No monotherapy is able to tackle effectively all atherogenic features of
familial combined hyperlipidemia: high
low-density lipoprotein (
LDL) cholesterol,
triglycerides (TG), and plasma
fibrinogen, as well as low
high-density lipoprotein (
HDL) cholesterol. The present study investigated the safety and efficacy of combined pravastotin or
simvastatin with
gemfibrozil or
ciprofibrate treatment on total
cholesterol, LDL, TG, plasma
fibrinogen, and
apoproteins B and A-I in patients with refractory
familial combined hyperlipidemia, with or without
coronary artery disease. From the initial 420 patients included in the study, 389 (294 men and 95 women, mean age 51 years [range 30 to 65]) completed the study. These patients were followed for a mean period of 29 months (1 year [n = 107], 2 years [n = 102], 3 years [n = 95], and 4 years [n = 85]). Patients given a hypolipidemic diet were randomly assigned to
pravastatin +
gemfibrozil (n = 135, 20 and 1,200 mg/day, respectively),
simvastatin +
gemfibrozil (n = 130, 20 and 1,200 mg), or simvastotin +
ciprofibrate (n = 124, 20 and 100 mg).
Lipid parameters,
apoproteins B and A-I, and plasma
fibrinogen were assessed every 3 months. Physical and laboratory investigations for adverse effects were performed every month for the first 3 months and every 3 months thereafter. No patient exhibited
myopathy or
rhabdomyolysis. Five patients (1.3%) were withdrawn from the study because of high
transaminases (more than threefold the upper normal limit). Five nonfatal
coronary artery disease events were recorded. All 3 combination treatments were more effective in normalizing
lipid profile than any monotherapy in the past.
Simvastatin +
ciprofibrate was more effective than
pravastatin +
gemfibrozil in reducing
LDL, TG, and plasma
fibrinogen levels.
Simvastatin +
gemfibrozil increased HDL levels more than the other 2. The
apoprotein B decrease was analogous to the
LDL reduction by all combinations, whereas
apoprotein A-I was increased more with
simvastatin +
gemfibrozil. The data suggest that the
statin-
fibrate combinations used in the study are safe and have a favorable effect on all major
coronary artery disease risk factors in patients with refractory
familial combined hyperlipidemia with or without
coronary artery disease. Early detection of the rare
drug-induced reversible hepatotoxicity calls for close monitoring of patients.