Clinical drug investigation vol:9 issue:2 pages:116-126
This 24-week prospective, open-label study, conducted by 1198 general practitioners, evaluated the efficacy and safety of sequential fibrate and simvastatin therapy in 6745 patients (mean +/- SD; 60 +/- 11 years; 37% male) with severe hypercholesterolaemia [total cholesterol (TC) >290 mg/dl]. The study design closely matched the 1991 Belgian healthcare regulations that imposed fibrates as first-line drugs in diet-resistant dyslipidaemic subjects and restricted the use of a statin to patients not sufficiently controlled by diet and a fibrate. Lipid values at baseline after a 12-week diet run-in period, that resulted in a mean 3.8% TC decrease, were TC 329 +/- 37 mg/dl, low-density lipoprotein cholesterol (LDL-C) 236 +/- 39 mg/dl, high-density lipoprotein cholesterol (HDL-C) 55 +/- 18 mg/dl and triglycerides (TG) 187 +/- 79 mg/dl. Mean percentage changes in 6422 patients who completed the 12-week fibrate treatment (bezafibrate n = 792; ciprofibrate n = 2312; fenofibrate n = 2770; gemfibrozil n = 548) were -14%, -17%, +8% and -16% for TC, LDL-C, HDL-C and TG, respectively. Target goals [TC <300 mg/dl in subjects at moderate risk for coronary heart disease (CHD); TC <250 mg/dl or LDL-C <160 mg/dl in high CHD risk subjects] were reached in 45% of patients. Subsequently, 3311 subjects who had failed to achieve target goals with diet and a fibrate were enrolled in the diet plus simvastatin therapy phase (weeks 12 to 24). Median simvastatin dosages were 10 and 20mg daily at weeks 18 and 24, respectively. Mean percentage changes from baseline at weeks 18 and 24 were -23 and -29% for TC, -30 and -38% for LDL-C, +11 and +12% for HDL-C, and -11 and -13% for TG. Study protocol target goals were reached by 69 and 84% of patients at weeks 18 and 24, respectively. LDL-C target goals set by the 1993 National Cholesterol Education Program II guidelines were met by 13% of patients with fibrate (week 12) and, in those not sufficiently controlled with fibrate, by 19% receiving simvastatin 10mg daily (week 18) and by 34% on simvastatin 20mg daily (week 24). The study drugs were generally well tolerated. Drug-related adverse events occurred in 3.5% of patients on fibrate and in 6.5% on simvastatin. Single transaminase elevations greater than 3 times the upper limit of normal were observed in 0.4 and 0.7% of patients on fibrate and simvastatin, respectively. Myopathy was not observed.