Articles
Comparison of thrice-daily premixed insulin (insulin lispro premix) with basal-bolus (insulin glargine once-daily plus thrice-daily prandial insulin lispro) therapy in east Asian patients with type 2 diabetes insufficiently controlled with twice-daily premixed insulin: an open-label, randomised, controlled trial Weiping Jia, Xinhua Xiao, Qiuhe Ji, Kyu-Jeung Ahn, Lee-Ming Chuang, Yuqian Bao, Can Pang, Lei Chen, Fei Gao, Yinfang Tu, Pengfei Li, Jun Yang
Summary Lancet Diabetes Endocrinol 2015; 3: 254–62 Published Online March 6, 2015 http://dx.doi.org/10.1016/ S2213-8587(15)00041-8 See Comment page 229 Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, PR China (Prof W Jia MD, Y Bao MD, C Pang MD, L Chen MD, F Gao MD, Y Tu MD); Department of Endocrinology, Peking Union Medical College Hospital, Dongcheng District, Beijing, PR China (Prof X Xiao MD); Department of Endocrinology, First Affiliated Hospital of Fourth Military Medical University, Xi’an, PR China (Prof Q Ji MD); Department of Endocrinology, Kyung Hee University Hospital at Gangdong, Seoul, South Korea (Prof K-J Ahn MD); Internal Medicine Department, National Taiwan University Hospital, Zhongzheng District, Taipei, Taiwan (Prof L-M Chuang MD); and Medical Division, Eli Lilly Suzhou Pharmaceuticals Co. Ltd, Shanghai, PR China (P Li PhD, J Yang MD) Correspondence to: Prof Weiping Jia, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, No. 600 Yishan Road, Shanghai, 200233, PR China [email protected]
254
Background Unlike in western countries, premixed insulin is widely used as the starter insulin in Asian patients instead of basal insulin. The use of basal-bolus therapy as an intensification regimen is not common in Asia despite poor glycaemic control after starting insulin therapy. An alternative insulin intensification regimen with a similar efficacy and safety profile to basal-bolus therapy, but of higher convenience, is urgently needed. The efficacy and safety of insulin lispro mix thrice-daily was compared with basal-bolus therapy in Asian patients with type 2 diabetes who were insufficiently controlled on twice-daily premixed insulin. Methods This open-label, randomised, active comparator-controlled, parallel-group trial was done at 24 centres in China, Taiwan, and South Korea. Patients with type 2 diabetes who were inadequately controlled on twice-daily premixed insulin were randomly assigned (1:1) to receive either insulin lispro mix (mix 50 before breakfast and lunch plus mix 25 before dinner) or basal-bolus therapy (insulin glargine at bedtime plus prandial insulin lispro thricedaily) for 24 weeks. Randomisation was done by a computer-generated random sequence and was stratified by country or region and baseline HbA1c. Treatment assignments were masked from the study team assessing outcomes but not from investigators and patients. The primary outcome was change from baseline in HbA1c at week 24 in all randomly assigned patients who received at least one dose of study drug. Analysis was by modified intention to treat, with the per-protocol population used as a supportive analysis. This study is registered with ClinicalTrials.gov, number NCT01175811. Findings Between Feb 7, 2011, and Nov 7, 2012, 402 patients were enrolled (199 in the premix group, 203 in the basalbolus group) and 399 were included in the primary analysis (197 in the premix group, 202 in the basal-bolus group). HbA1c change at week 24 was –1·1% for both treatment groups. The least squares mean difference between groups in HbA1c change from baseline was 0% (95% CI –0·1 to 0·2). Insulin lispro mix was non-inferior to basal-bolus therapy based on the prespecified margin of 0·4%. The frequency of adverse events, and the incidences and 30-day rates of nocturnal and overall hypoglycaemia were comparable between groups. No severe hypoglycaemia was reported. Interpretation A premixed insulin lispro regimen thrice-daily was non-inferior to basal-bolus therapy in terms of overall glycaemic control and thus could be an option for intensified insulin regimen in Asian patients with type 2 diabetes who are inadequately controlled with twice-daily premixed insulin. Funding Eli Lilly and Company.
