Long-Term Effects of Fenofibrate on Carotid Intima-Media Thickness and Augmentation Index in Subjects With Type 2 Diabetes Mellitus

Hiukka, Anne; Westerbacka, Jukka; Leinonen, Eeva; Watanabe, Hiroshi; Wiklund, Olov; Hultén, L; Salonen, Jukka T.; Tuomainen, Tomi‐Pekka; Yki‐Järvinen, Hannele; Keech, Anthony; Taskinen, Marja‐Riitta

doi:10.1016/j.jacc.2008.09.049

Cited by 65 publications

(51 citation statements)

References 39 publications

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“…Although short-term fenofibrate therapy may improve endothelial function [136][137][138], a substudy of the longer-term FIELD (Fenofibrate Intervention and Event Lowering in Diabetes) study was not associated with beneficial changes in carotid intima-media thickness, augmentation index, or biomarkers of endothelial function in T2D patients [144]. However, the FIELD study subjects were mostly low risk (as evidenced by the low CVD event rate), and were not selected for having ED at baseline.…”

Section: Lipid-regulating Therapymentioning

confidence: 99%

Endothelial Dysfunction in Diabetes: Pathogenesis, Significance, and Treatment

2013

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■ AbstractType 2 diabetes (T2D) markedly increases the risk of cardiovascular disease. Endothelial dysfunction (ED), an early indicator of diabetic vascular disease, is common in T2D and independently predicts cardiovascular risk. Although the precise pathogenic mechanisms for ED in T2D remain unclear, at inception they probably involve uncoupling of both endothelial nitric oxide synthase activity and mitochondrial oxidative phosphorylation, as well as the activation of vascular nicotinamide adenine dinucleotide phosphate oxidase. The major contributing factors include dyslipoproteinemia, oxidative stress, and inflammation. Therapeutic interventions are designed to target these pathophysiological factors that underlie ED. Therapeutic interventions, including lifestyle changes, antiglycemic agents and lipid-regulating therapies, aim to correct hyperglycemia and atherogenic dyslipidemia and to improve ED. However, high residual cardiovascular risk is seen in both research and clinical practice settings. Well-designed studies of endothelial function in appropriately selected volunteers afford a good opportunity to test new therapeutic interventions, paving the way for clinical trials and utilization in the care of the diabetic patient. However, based on the results from a recent clinical trial, niacin should not be added to a statin in individuals with low high-density lipoprotein cholesterol and very well controlled low-density lipoprotein cholesterol.

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Section: Lipid-regulating Therapymentioning

confidence: 99%

Endothelial Dysfunction in Diabetes: Pathogenesis, Significance, and Treatment

2013

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“…[13][14][15][16] Furthermore, in a previous cIMT trial with fenofibrate, as a subset of the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial, there were no significant improvements in cIMT progression in 170 patients with diabetes mellitus. 17 The design of this trial was criticized for the relatively small sample size and for not selecting the subgroup of patients with hypertriglyceridemia that are most likely to be treated with a fibrate, and who ultimately seemed to experience improved clinical outcomes in the main FIELD study.…”

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confidence: 99%

Effects of Fenofibric Acid on Carotid Intima-Media Thickness in Patients With Mixed Dyslipidemia on Atorvastatin Therapy

Davidson

Rosenson

Maki

et al. 2014

ATVB

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Objective-To assess whether adding a fibrate to statin therapy reduces residual cardiovascular risk associated with elevated triglycerides and low high-density lipoprotein cholesterol, were randomized to FA 135 mg or placebo. The primary end point was rate of change from baseline through week 104 of the mean posterior-wall cIMT, measured by ultrasound. In patients with controlled low-density lipoprotein cholesterol while on atorvastatin background therapy, rate of change in posterior-wall cIMT was similar with FA plus atorvastatin (−0.006 mm/y) versus atorvastatin monotherapy (0.000 mm/y; P=0.22). FA plus atorvastatin was favored (P<0.05) in 5 of 24 prespecified subgroups: age ≥60 years, history of coronary artery disease, cIMT >0.795 mm, triglycerides 170 to 235 mg/dL, and statin use at entry. Adverse events were consistent with the known safety profiles of both drugs; however, FA plus atorvastatin was associated with a greater incidence of renal-related adverse events compared with atorvastatin monotherapy (6.5% versus 0.9%). Conclusions-Compared

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“…8,9 LDL-C-lowering statin drugs that are effective in reducing CHD also reduced progression of CIMT in proportion to the degree of LDL-C lowering. [10][11][12] However, interventions developed so far that reduce TGs or raise HDL-C have shown inconsistent effects on CIMT, [13][14][15] making it uncertain whether the specific agents are ineffective for CHD prevention, whether these 2 lipid fractions, in general, are not causally related to CHD and, therefore, invalid targets, or whether CIMT is an inadequate marker of HDL-C or TG-mediated effects on CHD risk.…”

mentioning

confidence: 99%

Causal Relevance of Blood Lipid Fractions in the Development of Carotid Atherosclerosis

Shah

Casas

Drenos

et al. 2013

Circ Cardiovasc Genet

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Background— Carotid intima–media thickness (CIMT), a subclinical measure of atherosclerosis, is associated with risk of coronary heart disease events. Statins reduce progression of CIMT and coronary heart disease risk in proportion to the reduction in low-density lipoprotein cholesterol. However, interventions targeting triglycerides (TGs) or high-density lipoprotein cholesterol (HDL-C) have produced inconsistent effects on CIMT and coronary heart disease risk, making it uncertain whether such agents are ineffective for coronary heart disease prevention or whether CIMT is an inadequate marker of HDL-C or TG-mediated effects. We aimed to determine the causal association among the 3 major blood lipid fractions and common CIMT using mendelian randomization analysis. Methods and Results— Genetic scores specific for low-density lipoprotein cholesterol, HDL-C, and TGs were derived based on single nucleotide polymorphisms from a gene-centric array in ≈5000 individuals (Cardiochip scores) and from a genome-wide association meta-analysis in >100 000 individuals (Global Lipids Genetic Consortium scores). These were used as instruments in a mendelian randomization analysis in 2 prospective cohort studies. A genetically predicted 1 mmol/L higher low-density lipoprotein cholesterol concentration was associated with a higher common CIMT by 0.03 mm (95% confidence interval, 0.01–0.04) and 0.04 mm (95% confidence interval, 0.02–0.06) based on the Cardiochip and Global Lipids Genetic Consortium scores, respectively. HDL-C and TGs were not causally associated with CIMT. Conclusions— Our findings confirm a causal relationship between low-density lipoprotein cholesterol and CIMT but not with HDL-C and TGs. At present, the suitability of CIMT as a surrogate marker in trials of cardiovascular therapies targeting HDL-C and TGs is questionable and requires further study.

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Long-Term Effects of Fenofibrate on Carotid Intima-Media Thickness and Augmentation Index in Subjects With Type 2 Diabetes Mellitus

Abstract: Fenofibrate treatment was not associated with beneficial changes in IMT, augmentation index, or biomarkers of inflammation and endothelial function. (Fenofibrate Intervention and Event Lowering in Diabetes; NCT00132886).

Cited by 65 publications

References 39 publications

Endothelial Dysfunction in Diabetes: Pathogenesis, Significance, and Treatment

Endothelial Dysfunction in Diabetes: Pathogenesis, Significance, and Treatment

Effects of Fenofibric Acid on Carotid Intima-Media Thickness in Patients With Mixed Dyslipidemia on Atorvastatin Therapy

Causal Relevance of Blood Lipid Fractions in the Development of Carotid Atherosclerosis

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