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
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
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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
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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 <7% at 24 weeks were 75%, 77.8%, and 60%, respectively. Changes between baseline and 24-week data for key parameters are shown in Fig. 4. For the whole study population, 24 weeks of combination therapy significantly increased CPI and SUIT (CPI, 1.4 ± 0.6 → 1.6 ± 0.7, p = 0.043) (SUIT, 36.4 ± 18.3 → 44.9 ± 22.5, p = 0.016), but did not influence FPG, HOMA-β, or P/I. However, if evaluated in subgroups, none of these parameters changed significantly after combination treatment. Correlation analyses for reduction of HbA1c Univariate analyses were conducted to evaluate which parameter was mainly correlated to the change in HbA1c (0 ‒ 24 weeks). As shown in Table
Sitagliptin plus low-dose glimepiride
Fig. 4 Changes in each variable at baseline and after 24 weeks of treatment with low-dose glimepiride (0.5 mg, 1 mg, or 2 mg/day) plus sitagliptin. Data are means ± SD. *p < 0.05 vs. baseline CPI, C-peptide index; SUIT, secretory unit of insulin in transplantation; HOMA-β, homeostasis model assessment-β-cell function; P/I, proinsulin/insulin; FPG, fasting plasma glucose.
2, ΔHbA1c was correlated with FPG (r = ‒0.269, p = 0.019), HbA1c (r = ‒0.613, p = 0.000), AST (r = 0.478, p = 0.029), and HOMA-β (r = 0.252, p = 0.038) at baseline. Multivariate analysis by stepwise method showed that baseline HbA1c level was the only explanatory variable correlated with ΔHbA1c (standardized partial regression coefficient= ‒0.63628, p = 0.0003). Safety No symptomatic hypoglycemia including severe hypoglycemia defined as the presence of any hypoglycemic symptoms that cannot be resolved by the patient themselves, was documented in any subjects during this study. Body weight did not change during 24 weeks (baseline, 63.6 ± 13.2 kg; 24 weeks, 63.0 ± 13.7 kg, p = 0.7841). No significant differences in changes of body weight were observed among the three groups (glimepiride 0.5 mg/day, ‒0.73±1.66 kg; 1 mg/day, ‒0.19±1.12 kg; 2 mg/day, ‒0.89±2.58 kg, p = 0.3827). There were no significant changes in other measured biochemical parameters, including serum creatinine,
Table 2 Univariate analysis of relationships between change in HbA1c at 24 weeks and baseline variables r
Duration of diabetes (yr)
Dose of glimepiride (mg)
BMI, body mass index; FPG, fasting plasma glucose; HbA1c, hemoglobin A1c; AST, aspartate aminotransferase; ALT, alanine aminotransferase; CPI, C-peptide index; SUIT, secretory unit of insulin in transplantation; HOMA-β, homeostasis model assessment-β-cell function; P/I, proinsulin/insulin.
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uric acid, low-density lipoprotein (LDL) cholesterol, and triglyceride (TG) levels (data not shown).
