Effect of evolocumab versus placebo added to standard lipid-lowering therapy on fasting and post fat load lipids and lipoproteins in familial dysbetalipoproteinemia

Abstract Background Familial Dysbetalipoproteinemia (FD) is the second most common genetic lipid disorder (prevalence ranging from 1 in 1000–2500), characterized by impaired postprandial lipoprotein clearance and associated with increased cardiovascular (CVD) risk. The majority of FD patients do not achieve non-HDL-cholesterol treatment goals, indicating the medical need for additional lipid-lowering treatment options. Purpose To evaluate the effect of the PCSK9 monoclonal antibody evolocumab added to standard lipid-lowering therapy on fasting and post fat load lipids and lipoproteins in FD patients. Methods A randomized placebo-controlled double-blind crossover trial comparing evolocumab (140 mg subcutaneous every 2 weeks) with placebo during two 12 week treatment periods. At the start and end of each treatment period FD patients received an oral fat load. The primary endpoint was the 8 hour post fat load non-HDL-cholesterol level expressed as area under the curve (AUC). Levels of other fasting and post fat load lipids and (apo)lipoproteins were assessed with ultracentrifugation, polyacrylamide gels, retinyl palmitate and SDS-PAGE. Results In total, 28 patients completed the study. Mean age was 62±9 years and 93% had an ɛ2ɛ2 genotype. Compared with placebo, evolocumab reduced fasting non-HDL-cholesterol with 51% (95% CI 43–57) and the 8 hours post fat load non-HDL-cholesterol AUC with 49% (95% CI 42–55). Fasting triglyceride levels were reduced with 24% (95% CI 14–37) and the 8 hours post fat load triglyceride AUC was reduced with 22% (95% CI 11–29). Except for HDL-cholesterol, all fasting and 8 hour post fat load lipids and (apo)lipoproteins were significantly reduced by evolocumab, including apolipoprotein B (8 hour post fat load AUC reduction 47% (95% CI 41–53) and remnant cholesterol (8 hour post fat load AUC reduction 49% (95% CI −38 to 59)), compared with placebo. After treatment with evolocumab, 89% of patients achieved their non-HDL-cholesterol treatment goal compared with 36% after placebo. Conclusion Evolocumab added to standard lipid-lowering therapy significantly reduced fasting and post fat load non-HDL-cholesterol and other atherogenic lipids and lipoproteins in FD patients. This is the largest clinical trial in FD to date and the first to investigate evolocumab in this very high-risk group. The large decrease in fasting and post fat load lipids and lipoproteins will likely lower CVD risk in these patients. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): AmgenThis project was funded by Amgen for an investigator-initiated research project. The University Medical Center Utrecht was the sponsor of the study. The financial funder had no role in the design, collection of the data, conduct of the analyses or reporting of the study results.