research letter
Diabetes, Obesity and Metabolism 2014. © 2014 John Wiley & Sons Ltd
We assessed the efficacy and safety of sitagliptin compared with α-glucosidase inhibitor (αGI) in 120 of Japanese patients with type 2 diabetes mellitus (T2DM) inadequately controlled on stable ≤2 mg/day glimepiride alone [mean hemoglobin A1c (HbA1c) 7.7%] by the randomized, active-controlled, non-inferiority trial. Patients were randomly assigned to receive additional sitagliptin or αGI for 24 weeks. The primary endpoint was change in HbA1c from baseline to week 12. After 12 weeks, sitagliptin reduced HbA1c by −0.44% (p < 0.001) relative to αGI. At 24 weeks, the reduction was almost identical between the groups (−0.091%, p = 0.47). Gastrointestinal disorders were more common with αGI than with sitagliptin, but only minor hypoglycaemia occurred in both groups at similar frequency. These data suggested that sitagliptin was not inferior to αGI for reduction of HbA1c in Japanese T2DM patients receiving glimepiride alone, and well tolerated with minimum risk of gastrointestinal symptoms and hypoglycaemia. Keywords: α-glucosidase inhibitor, DPP-IV inhibitor, randomized trial, sulphonylureas, type 2 diabetes Date submitted 24 October 2013; date of first decision 26 November 2013; date of final acceptance 14 January 2014
Introduction To prevent vascular complications in type 2 diabetes mellitus (T2DM), blood glucose levels should be maintained to as close to normal levels as possible, while preventing hypoglycaemia and weight gain [1]. Sulfonylureas, potent oral insulin secretagogues, are commonly used for T2DM patients [1,2], but most of them usually requires multiple drugs to attain or maintain glycaemic control [3]. The recent oral antidiabetic drug dipeptidyl peptidase-4 (DPP-4) inhibitor, including sitagliptin, lowers blood glucose levels by inhibiting the degradation of incretin hormones such as glucagonlike peptide-1 (GLP-1) [4] with the reportedly low risk of hypoglycaemia and weight gain [5,6]. On the other hand, α-glucosidase inhibitor (αGI) has been widely used in Japan for delaying the absorption of glucose and decreasing the postprandial glucose excursion with low risk of hypoglycaemia as well as gaining body weight [7]. Therefore, in the present SUCCESS-2 (Study for an Ultimate Combination therapy to Control diabetES with Sitagliptin) trial, we aimed to assess the efficacy and safety of sitagliptin compared with αGI in Japanese patients with T2DM inadequately controlled on sulfonylurea alone.
Subjects and Methods This multicenter, comparative, parallel-group, activecontrolled, randomized, open-label and non-inferiority trial Correspondence to: Koutaro Yokote, MD, PhD, Department of Medicine, Division of Metabolism and Endocrinology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. E-mail: [email protected]
was undertaken at 37 sites in Chiba prefecture, Japan. The study was approved by each center’s ethics committee and registered (UMIN-ID: UMIN 000004674; http://www.umin.ac.jp/ctr/). Eligible study participants were aged 20–79 years, had T2DM, had been receiving ≤2 mg/day glimepiride alone for ≥2 months, and had an hemoglobin A1c (HbA1c) of 6.9–8.8%. All patients provided written informed consent before participation, and were randomly assigned to either 24 weeks of treatment with sitagliptin (50 mg once a day) or αGI (0.2 mg voglibose or 50 mg miglitol three times a day) in addition to glimepiride (dose unchanged throughout the study). The primary efficacy endpoint was a change in HbA1c from baseline to week 12. Safety and tolerability were also assessed throughout the study. The details about secondary endpoints, data management and statistical analysis were described in Detailed Subjects and Methods (Appendix S1, Supporting Information).
