‐bolus regimen versus premix insulin analogs: When and for whom? Diabetes Care. 2013;36:S212‐S218.
    1. Chan JC, Gagliardino JJ, Baik SH, et al. Multifaceted determinants for achieving glycemic control: the International Diabetes Management Practice Study (IDMPS). Diabetes Care. 2009;32:227‐233.
    1. He X, Chen L, Wang K, Wu H, Wu J. Insulin adherence and persistence among Chinese patients with type 2 diabetes: a retrospective database analysis. Patient Prefer Adherence. 2017;11:237‐245.
    1. DECODE Study Group . Age‐ and sex‐specific prevalences of diabetes and impaired glucose regulation in 13 European cohorts. Diabetes Care. 2003;26:61‐69.
    1. Kataoka M, Venn BJ, Williams SM, Te Morenga LA, Heemels IM, Mann JI. Glycaemic responses to glucose and rice in people of Chinese and European ethnicity. Diabet Med. 2013;30:e101‐e107.
    1. Qiao Q, Hu G, Tuomilehto J, et al. Age‐ and sex‐specific prevalence of diabetes and impaired glucose regulation in 11 Asian cohorts. Diabetes Care. 2003;26:1770‐1780.
    1. European Commission . EU rice economic fact sheet. 2015. . Accessed November 8, 2018.
    1. Saisho Y. Beta‐cell dysfunction: Its critical role in prevention and management of type 2 diabetes. World J Diabetes. 2015;6:109‐124.
    1. Sanofi. Lantus ‐ Summary of Product Characteristics . 2010. . Accessed November 8, 2018.
    1. Havelund S, Ribel U, Hubalek F, Hoeg‐Jensen T, Wahlund PO, Jonassen I. Investigation of the physico‐chemical properties that enable co‐formulation of basal insulin degludec with fast‐acting insulin aspart. Pharm Res. 2015;32:2250‐2258.
    1. Administration UFaD . NovoLog® Mix 70/30 highlights of Prescribing Information. 2017. . Accessed November 8, 2018.
    1. Administration UFaD . Ryzodeg® highlights of Prescribing Information. 2016. . Accessed November 8, 2018.
    1. Heise T, Nosek L, Bottcher SG, Hastrup H, Haahr H. Ultra‐long‐acting insulin degludec has a flat and stable glucose‐lowering effect in type 2 diabetes. Diabetes Obes Metab. 2012;14:944‐950.
    1. Heise T, Heinemann L, Hovelmann U, et al. Biphasic insulin aspart 30/70: pharmacokinetics and pharmacodynamics compared with once‐daily biphasic human insulin and Basal‐bolus therapy. Diabetes Care. 2009;32:1431‐1433.
    1. Wielandt JO, Niemeyer M, Hansen MR, Bucher D, Thomsen NB. An assessment of dose accuracy and injection force of a novel prefilled insulin pen: comparison with a widely used prefilled insulin pen. Expert Opin Drug Deliv. 2011;8:1271‐1276.
    1. Niskanen L, Leiter LA, Franek E, et al. Comparison of a soluble co‐formulation of insulin degludec/insulin aspart vs biphasic insulin aspart 30 in type 2 diabetes: A randomised trial. Eur J Endocrinol. 2012;167:287‐294.
    1. Haluzik M, Fulcher G, Pieber TR, Bardtrum L, Tutkunkardas D, Rodbard HW. Insulin degludec/insulin aspart lowers fasting plasma glucose and rates of confirmed and nocturnal hypoglycaemia independent of baseline HbA1c levels, disease duration or BMI: A pooled meta‐analysis of phase 3 studies in patients with type 2 diabetes. Diabetes Obes Metab. 2018;20:1585‐1592.
    1. Fulcher GR, Christiansen JS, Bantwal G, et al. Comparison of insulin degludec/insulin aspart and biphasic insulin aspart 30 in uncontrolled, insulin‐treated type 2 diabetes: A phase 3a, randomized, treat‐to‐target trial. Diabetes Care. 2014;37:2084‐2090.
    1. Kaneko S, Chow F, Choi DS, et al. Insulin degludec/insulin aspart versus biphasic insulin aspart 30 in Asian patients with type 2 diabetes inadequately controlled on basal or pre−/self‐mixed insulin: A 26‐week, randomised, treat‐to‐target trial. Diabetes Res Clin Pract. 2015;107:139‐147.
    1. International Conference on Harmonisation . ICH harmonised tripartite guideline: Guideline for good clinical practice E6 (R1). Guideline for Good Clinical Practice 1996;E6 (R1), Step 4(Step4. 10 June). . Accessed November 8, 2018.
    1. Christiansen JS, Niskanen L, Rasmussen S, Johansen T, Fulcher G. Lower rates of hypoglycemia during maintenance treatment with insulin degludec/insulin aspart versus biphasic insulin aspart 30: A combined analysis of two phase 3a studies in type 2 diabetes. J Diabetes. 2016;8:720‐728.
    1. Heise T, Nosek L, Roepstorff C, Chenji S, Klein O, Haahr H. Distinct prandial and basal glucose‐lowering effects of insulin degludec/insulin aspart (IDegAsp) at steady state in subjects with type 1 diabetes mellitus. Diabetes Ther. 2014;5:255‐265.
    1. Heise T, Hermanski L, Nosek L, Feldman A, Rasmussen S, Haahr H. Insulin degludec: four times lower pharmacodynamic variability than insulin glargine under steady‐state conditions in type 1 diabetes. Diabetes Obes Metab. 2012;14:859‐864.
    1. Evans M, Gundgaard J, Hansen BB. Cost‐Effectiveness of Insulin Degludec/Insulin Aspart Versus Biphasic Insulin Aspart in Patients with Type 2 Diabetes from a Danish Health‐Care Perspective. Diabetes Ther. 2016;7:809‐823.
    1. Ajjan RA. How Can We Realize the Clinical Benefits of Continuous Glucose Monitoring? Diabetes Technol Ther. 2017;19:S27‐S36.

Source: PubMed

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir