DIABETES TECHNOLOGY & THERAPEUTICS Volume 17, Number 4, 2015 ª Mary Ann Liebert, Inc. DOI: 10.1089/dia.2014.0299
ORIGINAL ARTICLE
Differential Therapeutic Effects of Nateglinide and Acarbose on Fasting and Postprandial Lipid Profiles: A Randomized Trial Jian Zhou, MD, PhD,1,* Zixuan Deng, MD,1,* Jingyi Lu, PhD,1,* Hong Li, MD,2 Xiuzhen Zhang, MD,3 Yongde Peng, MD, PhD,4 Yifei Mo, MD,1 Yuqian Bao, MD,1 and Weiping Jia, MD, PhD1
Abstract
Background: Dyslipidemia is commonly seen in patients with type 2 diabetes mellitus (T2DM). The current study sought to compare the effects of nateglinide and acarbose, two antihyperglycemic agents, on both fasting and postprandial lipid profiles in Chinese subjects with T2DM. Subjects and Methods: For this multicenter, open-label, randomized, active-controlled, parallel-group study, 103 antihyperglycemic agent–naive patients with T2DM were recruited from four hospitals in China. In total, 85 subjects (44 in the nateglinide group, 41 in the acarbose group) with a known complete lipid profile underwent the entire clinical trial and were included in the final analysis. Serum was collected in the fasting state and 30 and 120 min after a standardized meal (postprandial states) to measure the baseline lipid profiles; the same testing was performed upon completion of a 2-week course of nateglinide (120 mg three times a day) or acarbose (50 mg three times a day). Results: Fasting triglyceride (TG) levels were significantly reduced by both nateglinide and acarbose (P < 0.001), with acarbose providing a significantly more robust improvement (vs. nateglinide, P = 0.005). Additionally, the TG levels at both postprandial times were significantly reduced by acarbose (P < 0.001 at 30 min and P = 0.002 at 120 min), whereas nateglinide treatment only significantly reduced the 30-min postprandial TG (P = 0.029). Neither nateglinide nor acarbose treatment had significant impact on total cholesterol, high-density lipoprotein, low-density lipoprotein, or non–high-density lipoprotein cholesterol. Conclusions: Compared with nateglinide, acarbose has superior therapeutic efficacy for reducing fasting and postprandial TG levels in patients with T2DM. Introduction
D
yslipidemia, an important contributor to the development of cardiovascular events,1–3 is commonly observed in patient with type 2 diabetes mellitus (T2DM). The characteristic features of dyslipidemia in T2DM include
a high plasma triglyceride (TG) concentration and a low high-density lipoprotein cholesterol (HDL-C) concentration4 secondary to insulin resistance,5 although total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels do not differ between T2DM patients and individuals without diabetes.
1 Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai Clinical Center for Diabetes, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Diabetes Institute, Shanghai, People’s Republic of China. 2 Department of Endocrinology and Metabolism, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China. 3 Department of Endocrinology and Metabolism, Tong Ji Hospital Affiliated with Tong Ji University, Shanghai, People’s Republic of China. 4 Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated First People’s Hospital, Shanghai, People’s Republic of China. *The first three authors contributed equally to this study. This trial is registered at www.ClinicalTrials.gov with clinical trial registration number NCT01030952.
229
230
Nateglinide and acarbose are two of the oral antihyperglycemic agents widely used to treat T2DM patients in China. The former is an insulinotropic agent that rapidly induces insulin secretion with a short duration. The latter delays carbohydrate digestion by competitive and dosedependent inhibition of a-glucosidase enzymes located in the brush border of the small intestine. Our studies and those of other researchers have demonstrated that both nateglinide and acarbose can reduce postprandial hyperglycemia6,7 and are comparably effective in reducing postprandial glycemic excursions.8 However, the effects of nateglinide and acarbose on lipid profiles remain inconclusive.9–13 Moreover, only a few have conducted a direct comparison between the two agents.14,15 Therefore, the current study sought to evaluate the effects of nateglinide versus acarbose on both fasting and postprandial lipid profiles in antihyperglycemic agent–naive patients with T2DM. Subjects and Methods Patient selection and study design
The study was designed as a prospective, randomized, open-label, and active-controlled 2-week assessment of nateglinide and acarbose therapies, as previously described.8 The study protocol was designed in accordance with the principles of the Helsinki Declaration II and carried out with pre-approval by the Independent Ethics Committee of Shanghai Jiao Tong University Affiliated Sixth People’s Hospital (Shanghai, People’s Republic of China). All study participants provided written informed consent. In brief, adult (‡18-year-old) Chinese patients diagnosed with T2DM (glycated hemoglobin [HbA1c] range, 6.5– 9.0%) and antihyperglycemic agentnaive (no treatment with antihyperglycemic agents for at least 3 consecutive months prior to study enrollment) were recruited for study enrollment between December 2009 and February 2011 from the following four metropolitan medical centers in China: Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai; Sir Run Run Shaw Hospital, Hangzhou, People’s Republic of China; Tong Ji Hospital Affiliated to Tong Ji University, Shanghai; and Shanghai Jiao Tong University Affiliated First People’s Hospital, Shanghai. Patients were denied study enrollment if they had known allergies to nateglinide or acarbose or had ongoing hepatic or renal dysfunction. Following study enrollment, subjects were fasted overnight and then given a standard test meal (70 g of bread/ instant noodles) containing 322 Kcal with 42 g of carbohydrates, 6.3 g of protein, and 14.7 g of fat, eaten within a 15min period. At this point, the subjects were randomized (1:1) to receive a 2-week course of either nateglinide (120 mg three times a day) (Novartis Pharma Ltd., Beijing, People’s Republic of China) or acarbose (50 mg three times a day) (Bayer HealthCare Pharmaceuticals Inc., Montville, NJ). After the 2week treatment, the participants were given a second standard meal test in the fasting state. The treatment strategy has been illustrated in our previous study.8 Anthropometric and biochemical measurements
Upon enrollment, blood pressure was measured in triplicate using a standard mercury sphygmomanometer, and the aver-
ZHOU ET AL.
age measurement was recorded. Body mass index was calculated as weight (in kg)/height (in m)2. Mean blood glucose (MBG) was obtained by using a continuous glucose monitoring system (Medtronic MiniMed Inc., Northridge, CA). During the standard meal test, blood samples were collected to obtain both the fasting and postprandial (at 30 min and 120 min after meal) measures. The serum lipid profile was measured on an automated enzymatic analyzer (model 7600-020; Hitachi, Tokyo, Japan) and included total cholesterol, TG, HDL-C, and LDL-C. Non–HDL-C was calculated by subtracting HDL-C from total cholesterol. Plasma insulin was measured by standard bio-antibody technique (Linco, St. Louis, MO), and insulin response was calculated as postprandial plasma insulin (at 30 min/120 min)/fasting plasma insulin. The HbA1c level was estimated by high-pressure liquid chromatography using the Variant II hemoglobin testing system (Bio-Rad Laboratories, Hercules, CA). Statistical analysis
Intergroup differences in serum lipid measurements at baseline and after treatment were analyzed by Student’s t test and analysis of covariance. Intragroup differences of parameters before and after treatment were analyzed by paired t test. The relationship between two variables was evaluated by Spearman’s correlation coefficient. All statistical analyses were performed with the SAS software package (version 9.1; SAS Institute Inc., Cary, NC). A two-tailed P value of 0.05). The acarbose treatment also significantly improved the postprandial TG levels (vs. baseline), at both 30 min (D = -0.34 – 0.46 mmol/L, P < 0.001) and 120 min (D = -0.37 –
0.72 mmol/L, P = 0.002). In contrast, the nateglinide treatment only significantly reduced the postprandial TG levels at 30 min (D = –0.25 – 0.73 mmol/L, P = 0.029) but not at 120 min (D = –0.19 – 0.89 mmol/L, P = 0.169) (Table 2 and Fig. 1). Comparison of the levels of improvement achieved with acarbose and nateglinide at 30 min showed that the difference fell just beyond the threshold for statistical significance (P = 0.056). Again, neither nateglinide nor acarbose exerted significant effects on any of the other postprandial lipids evaluated including non–HDL-C. The nateglinide and acarbose treatment-related changes in postprandial TG, at both 30 min and 120 min, were significantly correlated with the changes in fasting TG (Table 3). In addition, the improvement in TG at postprandial 30 min was shown to be correlated to an increased insulin response observed at that same stage (q = -0.34, P = 0.028) (Table 4). The MBG and body weight of participants were significantly decreased after the treatment with either nateglinide or acarbose (data not shown). The changes in MBG and weight were not significantly correlated with changes in fasting and postprandial TG (Fig. 2). Discussion
In this multicenter, open-label, randomized, activecontrolled, parallel-group study, the effects of nateglinide and acarbose on lipid profiles (administered separately in 2-week courses) were found to mediate a significant improvement in TG (i.e., reduction, but to differing extents) in antihyperglycemic agent–naive patients with T2DM. Both of these drugs are efficacious antihyperglycemic agents. However, achieving a reduction in the hyperglycemic
232
ZHOU ET AL.
Table 4. Correlations of Change in Insulin Response with Change in Triglycerides for the Postprandial Interval (30 Min and 120 Min) Stratified by Nateglinide or Acarbose Treatment Change in TG Netaglinide
Acarbose
Change in insulin response
30 min
120 min
30 min
120 min
30 min 120 min
-0.34a -0.13
-0.15 0.19
-0.08 -0.23
0.062 0.044
Insulin responses were calculated as postprandial plasma insulin (30 min or 120 min)/fasting plasma insulin. a P < 0.05. TG, triglycerides.
FIG. 1. Effects of nateglinide and acarbose on fasting and postprandial triglycerides (TG): (a) TG levels at baseline (solid line) and posttreatment (dashed line) for the nateglinide (black rectangle) and acarbose (gray triangle) groups and (b) comparison of the changes of fasting and postprandial TG levels between the nateglinide (black bar) and acarbose (gray bar) groups. *P < 0.05.
state does not equate to a significant reduction in the diabetes patients’ risk of developing subsequent major macrovascular disease. It has been reported that intensive and sustained glucose control can lower the risk of major macrovascular events (by approximately 9%, as compared with conventional treatment) but provides no benefit to all-cause and cardiovascular mortality. As such, multifactorial intervention strategies continue to be recommended for management of T2DM. Previous studies investigating the effects of acarbose on lipid profiles have shown some inconsistent results. For example, Ogawa et al.13 reported that administration of acar-
Table 3. Correlations of Change in Triglycerides for the Fasting and Postprandial (30 Min and 120 Min) States Stratified by Nateglinide or Acarbose Treatment Nateglinide DTG 30 min 120 min
Acarbose
Total
q
P
q
P
q
P
0.85 0.64
ORIGINAL ARTICLE
Differential Therapeutic Effects of Nateglinide and Acarbose on Fasting and Postprandial Lipid Profiles: A Randomized Trial Jian Zhou, MD, PhD,1,* Zixuan Deng, MD,1,* Jingyi Lu, PhD,1,* Hong Li, MD,2 Xiuzhen Zhang, MD,3 Yongde Peng, MD, PhD,4 Yifei Mo, MD,1 Yuqian Bao, MD,1 and Weiping Jia, MD, PhD1
Abstract
Background: Dyslipidemia is commonly seen in patients with type 2 diabetes mellitus (T2DM). The current study sought to compare the effects of nateglinide and acarbose, two antihyperglycemic agents, on both fasting and postprandial lipid profiles in Chinese subjects with T2DM. Subjects and Methods: For this multicenter, open-label, randomized, active-controlled, parallel-group study, 103 antihyperglycemic agent–naive patients with T2DM were recruited from four hospitals in China. In total, 85 subjects (44 in the nateglinide group, 41 in the acarbose group) with a known complete lipid profile underwent the entire clinical trial and were included in the final analysis. Serum was collected in the fasting state and 30 and 120 min after a standardized meal (postprandial states) to measure the baseline lipid profiles; the same testing was performed upon completion of a 2-week course of nateglinide (120 mg three times a day) or acarbose (50 mg three times a day). Results: Fasting triglyceride (TG) levels were significantly reduced by both nateglinide and acarbose (P < 0.001), with acarbose providing a significantly more robust improvement (vs. nateglinide, P = 0.005). Additionally, the TG levels at both postprandial times were significantly reduced by acarbose (P < 0.001 at 30 min and P = 0.002 at 120 min), whereas nateglinide treatment only significantly reduced the 30-min postprandial TG (P = 0.029). Neither nateglinide nor acarbose treatment had significant impact on total cholesterol, high-density lipoprotein, low-density lipoprotein, or non–high-density lipoprotein cholesterol. Conclusions: Compared with nateglinide, acarbose has superior therapeutic efficacy for reducing fasting and postprandial TG levels in patients with T2DM. Introduction
D
yslipidemia, an important contributor to the development of cardiovascular events,1–3 is commonly observed in patient with type 2 diabetes mellitus (T2DM). The characteristic features of dyslipidemia in T2DM include
a high plasma triglyceride (TG) concentration and a low high-density lipoprotein cholesterol (HDL-C) concentration4 secondary to insulin resistance,5 although total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels do not differ between T2DM patients and individuals without diabetes.
