Article 295

Authors

C. Erem1*, H. M. Ozbas1, İ. Nuhoglu1*, O. Deger2*, N. Civan1, H. O. Ersoz1

Affiliations

1

Division of Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey 2 Department of Medical Biochemistry, The Trabzon Endocrinological Studies Group, Trabzon, Turkey

Key words ▶ gliclazide-MR ● ▶ metformin ● ▶ pioglitazone ● ▶ type 2 diabetes ● ▶ cardiovascular risk factors ● ▶ glycemic control ●

Abstract

received 04.10.2013 first decision 11.02.2014 accepted 24.02.2014 Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1370989 Published online: April 7, 2014 Exp Clin Endocrinol Diabetes 2014; 122: 295–302 © J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York ISSN 0947-7349 Correspondence Prof. Dr. C. Erem K.T.Ü. Tıp Fakültesi İç Hastalıkları Anabilim Dalı Endokrinoloji ve Metabolizma Hastalıkları Bilim Dalı 61080, Trabzon Turkey Tel.: + 90/462/3775 449 Fax: + 90/462/325 22 70 [email protected] [email protected]

▼

Objective: The objective of this study was to evaluate and compare the effects of gliclazidemodified release (gliclazide-MR), metformine (MET) and pioglitazone (PIO) monotherapies on glycemic control and conventional/non-conventional cardiovascular risk factors in patients with newly diagnosed type 2 diabetes mellitus (T2DM). Material and Methods: A single center, randomized, 52-wk comparator-controlled clinical study was carried out in patients with newly diagnosed uncontrolled T2DM. A total of 57 patients were randomized into gliclazide-MR, metformin and pioglitazone groups. Drugs were administered for 12 months. Anthropometric measurements, fasting plasma glucose (FPG), postprandial plasma glucose (PPG), HbA1c, insulin, HOMA-IR, lipid parameters, the markers of coagulation/fibrinolysis, inflammation and endothelial dysfunction were measured at baseline and at months 3, 6, and 12. Results: In the gliclazide-MR group, HC, FPG, HbA1c, insulin, HOMA-IR, TC, trigylcerides, Lp (a),

Introduction

▼

Endothelial dysfunction, coagulation/fibrinolysis abnormalities, abnormal angiogenesis, subclinical systemic inflammation, increased homocysteine levels, and microalbuminuria are non-conventional CVD risk markers in patients with T2DM [1–4]. These markers have been shown, independent of conventional risk factors (e. g., hyperglycemia, hypertension, dyslipidemia, abdominal obesity, cigarette smoking, insulin resistance and hyperinsulinemia), to be associated with the risk of CVD and/or CVD mortality in type 2 diabetic patients [2].

* The Trabzon Endocrinological Studies Group, Trabzon, Turkey

E-selectin and Hcy were significantly decreased after treatment compared to baseline. In the MET group, BMI, WC, FPG, PPG, HbA1c, ICAM-1 and Hcy significantly decreased after treatment compared to baseline. In PIO group, WC, HC, FPG, PPG, HbA1c, C-peptid, HOMA-IR, trigylcerides, vWF, IL-6, ICAM-1, E-selectin and Hcy significantly decreased after treatment compared to baseline, whereas, HDL-C increased. At the end of the month 12, the decreases in insulin and HOMA-IR score were more pronounced with PIO compared to gliclazide. Conclusions: Gliclazide-MR, MET and PIO monotherapies, were equally effective in proving glycemic control in patients with newly diagnosed, oral antidiabetic (OAD)-naive T2DM. But, improvements in conventional/non-conventional cardiovascular risk factors were more pronounced in patients on PIO therapy compared to gliclazide and MET therapies. Also, all of the 3 drugs represent effective and safe first-line pharmacological treatment options in these patients.

For insulin resistance and β-cell dysfunction (relative insulin deficiency) play an important role in the pathogenesis of type 2 diabetes [5]. The 3 main options among oral antidiabetic drugs are metformin (MET), sulphonylureas (SUs) and thiazolidinedions (TZDs) [6]. They may be used as monotherapy. There has been some discussion on the best initial drug therapy in patients with T2DM, but most authors choose MET due to its efficacy, safety and lower cost [6, 7]. Gliclazide, is a second generation SU, while gliclazide-modified release (gliclazide-MR) is a new formulation of this drug designed for once-daily administration [6, 8]. Gliclazide, by its ability to reduce endothelial activation, may exert potential beneficial effects in the prevention of atherosclerosis associated with type 2 diabetes [9].

Erem C et al. Gliclazide-MR, Metformin and Pioglitazone Monotherapies in Type 2 Diabetes … Exp Clin Endocrinol Diabetes 2014; 122: 295–302

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

Comparison of Effects of Gliclazide, Metformin and Pioglitazone Monotherapies on Glycemic Control and Cardiovascular Risk Factors in Patients with Newly Diagnosed Uncontrolled Type 2 Diabetes Mellitus

296 Article

Subjects and Methods

▼

Study design A single center, randomized, 52-wk comparator-controlled clinical study was carried out in patients with newly diagnosed uncontrolled T2DM. The diagnosis of T2DM was based on the criteria established in the expert committee report of the American Diabetes Association [14]. At visit 1 (at diagnosis), laboratory tests were performed to determine patient egilibility; patients also received diabetes education and individualized dietary and physical activity instructions (screening/observation period). At the observation period (visit 2), 60 type 2 diabetic patients were randomized into gliclazide-MR (20 patients), metformin (20 patients) and pioglitazone (20 patients) groups. Gliclazide-MR was initiated at a dosage of 30 mg once a day and raised to 60–120 mg/day in those patients for reaching maximally effective dose according to glycemic control. Metformin was initiated at a dosage of 500 mg/day, and if no side/adverse effects were observed, increased to 2 × 1 000 mg/day at 1–2 wk intervals. Pioglitazone was initiated at a dosage of 15 mg/day and raised to maximally effective dose of 45 mg/day according to glycemic control. After drug titration period, once optimal dosages had been reached, patients were monitored for a total 12-months including titration period (4–8 wk) and examined at 2–4 wk intervals. At each visit, patient compliance was assessed and recorded on the basis of an individual determination of each patient’s metabolic control, adherance to the visit schedule, adherence to diet and exercise plan, diabetes education, and the

amount of returned medication, along with other parameters as deemed appropriate by the investigators. Measurements of clinical and laboratory parameters were performed at baseline and at months 3, 6, and 12. Adverse events were recorded throughout the study. Safety and tolerability were also evaluated by regular measurements of body weight, BMI, WC, HC, body fat ratio, systolic and diastolic blood pressure, pulse rate and standard hematology and clinical biochemistry laboratory tests, and physical examination was performed at baseline and at months 3, 6, and 12.

