DIABETES TECHNOLOGY & THERAPEUTICS Volume 16, Number 10, 2014 ª Mary Ann Liebert, Inc. DOI: 10.1089/dia.2014.0075
ORIGINAL ARTICLE
Efficacy of Adding Once-Daily Insulin Glulisine in Japanese Type 2 Diabetes Patients Treated with Insulin Glargine and Sitagliptin Mitsuyoshi Takahara, MD, PhD,1 Toshihiko Shiraiwa, MD, PhD,2 Naoto Katakami, MD, PhD,1 Taka-aki Matsuoka, MD, PhD,1 and Iichiro Shimomura, MD, PhD1
Abstract
Background: Glucose fluctuation often remains to be corrected under basal-supported oral therapy. We investigated the efficacy of adding once-daily rapid-acting insulin in Japanese diabetes patients treated with basalsupported oral therapy. Subjects and Methods: In this 8-week, parallel-group, randomized, open-label trial, 62 Japanese adults with type 2 diabetes treated with insulin glargine and 50 mg of sitagliptin were randomized into the following two arms: the single-bolus group, in which once-daily insulin glulisine was initiated at a main meal at a fifth (i.e., 20%) the dose of insulin glargine, and the control group, in which the dose of sitagliptin was maximized to 100 mg. The primary end point was the change of glycemic fluctuation assessed with the M-value. Results: Baseline hemoglobin A1c levels, mean blood glucose profiles, and M-value were 7.2 – 0.6%, 9.3 – 1.7 mmol/L, and 21 – 13 units, respectively. At the end of the study, the single-bolus group had a greater reduction of M-value than the control group (P = 0.02); the difference was 6.5 units (95% confidence interval, 1.1–11.9 units). The single-bolus group also had a greater reduction of mean blood glucose levels (P = 0.01). There were no significant differences in the incidence of hypoglycemia or the weight change between the two groups (P > 0.05). Conclusions: Adding once-daily insulin glulisine was more effective in controlling the glycemic fluctuation in Japanese type 2 diabetes patients treated with insulin glargine together with sitagliptin. Introduction
T
he combined use of long-acting insulin analogs with oral hypoglycemic agents, so-called ‘‘basal-supported oral therapy’’ (BOT), is an effective option for glycemic control in type 2 diabetes mellitus.1 BOT can improve glycemic control with a simple regimen of long-acting insulin titration sufficient to target fasting glucose levels and is now widely used in clinical practice. Although the efficacy of BOT was originally often shown in studies in which longacting insulin was added to ongoing treatment with sulfonylureas, recent studies also revealed that the combined use of dipeptidyl peptidase-4 (DPP-4) inhibitors and long-acting insulin analogs is beneficial in glycemic control.2–8 However, some patients receiving BOT have uncontrolled postprandial hyperglycemia, despite their good control of
fasting glucose levels.9,10 Consequently, daily glycemic variability, or fluctuation, is observed in these patients. Although the additional multiple injection of rapid-acting insulin at every meal, so-called intensive insulin therapy, may reliably lower postprandial glycemia,11,12 substantial numbers of patients in clinical practice hesitate to receive this therapy because the inconvenience of many injections would burden their lifestyle. In previous reports, proposals were made to initiate a single daily prandial bolus of a rapid-acting insulin analog, as the first step toward intensive insulin therapy in these patients.13,14 However, few clinical studies have investigated the efficacy of adding a once-daily prandial bolus on glycemic control, by comparing with other strategies, such as an increase in dosage of ongoing oral hypoglycemic agents.