Introduction Type 2 diabetes is an important public health problem, and poses a heavy economic burden worldwide. Progressive pancreatic β-cell dysfunction is a major pathological trait of type 2 diabetes, with patients needing gradually more antidiabetic medications and, ultimately, insulin replacement therapy.1 Basal insulin is typically used as the initial insulin therapy in western countries.1 A recent national survey in China estimated that about 9·7% of Chinese adults might have had diabetes,2 suggesting that China has the largest population of
individuals with type 2 diabetes in the world. Concordance between fasting glucose and 2 h postprandial glucose concentrations was only seen in 37% of Asian patients with type 2 diabetes,3 which is different from US patients in whom around 70% concordance is seen.4 The prevalence of isolated postprandial hyperglycaemia is higher in Chinese patients (2·6–2·9%2) and Korean patients (3·6%5) than in white patients (1·9%6). More than 46% of patients in China were diagnosed with diabetes by abnormal postprandial glucose only.2 These pathophysiological characteristics, which might be related to the early www.thelancet.com/diabetes-endocrinology Vol 3 April 2015
Articles
deterioration of β-cell function,7 the late diagnosis of disease,8 and late initiation of insulin treatment9 in Chinese patients with type 2 diabetes, mean that insulin regimens that provide tight control of postprandial glucose are needed. Consequently, a premixed insulin regimen is recommended as a starter insulin by the Chinese type 2 diabetes treatment guidelines10,11 and International Diabetes Federation guidelines.12 This advice is different from guidelines for treating patients in western countries.1 Premixed insulins are, therefore, widely used as the starting insulin therapy in clinical practice in China (premixed 69·4–74·3%; basal 11·2%).9,13 In the USA and European countries, when optimal glycaemic control cannot be achieved by basal insulin a more intensive basal-bolus therapy is commonly recommended to add prandial insulin.1 However, basalbolus therapy is scarcely used in China (7·9% of patients treated with insulin), even though only 26–31% of patients using basal or premixed insulin achieve the target HbA1c of less than 7·0%.14 The main reasons why Chinese patients refuse basal-bolus therapy are inconvenience, fear of addiction to insulin, and injection phobia.15 Therefore, an intensified insulin regimen with a similar efficacy and safety profile to basal-bolus therapy, but that is more convenient and has fewer injections, is needed for Chinese patients with type 2 diabetes. Thrice-daily premixed insulin and basal-bolus therapy are both recommended by the Chinese type 2 diabetes guidelines10 as the next step in treatment after failure of initial insulin therapy. One randomised controlled trial has directly compared these two intensification regimens, but only in white patients with type 2 diabetes inadequately controlled on insulin glargine alone. The study showed that both thrice-daily insulin lispro premix 50 (50% insulin lispro, 50% insulin lispro protamine suspension) and basal-bolus therapy effectively reduced HbA1c; however, non-inferiority of the thrice-daily premixed insulin to basal-bolus therapy was not shown.16 Based on the differences in clinical practice and disease characteristics between Asian and white patients, our study was designed to verify the hypothesis that these two intensification insulin regimens had comparable efficacy and safety in Asian, especially Chinese, patients inadequately controlled with twice-daily premixed insulin. The study aimed to bridge the gap between treatment guidelines and clinical evidence, and to investigate an alternative way to encourage patients to add one more injection to improve glycaemic control. We compared thrice-daily insulin lispro premix (insulin lispro mix 50 before breakfast and lunch plus insulin lispro mix 25 [25% insulin lispro, 75% insulin lispro protamine suspension] before dinner) with basal-bolus therapy (insulin glargine at bedtime plus thrice-daily prandial insulin lispro) in Asian patients with type 2 diabetes who were inadequately controlled with twice-daily premixed insulin, with or without metformin or an α glucosidase inhibitor, or both. www.thelancet.com/diabetes-endocrinology Vol 3 April 2015
Methods Study design and participants This 24-week, open-label, multicentre, randomised, active comparator-controlled clinical trial was done at 24 investigative sites across three countries or regions (China, Taiwan, and South Korea). Eligible patients were men and women, aged 18–80 years, with type 2 diabetes, an HbA1c of 7·0–12·0% (non-exclusive) while taking twice-daily premixed insulin (human insulin mixtures [human insulin and isophane insulin suspension], insulin lispro mixtures [insulin lispro and insulin lispro protamine suspension], or insulin aspart mixtures [insulin aspart and insulin aspart protamine suspension]) for at least 6 months before study entry, and were willing to use insulin injection devices and do self-monitoring of blood glucose concentrations. Key exclusion criteria were more than one episode of severe hypoglycaemia within 24 weeks before study entry, BMI greater than 35 kg/m², treatment with systemic glucocorticoid therapy or glucose-lowering agents other than metformin or an α glucosidase inhibitor within 3 months of screening, cardiac disease with a class III or class IV functional capacity, history of renal insufficiency, and active liver disease. The study was approved by the ethics review board and done in accordance with the Declaration of Helsinki and good clinical practice guidelines. All patients provided written informed consent before study entry.