Patients We included in the study oral antihyperglycemic drug (OAD)naive newly diagnosed 60 type 2 diabetics. Entry criteria included the following: age between 30 and 70 years, fasting plasma glucose (FPG) ≥ 140 mg/dl or HbA1c ≥ 8 %. In addition, type 2 diabetics with FBG 126–139 mg/dl or HbA1c between 7 and 8 % and homeostasis model assessment of insulin resistance index (HOMAIR) > 3 were also enrolled [3, 15]. Patients were not admitted to the study if any of the following criteria were present: type 1 diabetes, ketoacidosis, ketonuria, renal function impairment (serum creatinine > 1.4 mg/dl for women and > 1.5 mg/dl for men), liver disease, impairment liver function [aspartate transaminase (AST) or alanine transaminase (ALT) ≥ 2 × the upper limit of the normal range)], New York Heart Association Cardiac Status Class III or IV congestive heart failure, history of lactic acidosis, malignancy, chronic inflammatory diseases, acute malabsorbtion, chronic pancreatitis, familial polyposis coli, active infection, pregnancy, hoping to conceive, breastfeeding, chronic obstructive pulmonary disease, angina pectoris, myocardial infarction, documented cerebrovascular disease, stroke, peripheral vascular disease, rheumatic disease, substance abuse, allergy to SUs, biguanides or TZDs, thyroid disease, or corticosteroid tretment. Patients’ anthropometric measurements [height, weight, BMI, waist circumference (WC) and hip circumference (HC)] were recorded, and a diabetic diet provided based on their ideal weights. New statin, ezetimibe, angiotensin receptor blocker (ARB), and angiotensin-converting enzyme inhibitor (ACE inhibitor) were not started, although patients already using them continued to take them. The study was performed according to the Declaration of Helsinki and was approved by the local ethics committee, and informed consent was obtained from all participants

Laboratory methods After 10–12 h overnight fasting, approximately 12 ml of blood samples were obtained in the morning from an antecubital vein to measure serum glucose, insulin, C-peptid, lipid profile, and other routine biochemical parameters. The exception was postprandial plasma glucose (PPG), for which samples were obtained 2 h after lunch. Blood was allowed to clot for 2 h at room temperature and the serum was obtained by centrifugation (1 000 × g for 10 min). Sera obtained were transferred to the laboratory immediately in cold boxes filled with ice and analyzed at a central, certified laboratory (K.T.U Farabi Hospital, Clinical Chemistry Laboratory) on the same day. For coagulation and fibrinolysis, a venous blood sample (9 vol) was collected into Vacutainer tubes (Becton Dickinson, Mountain View, CA) containing 0.129 mol/L trisodium citrate (1 vol). Platelet-poor plasma was obtained by centrifugation 1 200 × g at 10 °C for 10 min. Fibrinogen measurement was performed immediately. Aliquots of plasma were transferred into plastic tubes without delay and frozen at − 80 °C until assays for the determination of von-Wille-

Erem C et al. Gliclazide-MR, Metformin and Pioglitazone Monotherapies in Type 2 Diabetes … Exp Clin Endocrinol Diabetes 2014; 122: 295–302

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

Both MET and TZDs are insulin sensitizers, but their mechanisms of action are markedly different [10]. Although the effects of MET, a biguanide, are not fully understood, it improves glycemic control primarily by enhancing insulin sensitivity in the liver and peripheral tissues (e. g., adipose and muscle tissues) [2, 5, 6, 11]. Metformin also decreases hepatic glucose output through a reduction in gluconeogenesis in the liver [8]. In T2DM, MET treatment has been associated with a decrease in microvascular and macrovascular morbidity and mortality [2]. Pioglitazone (PIO), a TZD, activates nuclear peroxisome proliferator-activated receptor-γ (PPAR-γ) that is involved in the regulation of carbohydrate and lipid metabolism [5, 12]. Insulin resistance is reduced and glucose disposal in peripheral tissues is enhanced, thereby reducing levels of blood glucose [11, 13]. Pioglitazone suppresses gluconeogenesis in the liver and reduces lipolysis in the adipose tissue [11]. It may also improve endothelial dysfunction and other inflammatory conditions in the vasculature [5]. Thus, PIO improves glycemic control and dyslipidemia in patients with T2DM [5]. The effects of PIO on lipid profile may be potentially beneficial in reducing cardiovascular risk in T2DM [12]. In the medical literature, monotherapies of gliclazide, MET and PIO have positive effects on glycemic control and CVD risk; however, there have been no comprehensive studies comparing the effects of gliclazide, MET and PIO monotherapies on both glycemic control and non conventional cardiovascular risk factors. The main objective of the present study was to evaluate and compare the effects of gliclazide-MR, MET and PIO monotherapies on glycemic control and conventional/non-conventional cardiovascular risk factors including fibrinolysis, inflammation and endothelial functions in patients with newly diagnosed T2DM.

Article 297

Statistical analyses Statistical analyses were performed by SPSS version 13.0. Data normality was assessed by the Kolmogorov-Smirnov test in each group. Comparisons among groups were performed using ANOVA (Bonferroni test as post hoc) for normally distributed data, and Kruskal Wallis test (Mann Whitney U test with Bonferroni correction as post hoc) otherwise. Comparisons within

groups were performed using the paired-t test for normally distributed data, and the Friedman test (Post-hoc Wilcoxon test) otherwise. Comparisons between groups for quantitative data were performed using the χ2 test. Results are presented as mean ± standard deviation for quantitative data, and as percentages for qualitative data. The value of p < 0.05 was considered to be statistically significant.

Results

▼

In open-label, randomized study, 60 patients with T2DM were initially recruited. Total 57 patients completed the study. Optimal drug dosage was 30 mg/day in 14 patients and 60 mg/day in 5 patients in gliclazide group; 2 000 mg/day in all patients in MET group; 15 mg/day in 6 patient, 30 mg/day in 12 patients, and 45 mg/day in 1 patient in PIO group. Of the 57 patients, 18 patients (32 %) were men and 39 patients (68 %) were women. The baseline clinical and metabolic characteristics of the patient population in the study, were similar in the 3 treatment groups ▶ Table 1). (●

Evaluation of anthropometric measurements There were no significant differences in body weight, BMI, WC, and body fat ratio at months 3, 6 or 12 compared to baseline in gliclazide-MR group. A significant decreasing in HC was obtained ▶ Table 2). In metformin and pioglitazone at months 6 and 12 (● groups, marked but not statistically significant decrease was seen on body weight. In metformin group, a statistically significant decrease was observed in BMI and WC at the end of the 12 ▶ Table 3). The decrease in HC was borderline signifimonths (● cant (p = 0.053). In PIO group, there were significant decreases in ▶ Table WC and HC at 3, 6 and 12 months compared to baseline (● 4).

The effects on glycemic control and insulin sensitivity The values of FPG and HbA1c significantly decreased since 3rd ▶ Table 2–4). month compared to baseline in all study groups (● Insulin, and HOMA-IR in gliclazide-MR group, PPG in MET group and PPG, C-peptid and HOMA-IR score in PIO group significantly decreased since 3rd month compared to baseline. These decreases persisted during treatment in all groups. The reduction of FPG, PPG, and HbA1c was similar in the 3 treatment groups at months 3, 6, and 12. The reduction of insulin, C-peptide, and HOMA-IR score was similar in the 3 treatment groups at months 3 and 6. However, at the end of the month 12, the decreases in insulin and HOMA-IR score were more pronounced with PIO compared to gliclazide. Also, the decrease in C-peptide was more pronounced with PIO compared to MET and gliclazide (p < 0.05).