1 Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai Clinical Center for Diabetes, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Diabetes Institute, Shanghai, People’s Republic of China. 2 Department of Endocrinology and Metabolism, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China. 3 Department of Endocrinology and Metabolism, Tong Ji Hospital Affiliated with Tong Ji University, Shanghai, People’s Republic of China. 4 Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated First People’s Hospital, Shanghai, People’s Republic of China. *The first three authors contributed equally to this study. This trial is registered at www.ClinicalTrials.gov with clinical trial registration number NCT01030952.
229
230
Nateglinide and acarbose are two of the oral antihyperglycemic agents widely used to treat T2DM patients in China. The former is an insulinotropic agent that rapidly induces insulin secretion with a short duration. The latter delays carbohydrate digestion by competitive and dosedependent inhibition of a-glucosidase enzymes located in the brush border of the small intestine. Our studies and those of other researchers have demonstrated that both nateglinide and acarbose can reduce postprandial hyperglycemia6,7 and are comparably effective in reducing postprandial glycemic excursions.8 However, the effects of nateglinide and acarbose on lipid profiles remain inconclusive.9–13 Moreover, only a few have conducted a direct comparison between the two agents.14,15 Therefore, the current study sought to evaluate the effects of nateglinide versus acarbose on both fasting and postprandial lipid profiles in antihyperglycemic agent–naive patients with T2DM. Subjects and Methods Patient selection and study design
The study was designed as a prospective, randomized, open-label, and active-controlled 2-week assessment of nateglinide and acarbose therapies, as previously described.8 The study protocol was designed in accordance with the principles of the Helsinki Declaration II and carried out with pre-approval by the Independent Ethics Committee of Shanghai Jiao Tong University Affiliated Sixth People’s Hospital (Shanghai, People’s Republic of China). All study participants provided written informed consent. In brief, adult (‡18-year-old) Chinese patients diagnosed with T2DM (glycated hemoglobin [HbA1c] range, 6.5– 9.0%) and antihyperglycemic agentnaive (no treatment with antihyperglycemic agents for at least 3 consecutive months prior to study enrollment) were recruited for study enrollment between December 2009 and February 2011 from the following four metropolitan medical centers in China: Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai; Sir Run Run Shaw Hospital, Hangzhou, People’s Republic of China; Tong Ji Hospital Affiliated to Tong Ji University, Shanghai; and Shanghai Jiao Tong University Affiliated First People’s Hospital, Shanghai. Patients were denied study enrollment if they had known allergies to nateglinide or acarbose or had ongoing hepatic or renal dysfunction. Following study enrollment, subjects were fasted overnight and then given a standard test meal (70 g of bread/ instant noodles) containing 322 Kcal with 42 g of carbohydrates, 6.3 g of protein, and 14.7 g of fat, eaten within a 15min period. At this point, the subjects were randomized (1:1) to receive a 2-week course of either nateglinide (120 mg three times a day) (Novartis Pharma Ltd., Beijing, People’s Republic of China) or acarbose (50 mg three times a day) (Bayer HealthCare Pharmaceuticals Inc., Montville, NJ). After the 2week treatment, the participants were given a second standard meal test in the fasting state. The treatment strategy has been illustrated in our previous study.8 Anthropometric and biochemical measurements
Upon enrollment, blood pressure was measured in triplicate using a standard mercury sphygmomanometer, and the aver-
ZHOU ET AL.
