Population data indicate that at a TG value of 200mg/dl, the prevalence of subclass B is ~75% and when the TG is 100mg/dl, the prevalence of subclass B is ~18%.¹⁰ The threshold model would suggest that TG lowering will not substantially alter LDL subclass distribution if the TG level remains above the individual’s threshold for conversion from pattern B to pattern A. In our study, by pairing fenofibrate-treated subjects with on-treatment TG values <200 or ≥200mg/dl, we were able to isolate the influences of the TG value achieved from the degree of TG lowering.

The subset of patients with end-of-treatment TG ≥200mg/dl showed no increase in LDL particle diameter despite a median decline of >50% from baseline in TG concentration. In addition, very little increase in LDL particle diameter was observed in subjects with end-of-treatment TG values <200mg/dl in the absence of a conversion to LDL subclass pattern A. These results support the threshold model and go some way to explain the findings of the recently published Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, which failed to reach its primary end-point of reducing coronary heart disease events in patients with type 2 diabetes.

The median baseline TG concentration in the FIELD study was approximately 153mg/dl, suggesting that a substantial proportion of the study sample may have had TG levels below the threshold for conversion to LDL subclass pattern B. To date, no data on LDL subclass distribution have been published from the FIELD study.However, results from previous outcomes studies have suggested that the greatest risk reduction with fibrate therapy occurs in subjects with TG >200mg/dl or 2.3mmol/l.^9,11-13

One potential explanation for the greater risk reduction in those with hypertriglyceridemia, and for the failure of the FIELD study to demonstrate a reduction in risk for the primary outcome, is that the greatest benefit of fibrate therapy accrues to subjects in whom treatment induces a shift from LDL subclass pattern B to pattern A. For many patients with high or very high TG concentrations, a single agent will not reduce the TG level to a degree sufficient to induce a shift in LDL subclass distribution pattern. What is needed is a target TG level approach in the clinic. In a recent national survey of lipid management in clinical practice, 25% of patients receiving treatment for dyslipidemia had an on-treatment TG concentration ≥200mg/dl.¹⁴