Endocrine Journal 2014, 61 (12), 1163-1170
Low-dose glimepiride with sitagliptin improves glycemic control without dose-dependency in patients with type 2 diabetes inadequately controlled on high-dose glimepiride Rieko Umayahara*, Takako Yonemoto*, Chika Kyou, Kae Morishita, Tatsuo Ogawa, Yoshitaka Taguchi and Tatsuhide Inoue Center for Diabetes, Endocrinology and Metabolism, Shizuoka General Hospital, Shizuoka 420-8527, Japan
Abstract. This randomized, prospective study was conducted in 76 subjects to assess whether low-dose (0.5‒2 mg/day) glimepiride, in combination therapy with sitagliptin, improves glycemic control in a dose-dependent manner in Japanese patients with type 2 diabetes. Eligible subjects had been treated with glimepiride at doses of 3‒6 mg/day for at least 3 months and had a HbA1c level of ≥6.9%. Subjects were randomly assigned to three treatment groups of reduced doses of glimepiride (0.5 mg/day, 1 mg/day, or 2 mg/day) in addition to sitagliptin for 24 weeks. The primary efficacy analysis evaluated the change in HbA1c from baseline to week 24. Secondary efficacy endpoints included the changes in fasting plasma glucose, insulin secretion capacity, and β-cell function. Safety endpoints included hypoglycemia and any adverse event. Despite dose reduction of glimepiride, combination therapy with sitagliptin induced significant improvements in HbA1c levels (‒0.8%, p < 0.001). Insulin secretion parameters (CPI, SUIT) also increased significantly. There were no significant differences between groups in changes from baseline HbA1c, insulin secretion capacity, and β-cell function (proinsulin/insulin) at 24 weeks of combination therapy. Multivariate analysis showed that baseline HbA1c was the only predictor for efficacy of combination therapy with sitagliptin and low-dose glimeripide. No changes in body weight were noted and no symptomatic hypoglycemia was documented. These findings indicate that combination therapy with sitagliptin and low-dose glimepiride (0.5 mg/day) is both effective for glycemic control and safe in Japanese patients with type 2 diabetes inadequately controlled with high-dose glimepiride. Key words: Sitagliptin, Low-dose glimepiride, Combination therapy, Dose-dependency, Glycemic control
SITAGLIPTIN is a potent and highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor known to have greater efficacy in Japanese patients with type 2 diabetes. A treatment regimen including DPP-4 inhibitors has become popular in Japan. Glimepiride, a sulfonylurea (SU), acts by increasing insulin release from β-cells in a glucose-independent fashion. Glimepiride stimulates insulin secretion in two ways: by closing pancreatic β cell KATP channels through SU receptors  and by activating cAMP sensor Epac2 . Incretins potentiate insulin secretion through cAMP signaling in Submitted Feb.13, 2014 as EJ14-0065; Accepted Aug.1, 2014 as EJ14-0233 Released online in J-STAGE as advance publication Aug. 27, 2014
Correspondence to: Tatsuhide Inoue, Center for Diabetes, Endocrinology and Metabolism, Shizuoka General Hospital, 4-271, Kita-Ando, Aoi-ku, Shizuoka 420-8527, Japan. E-mail: [email protected]
*These authors contributed equally to this work. ©The Japan Endocrine Society
pancreatic β-cells . Therefore, the Epac2 signaling pathway is a common target of SU and incretin-related drugs , possibly demonstrating the synergistic effect on insulin secretion with this combination therapy . Intact glucagon-like peptide-1 (GLP-1), increased by DPP-4 inhibitors, decreases glucagon secretion from the pancreatic α-cells when blood glucose levels are elevated, which is likely to also contribute to the glucose-lowering effect seen with sitagliptin . As the initiation of combination therapy with sitagliptin and glimepiride was shown to induce severe hypoglycemia in Japan, a reduced dose of glimepiride ≤2 mg/day was recommended when starting combination therapy with a DPP-4 inhibitor . This recommendation should be evaluated in terms of its impact on the incidence of severe hypoglycemia as well as whether the combination of sitagliptin and different doses of glimepiride (0.5 mg/day‒2.0 mg/day) could
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improve glycemic control in a dose-dependent manner. This randomized study was designed to compare the efficacy and safety profiles of low-dose glimepiride in combination therapy with sitagliptin.
