CLINICAL TRIAL
28-week, randomized, multicenter, open-label, parallel-group phase III trial to investigate the efficacy and safety of biphasic insulin aspart 70 thrice-daily injections vs twice-daily injections of biphasic insulin aspart 30 in patients with type 2 diabetes Takashi Kadowaki1*, Tomoyuki Nishida2, Kohei Kaku3 ABSTRACT Aims/Introduction: An insulin analogue formulation with a 7:3 ratio of rapid-acting and intermediate-acting fractions, biphasic insulin aspart 70 (BIAsp70) was developed to supplement basal insulin between meals and mimic the physiological pattern of postprandial insulin secretion. Materials and Methods: We carried out a randomized, open-label study to compare the efficacy and safety profiles of BIAsp70 and an insulin analogue formulation with a 3:7 ratio of rapid-acting and intermediate-acting fractions (BIAsp30) in type 2 diabetes mellitus patients. Patients were randomized and received either thrice-daily BIAsp70 (n = 145) or twice-daily BIAsp30 (n = 144) for 28 weeks. The primary end-point was glycated hemoglobin (HbA1c) after 16 weeks of treatment. Results: Non-inferiority of BIAsp70 vs BIAsp30 was confirmed and superiority was established with a between-group difference (BIAsp70–BIAsp30) in HbA1c after 16 weeks of treatment of )0.35% (95% CI: )0.51 to )0.19; P < 0.0001 for superiority). The mean postprandial glucose increment (19.96 vs 54.35 mg/dL; P < 0.0001) and M-value (12.99 vs 17.94; P < 0.0001) at 16 weeks were smaller in the BIAsp70 group than in the BIAsp30 group, and were maintained at 28 weeks. Pre-breakfast glucose (157.9 vs 140.7 mg/dL), total insulin dose (46.8 vs 38.1 U/day) and weight gain (+1.94 vs 1.23 kg) at week 28 were greater in the BIAsp70 group. Incidence of nocturnal hypoglycemia was significantly lower with BIAsp70 vs BIAsp30 (1.23 vs 3.21 events/subject year; P = 0.0002) at week 28. Conclusions: Thrice-daily BIAsp70 was superior to twice-daily BIAsp30 in terms of HbA1c change, with less variation in daytime plasma glucose profiles. BIAsp70 was well tolerated, with a lower incidence of nocturnal hypoglycemia vs BIAsp30. This trial was registered with ClinicalTrial.gov (no. NCT00318786). (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00015.x, 2010) KEY WORDS: Biphasic insulin aspart 70, Postprandial hyperglycemia, Type 2 diabetes mellitus
INTRODUCTION A number of landmark clinical trials have conclusively verified that rigorous glycemic control with intensive insulin therapy significantly reduces the onset and rate of progression of complications1–3, and suggest that approximating a physiological insulin secretion pattern through supplementation with exogenous insulin inhibits the progression of complications. It is also known that excessive postprandial blood glucose concentration and impaired glucose tolerance, as estimated by the glucose Department of Diabetes and Metabolic Diseases, The University of Tokyo, Development Division, Novo Nordisk Pharma Ltd., Tokyo, and 3Department of Medicine, Kawasaki Medical School, Okayama, Japan *Corresponding author. Takashi Kadowaki Tel.: +81-3-5800-8815 Fax: +81-3-5800-9797 E-mail address: [email protected] [Corrections added after online publication 5 April 2010.] Received 27 October 2009; revised 25 December 2009; accepted 2 February 2010
concentration 2 h after an oral glucose tolerance test, are significant risk factors for the onset and progression of cardiovascular disease4,5, and that addressing postprandial glucose is an important therapeutic target to reduce the risk or progression of cardiovascular disease6–8. Therefore, besides lowering glycated hemoglobin (HbA1c), inhibiting fluctuations of blood glucose levels are also important goals for preventing the development and progression of macrovascular and microvascular complications. One of the most widely-used insulin therapies for type 2 diabetes in Japan is twice-daily treatment with mixed insulin formulations containing both rapid-acting and intermediate-acting fractions in the ratio 3:7; this strategy offers effective glycemic control for many patients, with a small number of daily injections9,10. In patients in whom this approach
ª 2010 Asian Association for the Study of Diabetes and Blackwell Publishing Asia Pty Ltd
Journal of Diabetes Investigation Volume 1 Issue 3 June 2010
1 2
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Kadowaki et al.
