What are the effects of Fenofibrates (Fibric acid derivatives)?

From the Guidelines

Fenofibrates are effective in reducing triglyceride levels and increasing HDL cholesterol levels, but their use should be carefully considered due to potential risks, particularly when combined with statins, as evidenced by the 2013 ACC/AHA guideline 1. The primary use of fenofibrates is to lower elevated triglyceride levels in the blood and increase HDL ("good") cholesterol levels. They work by activating peroxisome proliferator-activated receptor alpha (PPAR-α), which enhances the breakdown of triglyceride-rich particles and reduces their production in the liver. Some key points to consider when prescribing fenofibrates include:

• Typical dosing ranges from 48-200 mg daily, depending on the specific formulation, as noted in the example answer.
• Fenofibrates are most effective for patients with severe hypertriglyceridemia (triglycerides >500 mg/dL) and are often prescribed alongside lifestyle modifications, including diet changes and exercise, as seen in the FIELD trial 1.
• Common side effects include muscle pain, liver function abnormalities, and gastrointestinal disturbances.
• Patients with kidney disease typically require dose adjustments, and fenofibrates may interact with certain medications, including statins (increasing risk of muscle damage) and warfarin (potentially enhancing its anticoagulant effect), as highlighted in the 2013 ACC/AHA guideline 1.
• Regular monitoring of liver enzymes, kidney function, and blood lipid levels is recommended during treatment. It is essential to weigh the benefits and risks of fenofibrate therapy, particularly in patients with kidney disease or those taking statins, as the 2013 ACC/AHA guideline recommends that fenofibrate may be considered concomitantly with a low- or moderate-intensity statin only if the benefits from ASCVD risk reduction or triglyceride lowering outweigh the potential risk for adverse effects 1.

From the FDA Drug Label

The lipid-modifying effects of fenofibric acid seen in clinical practice have been explained in vivo in transgenic mice and in vitro in human hepatocyte cultures by the activation of peroxisome proliferator activated receptor α (PPARα) Through this mechanism, fenofibrate increases lipolysis and elimination of triglyceride-rich particles from plasma by activating lipoprotein lipase and reducing production of apoprotein C-III (an inhibitor of lipoprotein lipase activity) The resulting decrease in TG produces an alteration in the size and composition of LDL from small, dense particles (which are thought to be atherogenic due to their susceptibility to oxidation), to large buoyant particles. These larger particles have a greater affinity for cholesterol receptors and are catabolized rapidly Activation of PPARα also induces an increase in the synthesis of apolipoproteins A-I, A-II and HDL-cholesterol. Fenofibrate also reduces serum uric acid levels in hyperuricemic and normal individuals by increasing the urinary excretion of uric acid.

The effects of Fenofibrates (Fibric acid derivatives) are:

• Lipid modification: increases lipolysis and elimination of triglyceride-rich particles from plasma
• LDL modification: alters the size and composition of LDL from small, dense particles to large buoyant particles
• HDL increase: induces an increase in the synthesis of apolipoproteins A-I, A-II and HDL-cholesterol
• Uric acid reduction: reduces serum uric acid levels by increasing the urinary excretion of uric acid
• Triglyceride reduction: produces reductions in total triglycerides and triglyceride rich lipoprotein (VLDL) in treated patients 2 2 2

From the Research

Effects of Fenofibrates on Lipid Profiles

• Fenofibrates have been shown to decrease triglyceride (TG) levels, increase high-density lipoprotein cholesterol (HDL-C) levels, and reduce low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) levels in patients with dyslipidemia 3, 4, 5, 6.
• The magnitude of the effect of fenofibrates on lipid profiles varies depending on the patient's baseline lipid levels, with greater effects seen in patients with high triglyceride levels or atherogenic dyslipidemia profile 7.
• Fenofibrates have been shown to shift low-density lipoprotein particles from small, dense particles to larger, more buoyant particles, which may contribute to their clinical efficacy 4, 6.

Effects of Fenofibrates on Cardiovascular Risk

• Fenofibrates have been shown to reduce the risk of major cardiovascular events, particularly in patients with high triglyceride levels or atherogenic dyslipidemia profile 4, 6, 7.
• The FIELD trial found that fenofibrate reduced the risk of total cardiovascular disease events, primarily through the prevention of non-fatal myocardial infarction and coronary revascularisation 4, 6.
• Subgroup analyses have suggested that fenofibrates may have a greater effect on cardiovascular risk in patients with no previous cardiovascular disease, suggesting a potential role for primary prevention with fenofibrates in patients with early type 2 diabetes 6.

Safety and Tolerability of Fenofibrates

• Fenofibrates are generally well tolerated, with common adverse events including increases in transaminase levels, gastrointestinal signs and symptoms, and minor, asymptomatic changes in laboratory parameters 4, 5, 6.
• Combination therapy with fenofibrates and statins appears to be associated with a low risk of rhabdomyolysis, with no cases reported in the FIELD trial 6.