Metabolic and vascular effects of antidiabetic drugs Machado HA et al. In contrast, sulfonylureas enhance insulin release primar- ily by closing the ATP-sensitive K+ channels of pancreatic b-cells. The glucose-lowering potency of sulfonylureas is similar to that of metformin. However, by stimulating insulin secretion, sulfonylureas are believed to favor the development of hypoglycemia and weight gain, accelerate beta-cell apoptosis and beta-cell exhaustion and impair endothelial function, thereby increasing the risk for ischemic complications. The blocking of potassium channels in the heart by sulfonylureas has raised concern regarding the drugs’ potential adverse effects in cases of ischemic heart episodes (5). Glimepiride is a long-acting and low potency insulin secretagogue sulfonylurea that has an insulin-sensitizer effect on the muscles and liver (6) and rarely causes hypoglycemia (5). Data from studies in humans are scarce but have suggested that the risks of developing coronary artery disease and mortality do not appear to be increased by glimepiride (7-8). In addition, no deleterious effects of glimepiride on brachial vasodilatation — an acute effect (9) — or ischemic preconditioning — acute (10) and chronic (11) effects — have been observed Only two studies have investigated the chronic vascular effects of glimepiride measured by forearm arterial blood flow, and the results were similar to those of glibenclamide (12-13) and metformin (12). There have been no reports comparing carotid artery blood flow during glimepiride and metformin therapy, and only a few have measured hemo- static factors (14-19), specifically plasminogen activator inhibitor (PAI-1), fibrinogen and adhesion molecules. In our study, the effects of glimepiride in patients with type 2 diabetes on vascular reactivity, hemostatic factors, and fat and carbohydrate metabolism were compared with those of metformin, the first-line therapy. This comparison is valuable in that these different classes of oral anti-diabetic agents — metformin and glimepiride — target the two main pathophysiological defects of type 2 diabetes, and their safety is fundamental. METHODS Patients A prospective study was performed in 16 uncontrolled patients with type 2 diabetes according to the ADA criteria (2); the cohort included ten women and six men with a mean age of 51.8¡6.5 years (mean¡SD) previously treated with dietary intervention. Subjects who had fasting blood glucose values .7.78 mmol/L and/or glycated hemoglobin exceeding the normal range (4-8.5%) by 1.0% or more after two or more months of a diet therapy program without medications (basal values) were included. The participants were randomly assigned to receive either metformin (M group) or glimepiride (G group). The drug dosage was titrated to achieve fasting glucose levels lower than 7.0 mmol/L using domiciliary capillary glucose measurements. After four months, the patients were crossed over with no washout period to the alternative treatment for an addi- tional four-month period on a similar dosage schedule. The subjects were followed on an outpatient basis every 1-2 weeks throughout the study period for drug and weight- maintaining diet adjustments. The clinical characteristics of the patients are depicted in Table 1. Three of the sixteen subjects smoked, and six had systemic arterial hypertension, which was treated with converting-enzyme inhibitors. 712 CLINICS 2012;67(7):711-717 Table 1 - Anthropometric data. Age (yr) Sex (F:M) Dose (mg/day) Weight (kg) BMI (kg/m2) W/H DBP (mm Hg) SBP (mm Hg) Pre- treatment 51.8¡6.5 10:06 71.1¡13.4 27.6¡3.6 0.9¡0.1 83.3¡9.3 141.5¡14.0 Metformin Group Glimepiride Group 1907¡558 68.9¡12.5 26.7¡3.4 0.9¡0.1 79.4¡7.5 129.2¡16.4 4¡2 70.5¡14.2 27.2¡3.7 0.9¡0.1 81.1¡8.5 134.0¡14.0 Ns Ns Ns Ns Ns Values are expressed as means¡SDs. DBP = diastolic blood pressure; SBP = systolic blood pressure; BMI = body mass index; W/H = waist-to-hip ratio. Seven of the ten women were postmenopausal, and none had received hormone replacement therapy, while the pre- menopausal women were tested up to the 8th day of the follicular phase of their cycles. At the time of enrollment, a complete medical history, physical examination, and laboratory evaluation, including urinalysis, renal, hepatic, and thyroid function tests and serum lipid and electrolyte levels, were obtained for all of the subjects. An ECG and echocardiogram were performed, and subjects with left ventricular systolic dysfunction, valve abnormalities, arrhythmias and ischemic heart disease were not enrolled. None of the patients exercised on a regular basis. Other exclusion criteria included any severe concomitant illness, nephropathy (serum creatinine .1.6 mg/dL or microalbu- minuria), uncontrolled hypertension (BP .190x120 mm Hg), stroke, peripheral vascular disease, marked dyslipide- mia (total cholesterol .6.5 mmol/L and triglyceride levels .2.8 mmol/L), coagulopathy, proliferative diabetic retino- pathy and use of hypolipidemic and anticoagulant medica- tions. None of the subjects demonstrated clinical evidence of autonomic neuropathy as assessed by blood pressure response to standing, beat-to-beat heart rate variation, the Valsalva maneuver and the handgrip test. The Medical Ethics Committee of Hospital das Cl´ınicas and Heart Institute (INCOR) approved the study protocol, and all of the subjects provided written informed consent. Study protocol The patients were instructed to continue a similar food intake and abstain from the use of tobacco, alcohol, coffee, salty food, and any physical activity for 24 h before test days and discontinue converting-enzyme inhibitors 72 h before the evaluation. The following procedures were performed before (basal values) and after each four-month treatment period (M and G groups): 1) hormonal and metabolic evaluations: fasting plasma glucose, insulin and catecholamine levels, lipid profiles and HbA1; 2) hemostatic factor determination: tissue plasminogen activator (t-PA) antigen and activity, plasminogen activator inhibitor (PAI-1) antigen and activity, platelet aggregability, fibrinogen and plasminogen levels; and 3) a cardiovascular evaluation: by high-resolution ultrasound of the carotid and brachial arteries. At the end of each treatment period, a 12-h metabolic profile, including measurements of glucose, insulin, gluca- gon, proinsulin, and triglyceride levels at fasting and every 2 h (from 7 am to 7 pm), was obtained. The meals offered to patients (breakfast, lunch, and dinner) contained 50% of