How does fenofibrate (Fenofiber) lower triglycerides?

From the Guidelines

Fenofibrate lowers triglycerides by activating peroxisome proliferator-activated receptor alpha (PPAR-α) in the liver, which increases the breakdown of triglyceride-rich particles and enhances the production of high-density lipoprotein (HDL), or "good" cholesterol. This mechanism of action is supported by the FIELD trial, which demonstrated a 19% reduction in total cardiovascular events in patients with type 2 diabetes mellitus treated with fenofibrate 1. The activation of PPAR-α by fenofibrate stimulates the enzyme lipoprotein lipase, which helps clear triglycerides from the bloodstream, while simultaneously reducing the liver's production of very low-density lipoprotein (VLDL), a major carrier of triglycerides. Some key points to consider when using fenofibrate to lower triglycerides include:

• Typical dosing ranges from 48 mg to 145 mg daily, with the medication usually taken once daily with food.
• Patients may see triglyceride reductions of 20-50% within several weeks of starting treatment.
• For best results, fenofibrate should be combined with lifestyle modifications including a low-fat diet, regular exercise, weight management, and limiting alcohol consumption.
• Common side effects include digestive issues, muscle pain, and potential liver enzyme elevations, so regular monitoring of liver function is recommended during treatment, as noted in the 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults 2. It is also important to evaluate renal status before initiating fenofibrate, as it should not be used in patients with moderate or severe renal impairment, defined as eGFR <30 mL/min per 1.73 m2 2. Overall, fenofibrate is a useful medication for lowering triglycerides, particularly in patients with high triglycerides and low HDL-C, especially when the patients have diabetes or characteristics of the metabolic syndrome, as supported by the FIELD trial and other studies 1, 3.

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)

Fenofibrate lowers triglycerides by activating lipoprotein lipase and reducing production of apoprotein C-III, which leads to increased lipolysis and elimination of triglyceride-rich particles from plasma, through the activation of peroxisome proliferator activated receptor α (PPARα) 4.

From the Research

Mechanism of Fenofibrate in Lowering Triglycerides

• Fenofibrate is a lipid-regulating drug that produces substantial reductions in plasma triglyceride levels in hypertriglyceridaemic patients 5.
• The drug has been shown to decrease triglycerides by 29% in patients with hypertriglyceridemia, and also improves flow-mediated dilation 6.
• Fenofibrate therapy has been found to decrease total cholesterol, triglycerides, and triglycerides/HDL-cholesterol, while increasing HDL cholesterol and apolipoprotein AI 6.
• The optimal dose of fenofibrate for lowering triglycerides has been found to be 400 mg/day, which reduces elevated VLDL-TG by 65% in type IIB + IV patients 7.

Comparison with Other Treatments

• Fenofibrate has been compared with omega-3 fatty acids in patients with hypertriglyceridemia, and has been found to have better effects on lipoprotein and metabolic profiles 6.
• Fenofibrate has also been compared with clofibrate, and has been found to have higher HDL-cholesterol in type IIA, lower LDL-cholesterol in type IIB, and lower TG and cholesterol in both VLDL and LDL in type IV patients 7.
• Combination therapy of omega-3 fatty acids and fenofibrate has been found to decrease triglycerides by 41% and triglycerides/HDL cholesterol ratio by 45% in patients with hypertriglyceridemia 8.

Effects on Glycemic Control and Insulin Sensitivity

• Fenofibrate treatment has been found to be associated with better glycemic control and lower serum leptin and insulin levels in type 2 diabetic patients with hypertriglyceridemia 9.
• Fenofibrate therapy has been found to decrease fasting insulin and increase plasma adiponectin and insulin sensitivity in patients with hypertriglyceridemia 6.
• Combination therapy of omega-3 fatty acids and fenofibrate has been found to reduce insulin and glucose and improve insulin sensitivity in patients with hypertriglyceridemia 8.