Discussion In this prospective study, 24-week treatment with sitagliptin as an add-on to glimepiride, which was reduced from 3‒6 mg/day to ≤2 mg/day, led to a significant improvement in glycemic control in Japanese patients with type 2 diabetes. There was no glimepiride dosedependency in terms of glycemic control or insulin secretion capacity; thus 0.5 mg/day of glimepiride is sufficient for glycemic control in combination with sitagliptin. To avoid severe hypoglycemia, a private committee of diabetologists in Japan recommended that the dosage of glimepiride should be decreased to ≤2 mg/day at the initiation of incretin-based therapy in Japanese patients with type 2 diabetes . This recommendation should be evaluated in terms of its impact on the frequency of severe hypoglycemic episodes and any dosedependency associated with low-dose glimepiride. Recently, Harashima et al. reported that combination therapy with sitagliptin and low-dose (≤2 mg/day) glimepiride was safe and effective for glycemic control in Japanese patients with type 2 diabetes . The present study is the first to investigate the dose-dependency of glimepiride, below 2 mg (0.5 mg, 1 mg, and 2 mg), in combination with sitagliptin. This study showed that combination therapy with low-dose glimepiride and sitagliptin induced a greater reduction in HbA1c than seen with higher doses of glimepiride and was not associated with the symptomatic hypoglycemia often seen with high-dose glimepiride. In the whole study population, the significant increase in CPI and SUIT, but not in HOMA-β, was shown at 24 weeks after combination therapy. The lack of significant changes in CPI and SUIT, when evaluated in subgroups, might be explained by a lack of statistical power because of our small sample size. The extent of increments in these markers of insulin secretion was not enough to explain the reduction in HbA1c in this study. It is possible that DPP-4 inhibitors suppress glucagon secretion as a result of increased intact GLP-1 concentration. Thus, it appears likely that the combination therapy improved glycemic control by decreasing glucagon levels. Although HbA1c levels were significantly decreased, FPG remained unchanged in this study, indicating the significant improvement of postprandial hyperglyce-
mia. It is also well known that incretins stimulate both the first and second phase of insulin secretion and especially decrease postprandial glucose levels by amelioration of first-phase insulin secretion [8, 9]. This mechanism may contribute to the improvement of glycemic control observed in this study. The finding that ΔHbA1c were not different among the three groups may be explained by similar changes in markers of insulin secretion (CPI, SUIT index, HOMA-β) and β-cell function (P/I). This may also suggest that the suppression of postprandial glucagon levels induced by sitagliptin was the same among the three groups. Glimepiride stimulates insulin secretion by closing pancreatic β cell KATP channels through binding to SUR1  and activating cAMP sensor Epac2 to Rap1 signaling . Incretins potentiate insulin secretion through cAMP signaling in pancreatic β-cells. Mukai et al. recently reported that exendin-4 decreases endogenous reactive oxygen species (ROS) production and increases ATP production in diabetic GK rat islets through suppression of Src activation, dependent on Epac , indicating another mechanism of incretins on insulin secretion. Therefore, the Epac2-Rap1 signaling pathway is a common target of SU and incretin-related drugs, and induces the synergistic effect on insulin secretion seen with this combination therapy . However, no dose-responsiveness of low-dose glimepiride was seen for glycemic control in combination therapy with sitagliptin. Our finding may suggest that 0.5 mg/day glimepiride, as far as we studied, is sufficient to achieve the maximum clinical effects of combination therapy with sitagliptin on pancreatic α cell and β cell function. Further studies are needed to clarify the precise mechanism of the lack of dose-dependency of low-dose glimepiride on improvement of glycemic control. On the other hand, Arai et al. reported that withdrawal of glimepiride significantly deteriorated glycemic control in patients with type 2 diabetes adequately controlled with sitagliptin, low-dose (0.5‒1 mg) glimepiride, and metformin . Taken together, in the combination therapy with sitagliptin and glimepiride, low-dose glimepiride of 0.5 mg/day may be sufficient to make it the most effective dose in Japanese patients with type 2 diabetes. Similar results, when evaluated only in subjects treated with clinical maximum dose of glimepiride (6 mg/day) before addition of sitagliptin, were obtained in this study (data not shown). In the present study, multivariate analysis by stepwise method demonstrated that baseline HbA1c was the
Sitagliptin plus low-dose glimepiride