The effects on lipid profile In the gliclazide-MR group, TC significantly decreased 6 months after the initiation of drug administration (p < 0.05) and this ▶ Table 2). decrease was maintained during the treatment (● Lp(a) only significantly decreased 6 months after the initiation of drug administration. TG decreased from 187.7 ± 116.5 to 136.7 ± 68.5 at month 12. But, statistical significance was remained in borderline (p = 0.05). In the PIO group, serum TG levels significantly decreased at month 6 compared to baseline ▶ Table 4). This reduction was maintained throughout the (● study. Serum HDL-C levels significantly increased at month 6 compared to baseline. This increase was maintained throughout

Erem C et al. Gliclazide-MR, Metformin and Pioglitazone Monotherapies in Type 2 Diabetes … Exp Clin Endocrinol Diabetes 2014; 122: 295–302

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

brand factor (vWF), tissue plasminogen activator (t-PA), tissue plasminogen activator inhibitor-1 (PAI-1), thrombin-activatable fibrinolysis inhibitor (TAFI), and E-selectin as biomarkers of endothelial dysfunction and coagulation/fibrinolysis and intercellular adhesion molecule-1 (ICAM-1), tumor necrosis factor-α (TNF-α), interleukin-1, and interleukin-6 as inflammatory activity markers. HOMA-IR levels were calculated by the formula of FPG (mg/dl) × fasting insülin (μIU/ml)/405 [16]. Plasma glucose and total cholesterol (TC) was measured in EDTA-plasma samples by using hexokinase and cholesterol oxidase methods, respectively. TG was measured using the enzymatic peroxidase method. HDL-cholesterol was measured using direct enzymatic assay. Low density lipoprotein cholesterol (LDL-C) was calculated in plasma specimens having a triglycerides (TG) value < 400 mg/dl by the formula described by Friedewalt et al. [17]. Otherwise, LDL-C was measured using direct homogenous enzymatic assay. All determinations were performed using a Cobas 8000 autoanalyzer (Roche, Hitachi Modular, Switzerland). Reagents used were supplied by the same manufacturer. HbA1c was measured by an high-performance liquid chromatography (HPLC) (Ultra Primus 2, Trinity Biotech Affinity Baronate Colons, U.S.A.). Insulin and C-peptid were measured by chemiluminescent method using an Immulite 2000 immunoassay analyzer (DPC, Los Angeles, USA). Betweenrun CVs were 6.1 % at 17.8 μIU/ml for insulin and 7 % at 3.02 ng/ ml for C-peptide. According to our laboratory, normal ranges are 70–100 mg/dl for APG, 120–200 mg/dl for TC, 50–150 mg/dl for TG, 65–160 mg/dl for LDL-C, 45–65 mg/dl for HDL-C, 6–27 μIU/ mL for insulin and 1.1–5 ng/mL for C-peptide. Plasma fibrinogen and lipoprotein (a) [Lp(a)] were determined using a immunoturbidimetric assay by commercial kits (Cat No.OSCA 09 for fibrinogen and DQHL 11 for Lp(a), Dade Behring Marburg GmbH, Germany). vWF ag was determined by ELISA method using commercial kits (Assaypro catalog: EV2030-1 USA). T-PA (Imubind ref: 860 American Diagnostica inc. Pfungstadt, Germany), PAI-1 (Assaypro catalog no: EP1100-1 USA), and TAFI Ag (Imuclone Product no:873 American Diagnostica Inc, Stamford, USA) assays were performed with enzyme-linked immunosorbent assay (ELISA) using commercial kits. According to our laboratory, normal ranges are 200–400 mg/dL for fibrinogen, 0.3–1.57 IU/mL for vWF, < 9 ng/mL for t-PA Ag, 5–40 ng/mL for PAI-1 Ag, and 40–250 % for TAFI. Also, we measured serum levels of IL-1 (Assaypro catalog no: EI2200-1 USA), IL-6 (Biosource catalog no: KAP1261 Belgium), TNF-α (Biosource catalog no: KAP1751 Belgium), soluble ICAM-1 (RayBio catalog no: ELH-sICAM-001 USA), E-selectin (RayBio catalog no: ELH-E selectin-001 USA), and homocysteine (Hcy) (Axis no: FHCY 100 United Kingdom) in duplicate by use of commercially available ELISA kits. According to our laboratory, normal ranges are < 3 pg/mL (typically minimally measurable level) for IL-1, 0–50 pg/mL for IL-6, 4.6–12.4 pg/mL for TNF-α, < 0.004 ng/mL (typically minimally measurable level) for ICAM1, < 0.03 ng/mL (typically minimally measurable level) for E-selectin and 5–15 μmol/L for Hcy.

298 Article the study. At 6th month, the decrease in TC was more pronounced in gliclazide-MR group compared to PIO group (p < 0.05). The

changes in lipid parameters were similar between groups in the 3 treatment groups at 12 months after treatment.

The effects on coagulation and fibrinolytic system

Parameter

Gliclazide-MR

MET Group

PIO Group

6/13 52.2 ± 10.5 % 52.6 (n:10) % 10.5 (n:2) % 10.5 (n:2) % 10.5 (n:2) % 0 (n:0) 161.5 ± 8.9 87.47 ± 12.93 33.56 ± 4.56 102.89 ± 10.91 111.26 ± 8.83 39.41 ± 7.77 133.7 ± 18.6 86.32 ± 10.1 % 21.1(n:4) 31.8 ± 19.8 24.9 ± 11.4 13.5 ± 3.27 0.72 ± 0.4

5/14 52.5 ± 5.2 % 47.4 (n:9) % 0 (n:0) % 10.5 (n:2) % 15.8 (n:3) % 0 (n:0) 161.6 ± 7.7 81.93 ± 13.43 31.31 ± 4.69 98.89 ± 11.05 107.63 ± 10.2 37.27 ± 6.65 130.8 ± 11.9 82.37 ± 11 % 15.8 (n:3) 28.4 ± 8.9 23.1 ± 5.7 14.5 ± 4.8 0.77 ± 0.1

Group gender (male/female) age (years) hypertension coronary heart disease hyperlipidemia smoking alcohol drinking height (cm) weight (kg) BMI (kg/m2) WC (cm) HC (cm) body fat ratio ( %) SBP (mmHg) DBP (mmHg) microalbuminuria ALT (U/L) AST (U/L) BUN (mg/dl) creatinine (mg/dl)

7/12 55 ± 8.7 % 42.1 (n:5) % 10.5 (n:2) % 15.8 (n:3) % 0 (n:0) % 0 (n:0) 165.7 ± 9.4 90.06 ± 18.13 32.72 ± 3.86 101.37 ± 12.42 111.74 ± 16.08 38.43 ± 6.07 143.4 ± 14.3 86.84 ± 10.6 % 15.8 (n:3) 32.6 ± 21.6 28.2 ± 16 15.8 ± 4.7 0.81 ± 0.1

BMI: body mass index; WC: Waist circumference, HP: Hip circumference, SBP: systolic blood pressure; DBP: diastolic blood pressure; FPG: Fasting plasma glucose

In the PIO group, vWF significantly decreased in 3rd month com▶ Table 4). This decrease was pared to baseline (p < 0.001) (● maintained throughout the study. The decrease in vWF was more pronounced in PIO group compared to gliclazide-MR group at 6th month (p < 0.05). There were no significant differences in the markers of coagulation/fibrinolyisis after 12 months ▶ Table 2–4). of treatment between groups (●

The effects on inflammation Significant increases in IL-1 were observed in the groups of gliclazide and MET compared to baseline after 3 months of treat▶ Table 2, 3). The increase was maintained throughout ment (● the study. In PIO group, IL-6 significantly decreased at 3rd month ▶ Table 4). This decrease was maintained compared to baseline (● throughout the study. There were no significant differences in the markers of inflammation in the 12th-month of the treatment between groups.

