Hypertriglyceridemia and the fibrate trials

Epidemiological studies published since 1996 have established that hypertri glyceridemia can predict risk of cardiovascular disease in a manner statist ically independent of HDL cholesterol. Nevertheless, the relationship of co ncentrations of plasma triglycerides to risk of cardiovascular disease rema ins less than straightforward, partly because triglycerides are carried in lipoproteins of different atherogenicity, partly because hypertriglyceridem ia is associated with non-lipid atherogenic and thrombogenic processes, For example, the association of highest risk of cardiovascular disease to mode rate rather than to severe hypertriglyceridemia can be understood in terms of the distribution of triglycerides between different classes of plasma li poproteins. It is counter-intuitive to most clinicians, however, and hence it can result in the misdirection of clinical efforts including drug therap y. Fibrates lower plasma triglycerides, and raise HDL, efficiently and with fe w immediate side-effects. Central to their mode of action is activation of certain nuclear receptors in cells. There is no necessary connection, howev er, between that fascinating biochemistry and clinical benefit as defined b y reductions in rates of death by coronary artery disease, A review of tria ls of cholesterol-lowering by diet and drugs, published between 1966 and 19 96, included 12 trials of therapy with fibrates or placebo in more than 21 000 patients. Overall, these trials indicated no benefit in terms of reduct ion in risk of coronary deaths. The period since 1996 has seen the publicat ion of four additional trials of treatment of 6144 patients with fibrates o r placebo. Two of them were major trials. The VA-HIT was very encouraging, because treatment with gemfibrozil produced a significant reduction in the combined incidence of fatal and non-fatal coronary events. There was no sig nificant reduction in coronary deaths, however. The results of BIP were fra nkly disappointing, because they demonstrated no significant effect of trea tment with bezafibrate on either the primary end-point of the trial or on r ates of coronary death.