Subjects and Methods Subjects Patients recruited for the study had type 2 diabetes and were receiving outpatient treatment at our medical center. Eligible subjects had been treated with glimepiride at doses of 3-6 mg/day (with or without metformin, α-glucosidase inhibitor, and thiazolidinedione) for at least 3 months and had a HbA1c level ≥6.9%. Subjects with type 1 diabetes, secondary diabetes, diabetic nephropathy stage 4‒5, malignancy or other severe conditions, and younger than 20 years, were excluded. Antidiabetic agents, antihypertensive agents, statins, or fibrates were not newly administered and doses were not changed from 12 weeks before the start until the end of the study. Subjects were asked not to alter their lifestyle, including diet, exercise, and other habits during the study. Diabetic complications were diagnosed as follows: neuropathy according to ‘Abbreviated Diagnostic Criteria for Diabetic Polyneuropathy’ proposed by the Diabetic Neuropathy Study Group in Japan , nephropathy as spot urinary albumin excretion ≥30mg/gCr, and retinopathy as simple, preproliferative, and proliferative diabetic retinopathy by an ophthalmologist. The study was designed in accordance with the principles stated in the Declaration of Helsinki. The study protocol was approved by the ethics committee of Shizuoka General Hospital and registered on the University Hospital Medical Information Network in Japan (UMIN000013827). All subjects gave written informed consent. Study design This was a prospective, 24-week, single center, intervention study. Subjects were randomized to receive 0.5 mg/day, 1 mg/day, or 2 mg/day of glimepiride in addition to 50mg/day sitagliptin (a lower dose of 25 mg was administered if estimated glomerular filtration rate was lower than 60 mL/min). Subjects were encouraged to visit the hospital every month during the study. Blood samples were taken from all subjects in a fasting state at baseline and after 12 and 24 weeks.
Endpoints The primary endpoint was the change from baseline in HbA1c (∆HbA1c) at 12 and 24 weeks. Secondary endpoints included changes from baseline in fasting plasma glucose (FPG), C-peptide index (CPI), secretory units of islets in transplantation (SUIT), homeostasis model assessment of β (HOMA-β), proinsulin/ insulin (P/I), and body weight at 24 weeks. CPI, SUIT, and HOMA-β were measured to assess insulin secretion capacity. P/I was measured to assess β-cell function. CPI, SUIT, HOMA-β, and P/I were calculated by the following formula: CPI = fasting serum C-peptide (ng/mL) × 100 / FPG (mg/dL), SUIT =1485 × fasting serum C-peptide (ng/mL) / (FPG – 61.8 (mg/dL)), HOMA-β = 360 × fasting insulin (μU/mL) / (FPG (mg/ dL) − 3.5 × 18), P/I = fasting proinsulin (pM) / insulin (pM). Safety endpoints were symptomatic hypoglycemia and any adverse events.
Statistical Analysis Data are expressed as means ± standard deviation. Differences between groups were assessed by the chisquare test for categorical variables and by analysis of variance (ANOVA) for continuous variables. The paired t-test was used to assess differences between baseline and each time point. Two-way repeated measured ANOVA was used to assess differences in time courses of mean HbA1c at each point in three groups. In our clinical study, an appropriate sample size was computed, based on repeating measure ANOVA design using PASS 11 software for sample size calculation; each group needed at least 13 patients. As a result, a minimum of 39 patients were needed for this clinical study. We decided to use about twice of the numbers of patients calculated by PASS 11 to obtain more safety data. Seventy six subjects were randomly allocated into 3 groups of glimepiride dose using PASS11 software program. Univariate analysis was performed to determine the relationship between the characteristics and changes in HbA1c at 24 weeks. The following characteristics were analyzed: age, duration of diabetes, body mass index (BMI), dose of glimepiride, FPG, HbA1c, aspartate aminotransferase (AST), alanine aminotransferase (ALT), CPI, SUIT, HOMA-β, and P/I at baseline. Multivariate analysis by the stepwise method was undertaken to identify the predictive factors for the efficacy of combination treatment. P values < 0.05
