Fenofibrate and pioglitazone improve endothelial function and reduce arterial stiffness in obese glucose tolerant men

Abstract

Obesity is a low grade inflammatory state associated with premature cardiovascular morbidity and mortality. Along with traditional risk factors the measurement of endothelial function, insulin resistance, inflammation and arterial stiffness may contribute to the assessment of cardiovascular risk.

We conducted a randomised placebo controlled trial to assess the effects of 12 weeks treatment with a PPARα agonist (fenofibrate) and a PPARγ agonist (pioglitazone) on these parameters in obese glucose tolerant men. Arterial stiffness was measured using augmentation index and pulse wave velocity (PWV). E-selectin, VCAM-1 and ICAM-1 were used as markers of endothelial function.

Insulin sensitivity improved with pioglitazone treatment (p = 0.001) and, in keeping with this, adiponectin increased by 85.2% (p < 0.001). Pro-inflammatory cytokine levels (TNFα, IL-6 and IL-1β) fell with both treatments (p < 0.01 for TNFα and IL-1β, p < 0.001 for IL-6). VCAM-1 and ICAM-1 were reduced with both treatments (p < 0.001 for VCAM-1, p < 0.05 for ICAM-1) and E-selectin improved with pioglitazone treatment (p = 0.05). Both treatments resulted in a fall in augmentation index. PWV fell by 17.4% with fenofibrate treatment (p < 0.001) and 16.3% with pioglitazone treatment (p < 0.001).

Pioglitazone and fenofibrate treatment of obese, glucose tolerant men reduces inflammation, improves markers of endothelial function and reduces arterial stiffness. These results suggest that treatment with PPAR agonists has potential to reduce the incidence of premature cardiovascular disease associated with obesity.

Introduction

Obesity is associated with premature cardiovascular morbidity and mortality. Although management of traditional risk factors is a key element in primary prevention it is suggested that up to 20% of cardiovascular events are not predicted by the information used in the Framingham coronary risk score [1]. Novel risk factors which may provide additional information to assess the probability of a vascular event include those related to endothelial dysfunction and markers of inflammation [2].

The intact endothelium provides a physical barrier, balances thrombosis and fibrinolysis and regulates vascular tone through the secretion of vasoactive mediators which influence vascular smooth muscle contraction. Endothelial dysfunction appears to occur early in atherosclerosis and can be detected before there is clinical evidence of vascular disease [3]. The adhesion of leucocytes to the endothelium is important in the early development of atherosclerotic plaques and endothelial cell expression of adhesion molecules promotes recruitment of leucocytes at this site. Endothelial function may be assessed by quantifying plasma levels of endothelial products such as soluble forms of these adhesion molecules shed into the plasma from activated endothelial cells. Plasma levels of VCAM-1, ICAM-1 and E-selectin are increased in patients with cardiovascular disease [4]. Early changes in the endothelium affect the rate at which the pulse wave is propagated and also result in an altered waveform related to arterial reactivity (‘stiffness’).

Measurement of arterial stiffness may be used as a functional measure of the vasculature in order to estimate the risk of cardiovascular events. Arterial stiffness, which is predictive of vascular disease outcomes, can be measured by analysis of the arterial waveform to determine the pulse wave velocity (PWV) and augmentation index [5]. Increased augmentation index is associated with both all-cause and cardiovascular mortality in patients with end stage renal failure [6], while a PWV greater than 13 m/s has been demonstrated to be a strong predictor of cardiovascular mortality in hypertension [7]. Its assessment will therefore be useful in obese patients both to identify individuals at high risk of cardiovascular disease and indicate if intervention has been beneficial.

Inflammation is central to the pathophysiology of atherosclerosis and is also thought to have a role in inducing insulin resistance. Adipose tissue is a source of inflammatory cytokines and in particular TNFα and IL-6; the levels of inflammatory markers may relate to adipose tissue mass [8] and potentially contribute to both the increased risk of cardiovascular disease and insulin resistance observed in obesity. By contrast increased levels of adiponectin, another cytokine derived from adipose tissue, are associated with insulin sensitivity; there is a tendency for lower levels of adiponectin in obesity [9]. The measurement of inflammatory markers, endothelial-derived adhesion molecules and arterial stiffness provides an assessment of cardiovascular risk which can be used to indicate response to treatment.

Obesity is associated with the metabolic syndrome and therefore dyslipidaemia and insulin resistance. PPARα ligands are established agents in the management of hypertriglyceridaemia but may have additional effects on the arterial wall which could improve cardiovascular outcome [10]. PPARγ ligands were developed to improve insulin sensitivity however they demonstrate additional properties which suggest that they also could reduce cardiovascular risk in the metabolic syndrome [10]. This study was performed to assess the impact of PPARα and PPARγ agonists on novel cardiovascular risk factors associated with obesity.