Determinants of variable response to statin treatment in patients with refractory familial hypercholesterolemia

Interindividual variability in low density lipoprotein (LDL) cholesterol (L DL-C) response during treatment with statins is well documented but poorly understood. To investigate potential metabolic and genetic determinants of statin responsiveness, 19 patients with refractory heterozygous familial hy percholesterolemia were sequentially treated with placebo, atorvastatin (10 mg/d), bile acid sequestrant, and the 2 combined, each for 4 weeks. Levels of LDL-C, mevalonic acid (MVA), 7-alpha -OH-4-cholesten-3-one. and leukocy te LDL receptor and hydroxymethylglutaryl coenzyme A reductase mRNA were de termined after each treatment period. Atorvastatin (10 mg/d) reduced LDL-C by an overall mean of 32.5%. Above-average responders (Delta LDL-C -39.5%) had higher basal MVA levels (34.4+/-6.1 mu mol/L) than did below-average re sponders (Delta LDL-C -23.6%, P<0.02; basal MVA 26.3+/-6.1 <mu>mol/L, P<0.0 1). Fewer good responders compared with the poor responders had an apolipop rotein E4 allele (3 of 11 versus 6 of 8, respectively; P<0.05). There were no baseline differences between them in 7-alpha -OH-4-cholesten-3-one, hydr oxymethylglutaryl coenzyme A reductase mRNA, or LDL receptor mRNA, but the latter increased in the good responders on combination therapy (P<0.05). Se vere mutations were not more common in poor than in good responders. We con clude that poor responders to statins have a low basal rate of cholesterol synthesis that may be secondary to a genetically determined increase in cho lesterol absorption, possibly mediated by apolipoprotein E4. If so, statin responsiveness could be enhanced by reducing dietary cholesterol intake or inhibiting absorption.