The effects on endothelial dysfunction In gliclazide-MR group, E-selectin significantly decreased at ▶ Table 2). Serum Hcy levels month 12 compared to baseline (● significantly decreased at 3rd month compared to baseline ▶ Table 2). This decrease was maintained throughout the study. (● In the MET group, ICAM-1 and homocysteine significantly ▶ Table 3). This decreased at 3rd month compared to baseline (●

Table 2 Baseline characteristics and parameter changes at 3rd, 6th, and 12th months of the study in gliclazide-MR group. Parameter weight (kg) BMI (kg/m2) WC (cm) HC (cm) body fat ratio ( %) FPG (mg/dl) PPG (mg/dl) HbA1c ( %) insulin (μIU/ml) C-peptide (ng/ml) HOMA-IR score TC (mg/dl) triglycerides (mg/dl) HDL-C (mg/dl) LDL-C (mg/dl) lipoprotein (a) (mg/dl) fibrinogen (mg/dL) TAFI ( %) t-PA (ng/mL) PAI-1(ng/mL) vWF (IU/mL) IL-1 (pg/mL) IL-6 (pg/mL) TNF-α (pg/mL) ICAM-1 (ng/mL) E-selectin (ng/mL) homocysteine (μmol/L)

Baseline

3 months

6 months

90.06 ± 18.1 32.72 ± 3.9 101.4 ± 12.4 111.7 ± 16.1 38.43 ± 6.1 172.2 ± 55.2 233.6 ± 77 8.26 ± 1.65 17.8 ± 13.5 3.96 ± 1.8 8.15 ± 7.3 190.7 ± 40.8 187.7 ± 116.5 44 ± 6.9 121.6 ± 32.9 39.05 ± 37.5 402.8 ± 95.8 132.97 ± 29.7 47.7 ± 22.2 67.3 ± 21.5 0.84 ± 0.7 11.1 ± 6 56.9 ± 23.8 34.2 ± 10.3 77.14 ± 63.1 130.86 ± 85.2 38.42 ± 14.7

89.41 ± 18.5 32.37 ± 3.7 98.2 ± 10.7 106.7 ± 9 38.43 ± 5.8 123.8 ± 23.3 173.7 ± 48.4 6.93 ± 0.9 11.65 ± 6.9 3 ± 0.8 3.5 ± 2.4 181.1 ± 38.6 139.2 ± 73.3 46.4 ± 7.5 111.5 ± 37 37.26 ± 38.5 363.4 ± 61.3 144.9 ± 34.5 31.7 ± 12.2 84.4 ± 30.3 0.78 ± 0.5 25.1 ± 11.1 154.3 ± 284 65.2 ± 67.6 30.6 ± 44.2 107.08 ± 64.2 24.34 ± 22.5

88.72 ± 19.7 32.35 ± 3.8 98.7 ± 10.6 107.3 ± 9.9 38.01 ± 5.8 122.9 ± 31.6 171.87 ± 43.3 6.92 ± 0.6 10.93 ± 6.5 2.75 ± 0.9 3.52 ± 2.4 172.1 ± 30 144.7 ± 67.6 44.7 ± 7.9 106.9 ± 30.9 38.09 ± 44.6 365.1 ± 78.8 124.31 ± 34.3 30.5 ± 12.6 67.7 ± 40.4 0.74 ± 0.4 75.2 ± 151.5 79.1 ± 70.3 45.9 ± 33.5 16.61 ± 15.5 96.7 ± 55.9 10.86 ± 7.6

12 months

P-value

91.0 ± 26.2 31.64 ± 4.8 98.6 ± 14 107 ± 13 37.03 ± 7.8 109 ± 13.4 147.38 ± 43 6.98 ± 0.5 11.51 ± 5.4 2.52 ± 0.9 3.06 ± 1.5 166.4 ± 39.7 136.7 ± 68.5 44.9 ± 7.7 103.5 ± 36.4 18.89 ± 13.5 368.6 ± 78.5 110.65 ± 35.6 34.2 ± 14.4 60.1 ± 31.4 0.5 ± 0.3 31.5 ± 14.7 55.2 ± 43.5 44.5 ± 31.3 25.66 ± 23.6 66.76 ± 37.6 9.32 ± 6.2

0.472 0.229 0.089 0.026 0.822 0.0001 0.075 0.045 0.026 0.057 0.036 0.036 0.05 0.453 0.170 0.038 0.600 0.522 0.143 0.661 0.082 0.004 0.522 0.128 0.543 0.020 0.0001

BMI: body mass index; WC: Waist circumference, HP: Hip circumference, SBP: systolic blood pressure; DBP: diastolic blood pressure; FPG: Fasting plasma glucose, PPG: Postprandial plasma glucose, HbA1c: Hemoglobin A1c, TC: total cholesterol, LDL-C: low density lipoprotein cholesterol, HDL-C: high density lipoprotein cholesterol, TAFI: thrombin activatable fibrinolysis inhibitor, t-PA: tissue plasminogen activator, PAI-1: plasminogen activator inhibitor-1, vWF: von Willebrand Factor, IL-1: interleukin-1, IL-6: interleukin-6, TNF-α: tumor necrosis factor- α, ICAM-1: intercellular adhesion molecule-1

Erem C et al. Gliclazide-MR, Metformin and Pioglitazone Monotherapies in Type 2 Diabetes … Exp Clin Endocrinol Diabetes 2014; 122: 295–302

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

Table 1 Baseline demographic, clinical and laboratory characteristics of the treatment groups.

Article 299

Table 3 Baseline characteristics and parameter changes at 3rd, 6th, and 12th months of the study in MET group. Baseline

3 months

6 months

12 months

87.5 ± 12.9 33.56 ± 4.6 102.9 ± 10.9 111.3 ± 8.8 39.41 ± 7.8 172.68 ± 37.6 211.6 ± 52.2 7.62 ± 1.06 14.68 ± 12.9 3.54 ± 1.9 5.82 ± 5 197.8 ± 44.9 205.5 ± 132.3 43.9 ± 10.2 125.3 ± 36.9 23.82 ± 16.1 351.7 ± 45.8 123.84 ± 29.9 41.27 ± 19.3 57.32 ± 24.8 0.881 ± 0.7 13.67 ± 8.6 68.01 ± 55.3 39.41 ± 16.2 196.16 ± 213.3 106.41 ± 62.3 42.05 ± 12.4

85.9 ± 12.6 33.03 ± 4.2 98.5 ± 9.4 107.4 ± 8.3 36.79 ± 9.2 114.6 ± 25.9 151.9 ± 48.7 6.67 ± 1.2 10.48 ± 6.9 2.84 ± 1.3 2.96 ± 2.1 181.5 ± 29.3 156.8 ± 66.3 44.2 ± 9.4 115.3 ± 28 23.99 ± 15.1 349.3 ± 45.8 143 ± 37 38.24 ± 14 82.46 ± 27.1 0.582 ± 0.5 21.31 ± 11.5 59.31 ± 36.3 30.87 ± 4.4 28.45 ± 60.3 84.78 ± 50.8 20.84 ± 14.9

84.7 ± 12.4 33.3 ± 4.2 97.1 ± 10 106.2 ± 8.8 36.18 ± 9 119.3 ± 28.2 150.4 ± 32.4 6.42 ± 0.71 8.15 ± 7.4 2.68 ± 1.1 2.49 ± 2.2 180.5 ± 32.2 161.6 ± 75.9 41.7 ± 8.2 116.4 ± 29 23.81 ± 14.9 342.4 ± 58.3 127.32 ± 29.3 29.67 ± 11.6 76.53 ± 23.6 0.5 ± 0.3 32.81 ± 26.15 48.42 ± 38.9 50.24 ± 51.5 22.36 ± 50.4 91.63 ± 91.2 10.32 ± 7.2

