Low-Density Lipoprotein and High-Density Lipoprotein Particle Subclasses Predict Coronary Events and Are Favorably Changed by Gemfibrozil Therapy in the Veterans Affairs High-Density Lipoprotein Intervention Trial

This MESA sub-study used NMR spectroscopy to measure LDL particle number (LDL-P) and compared its predictive value for incident cardiovascular events with LDL cholesterol (LDL-C) concentration in 6,814 participants free of cardiovascular disease at baseline.

When LDL-P and LDL-C were discordant — meaning they did not rank patients in the same cardiovascular risk order — LDL-P was the superior predictor. Patients with high LDL-P but low-to-normal LDL-C had significantly higher event rates than their LDL-C measurement would suggest. Conversely, patients with low LDL-P but elevated LDL-C were at lower risk than LDL-C alone predicted.

The LDL-P/LDL-C discordance phenomenon is most common in patients with metabolic syndrome, insulin resistance, or hypertriglyceridemia. In these patients, small, dense LDL particles are abundant — each carrying less cholesterol per particle, so LDL-C understates the true atherogenic particle burden. Measuring LDL-P (or its proxy, apolipoprotein B) captures this risk that LDL-C misses.

The clinical implication is that when standard risk factors underpredict risk — particularly in patients with metabolic syndrome — adding LDL-P or apoB measurement reclassifies patients who would otherwise be undertreated.

We rate the evidence moderate. A well-analyzed MESA cohort study establishing LDL particle number as a superior predictor over LDL-C when the two are discordant — supporting broader use of advanced lipoprotein testing in specific patient populations.