There is a high prevalence of mixed dyslipidaemia among patients with metabolic syndrome or diabetes mellitus.¹ This highly atherogenic phenotype, characterised by increased low-density lipoprotein cholesterol (LDL-C), elevated triglycerides and low high-density lipoprotein cholesterol (HDL-C), is associated with an increased risk of coronary artery disease (CAD).^2,3 In addition, the predominance of small dense LDL (dLDL) particles further increases the atherogenic risk in these patients.⁴ Patients with elevated LDL-C who also have low HDL-C and elevated triglycerides are at greater risk of CAD than those with elevated LDL-C alone.⁵ Recognising this residual risk, the National Cholesterol Education Program Adult Treatment Panel (NCEP ATP III) guidelines recommend both LDL-C and non-HDL-C goals for high-risk patients.⁶

The majority of patients can achieve the NCEP ATP III goals with statin therapy alone.⁷ Statins are structural inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting enzyme for hepatic cholesterol biosynthesis that results in the upregulation of the LDL receptor and the lowering of LDL-C in the blood. Outcome trials of statins have proved conclusively that this class of drugs lowers LDL-C levels, resulting in a significant reduction of CV events in many high-risk patients.^8,9 Statins have also been shown to increase HDL and lower triglyceride levels. In addition, although of unknown clinical significance, statins have been reported to have effects independent of lipid-level alterations. These ‘pleiotropic’ effects include, among others, vasodilation, plaque stabilisation and antioxidant, anti-inflammatory and antithrombotic effects.¹⁰

The relation between LDL-C and CAD events appears to be linear, supporting the ‘lower is better’ hypothesis.¹¹ However, many patients have initial or recurrent coronary heart disease events despite aggressive reductions in LDL-C by statins.¹² Even with LDL-C levels at NCEP ATP III goals, there remains a residual risk for subsets of high-risk patients. For example, in the Treating to New Target (TNT) trial, patients taking atorvastatin 80mg (mean LDL-C level 77mg/dl) had a 28% CV event rate compared with a 33% event rate for patients taking atorvastatin 10mg (mean LDL-C level 101mg/dl), which is a 22% relative risk reduction.⁹ Therefore, approximately 70% of the events were not avoided even with significant LDL-C eduction.¹³ An important clinical challenge is to further reduce the residual CAD risk in patients taking optimal statin therapy without adversely affecting patient safety.

Fibrate therapy, which significantly decreases triglyceride levels and increases HDL-C without reducing LDL-C, is also associated with a reduction in CV events.¹⁴ Fibrates reduce the production of triglyceride-rich lipoproteins and increase the catabolism of triglycerides by the induction of lipoprotein lipase (LPL) and reduced expression of apolipoprotein C-III (apoC III) via activation of peroxisome proliferator activated receptor (PPAR)-alpha. The benefit of fibrate therapy on lipid profile in atherogenic dyslipidaemia was demonstrated in the Triglyceride Reduction in Metabolic Syndrome (TRIMS)¹⁵ study. After eight weeks of treatment with fenofibrate, favourable changes were noted in terms of decreased levels of non-HDL as well as increased levels of HDL. In addition, treatment with fenofibrate produced a shift towards larger LDL particle size.