Results Details of demographics throughout this study is showed as flow chart in Figure S1. Patient characteristics were well balanced between treatment groups (Table S1). HbA1c was significantly reduced with sitagliptin when compared with αGI at 12 weeks after treatment. However, at 24 weeks, the reduction in HbA1c from baseline was similar between the groups (Figure 1A, B). At 12 weeks, adjusted mean reductions in HbA1c from baseline were −0.72% (95% confidence interval (CI): –0.86 to −0.57) with sitagliptin and −0.28% (−0.43 to −0.12) with αGI in the full analysis set (Figure 1B). The least squares mean of the treatment difference
research letter
Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin compared with α-glucosidase inhibitor in Japanese patients with type 2 diabetes inadequately controlled on sulfonylurea alone (SUCCESS-2): a multicenter, randomized, open-label, non-inferiority trial
research letter A
DIABETES, OBESITY AND METABOLISM
8.5
B
†
7.5
†㼲
7.0
‡ ||
‡ 6.5 6.0 0
12 Weeks
Change in HbA1c(%)
HbA1c (%)
8.0
24
†
8.0 ‡ ||
‡
7.0 6.0 5.0 0
12 Weeks
24
Change in FPG (mmol/L)
9.0
*
F
100 †㼲
†
60
‡
‡
12 Weeks
24
40 20 0 0
12
24
-0.2 -0.4 -0.6 -0.8 -1 -1.2
120
80
24
Weeks 0
Change in 1,5-AG (μmol/L)
FPG (mmol/L)
10.0
1,5-AG (μmol/L)
0 -0.1 -0.2 -0.3 -0.4 -0.5 -0.6 -0.7 -0.8 -0.9
D
C 11.0
E
Weeks 12
45 40 35 30 25 20 15 10 5 0
*
12
24 Weeks
Change in body weight (kg)
G 1 0.5 0 -0.5 †
-1
*
† *
-1.5 0
12 Weeks
24
Figure 1. Changes in representative endpoints. (A) Mean ± standard deviation (s.d.) hemoglobin A1c (HbA1c) during the study period. (B) Change ± standard error (s.e.) from baseline in HbA1c values. (C) Mean ± s.d. fasting plasma glucose (FPG) during the study period. (D) Change ± s.e. from baseline in FPG values. (E) Mean ± s.d. 1,5-anhydroglucitol (AG) during the study period. (F) Change ± s.e. from baseline in 1,5-AG values. (G) Change ± s.e. from baseline in body weight. Black squares and bars represent sitagliptin, white squares and bars represent α-glucosidase inhibitor (αGI). *P < 0.05 between sitagliptin and αGI with same week. †, §P < 0.05 compared with week 0 or week 12 in αGI, respectively. ‡, ||P < 0.05 compared with week 0 or week 12 in sitagliptin, respectively.
2 Kobayashi et al.
2014
research letter
DIABETES, OBESITY AND METABOLISM
Table 1. Changes in secondary endpoints from baseline to week 12 and 24∗.
Mean change from baseline (week 12)
Glycaemic control Glycoalbumin (%) β-cell function Fasting insulin (pmol/l) Fasting C-peptide (nmol/l) Fasting proinsulin-to-insulin molar ratio HOMA-β HOMA-IR Vital signs Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Heart rate (beats per min) Fasting lipid profiles Total cholesterol (mmol/l) LDL cholesterol (mmol/l) HDL cholesterol (mmol/l) Triglycerides (mmol/l) Non-HDL cholesterol (mmol/l)
Mean change from baseline (week 24)
Sitagliptin
α-Glucosidase inhibitor
P value† Sitagliptin
α-Glucosidase inhibitor
P value†
−2.6 (−3.1 to −2.1)
−1.0 (−1.6 to −0.47)
Diabetes, Obesity and Metabolism 2014. © 2014 John Wiley & Sons Ltd
We assessed the efficacy and safety of sitagliptin compared with α-glucosidase inhibitor (αGI) in 120 of Japanese patients with type 2 diabetes mellitus (T2DM) inadequately controlled on stable ≤2 mg/day glimepiride alone [mean hemoglobin A1c (HbA1c) 7.7%] by the randomized, active-controlled, non-inferiority trial. Patients were randomly assigned to receive additional sitagliptin or αGI for 24 weeks. The primary endpoint was change in HbA1c from baseline to week 12. After 12 weeks, sitagliptin reduced HbA1c by −0.44% (p < 0.001) relative to αGI. At 24 weeks, the reduction was almost identical between the groups (−0.091%, p = 0.47). Gastrointestinal disorders were more common with αGI than with sitagliptin, but only minor hypoglycaemia occurred in both groups at similar frequency. These data suggested that sitagliptin was not inferior to αGI for reduction of HbA1c in Japanese T2DM patients receiving glimepiride alone, and well tolerated with minimum risk of gastrointestinal symptoms and hypoglycaemia. Keywords: α-glucosidase inhibitor, DPP-IV inhibitor, randomized trial, sulphonylureas, type 2 diabetes Date submitted 24 October 2013; date of first decision 26 November 2013; date of final acceptance 14 January 2014
Introduction To prevent vascular complications in type 2 diabetes mellitus (T2DM), blood glucose levels should be maintained to as close to normal levels as possible, while preventing hypoglycaemia and weight gain [1]. Sulfonylureas, potent oral insulin secretagogues, are commonly used for T2DM patients [1,2], but most of them usually requires multiple drugs to attain or maintain glycaemic control [3]. The recent oral antidiabetic drug dipeptidyl peptidase-4 (DPP-4) inhibitor, including sitagliptin, lowers blood glucose levels by inhibiting the degradation of incretin hormones such as glucagonlike peptide-1 (GLP-1) [4] with the reportedly low risk of hypoglycaemia and weight gain [5,6]. On the other hand, α-glucosidase inhibitor (αGI) has been widely used in Japan for delaying the absorption of glucose and decreasing the postprandial glucose excursion with low risk of hypoglycaemia as well as gaining body weight [7]. Therefore, in the present SUCCESS-2 (Study for an Ultimate Combination therapy to Control diabetES with Sitagliptin) trial, we aimed to assess the efficacy and safety of sitagliptin compared with αGI in Japanese patients with T2DM inadequately controlled on sulfonylurea alone.
