Composition and distribution of lipoproteins after evolocumab in familial dysbetalipoproteinemia: A randomized controlled trial

•In FD, PCSK9 mAbs in particular reduce smaller and cholesterol-rich lipoproteins.•PCSK9 mAbs do not affect CM metabolism.•PCSK9 mAbs probably achieve their effects by increased hepatic clearance. BackgroundPCSK9 monoclonal antibodies (mAbs) reduce fasting and post fat load cholesterol in non-HDL and IDL in familial dysbetalipoproteinemia (FD). However, the effect of PCSK9 mAbs on the distribution and composition of atherogenic lipoproteins in patients with FD is unknown.ObjectiveTo evaluate the effect of the PCSK9 mAb evolocumab added to standard lipid-lowering therapy in patients with FD on fasting and post fat load lipoprotein distribution and composition.MethodsRandomized placebo-controlled double-blind crossover trial comparing evolocumab (140 mg subcutaneous every 2 weeks) with placebo during two 12-week treatment periods. Patients received an oral fat load at the start and end of each treatment period. (Apo)lipoproteins were measured with ultracentrifugation, gradient gel electrophoresis, retinyl palmitate and SDS-PAGE.ResultsPCSK9 mAbs significantly reduced particle number of all atherogenic lipoproteins, with a stronger effect on smaller lipoproteins than on larger lipoproteins (e.g. IDL-apoB 49%, 95%CI 41–59 and VLDL-apoB 33%, 95%CI 16-50). Furthermore, PCSK9 mAbs lowered cholesterol more than TG in VLDL, IDL and LDL (e.g. VLDL-C 48%, 95%CI 29–63%; and VLDL-TG 20%, 95%CI 6.3–41%). PCSK9 mAbs did not affect the post fat load response of chylomicrons.ConclusionPCSK9 mAbs added to standard lipid-lowering therapy in FD patients significantly reduced lipoprotein particle number, in particular the smaller and more cholesterol-rich lipoproteins (i.e. IDL and LDL). PCSK9 mAbs did not affect chylomicron metabolism. It seems likely that the observed effects are achieved by increased hepatic lipoprotein clearance, but the specific working mechanism of PCSK9 mAbs in FD patients remains to be elucidated. PCSK9 monoclonal antibodies (mAbs) reduce fasting and post fat load cholesterol in non-HDL and IDL in familial dysbetalipoproteinemia (FD). However, the effect of PCSK9 mAbs on the distribution and composition of atherogenic lipoproteins in patients with FD is unknown. To evaluate the effect of the PCSK9 mAb evolocumab added to standard lipid-lowering therapy in patients with FD on fasting and post fat load lipoprotein distribution and composition. Randomized placebo-controlled double-blind crossover trial comparing evolocumab (140 mg subcutaneous every 2 weeks) with placebo during two 12-week treatment periods. Patients received an oral fat load at the start and end of each treatment period. (Apo)lipoproteins were measured with ultracentrifugation, gradient gel electrophoresis, retinyl palmitate and SDS-PAGE. PCSK9 mAbs significantly reduced particle number of all atherogenic lipoproteins, with a stronger effect on smaller lipoproteins than on larger lipoproteins (e.g. IDL-apoB 49%, 95%CI 41–59 and VLDL-apoB 33%, 95%CI 16-50). Furthermore, PCSK9 mAbs lowered cholesterol more than TG in VLDL, IDL and LDL (e.g. VLDL-C 48%, 95%CI 29–63%; and VLDL-TG 20%, 95%CI 6.3–41%). PCSK9 mAbs did not affect the post fat load response of chylomicrons. PCSK9 mAbs added to standard lipid-lowering therapy in FD patients significantly reduced lipoprotein particle number, in particular the smaller and more cholesterol-rich lipoproteins (i.e. IDL and LDL). PCSK9 mAbs did not affect chylomicron metabolism. It seems likely that the observed effects are achieved by increased hepatic lipoprotein clearance, but the specific working mechanism of PCSK9 mAbs in FD patients remains to be elucidated.