inadequately controls glycemia during the day, and in those whose pathological state is more advanced, a basal-bolus therapeutic regimen is currently favored. However, this approach requires 4–5 injections/day, which, in addition to the perceived complexity of the regimen, might have negative effects on quality of life, treatment satisfaction and compliance relative to twice-daily mixed insulin11.This situation has led to the innovation of thrice-daily (preprandial) administration of rapid-acting insulin analogues12, although the insulin action might drop away and blood glucose levels rise between successive injections. For example, in one clinical study of Japanese patients with type 1 diabetes using a basal-bolus regimen with insulin aspart as the rapid-acting insulin analogue, the average ratio of bolus and basal insulin was approximately 7:313. Therefore, we hypothesized that a ratio of 7:3 would be more appropriate than a ratio of 3:7 in Japanese patients. However, because insulin demand, dietary habits and lifestyle factors vary among individual patients, it was hypothesized that administration of biphasic insulin aspart 70 (BIAsp70) alone or in combination with a biphasic insulin analogue containing a rapid-acting fraction and an intermediate-acting fraction in the ratio 3:7 (BIAsp30) thrice daily might be a suitable alternative regimen that would allow physicians to cater to diverse requirements for insulin therapy among diabetes patients. Therefore, the present randomized, multicenter, open-label, parallel-group trial was carried out to compare the efficacy and safety of thrice-daily BIAsp70 with those of BIAsp30 given twice daily.
MATERIALS AND METHODS Subjects
The subjects of the present trial were patients with type 2 diabetes mellitus having HbA1c levels between 7.5% and 10.0%, and who were previously receiving once- or twice-daily injections of an intermediate-acting human insulin preparation, long-acting insulin analogue or a mixed human insulin preparation. Before their participation in the trial, written informed consent was obtained from all patients. The study protocol was reviewed and approved by institutional review boards at each of the participating trial sites (Appendix S1), and the trial was carried out in accordance with the Declaration of Helsinki and with Japanese Good Clinical Practice and other applicable regulations. Investigational Products
BIAsp70 and BIAsp30 were given in a 3-mL cartridge formulation containing 100 U of active ingredient per mL. The investigational products were manufactured by Novo Nordisk A/S (Bagsvaerd, Denmark) and supplied by Novo Nordisk Pharma Ltd (Tokyo, Japan). Methodology
The primary objective was to show non-inferiority of thricedaily (before each meal) BIAsp70 vs twice-daily (before breakfast
104
Journal of Diabetes Investigation Volume 1 Issue 3 June 2010
and dinner) BIAsp30 for glycemic control as shown by HbA1c after 16 weeks of treatment. HbA1c was measured by highperformance liquid chromatography, and all HbA1c data are shown in Japan Diabetes Society (JDS) values. Secondary efficacy end-points were HbA1c after 28 weeks of treatment, proportion of subjects achieving HbA1c
28-week, randomized, multicenter, open-label, parallel-group phase III trial to investigate the efficacy and safety of biphasic insulin aspart 70 thrice-daily injections vs twice-daily injections of biphasic insulin aspart 30 in patients with type 2 diabetes Takashi Kadowaki1*, Tomoyuki Nishida2, Kohei Kaku3 ABSTRACT Aims/Introduction: An insulin analogue formulation with a 7:3 ratio of rapid-acting and intermediate-acting fractions, biphasic insulin aspart 70 (BIAsp70) was developed to supplement basal insulin between meals and mimic the physiological pattern of postprandial insulin secretion. Materials and Methods: We carried out a randomized, open-label study to compare the efficacy and safety profiles of BIAsp70 and an insulin analogue formulation with a 3:7 ratio of rapid-acting and intermediate-acting fractions (BIAsp30) in type 2 diabetes mellitus patients. Patients were randomized and received either thrice-daily BIAsp70 (n = 145) or twice-daily BIAsp30 (n = 144) for 28 weeks. The primary end-point was glycated hemoglobin (HbA1c) after 16 weeks of treatment. Results: Non-inferiority of BIAsp70 vs BIAsp30 was confirmed and superiority was established with a between-group difference (BIAsp70–BIAsp30) in HbA1c after 16 weeks of treatment of )0.35% (95% CI: )0.51 to )0.19; P < 0.0001 for superiority). The mean postprandial glucose increment (19.96 vs 54.35 mg/dL; P < 0.0001) and M-value (12.99 vs 17.94; P < 0.0001) at 16 weeks were smaller in the BIAsp70 group than in the BIAsp30 group, and were maintained at 28 weeks. Pre-breakfast glucose (157.9 vs 140.7 mg/dL), total insulin dose (46.8 vs 38.1 U/day) and weight gain (+1.94 vs 1.23 kg) at week 28 were greater in the BIAsp70 group. Incidence of nocturnal hypoglycemia was significantly lower with BIAsp70 vs BIAsp30 (1.23 vs 3.21 events/subject year; P = 0.0002) at week 28. Conclusions: Thrice-daily BIAsp70 was superior to twice-daily BIAsp30 in terms of HbA1c change, with less variation in daytime plasma glucose profiles. BIAsp70 was well tolerated, with a lower incidence of nocturnal hypoglycemia vs BIAsp30. This trial was registered with ClinicalTrial.gov (no. NCT00318786). (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00015.x, 2010) KEY WORDS: Biphasic insulin aspart 70, Postprandial hyperglycemia, Type 2 diabetes mellitus