83.4 ± 13.3 31.92 ± 4 95.2 ± 7.7 104.9 ± 7.8 34.53 ± 8.9 113.45 ± 19.6 147.64 ± 34.3 6.40 ± 0.7 8.87 ± 6.8 2.64 ± 0.9 2.53 ± 1.9 178.6 ± 27.5 136.3 ± 85.7 45 ± 11.3 111.4 ± 21.9 27.88 ± 10.9 353.5 ± 88.6 122.31 ± 39.6 38.05 ± 10.2 73.27 ± 16.5 0.308 ± 0.4 29.29 ± 17.6 64.07 ± 23.12 29.09 ± 5.4 9.03 ± 12.3 77.25 ± 44.1 7.67 ± 6.4

decrease was maintained throughout the study. In the PIO group, patients exhibited a significant decrease in ICAM-1, E-selectin and Hcy from the baseline measurements to those at 3, 6 and 12 ▶ Table 4). The decrease in ICAM-1 was more promonths (● nounced in MET group compared to gliclazide-MR and PIO groups at 6th month (p < 0.05). There were no significant differences in the ICAM-1, E-selectin and Hcy at 12th month of treatment between groups.

Safety and tolerability Gliclazide MR, MET and PIO were well tolerated. There were no adverse events and side efffects (hypoglycemia, gastrointestinal side effects, skin rash, ankle edeme, pulmonary edeme, congestive heart failure, myocardial infarction or cardiovascular death) in all treatments groups. No patient exhibited a value of AST or ALT higher 2 times than the normal in either group.

Discussion

▼

Gliclazide and TZDs monotherapies are associated with weight gain (e. g., 1–5 kg), which is problematic in a population characterized by overweight/obese people [7]. MET monotherapy is associated with small weight loss or weight neutrality [7, 18]. Yener et al. reported that no significant change was observed in BMI, WC and WHR in patients with T2DM after 12-wk MET therapy [19]. Belcher et al. reported an increase in mean body weight with both gliclazide and PIO treatment, but a decrease with MET treatment [20]. Derosa et al. reported an increased BMI with PIO and rosiglitazone treatment after 12 months compared to baseline [21]. In the present study, body weight did not change significantly in the 3 treatment groups. HC in gliclazide group, BMI and WC in MET group, and WC and HC in PIO group decreased

P-value 0.162 0.019 0.0001 0.053 0.097 0.0001 0.012 0.001 0.129 0.255 0.111 0.078 0.083 0.259 0.094 0.279 0.139 0.368 0.871 0.059 0.146 0.002 0.813 0.706 0.013 0.173 0.0001

during the study. These reductions, especially in MET and PIO groups, may contribute to reduction in cardiovascular risk and mortality in patients with T2DM. Different studies show that SUs, MET and TZDs provide similar reductions in HbA1c (1–2 % with SUs and MET, 1–1.5 % with TZDs) [6, 22]. However, TZDs may have greater long-term durability of glycemic control than SU or MET [6, 7]. Indeed, the ADOPT study showed a cumulative incidence of monotherapy failure at 5 years of 34 % for glyburide, 21 % with MET, and 15 % with rosiglitazone [22]. In addition, in a direct comparison of gliclazide vs. PIO as monotherapy, significantly more PIO-treated patients maintained their glycemic control at 2 years than did patients treated with gliclazide [23, 24]. In the present study, we found that therapy for 12 months with gliclazide-MR, MET or PIO as monotherapy was equally effective in improving glycemic control (reduction of FBG and HbA1c) in patients with newly diagnosed uncontrolled T2DM who were also OAD-naive. These data are in agreement with observations from previous studies [5–7, 20, 22, 25]. Both MET and PIO have been shown to improve IR [1, 26]. Pavo et al. reported that PIO monotherapy was significantly more effective than MET monotherapy in improving indicator of insulin sensitivity in patients recently diagnosed with T2DM who are OAD-naive [5]. PIO improves glycemic control primarily by increasing peripheral insulin sensitivity in T2DM, whereas MET exerts its effect primarily on the liver by decreasing hepatic glucose output [7]. Gliclazide acts primarily by stimulating insulin secretion of the pancreatic β-cells [27]. It was suggested that SUs increase insulin sensitivity in liver, peripheral fat and muscle tissues. However, it is not clear that this effect is primarily or secondary to glucotoxicity decrease. Also, gliclazide is one of the most commonly prescribed SUs in Europe. Therefore, a direct comparison of these 3 drugs is of particular clinical interest. In

Erem C et al. Gliclazide-MR, Metformin and Pioglitazone Monotherapies in Type 2 Diabetes … Exp Clin Endocrinol Diabetes 2014; 122: 295–302

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

Parameter weight (kg) BMI (kg/m2) WC (cm) HC (cm) body fat ratio ( %) FPG (mg/dl) PPG (mg/dl) HbA1c ( %) insulin (μIU/ml) C-peptide (ng/ml) HOMA-IR score TC (mg/dl) triglycerides (mg/dl) HDL-C (mg/dl) LDL-C (mg/dl) lipoprotein (a) (mg/dl) fibrinogen (mg/dL) TAFI ( %) t-PA (ng/mL) PAI-1(ng/mL) vWF (IU/mL) IL-1 (pg/mL) IL-6 (pg/mL) TNF-α (pg/mL) ICAM-1 (ng/mL) E-selectin (ng/mL) homocysteine (μmol/L)

300 Article

Parameter weight (kg) BMI (kg/m2) WC (cm) HC (cm) body fat ratio ( %) FPG (mg/dl) PPG (mg/dl) HbA1c ( %) insulin (μIU/ml) C-peptide (ng/ml) HOMA-IR score TC (mg/dl) triglycerides (mg/dl) HDL-C (mg/dl) LDL-C (mg/dl) lipoprotein (a) (mg/dl) fibrinogen (mg/dL) TAFI ( %) t-PA (ng/mL) PAI-1(ng/mL) vWF (IU/mL) IL-1 (pg/mL) IL-6 (pg/mL) TNF-α (pg/mL) ICAM-1 (ng/mL) E-selectin (ng/mL) homocysteine (μmol/L)

Baseline 81.93 ± 13.4 31.31 ± 4.7 98.9 ± 11.1 107.6 ± 10.2 37.27 ± 6.6 165.7 ± 34.2 218 ± 62.3 8.03 ± 1.7 15.35 ± 16.2 3.86 ± 2.5 6.23 ± 6.6 206.4 ± 43.2 208.3 ± 89 42.5 ± 9 144.4 ± 33.3 32.23 ± 12 377.74 ± 51.7 137.54 ± 27.3 35.7 ± 21.5 67.35 ± 25 0.824 ± 0.6 14.77 ± 10 218.6 ± 710.6 91.3 ± 231.4 102.3 ± 123.8 104.85 ± 69 38.45 ± 15.2

