Vascular and metabolic effects of treatment of combined hyperlipidemia: focus on statins and fibrates

Abstract

Combined hyperlipidemia results from overproduction of hepatically synthesized apolipoprotein B in very low-density lipoproteins in association with reduced lipoprotein lipase activity. Thus, this condition is typically characterized by concurrent elevations in total cholesterol and triglycerides with decreased high-density lipoprotein cholesterol. High levels of apolipoprotein B-containing lipoproteins, most prominently carried by low-density lipoprotein (LDL) particles, are an important risk factor for coronary heart disease. Statin therapy is highly effective at lowering LDL cholesterol. Despite the benefits of statin treatment for lowering total and LDL cholesterol, many statin-treated patients still have initial or recurrent coronary heart disease events. In this regard, combined therapy with statins and fibrates is more effective in controlling atherogenic dyslipidemia in patients with combined hyperlipidemia than either drug alone. Furthermore, statins and fibrates activate PPARalpha in a synergistic manner providing a molecular rationale for combination treatment in coronary heart disease. Endothelial dysfunction associated with cardiovascular diseases may contribute to insulin resistance so that there may also be additional beneficial metabolic effects of combined statin/fibrates therapy. However, there has been little published evidence that combined therapy is synergistic or even better than monotherapy alone in clinical studies. Therefore, there is a great need to study the effects of combination therapy in patients. When statins are combined with gemfibrozil therapy, this is more likely to be accompanied by myopathy. However, this limitation is not observed when fenofibrate, bezafibrate, or ciprofibrate are used in combination therapy.

Fig. 1

Fenofibrate alone or combined therapy significantly lowered triglycerides and increased HDL cholesterol levels when compared with atorvastatin alone. Used with permission from Koh et al. [18].

Fig. 2

Percent change in flow-mediated dilation from respective pretreatment values after treatment with atorvastatin alone, combined therapy, and fenofibrate alone. Used with permission from Koh et al. [18].

Fig. 3

In experimental studies with endothelial cells in culture, many stimuli initiate transcription of genes that encode protein mediators of inflammation. Statins and fibrates may modulate this process by inhibiting the activation of nuclear transcription factors. Used with permission from Koh et al. [54,55].

Fig. 4

Percent change in adiponectin levels (left) and in QUICKI (Quantitative Insulin-Sensitivity Check Index, right) from respective pretreatment values after treatment with atorvastatin alone, combined therapy, and fenofibrate alone. Used with permission from Koh et al. [18].