Not All Fibrates Are Equal: Fenofibrate Demonstrates Clear Superiority in Reducing Residual Cardiovascular Risk, Atherosclerosis Study Finds

The review findings are published in December 2025 in the Journal Atherosclerosis.

Identifying and Measuring Residual Atherogenic Risk

Despite high-intensity statin therapy, a significant residual cardiovascular risk persists, especially in patients exhibiting atherogenic dyslipidemia (AD). AD is characterized by a triad of high triglyceride (TG)-rich lipoproteins (TRLs), an excess of small dense low-density lipoprotein (sdLDL) particles, and low high-density lipoprotein cholesterol (HDL-C) levels. Clinical evidence confirms that TRLs and their remnants are highly atherogenic, contributing substantially to ASCVD risk alongside LDL. In this context, Apolipoprotein B (apoB) is deemed a superior measure of this residual risk because it reflects the concentration of all atherogenic lipoproteins (LDL, TRL, remnants), each of which contains a single apoB molecule. Non-high-density lipoprotein cholesterol (non-HDL-C) is also considered a better and more comprehensive assessment of risk compared to LDL-C alone.

Fenofibrate’s Superiority in Targeting ApoB

Fibrates function as PPARα agonists and are known to effectively lower TRLs, TRL remnants, and sdLDL particles, while simultaneously increasing HDL-C. However, not all fibrates are interchangeable. The critical clinical difference lies in their impact on ApoB levels: Only fenofibrate appears to reduce ApoB when used alongside statins.

This molecular difference translates directly into clinical outcomes. For example, the PROMINENT trial, which tested the potent fibrate pemafibrate in high-risk T2DM patients already on statins, failed to reduce cardiovascular events. This disappointing result is attributed to pemafibrate’s unexpected increase in LDL-C (+12.3%) and ApoB (+4.8%), despite successfully lowering TG. Conversely, clinical trials and meta-analyses consistently show that the fenofibrate-statin combination reduces ApoB and non-HDL-C levels. Clinicians should also note that gemfibrozil is generally not recommended in combination with statins due to an increased risk of myopathy/rhabdomyolysis.

Clinical Efficacy in High-Risk Subgroups

While early fibrate outcome trials showed mixed results in overall populations, post-hoc and subgroup analyses strongly support the use of fenofibrate in specific, high-risk cohorts:

• Atherogenic Dyslipidemia: In the ACCORD-Lipid trial, the overall results were neutral, but in the crucial subgroup of patients with marked AD (TG >204 mg/dL and HDL-C <34 mg/dL), fenofibrate addition to statin therapy achieved a significant 31% reduction in the primary composite endpoint of CVD. Long-term follow-up confirmed significant CVD event reduction in patients with AD.

• Type 2 Diabetes and Metabolic Syndrome: Real-world studies, particularly in patients with T2DM and metabolic syndrome, provide further evidence that adding fenofibrate to statins improves cardiovascular outcomes, reduces events, and lowers mortality.

• Microvascular Benefits Beyond Lipid Lowering: Fenofibrate offers documented benefits beyond lipid lowering by reducing the progression of microvascular complications such as diabetic retinopathy and nephropathy through lipid-independent mechanisms.

Clinical Practice Implications

Fenofibrate stands out as the only fibrate that consistently lowers apoB and non-HDL-C—key drivers of atherogenic risk—making it the most clinically relevant option for patients with atherogenic dyslipidemia, diabetes, or metabolic syndrome (Met-S) when added to statin therapy. In contrast, other fibrates, including pemafibrate, fail to reduce apoB and therefore do not translate triglyceride lowering into cardiovascular benefit. These findings reinforce that fibrates are not interchangeable and that fenofibrate could be the preferred agent when targeting residual ASCVD risk.

Reference: Zambon A, Staels B, Farnier M, Vrablik M, Catapano AL. Not all fibrates are made equal: Learning from biology and clinical trials. Atherosclerosis. 2025 Oct 29:120555.