INTRODUCTION A number of landmark clinical trials have conclusively verified that rigorous glycemic control with intensive insulin therapy significantly reduces the onset and rate of progression of complications1–3, and suggest that approximating a physiological insulin secretion pattern through supplementation with exogenous insulin inhibits the progression of complications. It is also known that excessive postprandial blood glucose concentration and impaired glucose tolerance, as estimated by the glucose Department of Diabetes and Metabolic Diseases, The University of Tokyo, Development Division, Novo Nordisk Pharma Ltd., Tokyo, and 3Department of Medicine, Kawasaki Medical School, Okayama, Japan *Corresponding author. Takashi Kadowaki Tel.: +81-3-5800-8815 Fax: +81-3-5800-9797 E-mail address: [email protected] [Corrections added after online publication 5 April 2010.] Received 27 October 2009; revised 25 December 2009; accepted 2 February 2010
concentration 2 h after an oral glucose tolerance test, are significant risk factors for the onset and progression of cardiovascular disease4,5, and that addressing postprandial glucose is an important therapeutic target to reduce the risk or progression of cardiovascular disease6–8. Therefore, besides lowering glycated hemoglobin (HbA1c), inhibiting fluctuations of blood glucose levels are also important goals for preventing the development and progression of macrovascular and microvascular complications. One of the most widely-used insulin therapies for type 2 diabetes in Japan is twice-daily treatment with mixed insulin formulations containing both rapid-acting and intermediate-acting fractions in the ratio 3:7; this strategy offers effective glycemic control for many patients, with a small number of daily injections9,10. In patients in whom this approach
ª 2010 Asian Association for the Study of Diabetes and Blackwell Publishing Asia Pty Ltd
Journal of Diabetes Investigation Volume 1 Issue 3 June 2010
1 2
103
Kadowaki et al.
inadequately controls glycemia during the day, and in those whose pathological state is more advanced, a basal-bolus therapeutic regimen is currently favored. However, this approach requires 4–5 injections/day, which, in addition to the perceived complexity of the regimen, might have negative effects on quality of life, treatment satisfaction and compliance relative to twice-daily mixed insulin11.This situation has led to the innovation of thrice-daily (preprandial) administration of rapid-acting insulin analogues12, although the insulin action might drop away and blood glucose levels rise between successive injections. For example, in one clinical study of Japanese patients with type 1 diabetes using a basal-bolus regimen with insulin aspart as the rapid-acting insulin analogue, the average ratio of bolus and basal insulin was approximately 7:313. Therefore, we hypothesized that a ratio of 7:3 would be more appropriate than a ratio of 3:7 in Japanese patients. However, because insulin demand, dietary habits and lifestyle factors vary among individual patients, it was hypothesized that administration of biphasic insulin aspart 70 (BIAsp70) alone or in combination with a biphasic insulin analogue containing a rapid-acting fraction and an intermediate-acting fraction in the ratio 3:7 (BIAsp30) thrice daily might be a suitable alternative regimen that would allow physicians to cater to diverse requirements for insulin therapy among diabetes patients. Therefore, the present randomized, multicenter, open-label, parallel-group trial was carried out to compare the efficacy and safety of thrice-daily BIAsp70 with those of BIAsp30 given twice daily.
MATERIALS AND METHODS Subjects
The subjects of the present trial were patients with type 2 diabetes mellitus having HbA1c levels between 7.5% and 10.0%, and who were previously receiving once- or twice-daily injections of an intermediate-acting human insulin preparation, long-acting insulin analogue or a mixed human insulin preparation. Before their participation in the trial, written informed consent was obtained from all patients. The study protocol was reviewed and approved by institutional review boards at each of the participating trial sites (Appendix S1), and the trial was carried out in accordance with the Declaration of Helsinki and with Japanese Good Clinical Practice and other applicable regulations. Investigational Products
BIAsp70 and BIAsp30 were given in a 3-mL cartridge formulation containing 100 U of active ingredient per mL. The investigational products were manufactured by Novo Nordisk A/S (Bagsvaerd, Denmark) and supplied by Novo Nordisk Pharma Ltd (Tokyo, Japan). Methodology
The primary objective was to show non-inferiority of thricedaily (before each meal) BIAsp70 vs twice-daily (before breakfast
104
Journal of Diabetes Investigation Volume 1 Issue 3 June 2010
and dinner) BIAsp30 for glycemic control as shown by HbA1c after 16 weeks of treatment. HbA1c was measured by highperformance liquid chromatography, and all HbA1c data are shown in Japan Diabetes Society (JDS) values. Secondary efficacy end-points were HbA1c after 28 weeks of treatment, proportion of subjects achieving HbA1c
