Hypercholesterolemia

Proprotein convertase subtilisin/kexin type 9 (PCSK9) has evolved as a pivotal enzyme in lipid metabolism and a revolutionary therapeutic target for hypercholesterolemia and its related cardiovascular diseases (CVD). This comprehensive review delineates the intricate roles and wide-ranging implications of PCSK9, extending beyond CVD to emphasize its significance in diverse physiological and pathological states, including liver diseases, infectious diseases, autoimmune disorders, and notably, cancer. Our exploration offers insights into the interaction between PCSK9 and low-density lipoprotein receptors (LDLRs), elucidating its substantial impact on cholesterol homeostasis and cardiovascular health. It also details the evolution of PCSK9-targeted therapies, translating foundational bench discoveries into bedside applications for optimized patient care. The advent and clinical approval of innovative PCSK9 inhibitory therapies (PCSK9-iTs), including three monoclonal antibodies (Evolocumab, Alirocumab, and Tafolecimab) and one small interfering RNA (siRNA, Inclisiran), have marked a significant breakthrough in cardiovascular medicine. These therapies have demonstrated unparalleled efficacy in mitigating hypercholesterolemia, reducing cardiovascular risks, and have showcased profound value in clinical applications, offering novel therapeutic avenues and a promising future in personalized medicine for cardiovascular disorders. Furthermore, emerging research, inclusive of our findings, unveils PCSK9's potential role as a pivotal indicator for cancer prognosis and its prospective application as a transformative target for cancer treatment. This review also highlights PCSK9's aberrant expression in various cancer forms, its association with cancer prognosis, and its crucial roles in carcinogenesis and cancer immunity. In conclusion, this synthesized review integrates existing knowledge and novel insights on PCSK9, providing a holistic perspective on its transformative impact in reshaping therapeutic paradigms across various disorders. It emphasizes the clinical value and effect of PCSK9-iT, underscoring its potential in advancing the landscape of biomedical research and its capabilities in heralding new eras in personalized medicine.

The connection between triglyceride-rich lipoproteins and cardiometabolic multimorbidity, characterized by the concurrence of at least two of type 2 diabetes, ischemic heart disease, and stroke, has not been definitively established. We aim to examine the prospective associations between serum remnant cholesterol, triglycerides, and the risks of progression from first cardiometabolic disease to multimorbidity via multistate modeling in the UK Biobank. We also evaluate the causality of these associations via Mendelian randomization using 13 biologically relevant SNPs as the genetic instruments. Here we show that elevated remnant cholesterol and triglycerides are significantly associated with gradually higher risks of cardiometabolic multimorbidity, particularly the progression of ischemic heart disease to the multimorbidity of ischemic heart disease and type 2 diabetes. These results advocate for effective management of remnant cholesterol and triglycerides as a potential strategy in mitigating the risks of cardiometabolic multimorbidity.

Aims/hypothesisElevated remnant cholesterol is observationally and causally associated with increased risk of atherosclerotic cardiovascular disease (ASCVD) in the general population. This association is not well studied in individuals with diabetes, who are often included in clinical trials of remnant cholesterol-lowering therapy. We tested the hypothesis that elevated remnant cholesterol is associated with increased risk of ASCVD in individuals with diabetes. We also explored the fraction of excess risk conferred by diabetes which can be explained by elevated remnant cholesterol.MethodsWe included 4569 white Danish individuals with diabetes (58% statin users) nested within the Copenhagen General Population Study (2003-2015). The ASCVDs peripheral artery disease, myocardial infarction and ischaemic stroke were extracted from national Danish health registries without losses to follow-up. Remnant cholesterol was calculated from a standard lipid profile.ResultsDuring up to 15 years of follow-up, 236 individuals were diagnosed with peripheral artery disease, 234 with myocardial infarction, 226 with ischaemic stroke and 498 with any ASCVD. Multivariable adjusted HR (95% CI) per doubling of remnant cholesterol was 1.6 (1.1, 2.3; p=0.01) for peripheral artery disease, 1.8 (1.2, 2.5; p=0.002) for myocardial infarction, 1.5 (1.0, 2.1; p=0.04) for ischaemic stroke, and 1.6 (1.2, 2.0; p=0.0003) for any ASCVD. Excess risk conferred by diabetes was 2.5-fold for peripheral artery disease, 1.6-fold for myocardial infarction, 1.4-fold for ischaemic stroke and 1.6-fold for any ASCVD. Excess risk explained by elevated remnant cholesterol and low-grade inflammation was 14% and 8% for peripheral artery disease, 26% and 16% for myocardial infarction, 34% and 34% for ischaemic stroke, and 24% and 18% for any ASCVD, respectively. LDL-cholesterol did not explain excess risk, as it was not higher in individuals with diabetes. We also explored the fraction of excess risk conferred by diabetes which can be explained by elevated remnant cholesterol.Conclusions/interpretationElevated remnant cholesterol was associated with increased risk of ASCVD in individuals with diabetes. Remnant cholesterol and low-grade inflammation explained substantial excess risk of ASCVD conferred by diabetes. Whether remnant cholesterol should be used as a treatment target remains to be determined in randomised controlled trials.

Background and aimsLow-density lipoprotein cholesterol (LDL-C) is a causal risk factor for atherosclerotic cardiovascular (CV) disease development and progression. The European Society of Cardiology guidelines recommend combination treatment to achieve CV risk-based LDL-C treatment goals. Inclisiran, a small interfering ribonucleic acid (siRNA) that targets hepatic proprotein convertase subtilisin/kexin type 9 (PCSK9) messenger RNA, can provide sustained and effective LDL-C reduction.MethodsVICTORION-Difference, a phase 4 double-blind, placebo-controlled randomized clinical trial included adults with hypercholesterolaemia at high- or very high CV risk. Participants were randomized 1:1 to receive inclisiran sodium (300 mg subcutaneous injections; equivalent to 284 mg inclisiran) or placebo together with individually optimized lipid-lowering therapy (ioLLT), including up-titration with rosuvastatin (open-label) until either their individual LDL-C goal or maximally tolerated statin dose (open-label rosuvastatin) was achieved. The primary objective was assessment of LDL-C goal achievement at Day 90. Key secondary objectives were muscle-related adverse events (MRAEs) and mean LDL-C reduction. Overall, 1770 individuals (mean age, 63.7 years) were randomized to receive inclisiran (n = 898) or ioLLT (n = 872). At Day 90, a significantly higher proportion of participants receiving inclisiran vs. ioLLT achieved their individual LDL-C goals [84.9% vs 31.0%; odds ratio (OR) 12.09, P ResultsOverall, 1770 individuals (mean age, 63.7 years) were randomized to receive inclisiran (n=898) or ioLLT (n=872). At Day 90, a significantly higher proportion of participants receiving inclisiran vs. ioLLT achieved their individual LDL-C goals (84.9% vs. 31.0%; odds ratio [OR] 12.09, pConclusionsAn inclisiran-based treatment strategy was superior to ioLLT in LDL-C goal achievement, delivering early and sustained LDL-C reduction, with fewer MRAEs in individuals with hypercholesterolaemia.