Randomisation and masking Eligible patients were randomly assigned (1:1) with an interactive voice response system to either the premix or basal-bolus therapy group. Randomisation was done by a computer-generated random sequence and was stratified by country or region and baseline HbA1c (
Comparison of thrice-daily premixed insulin (insulin lispro premix) with basal-bolus (insulin glargine once-daily plus thrice-daily prandial insulin lispro) therapy in east Asian patients with type 2 diabetes insufficiently controlled with twice-daily premixed insulin: an open-label, randomised, controlled trial Weiping Jia, Xinhua Xiao, Qiuhe Ji, Kyu-Jeung Ahn, Lee-Ming Chuang, Yuqian Bao, Can Pang, Lei Chen, Fei Gao, Yinfang Tu, Pengfei Li, Jun Yang
Summary Lancet Diabetes Endocrinol 2015; 3: 254–62 Published Online March 6, 2015 http://dx.doi.org/10.1016/ S2213-8587(15)00041-8 See Comment page 229 Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, PR China (Prof W Jia MD, Y Bao MD, C Pang MD, L Chen MD, F Gao MD, Y Tu MD); Department of Endocrinology, Peking Union Medical College Hospital, Dongcheng District, Beijing, PR China (Prof X Xiao MD); Department of Endocrinology, First Affiliated Hospital of Fourth Military Medical University, Xi’an, PR China (Prof Q Ji MD); Department of Endocrinology, Kyung Hee University Hospital at Gangdong, Seoul, South Korea (Prof K-J Ahn MD); Internal Medicine Department, National Taiwan University Hospital, Zhongzheng District, Taipei, Taiwan (Prof L-M Chuang MD); and Medical Division, Eli Lilly Suzhou Pharmaceuticals Co. Ltd, Shanghai, PR China (P Li PhD, J Yang MD) Correspondence to: Prof Weiping Jia, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, No. 600 Yishan Road, Shanghai, 200233, PR China [email protected]
254
Background Unlike in western countries, premixed insulin is widely used as the starter insulin in Asian patients instead of basal insulin. The use of basal-bolus therapy as an intensification regimen is not common in Asia despite poor glycaemic control after starting insulin therapy. An alternative insulin intensification regimen with a similar efficacy and safety profile to basal-bolus therapy, but of higher convenience, is urgently needed. The efficacy and safety of insulin lispro mix thrice-daily was compared with basal-bolus therapy in Asian patients with type 2 diabetes who were insufficiently controlled on twice-daily premixed insulin. Methods This open-label, randomised, active comparator-controlled, parallel-group trial was done at 24 centres in China, Taiwan, and South Korea. Patients with type 2 diabetes who were inadequately controlled on twice-daily premixed insulin were randomly assigned (1:1) to receive either insulin lispro mix (mix 50 before breakfast and lunch plus mix 25 before dinner) or basal-bolus therapy (insulin glargine at bedtime plus prandial insulin lispro thricedaily) for 24 weeks. Randomisation was done by a computer-generated random sequence and was stratified by country or region and baseline HbA1c. Treatment assignments were masked from the study team assessing outcomes but not from investigators and patients. The primary outcome was change from baseline in HbA1c at week 24 in all randomly assigned patients who received at least one dose of study drug. Analysis was by modified intention to treat, with the per-protocol population used as a supportive analysis. This study is registered with ClinicalTrials.gov, number NCT01175811. Findings Between Feb 7, 2011, and Nov 7, 2012, 402 patients were enrolled (199 in the premix group, 203 in the basalbolus group) and 399 were included in the primary analysis (197 in the premix group, 202 in the basal-bolus group). HbA1c change at week 24 was –1·1% for both treatment groups. The least squares mean difference between groups in HbA1c change from baseline was 0% (95% CI –0·1 to 0·2). Insulin lispro mix was non-inferior to basal-bolus therapy based on the prespecified margin of 0·4%. The frequency of adverse events, and the incidences and 30-day rates of nocturnal and overall hypoglycaemia were comparable between groups. No severe hypoglycaemia was reported. Interpretation A premixed insulin lispro regimen thrice-daily was non-inferior to basal-bolus therapy in terms of overall glycaemic control and thus could be an option for intensified insulin regimen in Asian patients with type 2 diabetes who are inadequately controlled with twice-daily premixed insulin. Funding Eli Lilly and Company.