1
Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan. Shiraiwa Medical Clinic, Kashiwara, Osaka, Japan. This trial was registered with the University Hospital Medical Information Network at www.umin.ac.jp/ctr/ with trial identification number UMIN000010211. 2
633
634
The aim of the current study was to investigate whether initiating once-daily rapid-acting insulin according to a simple regimen would be more beneficial than maximizing the dosage of an ongoing DPP-4 inhibitor in Japanese type 2 diabetes patients treated by long-acting insulin together with the DPP-4 inhibitor. Subjects and Methods Study design
This 8-week, parallel-group, randomized, open-label trial compared the efficacy and safety between two study arms in Japanese type 2 diabetes adults treated with insulin glargine, a long-acting insulin analog, plus sitagliptin, a DPP-4 inhibitor, at 50 mg/day. In one arm (the single-bolus group), once-daily insulin glulisine, a rapid-acting insulin analog, was initiated at a prespecified dose, whereas in the other (the control group), the dosage of ongoing sitagliptin was doubled. In Japan, 50 mg/day of sitagliptin is approved and recommended as the normal dosage. Increase of the dosage up to 100 mg/day is also approved, in cases in which the glucoselowering effect is insufficient. The current study was conducted at Shiraiwa Medical Clinic, Osaka, Japan, between March and June 2013. The current study was performed in accordance with the Declaration of Helsinki and was approved by the ethics committee of Shiraiwa Medical Clinic. Written informed consent was obtained from every participant in the current study. Study population and procedures
The study population comprised Japanese adults (‡20 years old) with type 2 diabetes mellitus, who were treated by a titrated dose of insulin glargine together with 50 mg/day of sitagliptin but who had postprandial hyperglycemia and accompanying glycemic fluctuations. The participants had either postprandial glucose levels of ‡ 10.0 mmol/L (180 mg/dL) or hemoglobin A1c levels of ‡ 7.0%, or both, even after insulin glargine was titrated to target preprandial glucose levels of < 6.1 mmol/L (110 mg/dL). The exclusion criteria were difficulty in performing self-monitoring of blood glucose (SMBG), moderate or severe renal impairment (creatinine clearance below 50 mL/min or serum creatinine ‡1.5 mg/dL in males and 1.3 mg/dL in females, according to the manufacturer’s labeling), severe hepatic and/or cardiac disease, hypersensitivity to the drug using in the current study, and pregnant or breast-feeding females. We also excluded patients treated together with antidiabetes drugs other than low-dose sulfonylureas (defined as less than one-quarter of the highest approved dose) and/or metformin, for the purpose of minimizing the heterogeneity within the study population. Eligible participants were randomized and allocated to the single-bolus group or the control group (Fig. 1A). The allocation was performed using stratified block randomization, with a block size of 4. The stratification factors were sex (male or female) and age (
ORIGINAL ARTICLE
Efficacy of Adding Once-Daily Insulin Glulisine in Japanese Type 2 Diabetes Patients Treated with Insulin Glargine and Sitagliptin Mitsuyoshi Takahara, MD, PhD,1 Toshihiko Shiraiwa, MD, PhD,2 Naoto Katakami, MD, PhD,1 Taka-aki Matsuoka, MD, PhD,1 and Iichiro Shimomura, MD, PhD1
Abstract
Background: Glucose fluctuation often remains to be corrected under basal-supported oral therapy. We investigated the efficacy of adding once-daily rapid-acting insulin in Japanese diabetes patients treated with basalsupported oral therapy. Subjects and Methods: In this 8-week, parallel-group, randomized, open-label trial, 62 Japanese adults with type 2 diabetes treated with insulin glargine and 50 mg of sitagliptin were randomized into the following two arms: the single-bolus group, in which once-daily insulin glulisine was initiated at a main meal at a fifth (i.e., 20%) the dose of insulin glargine, and the control group, in which the dose of sitagliptin was maximized to 100 mg. The primary end point was the change of glycemic fluctuation assessed with the M-value. Results: Baseline hemoglobin A1c levels, mean blood glucose profiles, and M-value were 7.2 – 0.6%, 9.3 – 1.7 mmol/L, and 21 – 13 units, respectively. At the end of the study, the single-bolus group had a greater reduction of M-value than the control group (P = 0.02); the difference was 6.5 units (95% confidence interval, 1.1–11.9 units). The single-bolus group also had a greater reduction of mean blood glucose levels (P = 0.01). There were no significant differences in the incidence of hypoglycemia or the weight change between the two groups (P > 0.05). Conclusions: Adding once-daily insulin glulisine was more effective in controlling the glycemic fluctuation in Japanese type 2 diabetes patients treated with insulin glargine together with sitagliptin. Introduction