3 months 78.79 ± 13.8 30.43 ± 4.8 95.6 ± 12.7 103.4 ± 11.4 35.9 ± 7.1 119.4 ± 32.1 157.9 ± 48 6.9 ± 1.1 8.17 ± 5.9 2.38 ± 1.6 2.27 ± 1.4 200.3 ± 38.4 160.5 ± 51.4 45.2 ± 9 134.7 ± 33.2 27.99 ± 15.13 394.81 ± 74.5 145.65 ± 56.6 34.31 ± 17.2 76.31 ± 26.3 0.397 ± 0.3 29.83 ± 36.3 53.4 ± 33.9 44.23 ± 36.5 20.7 ± 23.81 78.69 ± 35.8 18.06 ± 17.5

our study, C-peptid and HOMA-IR score were significantly reduced in the PIO group during 52-wk of treatment, whereas a decrease in insulin was borderline significant (p = 0.057). In the present study, the lack of effect on IR with MET therapy may be related to the limitations of HOMA-IR assessment to detect small changes IR [5]. HOMA-IR is applicaple primarily in studies involving larger sample sizes and is not powered to detect small differences [5]. Also, the lack of detection of a significant improvement in HOMA-IR in the MET group could be related to the small numbers of case group and the characteristics of the patient population. On the other hand, very interestingly, insulin and HOMA score significantly decreased in gliclazide group throughout treatment (p < 0.05). A decrease in C-peptid was borderline significant (p = 0.057). These results may depend on positive effect of dietary and exercise suggestions, good glycemic control, recovery of negative effects of glucotoxicity on insulin sensitivity and positive effects of gliclazide primarily on possible insulin sensitivity. Indeed, Fukozawa et al. reported that gliclazide had inhibitory effect on TNF-α implicating in the pathogenesis of IR [28]. In general, no primary effects on lipid profile induced by SUs are seen [23]. However, in the some studies, improvement in the lipid profile abnormalities associated with T2DM has been reported with gliclazide therapy [29, 30]. Numerous studies have demonstrated improved lipid profiles in patients with type 2 diabetic dyslipidemia receiving MET [31]. PIO has also been shown to improve the lipid profile in patients with T2DM by increasing HDL-C levels and decreasing TG levels in combination regimens with SU [23, 32]. Prospective Pioglitazone Clinical Trial in Macrovascular Events In (PROactive) study, PIO treatment led to increased HDL-C and decreased TG levels independent of the baseline lipid or antihyperglycemic medication used [33]. The

6 months

12 months

P-value

77.33 ± 14.3 29.85 ± 5 93.7 ± 13.1 101.9 ± 11.4 34.61 ± 7.1 121.2 ± 25.6 156.2 ± 39.7 6.85 ± 1.15 6.4 ± 4.8 2.53 ± 1.2 2.56 ± 3.3 210.2 ± 42.2 163.9 ± 59.4 47 ± 12.2 137.5 ± 30.9 24.38 ± 15.8 368.1 ± 67.3 136.2 ± 42.5 38.84 ± 13.2 69.53 ± 22.3 0.369 ± 0.3 24.44 ± 14.5 47.34 ± 25 25.26 ± 9.6 31.02 ± 60.5 75.04 ± 46.8 8.9 ± 7

76.8 ± 14.7 30.11 ± 5 91.8 ± 12.7 101.1 ± 11.4 33.51 ± 7.1 105.11 ± 20.4 126.89 ± 28.3 6.46 ± 0.56 4.18 ± 3 1.65 ± 0.5 1.15 ± 1 186.2 ± 28.7 135.7 ± 47.8 45.2 ± 10.3 115.6 ± 26.3 24.87 ± 16.5 358.44 ± 65.3 122.82 ± 50.1 42.53 ± 27.9 62.39 ± 39 0.271 ± 0.3 27.73 ± 20.3 44.36 ± 25.3 24.43 ± 14.1 65.07 ± 156 51.67 ± 23.4 6.33 ± 4.9

0.109 0.132 0.0001 0.001 0.390 0.001 0.0001 0.033 0.057 0.032 0.014 0.639 0.038 0.033 0.124 0.641 0.145 0.557 0.920 0.657 0.0001 0.054 0.018 0.116 0.025 0.04 0.005

present study demonstrated significant improvements in lipid profile with gliclazide-MR and PIO monotherapies, whereas lipid profile was not significantly different from baseline in the MET group. TC, TG (in borderline) and Lp(a) in gliclazide-MR group, and TG in PIO group decreased. These improvements in lipid profile may be related to the IR reductions in both groups. These observations was probably dependent on 2 factors: the degree of glycemic improvements during the treatment phase and the degree of abnormality in the lipid profile pretreatment [34]. Increased levels of vWF in subjects with type 2 diabetes are associated with vascular injury and macrovascular mortality [4]. Increased vWF levels have also long been thought to represent an index of endothelial damage. Increased levels of PAI-1, t-PA and vWF predispose diabetic patient to various thromboembolic events, leading to increased mortality and morbidity [3, 4]. In the present study, only vWF levels significantly decreased in PIO group. Other coagulation/fibrinolytic markers did not change. Decreased vWF may contribute to cardiovascular risk reduction with PIO therapy in patients with T2DM. Generalized inflammation in T2DM is reflected by increased plasma level of IL-1, IL-6, CRP, TNF-α and complement components [35]. These inflammatory molecules also increased in IR, conforming to the association between this entity and atherosclerosis development and progression. The effects of SUs on inflammatory molecules are conflicting, and the studies examining these end points are relatively small, raising questions about their validity [35]. Drzewoski et al. reported that gliclazide-MR has a positive influence on the plasma level of some inflammatory markers and adiponectin [36]. Researchers suggested that decreased IL-6 and TNF-α and increased adiponectin in plasma may explain, at least in part, the antiatherogenic

Erem C et al. Gliclazide-MR, Metformin and Pioglitazone Monotherapies in Type 2 Diabetes … Exp Clin Endocrinol Diabetes 2014; 122: 295–302

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

Table 4 Baseline characteristics and parameter changes 3rd, 6th, and 12th months of the study in pioglitazone group.

Article 301

reported that MET increases Hcy levels, whereas rosiglitazone decreases in patients with T2DM [46]. Derosa et al. reported a significant decrease in Hcy in both MET-PIO and ME-rosiglitazone combination therapy in type 2 diabetic patients with metabolic syndrome [47]. In the present study, serum Hcy levels significantly decreased in all 3 treatment groups after 3,6,9 and 12 months. These beneficial effects of drugs may reduce the developments of cardiovascular and atherothrombotic risks in patients of T2DM.

Conclusion

▼

In conclusion, our data demonsrated that monotherapies of gliclazide-MR, MET and PIO, were equally effective in proving glycemic control in patients with newly diagnosed, OAD-naive T2DM. But, improvements in conventional/non-conventional cardiovascular risk factors were more pronounced in patients on PIO therapy compared to gliclazide and MET therapies. Also, the present study confirms that all of the 3 drugs represent effective and safe first-line pharmacological treatment options in these patients.

Acknowledgements

▼

This study was supported by a research grant from the Karadeniz Technical University (Project No. 2008.114.003.1).

