FLUVASTATIN IN FAMILIAL HYPERCHOLESTEROLEMIA - A COHORT ANALYSIS OF THE RESPONSE TO COMBINATION TREATMENT

A recent randomized, double blind, double-dummy trial revealed differe nces in the response of patients with heterozygous familial hyperchole sterolemia to combination therapy with the new,wholly synthetic 3-hydr oxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor fluvasta tin, 20 mg/day and then 40 mg/day, plus the fibric acid analogue bezaf ibrate, 400 mg/day, vs combination therapy with fluvastatin, 40 mg/day , plus the bile acid sequestrant (resin) cholestyramine, 8 g/day. The main purpose of the present cohort analysis was to determine whether t hese differences in lipid response were related to imbalances In the p atients' prior responses to up to 42 weeks of fluvastatin monotherapy, 20 mg/day, 40 mg/day, and, in some patients, 80 mg/day, in 2 earlier studies. For the present analysis, we identified 18 patients in the fl uvastatin plus bezafibrate group (cohort 1) and 16 patients in the flu vastatin plus cholestyramine group (cohort 2) for whom complete dose-r esponse data were available for the full 56-week duration of all 3 stu dies. Subsets of 7 patients in cohort 1 and 8 patients In cohort 2 had received the 60 mg/day fluvastatin dose during a previous monotherapy study. In cohort 1, law density lipoprotein cholesterol (U)L-C) decre ased by 19% with 20 mg/day fluvastatin, by 27% with 40 mg/day fluvasta tin, by 31% with 20 mg/day fluvastatin plus bezafibrate, and by 35% wi th 40 mg/day fluvastatin plus bezafibrate, and the LDL-C/high density lipoprotein cholesterol (HDL-C) ratio had fallen by 48% at the end of combination therapy. In cohort 2, LDL-C declined by 19% with 20 mg/day fluvastatin, by 23% with 40 mg/day fluvastatin, and by 31% with fluva statin plus cholestyramine, and the LDL-C/HDL-C ratio was lowered by 3 8% at the combination therapy endpoint. Thus, the LDL-C response was s imilar In both cohorts, except for the enhancement of the effect on th e LDL-C/HDLC ratio seen with the combination of fluvastatin plus bezaf ibrate, compared with the combination of fluvastatin plus cholestyrami ne. That is, the addition of either bezafibrate or cholestyramine lowe red LDL-C levels by an additional 9-10% relative to the decreases achi eved with 40 mg/day fluvastatin alone. According to the findings of th e cohort analysis, some of the differences in efficacy observed betwee n the 2 combination regimens were related to prior response to monothe rapy, which, in turn, may have reflected patient gender and/or complia nce with therapy. No clinically meaningful abnormalities In aspartate aminotransferase, alanine aminotransferase, or creatine kinase levels were noted with either combination regimen, which suggests that the re gimens were equally safe. Although both com combinations were effectiv e, fluvastatin plus bezafibrate appeared to be superior, since it lowe red triglyceride levels by 24%, in contrast to the 8% increase seen wi th fluvastatin plus cholestyramine. We conclude that the combination o f fluvastatin with bezafibrate is a good alternative for the treatment of severe familial hypercholesterolemia when a fluvastatin-resin comb ination is poorly tolerated and/or does not achieve goal lipid levels. However, careful monitoring is recommended In light of reports of the development of myopathy and rhabdomyolysis with the use of fibrates a lone or in combination with other fungally derived HMG-CoA reductase i nhibitors.