The Effect of Statin Therapy on Endothelial Function in Type 2 Diabetes Without Manifest Cardiovascular Disease

Abstract

OBJECTIVE -Cardiovascular disease (CVD) is the most important cause of mortality in patients with type 2 diabetes and is preceded by endothelial dysfunction. Flow-mediated dilation (FMD) is a noninvasive technique for measuring endothelial dysfunction. We aimed to determine the effect of long-term statin therapy versus placebo on FMD in patients with type 2 diabetes without manifest CVD. RESEARCH DESIGN AND METHODS-A randomized, placebo-controlled, doubleblind trial was performed with 250 type 2 diabetic patients. Patients were given 0.4 mg cerivastatin or placebo daily. In August 2001, when cerivastatin was withdrawn from the market, the 0.4 mg cerivastatin was replaced by 20 mg simvastatin, without deblinding the study. The primary end point was the change in FMD, measured by B-mode ultrasound, after 2 years.RESULTS -Determinants of baseline FMD were diabetes duration, common carotid intimamedia thickness, and brachial artery diameter. FMD at baseline was 1.51% in the placebo group and 1.66% in the statin group and did not change significantly after 2 years.CONCLUSIONS -The 2-year statin therapy had no effect on FMD in type 2 diabetes. Statin-induced improvement of cardiovascular risk in patients with type 2 diabetes may be mediated through mechanisms other than increased nitric oxide availability. Diabetes Care 28:1668 -1674, 2005C ardiovascular disease (CVD) is the most important cause of mortality in patients with type 2 diabetes (1). Endothelial dysfunction precedes the development of atherosclerotic plaques and is believed to be reversible (2). Nitric oxide (NO) is a key molecule in this process. It modulates blood flow and vascular permeability, limits inflammation and coagulation, and diminishes vascular smooth muscle cell proliferation and migration. Type 2 diabetes is associated with endothelial dysfunction; the underlying mechanisms are complex and related to hyperglycemia (sorbitol, hexosamine, protein kinase C, and advanced glycation end product pathways) and insulin resistance, resulting in mitochondrial superoxide overproduction and thus decreased NO availability (3). Regarding insulin, its vasodilatory capacity is at least in part NO dependent (4,5), thus explaining how insulin resistance might be related to endothelial dysfunction.Flow-mediated dilation (FMD) of the brachial artery is a noninvasive technique for measuring endothelial function. FMD of the brachial artery has been shown to be the result of endothelium-derived NO release (6) and is related to coronary vasoreactivity (7). FMD has proven to be predictive for the presence of coronary artery disease (8,9), for future cardiovascular events (10 -12), and for postoperative cardiovascular events (13) in high-risk populations. Improvement in FMD predicts a favorable cardiovascular outcome in postmenopausal hypertensive women (2). However, in patients at lower risk, FMD was not independently associated with outcome (14). FMD is impaired in patients with type 2 diabetes with reported FMD values of 4.47-12.3% in control subjects vs. 2.96 -6.1...

Short Term Effects of Atorvastatin on Endothelial Functions and Oxidized LDL Levels in Patients with Type 2 Diabetes

“…An impaired function of brachial artery can be correlated with an impaired coronary arterial function. Beishuizen et al did not find an effect of 20 mg simvastatin on FMD after a 2-year period [11]. Similarly, van Venrooji et al did not find an effect of 30 weeks of atorvastatin versus placebo on FMD [12].…”

Endothelial Dysfunction in Diabetes: Pathogenesis, Significance, and Treatment

“…However, a number of randomized, doubleblind, placebo-controlled studies have shown no effect of statin therapy on ED in subjects with T2D [117,118], despite improvements in dyslipidemia [119][120][121]. Forearm vascular reactivity in T2D subjects was improved with atorvastatin [122], but not with cerivastatin [123].…”

“…The evidence from studies examining the effects of statins on ED in T2D has been inconsistent and contradictory (Table 3) [109][110][111][112][113][114][115][116][117][118][119][120][121][122][123]. It is possible that in T2D, treatment with a single therapeutic agent may not adequately improve ED and that combination therapy is required.…”

Placebo-Controlled Trial of High-Dose Atorvastatin in Patients With Severe Cerebral Small Vessel Disease

“…23 Similarly, statins improved brachial EDV in patients with coronary artery disease 23,24 but not in patients with very severe endothelial dysfunction. 25,26 Only 1 study has tested the effect of statin treatment on endothelial function in stroke patients with multiple lacunes, and it found that 40 mg per day of atorvastatin for at least 3 months restored endothelial function completely. 7 At baseline, brachial flow-mediated dilation was severely impaired (0.06%) and returned to normal level after treatment (7%).…”