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Sulfonylurea Treatment of Type 2 Diabetic Patients Does Not Reduce the Vasodilator Response to Ischemia

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Sulfonylurea Treatment of Type 2 Diabetic Patients Does Not Reduce the Vasodilator Response to Ischemia Pathophysiology/Complications ORIGINAL ARTICLE Sulfonylurea Treatment of Type 2 Diabetic Patients Does Not Reduce the Vasodilator Response to Ischemia 1 1 PAOLO SPALLAROSSA, MD LUCA OLIVOTTI, MD vided by the discovery that sulfonylurea 2 2 MARA SCHIAVO, MD RENZO CORDERA, MD drugs stimulate insulin secretion by 1 1 ϩ PIERFRANCO ROSSETTIN, MD CLAUDIO BRUNELLI, MD ␤ 1 blocking -cell ATP-sensitive K (KATP) STEFANO CORDONE, MD channels (5). KATP channels are also abundantly present in the cardiac muscle and in vascular smooth muscle cells in coronary and peripheral arteries, where they play a key role in the protective OBJECTIVE — Sulfonylureas block the activation of vascular potassium-dependent ATP channels and impair the vasodilating response to ischemia in nondiabetic individuals, but it is mechanisms that are triggered during not known whether this occurs in type 2 diabetic patients under chronic treatment with these ischemia (6,7). Soon after the onset of drugs. Glimepiride, a new sulfonylurea, apparently has no cardiovascular interactions. The aim ischemia, the activation of KATP channels of our study was to compare the effect of the widely used compound glibenclamide, the pan- decreases vascular resistance and in- creas-specific glimepiride, and diet treatment alone on brachial artery response to acute forearm creases blood flow (ischemic vasodila- ischemia. tion) and renders myocardial cells more resistant to a subsequent bout of ischemia RESEARCH DESIGN AND METHODS — Brachial artery examination was performed Ϯ Ϯ (the so-called ischemic preconditioning) by a high-resolution ultrasound technique on 20 type 2 diabetic patients aged (mean SD) 67 (8,9). A great deal of experimental evi- 2 years and on 18 nondiabetic patients matched for age, hypertension, and dislipidemia. Diabetic subjects underwent three separate evaluations at the end of each 8-week treatment period, dence shows that glibenclamide and the during which they received glibenclamide, glimepiride, or diet alone according to crossover other sulfonylurea compounds, which are design. Scans were obtained before and after 4.5 min of forearm ischemia. Postischemic vaso- not ␤-cell–specific, block cardiovascular dilation and hyperemia were expressed as percent variations in vessel diameter and blood flow. KATP channels and prevent both protec- tive phenomena (8–11). Glimepiride is a RESULTS — Postischemic vasodilation and hyperemia were, respectively, 5.42 Ϯ 0.90 and new sulfonylurea compound that inter- 331 Ϯ 38% during glibenclamide, 5.46 Ϯ 0.69 and 326 Ϯ 28% during glimepiride, and 5.17 Ϯ ␤ acts more selectively with the -cell KATP 0.64 and 357 Ϯ 35% during diet treatment (NS). These results were similar to those found in the Ϯ Ϯ channels (12). In agreement with experi- nondiabetic patients (6.44 0.68 and 406 42%, NS). mental evidence, studies in humans have CONCLUSIONS — In type 2 diabetic patients, the vasodilating response to forearm isch- shown that acute administration of glib- emia was the same whether patients were treated with diet treatment alone or with glibenclamide enclamide, but not of the pancreas- or glimepiride at blood glucose–lowering equipotent doses. specific glimepiride, induces potentially harmful cardiovascular effects in both Diabetes Care 24:738–742, 2001 nondiabetic patients with coronary artery disease and healthy volunteers (13–17). Less is known about the clinical situ- ulfonylureas represent the most might increase cardiovascular mortality, ation of type 2 diabetic patients who are commonly prescribed pharmaco- but the more recent U.K. Prospective Di- chronically treated with sulfonylureas. S logical treatment for type 2 diabetic abetes Study (UKPDS) showed no evi- The evidence of poor outcome in diabetic patients, despite early observations sug- dence that intensive treatment with patients undergoing percutaneous coro- gesting a possible deleterious effect of these sulfonylureas had any specific adverse ef- nary angioplasty for acute myocardial in- drugs (1–3). However, the question is still fect on cardiovascular disease in type 2 farction while taking sulfonylureas is open. In fact, in the early 1970s, the Uni- diabetic patients (3,4). A physiological consistent with the hypothesis that long- versity Group Diabetes Program (UGPD) basis explaining the potentially detrimen- term inhibition of KATP channels may im- suggested that the use of sulfonylureas tal effects of sulfonylureas has been pro- pair myocardial tolerance to severe ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● ischemia (18). This hypothesis contrasts with the early observations by Paasikivi From the 1Division of Cardiology, Department of Internal Medicine and the 2Department of Endocrinology and Metabolism (MS, RC) University of Genova, Genova, Italy. and with a recent retrospective analysis