Pharmacological regulation of lipid metabolism in patients with dyslipidaemia is undeniably associated with significant reductions in risk of cardiovascular (CV) morbidity and mortality. There are strong clinical trial data to support the use of lipid-lowering therapies in the settings of both primary and secondary prevention. Statins and fibrates are two classes of drug that have demonstrated significantly reduced CV event rates in prospective, placebo-controlled clinical trials. However, monotherapy with either of these drugs does not always achieve lipid goals in the dyslipidaemic patient. Furthermore, even in those patients who do achieve lipid goals with monotherapy there often remains a high residual risk of CV events, warranting even further therapy. An effective therapeutic approach for many of these patients is combination therapy with statins and fibrates.
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 reduction.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.
Fibrates also change the relative proportions of LDL subfractions, markedly shifting the profile towards a less dense LDL. Studies comparing lipid-lowering therapies have shown that while atorvastatin reduces all LDL subfractions, fenofibrate reduces LDL density.16 This is due to a more pronounced reduction of the most dense LDL fraction (LDL-6) by fenofibrate compared with atorvastatin.17 In the Diabetes Atherosclerosis Intervention Study (DAIS),18 fenofibrate reduced the rate of CAD progression in subjects with type 2 diabetes. Multivariate analysis demonstrated that LDL particle size was an independent predictor of the degree of disease progression in models containing LDL-C and apoB.
Recognising that statin and fibrate therapies affect different aspects of lipoprotein metabolism, combination therapy with these two classes of drug is emerging as a possible therapeutic approach for many high-risk patients, especially those with atherogenic dyslipidaemia. The additive effects of statin–fibrate combinations on lipid profiles have been documented. The atorvastatin–fenofibrate combination has been shown to have a highly beneficial effect on lipid parameters in patients with type 2 diabetes and combined hyperlipidaemia (CHL).19 A total of 120 diabetes and CHL patients who were free of CAD were randomly assigned to atorvastatin 20mg/day, micronised fenofibrate 200mg/day or a combination of both. The atorvastatin–fenofibrate combination reduced total cholesterol by 37%, LDL-C by 46% and triglycerides by 50%, and increased HDL-C by 22%. These changes were significantly better than those of both monotherapies. The additive effects of simvastatin and fenofibrate on lipid parameters have been documented in the Simvastatin Plus Fenofibrate for Combined Hyperlipidemia (SAFARI) trial.20 Simvastatin monotherapy (20mg/day) was compared with combination therapy (simvastatin 20mg/day plus fenofibrate 160mg/day) in patients with CHL. The mean LDL levels were significantly decreased with combination therapy compared with monotherapy (31.2 and 25.8%, respectively; p<0.001). In addition, mean HDL-C levels significantly increased with combination therapy compared with monotherapy (18.6 and 9.7%, respectively; p<0.001).
Historically, however, fibrate–statin combination therapy has been a source of safety concerns. In the NEPTUNE survey,21 25% of patients receiving treatment for dyslipidaemia had triglyceride levels >200mg/dl. Only 27% of patients with hypertriglyceridaemia and CAD had achieved their non-HDL treatment goals. In addition, only 5% of those surveyed were receiving combination antilipidaemic therapy. The major reason that combination therapy with fibrates is seldom clinically used is the perception of adverse safety associated with combining a statin and a fibrate. Although there is an increase in reports of rhabdomyolysis with statin–fibrate combined therapy, this risk appears to be about 15 times higher for gemfibrozil than for fenofibrate when used with statins.13 Data from the several recent trials suggest that combining fenofibrate with statins does not significantly increase the risk of myopathy.19,20
As evidence for the safety and efficacy of statin–fibrate combination therapy continues to emerge, combination tablets are being developed as a fixed-dose single pill that will target high LDL, low HDL and high triglycerides. A fixed-dose tablet combining atorvastatin 40mg with low-dose fenofibrate 100mg (LCP-AtorFen) is currently in clinical development.22 The phase I study has already demonstrated safety, and recently the phase II study was announced, although it has not yet been published. The phase II trial compared LCP-AtorFen with atorvastatin 40mg and fenofibrate 145mg in approximately 200 patients with mixed dyslipidaemia over 12 weeks. LCP-AtorFen was found to be significantly more effective than atorvastatin in lowering triglycerides and raising HDL. In addition, LCP-AtorFen was significantly more effective than fenofibrate in lowering triglycerides and LDL. Another combination of fenofibric acid and rosuvastatin is in clinical development for the treatment of dyslipidaemia. Fenofibric acid (ABT-335) 135mg has previously been studied in combination with simvastatin, atorvastatin and rosuvastatin. These trials have been submitted for regulatory approval to receive an indication for combination of a fibrate with statin treatment.
An outcome trial with statin–fibrate therapy has yet to be completed. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial23 is comparing the efficacy of statin monotherapy with that of a fibrate–statin combination therapy in 5,800 patients with diabetes mellitus. This trial is expected to be completed by 2009 and will establish whether or not therapy with this combination leads to a greater reduction in the risk of CV morbidity and mortality than therapy with a statin alone.