Journal of Cardiovascular Magnetic Resonance
BioMed Central
Open Access
Research
Effect of rosiglitazone on progression of atherosclerosis: insights using 3D carotid cardiovascular magnetic resonance Anitha Varghese†1,2, Michael S Yee†3,4, Cheuk F Chan1,2, Lindsey A Crowe1, Niall G Keenan1,2, Desmond G Johnston3,4 and Dudley J Pennell*1,2 Address: 1National Heart and Lung Institute, Imperial College, London, UK, 2Cardiovascular Magnetic Resonance Unit, Royal Brompton Hospital, London, UK, 3Division of Medicine, Imperial College, London, UK and 4Department of Diabetes, Imperial College Health Care NHS Trust, London, UK Email: Anitha Varghese -
[email protected]; Michael S Yee -
[email protected]; Cheuk F Chan -
[email protected]; Lindsey A Crowe -
[email protected]; Niall G Keenan -
[email protected]; Desmond G Johnston -
[email protected]; Dudley J Pennell* -
[email protected] * Corresponding author †Equal contributors
Published: 27 July 2009 Journal of Cardiovascular Magnetic Resonance 2009, 11:24
doi:10.1186/1532-429X-11-24
Received: 13 January 2009 Accepted: 27 July 2009
This article is available from: http://www.jcmr-online.com/content/11/1/24 © 2009 Varghese et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract Background: There is recent evidence suggesting that rosiglitazone increases death from cardiovascular causes. We investigated the direct effect of this drug on atheroma using 3D carotid cardiovascular magnetic resonance. Results: A randomized, placebo-controlled, double-blind study was performed to evaluate the effect of rosiglitazone treatment on carotid atherosclerosis in subjects with type 2 diabetes and coexisting vascular disease or hypertension. The primary endpoint of the study was the change from baseline to 52 weeks of carotid arterial wall volume, reflecting plaque burden, as measured by carotid cardiovascular magnetic resonance. Rosiglitazone or placebo was allocated to 28 and 29 patients respectively. Patients were managed to have equivalent glycemic control over the study period, but in fact the rosiglitazone group lowered their HbA1c by 0.88% relative to placebo (P < 0.001). Most patients received a statin or fibrate as lipid control medication (rosiglitazone 78%, controls 83%). Data are presented as mean ± SD. At baseline, the carotid arterial wall volume in the placebo group was 1146 ± 550 mm3 and in the rosiglitazone group was 1354 ± 532 mm3. After 52 weeks, the respective volumes were 1134 ± 523 mm3 and 1348 ± 531 mm3. These changes (12.1 mm3 and -5.7 mm3 in the placebo and rosiglitazone groups, respectively) were not statistically significant between groups (P = 0.57). Conclusion: Treatment with rosiglitazone over 1 year had no effect on progression of carotid atheroma in patients with type 2 diabetes mellitus compared to placebo.
Background The prevalence of diabetes is increasing exponentially worldwide, and type 2 diabetes accounts for 90% of cases [1]. Insulin resistance is a fundamental feature of type 2 diabetes and is associated with increased cardiovascular
risk, which accounts for up to 80% of deaths in these patients [2,3]. The United Kingdom Prospective Diabetes Study (UKPDS) demonstrated that intensive blood glucose control with insulin or sulphonylurea in type 2 diabetic patients had only a limited effect on the incidence of Page 1 of 9 (page number not for citation purposes)
Journal of Cardiovascular Magnetic Resonance 2009, 11:24
http://www.jcmr-online.com/content/11/1/24
cardiovascular events, indicating the necessity for new treatment strategies [4].
ment of carotid atheroma which evaluates arterial wall remodeling in a 3-dimensional (3D) manner with good reproducibility in carotid disease of 4.4%, which allows small sample sizes [27,28]. For example, CMR showed atheroma regression using simvastatin in only 18 asymptomatic hypercholesterolaemic patients, with carotid CMR alone demonstrating a reduction of 15% in carotid vessel wall area after 1 year of statin use [14,29]. We performed a placebo-controlled, double-blind 3D carotid CMR study to evaluate the effect of rosiglitazone on atherosclerosis burden in patients with type 2 diabetes mellitus.
The thiazolidinediones are a class of oral hypoglycemic drugs which have gained rapid and widespread acceptance into clinical practice. Their pharmacological action is through the reduction of insulin resistance by sensitizing muscle, liver, and adipose tissue to insulin, and treatment is associated with delayed progression to type 2 diabetes [5,6]. Their agonist effect is mediated by peroxisome proliferator activated receptor gamma (PPARγ), a nuclear hormone receptor, with effects on carbohydrate and lipid metabolism, fat cell differentiation, and gene regulation similar to those seen when insulin combines with its receptor [7]. Two glitazones are available for clinical use: pioglitazone and rosiglitazone. Both have been shown to lower hemoglobin A1c (HbA1c) to a similar extent but they have distinct lipid modulation properties [8]. Both drugs raise high-density lipoprotein cholesterol (HDLc), but pioglitazone reduces triglyceride levels while rosiglitazone has shown either no consistent change or an increase in levels. Additionally, low-density lipoprotein cholesterol (LDLc) concentration is contentious [8,9], studies have generally suggested a reduction with pioglitazone, but an increase with rosiglitazone, although the shift from small dense LDLc to a large buoyant phenotype may be less atherogenic [10]. The beneficial effect of rosiglitazone on plaque progression has been shown in animal and human subjects [1113]. In a study of 92 sub-optimally controlled type 2 diabetic patients who were randomised to either metformin or rosiglitazone treatment, Stoker et al demonstrated that there was a significant reduction in carotid intima-media thickness (IMT) after 24 weeks in the rosiglitazone group [14]. Additionally, the effect of rosiglitazone on carotid intima-media thickness (IMT) over 12 months was studied in patients with type 2 diabetes and the insulin resistance syndrome and no statistically significant difference from placebo was shown [15]. However, this study suggested that rosiglitazone may have a beneficial effect in overt diabetes compared with the pre-diabetic group. Carotid IMT is an important surrogate marker of cardiovascular risk and there is a linear relationship between this measure and the angiographic presence and severity of coronary artery disease [16-21]. Therapeutic intervention with antiplatelet agents, angiotensin-converting enzyme (ACE) inhibitors, β-blockers, and statins prevent progression of carotid IMT and have been shown to favorably impact on cardiovascular morbidity and mortality [2225]. Of these, the most potent drugs are the statins [20,26]. High-resolution carotid cardiovascular magnetic resonance (CMR) is a comparatively new tool for the assess-
Methods This was a randomized, placebo-controlled, double-blind study in patients with type 2 diabetes and coexisting vascular disease or hypertension. After completing a 4–8 week single-blind placebo run-in period, eligible subjects entered a 52 week double-blind treatment period during which they received either rosiglitazone (4 mg once daily for the first 12 weeks and then 4 mg twice daily for the remainder of the study) or placebo. Randomization was performed in a 1:1 manner to the rosiglitazone or placebo treatment group using the Registration and Medication Ordering System (RAMOS), and stratified by statin or fibrate use without distinction between the two. Eligible patients were those with type 2 diabetes, aged between 30–75 years, HbA1c