Disclosure: We, the authors, have nothing to declare regarding the study drugs and producing companies. Declaration of interest: The authors declare that there is no conflict of interest that would prejudice the impartiality of this scientific work. References 1 Haffner SM, Greenberg AS, Weston WM et al. Effect of rosiglitazone treatment on nontraditional markers of cardiovascular disease in patients with type 2 diabetes mellitus. Circulation 2002; 106: 679–684 2 Lund SS, Tarnow L, Stehouwer CD et al. Impact of metformin versus repaglinide on non-glycaemic cardiovascular risk markers related to inflammation and endothelial dysfunction in non-obese patients with type 2 diabetes. Eur J Endocrinol 2008; 158: 631–641 3 Fidan E, Onder Ersoz H, Yilmaz M et al. The effects of rosiglitazone and metformin on inflammation and endothelial dysfunction in patients with type 2 diabetes mellitus. Acta Diabetol 2011; 48: 297–302 4 Erem C, Hacihasanoğlu A, Celik S et al. Coagulation and fibrinolysis parameters in type 2 diabetic patients with and without diabetic vascular complications. Med Princ Pract 2005; 14: 22–30 5 Pavo I, Jermendy G, Varkonyi TT et al. Effect of pioglitazone compared with metformin on glycemic control and indicators of insulin sensitivity in recently diagnosed patients with type 2 diabetes. The Journal of Clinical Endocrinology & Metabolism 2003; 88: 1637–1645 6 Vilar L, Canadas V, Arruda MJ et al. Comparison of metformin, gliclazide MR and rosiglitazone in monotherapy and in combination for type 2 diabetes. Arq Bras Endocrinol Metabol 2010; 54: 311–318 7 Levetan C. Oral antidiabetic agents in type 2 diabetes. Curr Med Res Opin 2007; 23: 945–952 8 Drouin P, Standl E; Diamicron MR Study Group. Gliclazide modified release: results of a 2-year study in patients with type 2 diabetes. Diabetes Obes Metab 2004; 6: 414–421 9 Khanolkar MP, Morris RH, Thomas AW et al. Rosiglitazone produces a greater reduction in circulating platelet activity compared with gliclazide in patients with type 2 diabetes mellitus – an effect probably mediated by direct platelet PPARgamma activation. Atherosclerosis 2008; 197: 718–724

Erem C et al. Gliclazide-MR, Metformin and Pioglitazone Monotherapies in Type 2 Diabetes … Exp Clin Endocrinol Diabetes 2014; 122: 295–302

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

action of this drug. In the present study, the levels of IL-6 and TNF-α did not change in gliclazide group, whereas IL-1 levels significantly increased. The increase in IL-1 as a proinflammatory cytokine may be considered as a negative influence of this drug. Lund et al. reported that the levels TNF-α, PAI-1 Ag, t-PA, vWF, soluble (s) ICAM-1 and sE-selectin were significantly lower during MET vs. repaglinide treatments [2]. Fidan et al. reported a decrease in IL-6 and TNF-α levels with MET after 12 weeks of treatment [3]. De Jager et al. reported when compared with placebo, MET treatment was associated with a decrease in vWF, sVCAM-1, sE-selectin, t-PA, PAI-1, whereas CRP and sICAM did not change [37]. In our study, IL-1 significantly increased in MET group during treatment. The increase in IL-1 may be considered as a negative influence of this drug. In general, TZDs demonstrate inflammatory features, with reduction in TNF-α levels in treated patients [38]. You et al. reported that the levels TNF-α and IL-6 significantly decreased at the end of the 8th months of PIO treatment in patients with T2DM [38]. Kim et al. reported a significant decreases in TNF-α, IL-6, IL-18, CRP and resistin in the rosiglitazone-treated patients but not in the MET-treated patients with T2DM [10]. In a very recent study, Sacks et al. reported that PIO therapy in T2DM was associated with decreased expression of IL-1β and IL-10 [39]. In the present study, IL-6 decreased in PIO group. This decrease may reduce microinflammation in patients with T2DM. Elevation in circulating adhesion molecules are an indication of early endothelial damage. E-selectin is specific to activated endothelium and may be a particularly strong indicator of endothelial dysfunction [40]. Elevated levels of E-selectin have been shown to be a marker for development of atherosclerosis and CHD in non-T2DM subjects [40]. Gliclazide inhibits high glucose-mediated neutrophils-endothelial cells adhesion and expression of endothelial adhesion molecules (e. g., E-selectin, ICAM-1 and VCAM-1) through inhibition of a protein kinase C pathway [41]. Thus, gliclazide reduces endothelial activation and may exert potential beneficial effects in the prevention of atherosclerosis with T2DM. Räkel et al. reported that serum levels of sICAM and sE-selectin significantly decreased in patients with T2DM treated with gliclazide-MR [42]. Exposing endothelial cells to MET inhibits the expression of endothelial adhesion molecules, including E-selectin, ICAM-1 and VCAM-1. This is consistent with an antiatherogenic action of the drug [31]. PIO inhibits expression of adhesion molecules on endothelial cells [43]. Ryan et al. reported that E-selectin, ICAM-1, VCAM-1, TNFα, IL-6 and IL-1β decreased with PIO treatment in obese glucose tolerant men [44]. However, to our knowledge, there has been no study investigating the effects of PIO monotherapy on E-selectin and ICAM-1 in patients with type 2 diabetic patients. In our study, we found a significant decrease in E-selectin in gliclazide group and ICAM-1 in MET group, and significant decreases in E-selectin and ICAM-1 in PIO group. Our findings confirm the beneficial effects of gliclazide, MET or PIO on serum adhesion molecules shown by studies [31, 41, 45]. PIO is an insulin sentitizer but the direct effect of insulin on adhesion molecules is uncertain [44]. There are several mechanisms acting on the anti-inflammatory pathway which may produce the improvement in endothelial function with PIO [44]. Hyperhomocysteinemia has been found to be an independent risk factor for CVD and atherothrombotic events, even in diabetic subjects [46, 47]. Plasma homocysteine (Hcy) is elevated in patients with T2DM who have coexistent CVD [48]. Sahin et al.

