Fenofibric acid: a new fibrate approved for use in combination with statin for the treatment of mixed dyslipidemia

Abstract

The last two to three decades have seen an explosive growth in interest and information regarding cardiovascular disease (CVD) risk assessment and treatment. Evidence for the role of low-density lipoprotein (LDL) in risk has led to a series of clinical guidelines/recommendations on the importance of LDL lowering with statin treatment. There is also substantial evidence on a number of lipoproteins in the initiation and progression of atherosclerosis and CV events. Health care professionals have not embraced easily novel approaches to identifying those at increased risk and more aggressive treatment. This is especially true for non-LDL factors. The use of non-statin drugs such as fibrates has been modest and many health care professionals avoid consideration of combination therapy due to an inordinate fear of toxicity. This review will attempt to provide appropriate background information on lipids/lipoproteins, including non-high density lipoprotein and risk, as well as data available on fibrates and combination pharmacologic therapy. We will review a new agent, TriLipix((R)) (fenofibric acid), and its potential role in treatment.

Keywords: TriLipix; dyslipidemia; fenofibric acid; fibrate; non-high density lipoprotein; peroxisome proliferated activated receptors; triglycerides; very-low-density lipoprotein.

Figure 1

The neutral or non-polar plasma lipids.

Figure 2

Apo B lipoprotein with neutral lipids contained in the core. Reproduced with permission from Koschinsky ML, Marcovina SM. In: Ballantyne, CM, editor. Clinical Lipidology: A Companion to Braunwald’s Heart Disease. Philadelphia: Saunders Elsevier; 2009:130–143. Copyright © 2009 Elsevier.

Figure 3

Increases in triglycerides associated with increases in CHD risk: a meta-analysis of 17 prospective studies. Notes: For every increase in serum TG level of 89 mg/dL, the risk of CHD increases 32% in men and 76% in women. The 17 prospective studies reporting association between elevated TG and CV endpoints included 46,413 men with 2445 events (average follow-up 8.4 years) and 10,864 women with 439 CV events (average follow-up 11.4 years). Abbreviations: CHD, coronary heart disease; CV, cardiovascular; TG, triglycerides.

Figure 4

Prevalence of dyslipidemias in men <60 years with angiographic evidence of coronary atherosclerosis. Drawn from data of Genest et al. Notes: This figure reveals a variety of lipid/lipoprotein abnormalities in patients with premature coronary artery disease. Significantly elevated plasma LDL is not commonly seen. Abbreviations: HDL, high-density lipoprotein; LDL, low-density lipoprotein; Lp(a), lipoprotein a; TG, triglycerides.

Figure 5

The average RRR for CV events in the secondary population even in the most intensive statin studies is 30%. This leaves significant residual risk for recurrent events. Superko and King compared a variety of studies utilizing LDL lowering versus LDL lowering and HDL elevation. This latter combined approach resulted in projected RRR of 71% to 6% with a NNT of 9.6 overall and 3.4/year. Abbreviations: CV, cardiovascular; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; Lp(a), lipoprotein a; NNT, number needed to treate; RRR, relative risk reduction; TG, triglycerides.

Figure 6

Residual CVD risk in patients treated with intensive statin therapy. A closer look at 3 trials investigating intensive LDL-C lowering with statin therapy in patients with CHD revealed that residual CVD risk remains in these patients even after aggressive LDL cholesterol lowering therapy. All 3 trials compared LDL-C lowering to ∼100 mg/dL with more intensive LDL-C lowering to ∼70 mg/dL as a means of preventing major CVD events in patients with a history of CHD or acute coronary syndromes. In the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) study (N = 4162), pravastatin 40 mg reduced LDL-C to 95 mg/dL and atorvastatin 80 mg reduced LDL-C to 62 mg/dL in patients who had been hospitalized for an acute coronary syndrome. After 2 years, 22.4% of patients treated with intensive statin therapy (atorvastatin 80 mg/dL) suffered a major CVD event. In the Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) study (N = 8888), simvastatin 20 mg reduced LDL-C to 104 mg/dL and atorvastatin 80 mg reduced LDL-C to 81 mg/dL in patients with a history of acute myocardial infarction. After 4.8 years, 12.0% of patients experienced a major CVD event even after intensive LDL-C lowering with statin therapy (atorvastatin 80 mg). Finally, in the Treating to New Targets (TNT) study (N = 10,001), 10 mg atorvastatin reduced LDL-C to 101 mg/dL and 80 mg atorvastatin reduced LDL-C to 77 mg/dL in patients with stable CHD. After 4.9 years, a major CVD event occurred in 8.7% of patients receiving intensive statin therapy (80 mg atorvastatin). These 3 trials reveal that significant residual CVD risk remains in patients even after intensive statin treatment. Abbreviations: CVD, cardiovascular disease; CHD, coronary heart disease; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol.

Figure 7

Structure and metabolic pathway for fenofibrate and fenofibric acid (TriLipix) in humans.