Subjects and Methods This multicenter, comparative, parallel-group, activecontrolled, randomized, open-label and non-inferiority trial Correspondence to: Koutaro Yokote, MD, PhD, Department of Medicine, Division of Metabolism and Endocrinology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. E-mail: [email protected]
was undertaken at 37 sites in Chiba prefecture, Japan. The study was approved by each center’s ethics committee and registered (UMIN-ID: UMIN 000004674; http://www.umin.ac.jp/ctr/). Eligible study participants were aged 20–79 years, had T2DM, had been receiving ≤2 mg/day glimepiride alone for ≥2 months, and had an hemoglobin A1c (HbA1c) of 6.9–8.8%. All patients provided written informed consent before participation, and were randomly assigned to either 24 weeks of treatment with sitagliptin (50 mg once a day) or αGI (0.2 mg voglibose or 50 mg miglitol three times a day) in addition to glimepiride (dose unchanged throughout the study). The primary efficacy endpoint was a change in HbA1c from baseline to week 12. Safety and tolerability were also assessed throughout the study. The details about secondary endpoints, data management and statistical analysis were described in Detailed Subjects and Methods (Appendix S1, Supporting Information).
Results Details of demographics throughout this study is showed as flow chart in Figure S1. Patient characteristics were well balanced between treatment groups (Table S1). HbA1c was significantly reduced with sitagliptin when compared with αGI at 12 weeks after treatment. However, at 24 weeks, the reduction in HbA1c from baseline was similar between the groups (Figure 1A, B). At 12 weeks, adjusted mean reductions in HbA1c from baseline were −0.72% (95% confidence interval (CI): –0.86 to −0.57) with sitagliptin and −0.28% (−0.43 to −0.12) with αGI in the full analysis set (Figure 1B). The least squares mean of the treatment difference
research letter
Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin compared with α-glucosidase inhibitor in Japanese patients with type 2 diabetes inadequately controlled on sulfonylurea alone (SUCCESS-2): a multicenter, randomized, open-label, non-inferiority trial
research letter A
DIABETES, OBESITY AND METABOLISM
8.5
B
†
7.5
†㼲
7.0
‡ ||
‡ 6.5 6.0 0
12 Weeks
Change in HbA1c(%)
HbA1c (%)
8.0
24
†
8.0 ‡ ||
‡
7.0 6.0 5.0 0
12 Weeks
24
Change in FPG (mmol/L)
9.0
*
F
100 †㼲
†
60
‡
‡
12 Weeks
24
40 20 0 0
12
24
-0.2 -0.4 -0.6 -0.8 -1 -1.2
120
80
24
Weeks 0
Change in 1,5-AG (μmol/L)
FPG (mmol/L)
10.0
1,5-AG (μmol/L)
0 -0.1 -0.2 -0.3 -0.4 -0.5 -0.6 -0.7 -0.8 -0.9
D
C 11.0
E
Weeks 12
45 40 35 30 25 20 15 10 5 0
*
12
24 Weeks
Change in body weight (kg)
G 1 0.5 0 -0.5 †
-1
*
† *
-1.5 0
12 Weeks
24
Figure 1. Changes in representative endpoints. (A) Mean ± standard deviation (s.d.) hemoglobin A1c (HbA1c) during the study period. (B) Change ± standard error (s.e.) from baseline in HbA1c values. (C) Mean ± s.d. fasting plasma glucose (FPG) during the study period. (D) Change ± s.e. from baseline in FPG values. (E) Mean ± s.d. 1,5-anhydroglucitol (AG) during the study period. (F) Change ± s.e. from baseline in 1,5-AG values. (G) Change ± s.e. from baseline in body weight. Black squares and bars represent sitagliptin, white squares and bars represent α-glucosidase inhibitor (αGI). *P < 0.05 between sitagliptin and αGI with same week. †, §P < 0.05 compared with week 0 or week 12 in αGI, respectively. ‡, ||P < 0.05 compared with week 0 or week 12 in sitagliptin, respectively.
2 Kobayashi et al.
2014
research letter
DIABETES, OBESITY AND METABOLISM
Table 1. Changes in secondary endpoints from baseline to week 12 and 24∗.
Mean change from baseline (week 12)
Glycaemic control Glycoalbumin (%) β-cell function Fasting insulin (pmol/l) Fasting C-peptide (nmol/l) Fasting proinsulin-to-insulin molar ratio HOMA-β HOMA-IR Vital signs Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Heart rate (beats per min) Fasting lipid profiles Total cholesterol (mmol/l) LDL cholesterol (mmol/l) HDL cholesterol (mmol/l) Triglycerides (mmol/l) Non-HDL cholesterol (mmol/l)
Mean change from baseline (week 24)
Sitagliptin
α-Glucosidase inhibitor
P value† Sitagliptin
α-Glucosidase inhibitor
P value†
−2.6 (−3.1 to −2.1)
−1.0 (−1.6 to −0.47)
