Metabolic and vascular effects of antidiabetic drugs Machado HA et al. Table 3 - Total (TFI) and systolic (SFI) flow indices and percentage changes in the systolic diameter of the carotid artery. CLINICS 2012;67(7):711-717 TFI (L/min/m2) SFI (L/min/m2) % Systolic Diameter a(pre-treatment vs. metformin); c(metformin vs. glimepiride). Values are expressed as means ¡ SDs. Pre-treatment 0.319¡0.079 0.599¡0.155 Metformin Group 0.382¡0.094 0.738¡0.167 2.75¡9.93 Glimepiride Group 0.285¡0.091 0.563¡0.152 -3.50¡11.46 p-value a0.024; c0.003 a0.006 c0.003 ,0.05 Vascular reactivity The elastic arterial properties were evaluated. Carotid artery (Table 3): Both the total (p = 0.004) and systolic (p = 0.002) carotid flow indices increased with metfor- min therapy compared with baseline values and glimepiride therapy. Moreover, the carotid systolic diameter changed in opposite directions during the therapies; its percentage change (from basal levels) increased with metformin and decreased with glimepiride, and these different behaviors reached significance (p = 0.028). The compliance, distensibility and intima-media thickness of the carotid artery did not change significantly with any therapy (data not shown). Brachial artery: There was a similar increase in flow- mediated vasodilatation of the brachial artery after reactive hyperemia (endothelium-dependent) and sublingual nitro- glycerin (endothelium-independent) stimuli across the groups. There were no significant effects of medications on systolic diameter or the total and systolic flow indices of the brachial artery (data not shown). DISCUSSION This study compared the actions of two different classes of drugs (the biguanide metformin, an insulin sensitizer, and the sulfonylurea glimepiride, an insulin secretagogue) on carbohydrate and lipid metabolism, hemostatic factors and vascular reactivity. We evaluated the same patients with type 2 diabetes before and after four months of treatment with metformin or glimepiride. The aim of this strategy was to minimize the influence of metabolic control on specific drug effects other than glucose control. The data in the literature remain poor and contradictory re- garding the direct actions of these drugs on the cardiovas- cular risk-related factors analyzed in the present study (15- 19,30-33). Carbohydrate and lipid metabolism Both treatment groups achieved similar and significant mean decreases from baseline in fasting plasma glucose and HbA1 levels. The lower insulin and proinsulin levels (at fasting and during the 12-h metabolic profile) observed during metformin therapy compared with glimepiride were in agreement with reports of metformin’s sparing effects on beta cell function, thus lowering the basal and postprandial insulin requirements for the same metabolic control (3,17). These differences in insulin secretion could not be accounted for by changes in body weight, which were unaffected in both groups. Although some authors have found no increases in insulin levels (18) and others have reported that glimepiride’s insulin trophic effect might diminish in the presence of normoglycemia (34), the insulin levels in this study were found to be higher during therapy with glimepiride than metformin. 715 Despite these findings, the proinsulin-to-insulin ratio areas under the curve during the 12-h metabolic profile were similar for both therapies, suggesting that glimepiride did not worsen the previous secretor dysfunction of beta cells, as reported with other sulfonylureas (35). The overall effects on plasma lipids were small, with similar lowering of fasting VLDL cholesterol and triglyceride levels after the initial four months of both therapies. TG levels during the 12-h metabolic profile were also similar between the two drugs. LDL and HDL cholesterol levels were unaffected by treatment. Metformin. and glimepiride-asso- ciated improvements in lipid metabolism were expected, but the reported changes have been small (3,16,30). The near normal triglyceride and cholesterol levels of our patients prior to both therapies were likely factors that influenced these modest results. Despite causing lower insulin and higher glucagon secre- tion, metformin kept glucose and lipid profiles at similar levels compared with glimepiride. The blood glucose-low- ering actions of metformin result primarily from an ameliora- tion of insulin resistance, increase in peripheral glucose disposal, decrease in fatty acid oxidation and activation of the enzyme adenosine monophosphate (AMP) kinase to increase glucose transporter 4 (GLUT4) translocation to plasma membrane cells in the muscles and fat and reduce gluconeo- genesis in the liver (3,36). The higher glucagon levels are unlikely to have interfered with metformin’s action, as glucagon appears to have little effect on the presence of insulin, suggesting that its diabetogenic action occurs only under conditions of high insulin deficiency (37). In addition, glucagon’s effects on hepatic glucose production could have been strongly counteracted by metformin. Hemostatic factors Glimepiride and metformin had similar effects on hemo- static factors; both increased plasminogen levels (significant after four months on each therapy) and decreased t-PA activity. These findings observed in the G group have not been reported previously. The improvements in fibrinolysis after metformin and glimepiride therapy suggested by the increases in plasmi- nogen levels occurred along with an unexpected decrease in another marker of fibrinolysis — t-PA activity. In contrast to our results, an increase in t-PA activity during metformin therapy has been described (38). However, as active t-PA declines as a function of increasing concentrations of PAI-1 and considering that PAI-1 antigen and activity did not change in our experiment, we can speculate that the formed complexes of PAI-1 and t-PA cleared in an accelerated fashion by the liver (39) contributed to the decrease in t-PA activity and that an impairment of fibrinolysis continued to occur. These data are likely implicated in the high frequency of cardiovascular disease in type 2 diabetes. No additional effects of any of the therapies were observed on the other