Two-Year Statin Therapy Does Not Alter the Progression of Intima-Media Thickness in Patients With 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. We aimed to determine the effect of statin therapy versus placebo on the progression of carotid intima-media thickness (IMT) in type 2 diabetic patients without manifest CVD. RESEARCH DESIGN AND METHODS-A randomized, placebo-controlled, doubleblind clinical trial was performed in 250 patients with type 2 diabetes. Patients were given either 0.4 mg cerivastatin or placebo daily. In August 2001, when cerivastatin was withdrawn from the market, 0.4 mg cerivastatin was replaced by 20 mg simvastatin without deblinding the study. The primary end point was the change of mean common carotid IMT, as measured by B-mode ultrasound, over 2 years.RESULTS -Common carotid IMT at baseline was 0.780 mm in the placebo group and 0.763 mm in the statin group and did not change significantly after 2 years. There was no significant difference in IMT change in any carotid segment between the groups. LDL cholesterol was reduced by 25% in the statin group and increased by 8% in the placebo group (P Ͻ 0.001). Cardiovascular events occurred in 12 patients in the placebo group and two patients in the statin group (P ϭ 0.006).CONCLUSIONS -There was no effect of 2 years' statin therapy on carotid IMT in type 2 diabetic subjects. The natural history of IMT in our patients was milder than anticipated. In contrast, we observed a significantly lower cardiovascular event rate on statin therapy. Prognostic tools other than IMT should be explored in this patient group. Diabetes Care 27:2887-2892, 2004C ardiovascular disease (CVD), including cerebrovascular disease, coronary artery disease (CAD), and peripheral vascular disease, is the most important cause of mortality in patients with type 2 diabetes (1). The severity and progression of atherosclerosis can be assessed noninvasively by ultrasonographic measurements of the intima-media thickness (IMT) in the carotid and femoral arteries. Ultrasonographic IMT measurements of the far wall relate to histological IMT measurements (2). Carotid IMT correlates with prevalent CVD (3), angiographically proven coronary atherosclerosis (4), and risk factors for CVD, including LDL cholesterol (5,6). In prospective studies, carotid IMT has proven to be predictive of CVD (7-9), and as a consequence, IMT is increasingly used as an intermediate end point in clinical trials. Mean common carotid IMT in middle-aged subjects without CAD is reported to range from 0.71 to 0.91 mm in diabetic patients vs. 0.66 to 0.74 mm in control subjects (10,11). In diabetes, IMT is less consistently correlated to classical risk factors such as LDL cholesterol. Importantly, at the time our study was designed, data on the progression and predictive value of IMT in type 2 diabetes were lacking.During the last 10 years, large clinical trials have demonstrated that HMG-CoA (hydroxy-methylglutaryl coenzyme A) reductase inhibitors (statins) reduce the risk of cardiovascular events in the setting of secondary and primary preventio...

Progression of Coronary Artery Calcium and Occurrence of Myocardial Infarction in Patients With and Without Diabetes Mellitus

“…At the end of 2 years of follow-up, there was no difference in the progression of carotid artery IMT, although the number of cardiovascular events was significantly smaller (Pϭ0.006) in patients treated with statins. The findings by Beishuizen et al 30 were therefore consonant with those of the Heart Protection Study 31 and the Collaborative Atorvastatin Diabetes Study (CARDS), 32 in which statins significantly reduced events in diabetes. The reason there was a difference in imaging end points between the abovementioned IMT study and our CT-based study is unclear.…”

“…Furthermore, diabetes mellitus is associated not only with atherosclerotic calcification in the subintimal space, but also with calcification of the tunica media of the vessel wall, 28,29 which also poses a substantial risk of cardiovascular events in these patients. 29 Our results are partly discordant with those published by Beishuizen et al 30 These investigators used sequential carotid artery intima-media thickness (IMT) measurements to assess the effect of statin therapy compared with placebo in 250 type 2 diabetes patients. At the end of 2 years of follow-up, there was no difference in the progression of carotid artery IMT, although the number of cardiovascular events was significantly smaller (Pϭ0.006) in patients treated with statins.…”

“…The reason there was a difference in imaging end points between the abovementioned IMT study and our CT-based study is unclear. However, 2 main characteristics distinguished the studies: ours was retrospective and Beishuizen et al's 30 was prospective, and the changes in plaque burden at the level of the carotid and coronary arteries may follow different temporal patterns and not reflect the same pathobiological events.…”

Elevation of HDL-C in Response to Statin Treatment is Involved in the Regression of Carotid Atherosclerosis

“…Similarly, the TG levels were significantly reduced, by 11.9% in the pitavastatin group (P＜0.05) and by 13.6% in the LDL-C reduction in response to each statin 23) , we estimated the carotid IMT changes with statin treatment for 3 years to be −0.026 mm in the pitavastatin group and 0.008 mm in the pravastatin group, and the standard deviation for IMT change was 0.0708 mm. According to a previous report focusing on type 2 diabetes 24) , we estimated that 54 participants in each group would be required for 0.8 power at the alpha level of 0.05 for a one-sided test. Therefore, we enrolled 60 subjects in each group.…”

Letter by Ntaios et al Regarding Article, "Impact of Statin Therapy on Left Ventricular Function and Carotid Arterial Stiffness in Patients With Hypercholesterolemia"

“…9 In contrast, only 4 studies failed to confirm the effect of statins (namely, cerivastatin and pravastatin) on IMT. [10][11][12][13] As an example, we mention the study by Ito et al, which showed that cerivastatin and pravastatin did not improve carotid IMT after 6 months of treatment. 10 A possible explanation for the negative results of the Mizuguchi trial could be the modest duration of follow-up, although this same duration was sufficient to demonstrate a positive effect on IMT in many statin trials.…”