T
he combined use of long-acting insulin analogs with oral hypoglycemic agents, so-called ‘‘basal-supported oral therapy’’ (BOT), is an effective option for glycemic control in type 2 diabetes mellitus.1 BOT can improve glycemic control with a simple regimen of long-acting insulin titration sufficient to target fasting glucose levels and is now widely used in clinical practice. Although the efficacy of BOT was originally often shown in studies in which longacting insulin was added to ongoing treatment with sulfonylureas, recent studies also revealed that the combined use of dipeptidyl peptidase-4 (DPP-4) inhibitors and long-acting insulin analogs is beneficial in glycemic control.2–8 However, some patients receiving BOT have uncontrolled postprandial hyperglycemia, despite their good control of
fasting glucose levels.9,10 Consequently, daily glycemic variability, or fluctuation, is observed in these patients. Although the additional multiple injection of rapid-acting insulin at every meal, so-called intensive insulin therapy, may reliably lower postprandial glycemia,11,12 substantial numbers of patients in clinical practice hesitate to receive this therapy because the inconvenience of many injections would burden their lifestyle. In previous reports, proposals were made to initiate a single daily prandial bolus of a rapid-acting insulin analog, as the first step toward intensive insulin therapy in these patients.13,14 However, few clinical studies have investigated the efficacy of adding a once-daily prandial bolus on glycemic control, by comparing with other strategies, such as an increase in dosage of ongoing oral hypoglycemic agents.
1
Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan. Shiraiwa Medical Clinic, Kashiwara, Osaka, Japan. This trial was registered with the University Hospital Medical Information Network at www.umin.ac.jp/ctr/ with trial identification number UMIN000010211. 2
633
634
The aim of the current study was to investigate whether initiating once-daily rapid-acting insulin according to a simple regimen would be more beneficial than maximizing the dosage of an ongoing DPP-4 inhibitor in Japanese type 2 diabetes patients treated by long-acting insulin together with the DPP-4 inhibitor. Subjects and Methods Study design
This 8-week, parallel-group, randomized, open-label trial compared the efficacy and safety between two study arms in Japanese type 2 diabetes adults treated with insulin glargine, a long-acting insulin analog, plus sitagliptin, a DPP-4 inhibitor, at 50 mg/day. In one arm (the single-bolus group), once-daily insulin glulisine, a rapid-acting insulin analog, was initiated at a prespecified dose, whereas in the other (the control group), the dosage of ongoing sitagliptin was doubled. In Japan, 50 mg/day of sitagliptin is approved and recommended as the normal dosage. Increase of the dosage up to 100 mg/day is also approved, in cases in which the glucoselowering effect is insufficient. The current study was conducted at Shiraiwa Medical Clinic, Osaka, Japan, between March and June 2013. The current study was performed in accordance with the Declaration of Helsinki and was approved by the ethics committee of Shiraiwa Medical Clinic. Written informed consent was obtained from every participant in the current study. Study population and procedures
The study population comprised Japanese adults (‡20 years old) with type 2 diabetes mellitus, who were treated by a titrated dose of insulin glargine together with 50 mg/day of sitagliptin but who had postprandial hyperglycemia and accompanying glycemic fluctuations. The participants had either postprandial glucose levels of ‡ 10.0 mmol/L (180 mg/dL) or hemoglobin A1c levels of ‡ 7.0%, or both, even after insulin glargine was titrated to target preprandial glucose levels of < 6.1 mmol/L (110 mg/dL). The exclusion criteria were difficulty in performing self-monitoring of blood glucose (SMBG), moderate or severe renal impairment (creatinine clearance below 50 mL/min or serum creatinine ‡1.5 mg/dL in males and 1.3 mg/dL in females, according to the manufacturer’s labeling), severe hepatic and/or cardiac disease, hypersensitivity to the drug using in the current study, and pregnant or breast-feeding females. We also excluded patients treated together with antidiabetes drugs other than low-dose sulfonylureas (defined as less than one-quarter of the highest approved dose) and/or metformin, for the purpose of minimizing the heterogeneity within the study population. Eligible participants were randomized and allocated to the single-bolus group or the control group (Fig. 1A). The allocation was performed using stratified block randomization, with a block size of 4. The stratification factors were sex (male or female) and age (
