Recent advances in the understanding and care of familial hypercholesterolaemia: significance of the biology and therapeutic regulation of proprotein convertase subtilisin/kexin type 9

Abstract

Familial hypercholesterolaemia (FH) is an autosomal co-dominant disorder that markedly raises plasma low-density lipoprotein-cholesterol (LDL-C) concentration, causing premature atherosclerotic coronary artery disease (CAD). FH has recently come under intense focus and, although there is general consensus in recent international guidelines regarding diagnosis and treatment, there is debate about the value of genetic studies. Genetic testing can be cost-effective as part of cascade screening in dedicated centres, but the full mutation spectrum responsible for FH has not been established in many populations, and its use in primary care is not at present logistically feasible. Whether using genetic testing or not, cholesterol screening of family members of index patients with an abnormally raised LDL-C must be used to determine the need for early treatment to prevent the development of CAD. The metabolic defects in FH extend beyond LDL, and may affect triacylglycerol-rich and high-density lipoproteins, lipoprotein(a) and oxidative stress. Achievement of the recommended targets for LDL-C with current treatments is difficult, but this may be resolved by new drug therapies. Lipoprotein apheresis remains an effective treatment for severe FH and, although expensive, it costs less than the two recently introduced orphan drugs (lomitapide and mipomersen) for homozygous FH. Recent advances in understanding of the biology of proprotein convertase subtilisin/kexin type 9 (PCSK9) have further elucidated the regulation of lipoprotein metabolism and led to new drugs for effectively treating hypercholesterolaemia in FH and related conditions, as well as for treating many patients with statin intolerance. The mechanisms of action of PCSK9 inhibitors on lipoprotein metabolism and atherosclerosis, as well as their impact on cardiovascular outcomes and cost-effectiveness, remain to be established.

Emerging PCSK9 inhibitors for treating dyslipidaemia: buttressing the gaps in coronary prevention

“…No clinically significant differences in efficacy between the mAbs have yet become evident. Robust persistent Reproduced with permission from [97]. ApoB: Apolipoprotein B-100; CE: Cholesteryl esters; CETP: Cholesteryl ester transfer protein; HDL: High-density lipoprotein; HMG-CoA: Hydroxymethylglutaryl coenzyme-A; LDL: Low-density lipoprotein; MTTP: Microsomal triglyceride transfer protein; PCSK9: Proprotein convertase subtilisin/kexin type 9; SREBP-2: Sterol regulatory-element binding protein; TG: Triglyceride; VLDL: Very low-density lipoprotein.…”

Experimental and clinical pharmacology: PCSK9 inhibitors - mechanisms of action

“…These include intestinal and adipocyte lipid metabolism, development of atherosclerotic plaques and inflammation, apoptotic cell death, and regulation of blood pressure and glycaemia. 5 Clinically significant roles of PCSK9 other than in cholesterol metabolism have not been identified or emerged in the form of unexpected adverse effects despite thousands of patients being treated with anti-PCSK9 antibodies.…”

“…Molecules that bind to mature PCSK9, preventing it from interacting with LDL receptors, include the small adnectin polypeptides and monoclonal antibodies. 5 The anti-PCSK9 monoclonal antibodies are of most therapeutic interest and are currently in phase III trials. Details of their binding sites have not been fully disclosed, but earlier monoclonal antibodies are known to bind at or near PCSK9's binding site for the LDL receptor.…”

Cascade Screening in Familial Hypercholesterolemia: Advancing Forward

“…Based on the autosomal dominant inheritance patterns, recommendations support the use of cascade genetic screening to identify at-risk individuals 7,8) . Unfortunately, there are several barriers that must be overcome until cascade genetic screening is widely implemented 5,9) , as discussed below. I.…”

“…While these cost and time saving measures are imperative for cost effectiveness consideration, they also cast a doubt on regions not studied. Many related studies point out that these measures cause an increasing number of false negative cases, suggesting the need for more comprehensive analysis 5,9,13,14,19,41,[60][61][62][63][64][65][66][67][68][69][70] . In recent years, the landscape of genetic testing of FH has become more precarious in the notion that FH and elevations in LDL are a monogenic disorder.…”