Introduction Type 2 diabetes is an important public health problem, and poses a heavy economic burden worldwide. Progressive pancreatic β-cell dysfunction is a major pathological trait of type 2 diabetes, with patients needing gradually more antidiabetic medications and, ultimately, insulin replacement therapy.1 Basal insulin is typically used as the initial insulin therapy in western countries.1 A recent national survey in China estimated that about 9·7% of Chinese adults might have had diabetes,2 suggesting that China has the largest population of
individuals with type 2 diabetes in the world. Concordance between fasting glucose and 2 h postprandial glucose concentrations was only seen in 37% of Asian patients with type 2 diabetes,3 which is different from US patients in whom around 70% concordance is seen.4 The prevalence of isolated postprandial hyperglycaemia is higher in Chinese patients (2·6–2·9%2) and Korean patients (3·6%5) than in white patients (1·9%6). More than 46% of patients in China were diagnosed with diabetes by abnormal postprandial glucose only.2 These pathophysiological characteristics, which might be related to the early www.thelancet.com/diabetes-endocrinology Vol 3 April 2015
Articles
deterioration of β-cell function,7 the late diagnosis of disease,8 and late initiation of insulin treatment9 in Chinese patients with type 2 diabetes, mean that insulin regimens that provide tight control of postprandial glucose are needed. Consequently, a premixed insulin regimen is recommended as a starter insulin by the Chinese type 2 diabetes treatment guidelines10,11 and International Diabetes Federation guidelines.12 This advice is different from guidelines for treating patients in western countries.1 Premixed insulins are, therefore, widely used as the starting insulin therapy in clinical practice in China (premixed 69·4–74·3%; basal 11·2%).9,13 In the USA and European countries, when optimal glycaemic control cannot be achieved by basal insulin a more intensive basal-bolus therapy is commonly recommended to add prandial insulin.1 However, basalbolus therapy is scarcely used in China (7·9% of patients treated with insulin), even though only 26–31% of patients using basal or premixed insulin achieve the target HbA1c of less than 7·0%.14 The main reasons why Chinese patients refuse basal-bolus therapy are inconvenience, fear of addiction to insulin, and injection phobia.15 Therefore, an intensified insulin regimen with a similar efficacy and safety profile to basal-bolus therapy, but that is more convenient and has fewer injections, is needed for Chinese patients with type 2 diabetes. Thrice-daily premixed insulin and basal-bolus therapy are both recommended by the Chinese type 2 diabetes guidelines10 as the next step in treatment after failure of initial insulin therapy. One randomised controlled trial has directly compared these two intensification regimens, but only in white patients with type 2 diabetes inadequately controlled on insulin glargine alone. The study showed that both thrice-daily insulin lispro premix 50 (50% insulin lispro, 50% insulin lispro protamine suspension) and basal-bolus therapy effectively reduced HbA1c; however, non-inferiority of the thrice-daily premixed insulin to basal-bolus therapy was not shown.16 Based on the differences in clinical practice and disease characteristics between Asian and white patients, our study was designed to verify the hypothesis that these two intensification insulin regimens had comparable efficacy and safety in Asian, especially Chinese, patients inadequately controlled with twice-daily premixed insulin. The study aimed to bridge the gap between treatment guidelines and clinical evidence, and to investigate an alternative way to encourage patients to add one more injection to improve glycaemic control. We compared thrice-daily insulin lispro premix (insulin lispro mix 50 before breakfast and lunch plus insulin lispro mix 25 [25% insulin lispro, 75% insulin lispro protamine suspension] before dinner) with basal-bolus therapy (insulin glargine at bedtime plus thrice-daily prandial insulin lispro) in Asian patients with type 2 diabetes who were inadequately controlled with twice-daily premixed insulin, with or without metformin or an α glucosidase inhibitor, or both. www.thelancet.com/diabetes-endocrinology Vol 3 April 2015
Methods Study design and participants This 24-week, open-label, multicentre, randomised, active comparator-controlled clinical trial was done at 24 investigative sites across three countries or regions (China, Taiwan, and South Korea). Eligible patients were men and women, aged 18–80 years, with type 2 diabetes, an HbA1c of 7·0–12·0% (non-exclusive) while taking twice-daily premixed insulin (human insulin mixtures [human insulin and isophane insulin suspension], insulin lispro mixtures [insulin lispro and insulin lispro protamine suspension], or insulin aspart mixtures [insulin aspart and insulin aspart protamine suspension]) for at least 6 months before study entry, and were willing to use insulin injection devices and do self-monitoring of blood glucose concentrations. Key exclusion criteria were more than one episode of severe hypoglycaemia within 24 weeks before study entry, BMI greater than 35 kg/m², treatment with systemic glucocorticoid therapy or glucose-lowering agents other than metformin or an α glucosidase inhibitor within 3 months of screening, cardiac disease with a class III or class IV functional capacity, history of renal insufficiency, and active liver disease. The study was approved by the ethics review board and done in accordance with the Declaration of Helsinki and good clinical practice guidelines. All patients provided written informed consent before study entry.
Randomisation and masking Eligible patients were randomly assigned (1:1) with an interactive voice response system to either the premix or basal-bolus therapy group. Randomisation was done by a computer-generated random sequence and was stratified by country or region and baseline HbA1c (