Address correspondence and reprint requests to Claudio Brunelli, MD, Division of Cardiology, Internal showing that treatment with gliben- Medicine, University of Genova, Viale Benedetto XV, 6, 16132 Genova, Italy. E-mail: [email protected]. clamide does not affect infarct size and unige.it. in-hospital mortality in type 2 diabetic Received for publication 12 June 2000 and accepted in revised form 3 January 2001. ϩ patients with acute myocardial infarction Abbreviations: KATP, ATP-sensitive K . A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion (19,20). However, to our knowledge, no factors for many substances. studies have ever examined whether ther- 738 DIABETES CARE, VOLUME 24, NUMBER 4, APRIL 2001 Spallarossa and Associates Table 1—General characteristics of the study population Protocol All subjects were examined in the after- Characteristics Diabetic patients Nondiabetic patients noon, 120–180 min after the main meal of the day and intake of the study drug. n 20 18 High-resolution ultrasound (Acuson Se- Age (years) 67.4 Ϯ 1.9 67.5 Ϯ 1.8 quoia C256) with an 8-MHz linear array Sex (M/F) 14/6 13/5 transducer was used to measure the bra- BMI (kg/m2) 28.8 Ϯ 0.7* 26.9 Ϯ 0.5 chial artery diameter. Machine operating Hypertension (yes/no) 14/6 13/5 parameters were kept constant during Cholesterol (mmol/l) 5.17 Ϯ 0.17 5.24 Ϯ 1.17 each study. The subject was required to HDL cholesterol (mmol/l) 1.0 Ϯ 0.3 1.02 Ϯ 0.3 recline on an examination bed for 10 min LDL cholesterol (mmol/l) 3.27 Ϯ 0.16 3.03 Ϯ 0.12 in a quiet setting. The brachial artery was Triglycerides (mg/dl) 130 Ϯ 14 119 Ϯ 13 longitudinally imaged ϳ5 cm above the Glucose (mmol/l) 7.55 Ϯ 0.2† 5.22 Ϯ 0.14 antecubital crease. Once an optimal posi- Ace inhibitors (yes/no) 7/13 5/13 tion was obtained, the transducer was no ␤-blockers (yes/no) 5/15 5/13 longer moved. A baseline scan was ob- Calcium antagonists (yes/no) 2/18 2/16 tained and pulsed Doppler blood flow ve- Lipid-lowering drugs (yes/no) 7/13 5/13 locity was determined with the signal at a History of cardiovascular disease (yes/no) 5/15 4/14 70° angle to the vessel and with the range Data are means Ϯ SE or n.*P Ͻ 0.05 compared to nondiabetic patients; †P Ͻ 0.001 compared to gate adjusted to 1.5 mm and positioned in nondiabetic patients. the center of the artery. A cuff placed on the forearm was then inflated to 300 mmHg for 4.5 min. A second scan was apeutic doses of sulfonylureas in diabetic with acute coronary syndromes were also carried out continuously for 30 s before patients may compromise vascular blood excluded. and 90 s after cuff deflation. Measure- flow regulation in response to ischemia. ments were calculated on the basis of S- The aim of this work was to investigate VHS video recordings by two observers the effects of chronic administration of Design who were blinded to clinical data and the the widely used sulfonylurea gliben- Regardless of previous treatment, diabetic type of therapy being administered. Di- clamide and the more ␤-cell–specific patients were randomized to receive glib- ameter measurements were made at end- glimepiride on the reactive vasodilating enclamide (10 patients) or glimepiride diastole, incident with the R wave on a response to a brief episode of arterial oc- (10 patients) as monotherapy for 8 weeks, continuously recorded electrocardio- clusion in type 2 diabetic patients. after which they were crossed over to the gram, 45–60 s after cuff deflation. Dopp- alternative treatment for a further 8-week ler flow signals were recorded during the RESEARCH DESIGN AND period. During both phases, dosage titra- first 15 s after cuff release. Volume flow METHODS tion took place at 2-week intervals on the was calculated by multiplying the velocity Twenty type 2 diabetic subjects aged basis of blood glucose. Hypoglycemic time integral of the Doppler signal (cor- 57–80 years were recruited from the dia- agents were then discontinued, and ef- rected for angle) by the heart rate and the betes clinic at the University of Genova, forts were made to control hyperglycemia artery cross-sectional area. Changes in Genova, Italy. The known duration of di- vessel diameter and blood flow after cuff for at least 4 weeks by adjusting their diet. abetes (means Ϯ SD) was 5.4 Ϯ 0.9 years, deflation are expressed as the percentage Hypoglycemic drugs could not be discon- and the mean level of HbA was 7.59 Ϯ relative to the baseline scan. 1c tinued in four patients, and three patients 0.28%. Subjects received glibenclamide dropped out because they found the re- (n ϭ 2), glibenclamide plus metformin Statistical analysis (n ϭ 13), or glicazide (n ϭ 3) or were on strictive diet too demanding. At the end of Comparisons between subject groups diet treatment alone (n ϭ 2). One sub- each treatment period with glibenclamide were performed by using paired or un- ject had diabetic retinopathy, three had and glimepiride, all diabetic patients un- paired t tests for continuous variables and microalbuminuria, and two had both derwent noninvasive assessment of bra- a ␹2 test for categorical variables.
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