only predictor for the efficacy of combination therapy with sitagliptin and low-dose glimepiride. However, Kim et al. reported that sitagliptin responders had lower BMI and were younger than non-responders in Korean patients with type 2 diabetes . Nomiyama et al. reported that treatment with sitagliptin 50 mg/day for 24 weeks in a larger number of patients was especially effective in patients with higher baseline HbA1c, lower BMI, and shorter duration of diabetes  and similar results were reported by Maeda et al. . This discrepancy might be explained by the small number of subjects in our study or differences in study design and statistical analysis. Further studies in larger populations are needed to confirm the predictor for the efficacy of combination therapy with sitagliptin and lowdose SU. Insulin secretion capacity did not predict the efficacy of combination therapy in this study. This result is consistent with a previous study . Japanese patients with type 2 diabetes are characterized by a predominant decrease in first-phase insulin secretion, and insulin secretagogues have been the first-line drug. Recently, a meta-analysis indicated that DPP-4 inhibitors are more effective for glycemic control in Asian (including Japanese) subjects than in non-Asian subjects . Therefore, a treatment regimen including DPP-4 inhibitors has become popular in Japan. In contrast, although SU are the strongest insulin secretagogues, a treatment regimen including highdose SU has recently been decreased to avoid its disadvantages of deterioration of pancreatic β cell function and the increase in hypoglycemic events, body weight, and glucagon secretion . We demonstrated here that only 0.5 mg/day of glimepiride should be recommended with respect to efficacy and safety in this combination therapy. Although a tendency for reduction in P/I at 24 weeks was found in the group receiving 0.5 mg/day of glimepiride, it remains unclear whether 0.5 mg/day glimepiride combined with sitagliptin would have an advantage on pancreatic β cell protection compared with higher-dose glimepiride. Although previous studies have demonstrated that
DPP-4 inhibitors might have a favorable effect on the lipid profile , the combination therapy with sitagliptin and glimepiride did not change level of LDL cholesterol or TG in this study. There are several limitations to the present study. First, although it is well known that sitagliptin suppresses glucagon secretion significantly, serum glucagon levels were not measured in this study. Thus the effect of combination therapy with sitagliptin and several doses of glimepiride on glucagon secretion is still unclear. Second, as the mean baseline HbA1c was 7.5% in the present study, our conclusions may not be applicable to patients with less well controlled type 2 diabetes. Third, the present study was carried out over a short period, and we did not demonstrate the sustainability of glucose-lowering effects. However, we believe that our findings are important from a clinical point of view to understand how we could effectively use low-dose SUs in combination with DPP-4 inhibitors in clinical practice. A long-term study is required to prove the sustainability of this combination therapy. In conclusion, this randomized controlled study indicates that combination therapy with sitagliptin and lowdose glimepiride of 0.5‒2 mg/day is both effective for glycemic control without dose-dependency and safe in Japanese type 2 diabetes inadequately controlled with high-dose glimepiride. Low-dose glimepiride (0.5 mg/ day ) is sufficient for glycemic control as compared with higher doses in combination therapy with sitagliptin.
Acknowledgements We thank Dr T. Shimada, Director of Clinical Research Center in Shizuoka General Hospital, for assistance with data analysis. This study was sponsored by the Joint Research Association for Japanese Diabetes.
Disclosures None of the authors have any potential conflicts of interest associated with this research.
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The goal of the study was to examine the effects of sitagliptin dose-up or glimepiride dose-up in Japanese patients with type 2 diabetes who were controlled inadequately by sitagliptin and glimepiride in combination.
The aim of this study was to evaluate the efficacy and tolerability of sitagliptin compared with glimepiride in elderly patients with type 2 diabetes mellitus (T2DM) and inadequate glycemic control with diet and exercise alone.
Type 2 diabetes mellitus is a progressive disease that frequently requires patients to use more than one oral antihyperglycemic agent to achieve adequate glycemic control. The present multicenter, randomized study assessed the efficacy and safety of
Agents that augment GLP-1 effects enhance glucose-dependent β-cell insulin production and secretion and thus are hoped to prevent progressive impairment in insulin secretion characteristic of type 2 diabetes (T2D). The purpose of this study was to ev
Sitagliptin is a novel antidiabetic agent with a low risk for hypoglycemia. We investigated the efficacy and safety of sitagliptin when patients switched from a sulfonylurea to sitagliptin and identified good candidates for the switch.
Metformin is a preferred drug for starting treatment in type 2 diabetes mellitus. But, eventually most of the patients need additional drug to control blood sugar level. The choice of drug depends upon several factors including patient specific crite