Effect of Rosiglitazone on Common Carotid Intima-Media Thickness Progression in Coronary Artery Disease Patients Without Diabetes Mellitus

Abstract

Objectives-Thiazolidinediones, such as rosiglitazone, have been shown to retard atherosclerosis disease progression in diabetic subjects. These agents may have anti-atherosclerotic effects through direct inhibition of inflammatory processes in the vessel wall, and so their benefit may extend to patients with atherosclerotic disease, even in the absence of diabetes. In this study, we assessed the effect of rosiglitazone on common carotid intima-media thickness (IMT) progression in nondiabetic coronary artery disease (CAD) patients. Methods and Results-Consecutive subjects (nϭ92) with clinically stable, angiographically documented CAD and without diabetes mellitus were randomized in a double-blind manner to receive placebo or rosiglitazone for 48 weeks. They received single-dose placebo and rosiglitazone 4 mg daily for the initial 8 weeks, and the doses were doubled for the remainder of the study. Common carotid IMT together with fasting glucose, insulin, and lipid profile were measured at baseline and repeated after 24 and 48 weeks. Rosiglitazone-treated patients showed reduced IMT progression compared with the placebo group, Ϫ0.012 mm/48 weeks versus 0.031 mm/48 weeks (Pϭ0.03). Rosiglitazone treatment significantly reduced insulin resistance, estimated by homeostasis model of insulin resistance index, compared with placebo (Pϭ0.01). Key Words: PPAR-␥ Ⅲ agonists Ⅲ thiazolidinediones Ⅲ carotid intima-media thickness Ⅲ coronary artery disease. Conclusions-RosiglitazoneT he thiazolidinedione rosiglitazone, a peroxisome proliferator-activated receptor-␥ (PPAR-␥) agonist, is an insulin-sensitizing agent and is used in the treatment of type 2 diabetes mellitus. Data suggest that these agents may also retard atherosclerotic disease progression. Thiazolidinediones have been shown to reduce atherosclerotic lesion area in mouse models of atherosclerosis that exhibit hyperlipidemia and insulin-resistance. 1-3 Thiazolidinediones have also been reported to reduce common carotid arterial intima-media thickness (IMT) progression, a surrogate index of atherosclerotic disease progression, in type 2 diabetic subjects. 4,5 These results taken together suggest that insulin sensitization and glucose-lowering are important mechanisms underlying the antiatherogenic effects of these agents. [1][2][3][4][5] See page 798However, recent evidence suggests that PPAR-␥ agonists may also inhibit atherosclerotic disease progression by exerting anti-inflammatory effects within the artery wall. 6,7 Therefore, the potential antiatherogenic effects of PPAR-␥ agonists may not be confined to type 2 diabetic patients. 8 The PPAR-␥ agonist troglitazone has been shown to reduce atherosclerotic lesion formation and macrophage accumulation in plaques in nondiabetic low-density lipoprotein (LDL) receptor-deficient mice. 9 We recently found that rosiglitazone reduces circulating markers of inflammation, such as C-reactive protein, in nondiabetic patients with coronary artery disease (CAD). 10 In the present study, we measured the effect of treatment on com...

PPARα, but not PPARγ, Activators Decrease Macrophage-Laden Atherosclerotic Lesions in a Nondiabetic Mouse Model of Mixed Dyslipidemia

“…In this respect, it is interesting to note that TZD treatment has been shown to improve endothelial function and decrease intimamedia thickness also in nondiabetic patients. [7][8][9][10] Such activities may be mediated, in part, via their effects on the proliferation and migration of vascular SMCs and the antiinflammatory activities in these and other cell types involved in atherogenesis. 40 -46 Moreover, PPAR␣ and PPAR␥ ligands may influence thrombogenesis and inhibit proteins implicated in plaque rupture resulting in plaque stabilization.…”

“…3 Interestingly, even in nondiabetic patients with coronary artery disease, rosiglitazone treatment induced beneficial effects on the vascular endothelium, exerted antiplatelet activity, and reduced carotid intima-media thickness progression. [7][8][9][10] All these reports argue for potent antiatherogenic effects of TZDs, raising the possibility of their use in clinical conditions other than diabetes. Consistent with this therapeutic potential of TZDs against atherosclerosis in humans, results from experimental animal studies showed that PPAR␥ agonists reduce the development of atherosclerosis [11][12][13][14][15] and limit its complications.…”

Effects of Rosiglitazone on Lipids, Adipokines, and Inflammatory Markers in Nondiabetic Patients With Low High-Density Lipoprotein Cholesterol and Metabolic Syndrome

“…Thus, in patients with diabetes, rosiglitazone has a variety of effects that might reduce cardiovascular risk. Rosiglitazone has been shown to reduce the progression of carotid intimal-medial thickness, 11 and pioglitazone was recently shown to lower the incidence of the combined end point of death, myocardial infarction, and stroke in patients with diabetes. 12 A major question is whether these antiatherosclerotic effects of TZDs are secondary to favorable lipid effects or to other primary effects of PPAR-␥ activation.…”

A randomized, controlled trial of the effects of rosiglitazone on adipokines, and inflammatory and fibrinolytic markers in diabetic patients: Study design and protocol

“…In a 12-month study (27), treatment with rosiglitazone led to a significant beneficial effect on the progression of carotid intima-media thickness in people with type 2 diabetes mellitus. In another study (28), rosiglitazone reduced common carotid intima-media thickness progression in nondiabetic subjects with coronary artery disease.…”

“…As a nuclear peroxisome proliferatoractivated receptor-gamma agonist, rosiglitazone reduces insulin resistance, thereby sensitizing the liver, muscle and adipose tissue to the actions of circulating insulin (24). Treatment with rosiglitazone has been demonstrated to reduce coronary events following percutaneous coronary intervention (25,26) and to retard atherosclerosis disease progression (27,28). These effects have been, at least partially, attributed to the favourable effects of rosiglitazone on inflammatory biomarkers, insulin sensitivity and endothelial dysfunction (29)(30)(31)(32).…”