Sitagliptin plus low-dose glimepiride
Table 1 Baseline demographic and clinical characteristics of study subjects Glimepiride / day Study group Total P 0.5mg 1mg 2mg n 76 24 27 25 ─ Sex (male/female) 56/20 17/7 21/6 18/7 0.8309 Age (yr) 65.2±10.7 65.0±10.7 67.1±9.8 63.4±11.7 0.4703 Duration of diabetes (yr) 18.4±8.3 19.8±8.9 18.7±8.0 16.8±8.0 0.4390 23.7±3.6 23.3±3.3 23.4±2.5 24.6±4.7 0.3341 BMI (kg/m2) Ex dose of glimepiride (mg/day) 4.2±1.5 4.6±1.4 4.3±1.5 3.9±1.4 0.2383 FPG (mg/dL) 151.0±30.0 150.2±28.0 148.7±34.8 154.2±27.1 0.7991 HbA1c (%) 7.5±0.6 7.5±0.5 7.5±0.7 7.6±0.7 0.9254 CPI 1.4±0.6 1.3±0.7 1.3±0.5 1.4±0.7 0.9312 SUIT 36.4±18.3 36.6±21.4 36.5±15.4 36.2±19.2 0.9968 HOMA-β 32.2±23.0 33.2±24.2 26.1±17.8 32.7±28.3 0.5312 P/I 0.4±0.3 0.4±0.2 0.4±0.3 0.4±0.3 0.9353 LDL-C (mg/dL) 117.5±28.4 126.8±31.1 111.4±27.2 115.0±25.6 0.1363 TG (mg/dL) 108.9±48.4 114.7±56.2 108.3±49.8 102.9±39.0 0.6963 systolic BP (mmHg) 133.9±16.8 136.8±14.1 131.7±19.6 133.5±16.2 0.5661 diastolic BP (mmHg) 73.1±12.0 71.5±11.9 73.4±12.6 74.4±11.8 0.7004 AST (IU/L) 24.6±12.7 26.2±14.0 19.1±3.9 28.3±16.2 0.3812 ALT (IU/L) 30.8±23.2 24.7±11.1 23.6±10.6 42.3±34.2 0.2124 Complications Neuropathy, n (%) 44 (57.9) 14 (58.3) 17 (63.0) 13 (52.0) 0.7251 Nephropathy, n (%) 42 (55.3) 15 (62.5) 14 (51.9) 13 (52.0) 0.6896 Retinopathy, n (%) 33 (43.4) 11 (45.8) 14 (51.9) 8 (32.0) 0.3387 Medications Biguanide (%) 52 (68.4) 17 (70.8) 18 (66.7) 17 (68.0) 0.9488 Pioglitazone (%) 22 (28.9) 4 (16.7) 10 (37.0) 8 (32.0) 0.2551 α-glucosidase inhibitor (%) * 54 (71.1) 22 (91.7) 19 (70.4) 13 (52.0) 0.0092 BMI, body mass index; FPG, fasting plasma glucose; HbA1c, hemoglobin A1c; CPI, C-peptide index; SUIT, secretory unit of insulin in transplantation; HOMA-β, homeostasis model assessment-β-cell function; P/I, proinsulin/insulin; LDL-C, low-density lipoprotein cholesterol; TG, triglyceride; BP, blood pressure; AST, aspartate aminotransferase; ALT, alanine aminotransferase. Data are means ± SD. * p < 0.05 as a comparison among three groups.
were considered significant. All statistical analyses were performed with JMP ver. 9 for Windows.
Results Of 84 patients screened, 8 patients were excluded; thus 76 patients were included in the study (Fig. 1). Subjects were randomly assigned either to a group of 0.5 mg/day (n=24), 1 mg/day (n=27), or 2 mg/day (n=25) of glimepiride. A lower dose of 25 mg sitagliptin was administered in 7 subjects. All subjects completed the 24-week study and were eligible for statistical analysis. Baseline characteristics of the 76 subjects are shown in Table 1. For the entire study population, the mean duration of diabetes was 18.4 ± 8.3 years, the mean baseline HbA1c was 7.5 ± 0.6 %, and the mean baseline FPG was 151.0 ± 30.0 mg/dL. There were no clinically meaningful differences in baseline charac-
Fig .1 Disposition of study subjects
Umayahara et al.
Fig. 2 Time courses of mean HbA1c (A) and changes in HbA1c (B) at 12 and 24 weeks in the entire study cohort. Data are means ± SD. * p < 0.001 vs. baseline.
Fig. 3 Time courses of mean HbA1c (A) and changes in HbA1c (B) at 12 and 24 weeks in three glimepiride groups (0.5 mg, 1 mg, or 2 mg/day). Data are means ± SD. * p < 0.001 vs. baseline.
teristics among the groups, except for the rate of α-GI administration. The baseline characteristics of insulin secretion (CPI, SUIT, and HOMA-β) and β-cell function (P/I) were similar among treatment groups. Changes in HbA1c with combination therapy After 24 weeks of treatment, the mean HbA1c level in all subjects was significantly decreased from 7.5 ± 0.5 % to 6.7 ± 0.6 % (P < 0.001) (Fig. 2A). The change in HbA1c from baseline was ‒0.8 % at 24 weeks (P < 0.001) (Fig. 2B). No significant differences in ΔHbA1c were observed among the groups (glimepiride 0.5 mg/day, ‒0.9%; 1 mg/day, ‒ 0.8%; 2 mg/day, ‒ 0.8%, p=0.8627) (Fig. 3B). Compared with baseline levels, HbA1c levels at 24 weeks were significantly decreased in all three groups, while FPG remained unchanged
(Fig. 4A). The proportion of patients with HbA1c values meeting the therapeutic goal of