Gemfibrozil Reduces Plasma C-Reactive Protein Levels in Abdominally Obese Men With the Atherogenic Dyslipidemia of the Metabolic Syndrome
To the Editor:
Recent data from Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT) have recently reported that pharmacological treatment with a fibrate (gemfibrozil) significantly reduced coronary heart disease (CHD) risk among men with a history of CHD who had low HDL-cholesterol and LDL-cholesterol levels at baseline evaluation.1 Moreover, this study also demonstrated that changes in the lipoprotein-lipid profile only partially explained the beneficial effect of gemfibrozil on CHD risk, suggesting that other factors may be responsible for the reduction in the risk of CHD observed among patients undergoing fibrate therapy.2
On the other hand, the contribution of inflammation to the development of atherosclerosis and CHD is increasingly recognized, and recent studies have identified some inflammatory markers, such as plasma C-reactive protein (CRP) and cytokines, as CHD risk factors.3,4 ⇓ Recent data have suggested that statins and fibrates may favorably decrease markers of inflammation.5–8 ⇓ ⇓ ⇓
However, the effect of fibrates among abdominally obese men with the atherogenic dyslipidemia of the metabolic syndrome (a condition associated with markedly elevated inflammatory markers) has, to the best of our knowledge, never been reported. Thus, the aim of the present study was to examine the effect of a 6-month fibrate treatment on plasma CRP concentrations and cytokine levels such as interleukin (IL)-6 and tumor necrosis factor (TNF)-α in a sample of abdominally obese men with the atherogenic dyslipidemia of the metabolic syndrome.
Abdominally obese subjects (n=31 per treatment group) of the present study were asymptomatic volunteers who were between 25 and 55 years of age with a body mass index (BMI) between 27 and 40 kg/m2 and a waist-to-hip ratio ≥0.95, as previously described.9 Subjects received placebo or gemfibrozil (600 mg twice a day) for a period of 6 months. The study was approved by the Medical Ethics Committee of Laval University. Anthropometric as well as laboratory measurements were performed by using standardized techniques, as previously described.9 Measurement of CRP levels was obtained with a highly sensitive immunoassay which used a monoclonal antibody coated to polystyrene particles (hs-CRP) performed on the Behring BN-100 nephelometer (Dade Behring). Cytokine levels were measured with an immunoassay by using monoclonal antibodies specific for human TNF-α and IL-6.
Both treatment groups showed small but statistically significant reductions in weight, BMI, waist circumference, and visceral adipose tissue accumulation (P<0.05). Although decreases in total cholesterol and apolipoprotein B concentrations were significant for both groups after the 6-month period, the magnitude of changes was greater in the gemfibrozil group as compared with placebo (P<0.03). Moreover, significant changes in triglyceride (−1.08±0.89 mmol/L, P<0.0001; −36.8%) and HDL-cholesterol (+0.08±0.10 mmol/L, P<0.0001; +9.48%) levels as well as in the cholesterol/HDL-cholesterol ratio (−1.12±1.19, P<0.0001; −16.5%) were observed with only gemfibrozil treatment (P<0.0001).
The effects of 6-month placebo or gemfibrozil treatment on plasma CRP and TNF-α or IL-6 levels are shown in the Figure. Plasma CRP concentrations were significantly reduced by only gemfibrozil therapy (−32.7%) (2.58±1.99 vs 1.46±1.19 μg/mL, P<0.003 for baseline and follow-up values, respectively). Furthermore, the change in the gemfibrozil group was significantly greater than in the placebo arm (P<0.01). However, neither TNF-α nor IL-6 levels were significantly reduced by gemfibrozil therapy.
Atherosclerosis is recognized to have an inflammatory component. In that sense, plasma CRP levels have been found to be predictive of cardiac events,10 to be associated with elevated BMI and with a high abdominal fat accumulation10,11 ⇓ as well as to be related to the high triglyceride–low HDL-cholesterol dyslipidemia.10 Finally, plasma CRP has been reported to be significantly reduced by hypolipidemic drugs.5,7,8,12 ⇓ ⇓ ⇓
In this regard, studies have reported the beneficial effects of statin therapy on CRP levels.5,12 ⇓ Fibrates have also been shown not only to improve the high triglyceride–low HDL-cholesterol dyslipidemic state1,9,13 ⇓ ⇓ but also to reduce CHD risk1 and decrease plasma CRP levels.7,8 ⇓ In the present study, gemfibrozil treatment produced significant reductions in CRP levels. To the best of our knowledge, it is the first study to demonstrate that gemfibrozil therapy can favorably alter CRP concentrations among abdominally obese dyslipidemic patients with the features of the metabolic syndrome.