age measurement was recorded. Body mass index was calculated as weight (in kg)/height (in m)2. Mean blood glucose (MBG) was obtained by using a continuous glucose monitoring system (Medtronic MiniMed Inc., Northridge, CA). During the standard meal test, blood samples were collected to obtain both the fasting and postprandial (at 30 min and 120 min after meal) measures. The serum lipid profile was measured on an automated enzymatic analyzer (model 7600-020; Hitachi, Tokyo, Japan) and included total cholesterol, TG, HDL-C, and LDL-C. Non–HDL-C was calculated by subtracting HDL-C from total cholesterol. Plasma insulin was measured by standard bio-antibody technique (Linco, St. Louis, MO), and insulin response was calculated as postprandial plasma insulin (at 30 min/120 min)/fasting plasma insulin. The HbA1c level was estimated by high-pressure liquid chromatography using the Variant II hemoglobin testing system (Bio-Rad Laboratories, Hercules, CA). Statistical analysis
Intergroup differences in serum lipid measurements at baseline and after treatment were analyzed by Student’s t test and analysis of covariance. Intragroup differences of parameters before and after treatment were analyzed by paired t test. The relationship between two variables was evaluated by Spearman’s correlation coefficient. All statistical analyses were performed with the SAS software package (version 9.1; SAS Institute Inc., Cary, NC). A two-tailed P value of 0.05). The acarbose treatment also significantly improved the postprandial TG levels (vs. baseline), at both 30 min (D = -0.34 – 0.46 mmol/L, P < 0.001) and 120 min (D = -0.37 –
0.72 mmol/L, P = 0.002). In contrast, the nateglinide treatment only significantly reduced the postprandial TG levels at 30 min (D = –0.25 – 0.73 mmol/L, P = 0.029) but not at 120 min (D = –0.19 – 0.89 mmol/L, P = 0.169) (Table 2 and Fig. 1). Comparison of the levels of improvement achieved with acarbose and nateglinide at 30 min showed that the difference fell just beyond the threshold for statistical significance (P = 0.056). Again, neither nateglinide nor acarbose exerted significant effects on any of the other postprandial lipids evaluated including non–HDL-C. The nateglinide and acarbose treatment-related changes in postprandial TG, at both 30 min and 120 min, were significantly correlated with the changes in fasting TG (Table 3). In addition, the improvement in TG at postprandial 30 min was shown to be correlated to an increased insulin response observed at that same stage (q = -0.34, P = 0.028) (Table 4). The MBG and body weight of participants were significantly decreased after the treatment with either nateglinide or acarbose (data not shown). The changes in MBG and weight were not significantly correlated with changes in fasting and postprandial TG (Fig. 2). Discussion
In this multicenter, open-label, randomized, activecontrolled, parallel-group study, the effects of nateglinide and acarbose on lipid profiles (administered separately in 2-week courses) were found to mediate a significant improvement in TG (i.e., reduction, but to differing extents) in antihyperglycemic agent–naive patients with T2DM. Both of these drugs are efficacious antihyperglycemic agents. However, achieving a reduction in the hyperglycemic
232
ZHOU ET AL.
Table 4. Correlations of Change in Insulin Response with Change in Triglycerides for the Postprandial Interval (30 Min and 120 Min) Stratified by Nateglinide or Acarbose Treatment Change in TG Netaglinide
Acarbose
Change in insulin response
30 min
120 min
30 min
120 min
30 min 120 min
-0.34a -0.13
-0.15 0.19
-0.08 -0.23
0.062 0.044
Insulin responses were calculated as postprandial plasma insulin (30 min or 120 min)/fasting plasma insulin. a P < 0.05. TG, triglycerides.
FIG. 1. Effects of nateglinide and acarbose on fasting and postprandial triglycerides (TG): (a) TG levels at baseline (solid line) and posttreatment (dashed line) for the nateglinide (black rectangle) and acarbose (gray triangle) groups and (b) comparison of the changes of fasting and postprandial TG levels between the nateglinide (black bar) and acarbose (gray bar) groups. *P < 0.05.
state does not equate to a significant reduction in the diabetes patients’ risk of developing subsequent major macrovascular disease. It has been reported that intensive and sustained glucose control can lower the risk of major macrovascular events (by approximately 9%, as compared with conventional treatment) but provides no benefit to all-cause and cardiovascular mortality. As such, multifactorial intervention strategies continue to be recommended for management of T2DM. Previous studies investigating the effects of acarbose on lipid profiles have shown some inconsistent results. For example, Ogawa et al.13 reported that administration of acar-
Table 3. Correlations of Change in Triglycerides for the Fasting and Postprandial (30 Min and 120 Min) States Stratified by Nateglinide or Acarbose Treatment Nateglinide DTG 30 min 120 min
Acarbose
Total
q
P
q
P
q
P
0.85 0.64