10 Kim HJ, Kang ES, Kim DJ et al. Effects of rosiglitazone and metformin on inflammatory markers and adipokines: decrease in interleukin-18 is an independent factor for the improvement of homeostasis model assessment-beta in type 2 diabetes mellitus. Clin Endocrinol (Oxf) 2007; 66: 282–289 11 Matthews DR, Charbonnel BH, Hanefeld M et al. Long-term therapy with addition of pioglitazone to metformin compared with the addition of gliclazide to metformin in patients with type 2 diabetes: a randomized, comparative study. Diabetes Metab Res Rev 2005; 21: 167–174 12 Betteridge DJ, Vergès B. Long-term effects on lipids and lipoproteins of pioglitazone versus gliclazide addition to metformin and pioglitazone versus metformin addition to sulphonylurea in the treatment of type 2 diabetes. Diabetologia 2005; 48: 2477–2481 13 Tan MH. Current treatment of insulin resistance in type 2 diabetes mellitus. Int J Clin Pract Suppl 2000; 54–62 14 American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2010; 33 (Suppl 1): S62–S69 15 Taniguchi A, Fukushima M, Sakai M et al. Remnant-like particle cholesterol, triglycerides, and insulin resistance in nonobese Japanese type 2 diabetic patients. Diabetes Care 2000; 23: 1766–1769 16 McAuley KA, Williams SM, Mann JI et al. Diagnosing insulin resistance in the general population. Diabetes Care 2001; 24: 460–464 17 Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972; 18: 499–502 18 Rodbard HW, Blonde L, Braithwaite SS et al. AACE Diabetes Mellitus Clinical Practice Guidelines Task Force. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the management of diabetes mellitus. Endocr Pract 2007; 13 (Suppl 1): 1–68 19 Yener S, Comlekci A, Akinci B et al. Soluble CD40 ligand, plasminogen activator inhibitor-1 and thrombin-activatable fibrinolysis inhibitor1-antigen in normotensive type 2 diabetic subjects without diabetic complications. Effects of metformin and rosiglitazone. Medical Principles and Practice 2009; 18: 266–271 20 Belcher L, Lambert C, Edwards G et al. Safety and tolerability of pioglitazone, metformin, and gliclazide in the treatment of type 2 diabetes. Diabetes Research and Clinical Practice 2005; 70: 53–62 21 Derosa G, Cicero AF, Gaddi A et al. A comparison of the effects of pioglitazone and rosiglitazone combined with glimepiride on prothrombotic state in type 2 diabetic patients with the metabolic syndrome. Diabetes Res Clin Pract 2005; 69: 5–13 22 Kahn SE, Haffner SM, Heise MA et al. ADOPT Study Group. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 2006; 355: 2427–2443 23 Hanefeld M. Pioglitazone and sulfonylureas: effectively treating type 2 diabetes. Int J Clin Pract Suppl 2007; 61 (Suppl. 153): 20–27 24 Tan MH, Baksi A, Krahulec B et al. GLAL Study Group. Comparison of pioglitazone and gliclazide in sustaining glycemic control over 2 years in patients with type 2 diabetes. Diabetes Care 2005; 28: 544–550 25 Perriello G, Pampanelli S, Di Pietro C et al. Italian Pioglitazone Study Group. Comparison of glycaemic control over 1 year with pioglitazone or gliclazide in patients with Type 2 diabetes. Diabet Med 2006; 23: 246–252 26 Kato T, Sawai Y, Kanayama H et al. Comparative study of low-dose pioglitazone or metformin treatment in Japanese diabetic patients with metabolic syndrome. Exp Clin Endocrinol Diabetes 2009; 117: 593–599 27 Charbonnel BH, Matthews DR, Schernthaner G et al. QUARTET Study Group. A long-term comparison of pioglitazone and gliclazide in patients with Type 2 diabetes mellitus: a randomized, double-blind, parallel-group comparison trial. Diabet Med 2005; 22: 399–405 28 Fukuzawa M, Satoh J, Qiang X et al. Inhibition of tumor necrosis factoralpha with anti-diabetic agents. Diabetes Res Clin Pract 1999; 43: 147–154 29 Cathelineau G, de Champvallins M, Bouallouche A et al. Management of newly diagnosed non-insulin-dependent diabetes mellitus in the primary care setting: effects of 2 years of gliclazide treatment – the Diadem Study. Metabolism 1997; 46 (Suppl 1): 31–34

30 Chen KW, Juang JH, Huang HS et al. Effect of gliclazide on plasma lipids and pancreatic beta cell function in non-insulin-dependent diabetes mellitus. Changgeng Yi Xue Za Zhi 1993; 16: 246–250 31 Scarpello JH, Howlett HC. Metformin therapy and clinical uses. Diab Vasc Dis Res 2008; 5: 157–167 32 Perez A, Khan M, Johnson T et al. Pioglitazone plus a sulphonylurea or metformin is associated with increased lipoprotein particle size in patients with type 2 diabetes. Diab Vasc Dis Res 2004; 1: 44–50 33 Spanheimer R, Betteridge DJ, Tan MH et al. PROactive Investigators. Long-term lipid effects of pioglitazone by baseline anti-hyperglycemia medication therapy and statin use from the PROactive experience (PROactive 14). Am J Cardiol 2009; 104: 234–239 34 Tessier D, Maheux P, Khalil A et al. Effects of gliclazide versus metformin on the clinical profile and lipid peroxidation markers in type 2 diabetes. Metabolism 1999; 48: 897–903 35 Kassem SA, Raz I. Is there evidence that oral hypoglycemic agents reduce cardiovascular morbidity or mortality? No. Diabetes Care 2009; 32 (Suppl 2): S337–S341 36 Drzewoski J, Zurawska-Klis M. Effect of gliclazide modified release on adiponectin, interleukin-6, and tumor necrosis factor-alpha plasma levels in individuals with type 2 diabetes mellitus. Current Medical Research and Opinion 2006; 22: 1921–1926 37 De Jager J, Kooy A, Lehert P et al. Effects of short-term treatment with metformin on markers of endothelial function and inflammatory activity in type 2 diabetes mellitus: a randomized, placebo-controlled trial. J Intern Med 2005; 257: 100–109 38 You SH, Kim BS, Hong SJ et al. The effects of pioglitazone in reducing atherosclerosis progression and neointima volume in type 2 diabetic patients: prospective randomized study with volumetric intravascular ultrasonography analysis. Korean Circ J 2010; 40: 625–631 39 Sacks HS, Fain JN, Cheema P et al. Inflammatory genes in epicardial fat contiguous with coronary atherosclerosis in the metabolic syndrome and type 2 diabetes: changes associated with pioglitazone. Diabetes Care 2011; 34: 730–733 40 Albertini JP, McMorn SO, Chen H et al. Effect of rosiglitazone on factors related to endothelial dysfunction in patients with type 2 diabetes mellitus. Atherosclerosis 2007; 195: e159–e166 41 Itoh M, Omi H, Okouchi M et al. The mechanisms of inhibitory actions of gliclazide on neutrophils-endothelial cells adhesion and surface expression of endothelial adhesion molecules mediated by a high glucose concentration. J Diabetes Complications 2003; 17: 22–26 42 Räkel A, Renier G, Roussin A et al. Beneficial effects of gliclazide modified release compared with glibenclamide on endothelial activation and low-grade inflammation in patients with type 2 diabetes. Diabetes Obes Metab 2007; 9: 127–129 43 Derosa G, Cicero AF, D’Angelo A et al. Effects of 1 year of treatment with pioglitazone or rosiglitazone added to glimepiride on lipoprotein (a) and homocysteine concentrations in patients with type 2 diabetes mellitus and metabolic syndrome: a multicenter, randomized, doubleblind, controlled clinical trial. Clin Ther 2006; 28: 679–688 44 Ryan KE, McCance DR, Powell L et al. Fenofibrate and pioglitazone improve endothelial function and reduce arterial stiffness in obese glucose tolerant men. Atherosclerosis 2007; 194: e123–e130 45 Schöndorf T, Musholt PB, Hohberg C et al. The fixed combination of pioglitazone and metformin improves biomarkers of platelet function and chronic inflammation in type 2 diabetes patients: results from the PIOfix study. J Diabetes Sci Technol 2011; 5: 426–432 46 Sahin M, Tutuncu NB, Ertugrul D et al. Effects of metformin or rosiglitazone on serum concentrations of homocysteine, folate, and vitamin B12 in patients with type 2 diabetes mellitus. J Diabetes Complications 2007; 21: 118–123 47 Derosa G, D'Angelo A, Ragonesi PD et al. Metformin-pioglitazone and metformin-rosiglitazone effects on non-conventional cardiovascular risk factors plasma level in type 2 diabetic patients with metabolic syndrome. J Clin Pharm Ther 2006; 31: 375–383 48 Munshi MN, Stone A, Fink L et al. Hyperhomocysteinemia following a methionine load in patients with non-insulin-dependent diabetes mellitus and macrovascular disease. Metabolism 1996; 45: 133–135

Erem C et al. Gliclazide-MR, Metformin and Pioglitazone Monotherapies in Type 2 Diabetes … Exp Clin Endocrinol Diabetes 2014; 122: 295–302

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

302 Article

Copyright of Experimental & Clinical Endocrinology & Diabetes is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.