Circulating levels of TNF-α and IL-6 have been shown to stimulate the production of CRP.14 Accordingly, it has been demonstrated that bezafibrate therapy reduced the production capacity of these two cytokines as well as CRP concentrations.8 However, in the present study, gemfibrozil did not appear to affect the production of these cytokines, suggesting that this drug may rather alter the effect of IL-6 and TNF-α on CRP production. There are discrepancies in the literature regarding the impact of fibrates on CRP and cytokine levels and the type of patients as well as duration of trials may partly contribute to explain such differences.
In vitro studies have shown that fibrates have pleiotropic effects including the reduction of the inflammation process at the level of the vascular wall.15 Fibric acids such as gemfibrozil are PPARα ligands that inhibit the progressive formation of atherosclerosis lesions,15 which also involves the inflammatory component.16 Thus, fibrates may reduce/slow atherosclerosis development not only through their hypolipidemic properties but also by decreasing the inflammation of the vascular wall.17
In summary, these results suggest that the beneficial effect of gemfibrozil on plasma CRP levels could represent another mechanism by which fibric acids may favorably reduce CHD risk by improving the low chronic inflammation state of abdominally obese dyslipidemic patients with the atherogenic dyslipidemia of the metabolic syndrome. Moreover, this positive effect was not mediated by changes in the concentrations of some inflammatory cytokines potentially regulating the production of CRP. Whether this effect of gemfibrozil on CRP plays a role in explaining the favorable impact of this fibric acid on CHD events among low HDL-cholesterol patients with type 2 diabetes or the metabolic syndrome18 will require further studies.
This study was supported by Parke-Davis/Warner-Lambert Canada Inc. Jean-Pierre Després is chair professor of Human Nutrition, Lipidology and Prevention of Cardiovascular Disease, supported in part by Pfizer, Provigo and the Foundation of the Québec Heart Institute; Jean Bergeron is a clinical research scholar from the Fonds de la Recherche en Santé du Québec.
- ↵Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol: Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med. 1999; 341: 410–418.
- ↵Mendall MA, Patel P, Asante M, et al. Relation of serum cytokine concentrations to cardiovascular risk factors and coronary heart disease. Heart. 1997; 78: 273–277.
- ↵Ridker PM, Rifai N, Pfeffer M, et al. Elevation of tumor necrosis factor-alpha and increased risk of recurrent coronary events after myocardial infarction. Circulation. 2000; 101: 2149–2153.
- ↵Rezaie-Majd A, Maca T, Bucek RA, et al. Simvastatin reduces expression of cytokines interleukin-6, interleukin-8, and monocyte chemoattractant protein-1 in circulating monocytes from hypercholesterolemic patients. Arterioscler Thromb Vasc Biol. 2002; 22: 1194–1199.
- ↵Mendall MA, Patel P, Ballam L, Strachan D, Northfield TC. C reactive protein and its relation to cardiovascular risk factors: a population based cross sectional study. BMJ. 1996; 312: 1061–1065.
- ↵Lemieux I, Pascot A, Prud’homme D, et al. Elevated C-reactive protein: another component of the atherothrombotic profile of abdominal obesity. Arterioscler Thromb Vasc Biol. 2001; 21: 961–967.
- ↵Ridker PM, Rifai N, Pfeffer MA, Sacks F, Braunwald E. Long-term effects of pravastatin on plasma concentration of C-reactive protein: The Cholesterol and Recurrent Events (CARE) Investigators. Circulation. 1999; 100: 230–235.
- ↵Saku K, Gartside PS, Hynd BH, Kashyap ML. Mechanisms of action of gemfibrozil on lipoprotein metabolism. J Clin Invest. 1985; 75: 1702–1712.
- ↵Staels B, Dallongeville J, Auwerx J, et al. Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation. 1998; 98: 2088–2093.