Metabolic and vascular effects of antidiabetic drugs Machado HA et al. hemostatic factors analyzed (fibrinogen levels and platelet aggregation — data not shown). Vascular reactivity Increased carotid artery systolic diameter and blood flow were demonstrated only with metformin therapy, whereas an opposite trend in carotid diameter was observed with glimepiride use. Similar trends were observed even after patients treated for hypertension were excluded. No changes were observed for the other properties of the carotid (compliance, distensibility, and intima-media thick- ness) or brachial arteries (flow and diameter measurements after stimulus with reactive hyperemia and nitroglycerin). Metformin’s effects on carotid artery flow, independent of glucose decay or changes in systolic and diastolic blood pressure, likely afford more protection against cerebral diabetes complications. Its countering of insulin resistance action is likely implicated. Furthermore, we observed a negative correlation between fasting serum insulin levels and carotid compliance in the M group (r = -0.5; p = 0.04). Several observational analyses have suggested cardio- protective benefits with metformin use in patients with cardiovascular disease (3-4,40). Patients on metformin exhibited reduced nitroxidant metabolites and increased nitric oxide levels (30). As the carotid artery is more elastic and more proximal to the heart than the brachial artery, it might be more amenable to these improvements. As both therapies improved glucose control in very similar manners, their beneficial effects on lipid profiles, hemostatic factors and norepinephrine levels can likely be ascribed to improvement in the metabolic milieu and not to a specific drug effect. Our study is the first to demonstrate decreases in norepinephrine levels after the first four months of glimepiride therapy and similar trends for epinephrine levels. The same results were obtained for metformin. Although metformin has been confirmed as the first-line option for treating diabetes, troublesome gastrointestinal intolerance occasionally precludes its use (3). Thus, sulfo- nylureas remain important adjuvants for patients with intolerance to metformin or limited insulin secretion (5). When compared with metformin, glimepiride achieved similar efficacy in controlling weight and improving metabolic and hemostatic factors. Although it led to greater insulin secretion, glimepiride did not worsen beta cell function, as measured by the proinsulin-to-insulin ratio or vascular reactivity. Long-term studies are needed to ascertain whether glimepiride can reduce beta cell exhaus- tion or apoptosis. Our study has some limitations. The four-month treat- ment duration could have not been sufficient to demon- strate all of the effects of these medications. Additionally, as a crossover study with no washout period, a treatment period interaction effect was demonstrated for some variables (triglyceride, VLDL cholesterol, plasminogen and norepinephrine levels). To minimize this problem, only the values from the first treatment period were analyzed. In patients with type 2 diabetes inadequately controlled by dietary therapy, M and G resulted in similar overall improvements in glycemic control, lipid profiles, norepi- nephrine levels, and levels of the fibrinolytic factor plasminogen. All of these beneficial effects were likely due to improvement of the metabolic environment and were not drug-specific. However, as both therapies reduced t-PA 716 CLINICS 2012;67(7):711-717 activity, the coagulation process continued, which can worsen cardiovascular disease. Only metformin countered insulin resistance and induced an increase in carotid artery diameter and blood flow indices. Neither drug affected small brachial artery vasodilation. ACKNOWLEDGMENTS We are grateful to Greci de Paula Souza for assistance with procedures. This study was supported by the Fundac¸a˜o de Amparo a` Pesquisa do Estado de Sa˜o Paulo-FAPESP. AUTHOR CONTRIBUTIONS Machado HA and Cunha MR participated in designing the studies, conducting the clinical and experimental procedure and writing the paper. Vieira M provided the cardiovascular evaluation. Correia MRS performed the biochemical analysis. Fukui RT performed the hormonal analysis. Santos RF, Wajchenberg BL and Rocha DM collaborated on the clinical study. Lage SG collaborated on the clinical study and the cardiovascular evaluation. Silva MER collaborated on the clinical study and wrote, edited and finalized the manuscript for publication. REFERENCES 1. Stolar M. Glycemic control and complications in type 2 diabetes mellitus. Am J Med. 2010;123(Suppl. 3):S3-S11, http://dx.doi.org/10.1016/ j.amjmed.2009.12.004. 2. American Diabetes Association - Standards of medical care in diabetes. 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