Lipids and Lipid Lowering: Current Management With Statins and PCSK9 Inhibitors

Thomas F. Lüscher, MD, FESC

Disclosures

Eur Heart J. 2018;39(14):1117-1120. 

The cholesterol hypothesis is among the most successful concepts in medicine. Indeed, ever since Rudolf Virchow proposed that atherosclerosis might be an inflammation induced by cholesterol in the 19th century, evidence supporting this paradigm has steadily accumulated. In 1913, Nikolai Anitchkow supported the hypothesis by his seminal experimental studies in rabbits fed a high-fat diet.[1] Then, in the second half of the 20th century, the Framingham study provided the epidemiological evidence[2] and, in 1989, the 4S trial using the HMG coenzyme reductase inhibitor simvastatin proved that pharmacological lowering of plasma cholesterol levels indeed provides clinical benefit.[3] Finally, Mendellian randomization studies of a hitertho unknown protein, i.e. proprotein convertase subtilisin/kexin type 9, revealed that gain-of-function mutations were associated with increased risk, while individuals with loss-of-function mutations were protected from myocardial infarction and cardiac death.[4] This led to the development of novel lipid-lowering drugs that are discussed in the '2017 Update of ESC/EAS Task Force on Practical Clinical Guidance forproprotein convertase subtilisin/kexin type 9inhibition in patients with atherosclerotic cardiovascular disease or in familial hypercholesterolaemia' by Ulf Landmesser and colleagues.[5] Indeed, two randomized controlled outcomes trials with PCSK9 inhibitors have now reported positive results in patients after acute coronary syndromes. Based on the current evidence, the ESC/EAS Task Force met to propose practical novel clinical decision algorithms for the use of PCSK9 inhibitors.

Obviously, in prevention, we should not only prescribe drugs, but also assess the patient's cardiopulmonary fitness,[6] an aspect that is addressed in the '2016 Focused Update: clinical recommendations for cardiopulmonary exercise testing data assessment in specific patient populations' by Marco Guazzi from the University of Milano in Italy.[7] In 2012, the European Association for Cardiovascular Prevention & Rehabilitation and the American Heart Association developed a joint document with the primary intent of redefining cardiopulmonary exercise testing analysis. Because of new evidence, a focused update of the 2012 scientific statement appeared warranted. Therein, the authors confirm algorithms not requiring revision and propose certain revisions to algorithms as well as new algorithms based on emerging scientific evidence.

Homozygous familial hypercholesterolaemia is a rare inherited disorder characterized by extreme hypercholesterolaemia from birth, accelerated atherosclerosis, and premature death.[8–11] Many forms of lipid-lowering therapy have been used in the past, but definitive evidence of benefit has been lacking. This gap is closed by a manuscript entitled 'Survival in homozygous familial hypercholesterolaemia is determined by the on-treatment level of serum cholesterol', by Gilbert Thompson and colleagues from the Imperial College London in the UK.[12] They retrospectively divided 133 previously statin-naive homozygotes into quartiles according to their on-treatment levels of serum cholesterol. Patients in quartile 4, with an on-treatment serum cholesterol >15.1 mmol/L, had a hazard ratio of 11.5 for any death compared with those in quartile 1, with values <8.1 mmol/L. Those in quartiles 2 and 3 combined, with on-treatment cholesterol of 8.1–15.1 mmol/L, had a hazard ratio of 3.6 compared with quartile 1. Thus, these findings provide unequivocal evidence that the extent of reduction of serum cholesterol achieved by a combination of therapeutic measures, including statins, ezetimibe, lipoprotein apheresis, and evolocumab, is a major determinant of survival in homozygous familial hypercholesterolaemia. The clinical implications of these findings are discussed in an Editorial by John J.P. Kastelein from the Academic Medical Center of the University of Amsterdam in the Netherlands.[13]

The intensity of cholesterol lowering is still a controversial issue, as are target levels. The ACC/AHA Guidelines abandoned target levels and made statin dosages the major criterion in prevention.[14] However, with the advent of PCSK9 inhibitors, hitherto unachievably low LDL-cholesterol levels can be reached, which resurrected the debate.[15,16] In a clinical research paper entitled 'Effect of statins and non-statin LDL-lowering medications on cardiovascular outcomes in secondary prevention: ameta-analysis of randomized trials', Konstantinos Koskinas and colleagues from the Bern University Hospital in Switzerland compared the impact of more vs. less intensive LDL-cholesterol lowering by statins and non-statin medications in secondary prevention.[17] They included 19 trials with 152 507 patients randomly assigned to more intensive or less intensive treatment. More intensive treatment was associated with a 19% relative risk reduction for the primary outcome of major vascular events (Figure 1). Risk reduction was greater across higher baseline levels and greater reductions of LDL-cholesterol. The clinical benefit was significant across varying types of more intensive treatment, and was consistent for statins and non-statin agents including PCSK9 inhibitors and ezetimibe. Each 1.0 mmol/L reduction in LDL-cholesterol was associated with a 19% relative decrease in major vascular events. Death, cardiovascular death, myocardial infarction, stroke, and coronary revascularization also favoured more intensive treatment. Thus, reduction of major vascular events is proportional to the magnitude of LDL-cholesterol lowering across a broad spectrum of on-treatment levels in secondary prevention. Statin intensification and add-on treatment with PCSK9 inhibitors or ezetimibe are associated with significant reduction of cardiovascular morbidity in this very high-risk population.

Figure 1.

Stratified analyses for major vascular events. RR and corresponding CI for subgroups from individual trials were pooled, and interactions were evaluated by random-effects meta-analyses. Boxes and horizontal lines represent the respective RR and 95% CI for each stratum. In the stratification by intervention, the 'more-intensive' vs. 'less-intensive' stratum includes trials comparing more-statin vs. less-statin (n = 6) and trials comparing non-statin vs. placebo (n = 4) (from Koskinas KC, Siontis GCM, Piccolo R, Mavridis D, Räber L, Mach F, Windecker S. Effect of statins and non-statin LDL-lowering medications on cardiovascular outcomes in secondary prevention: ameta-analysis of randomized trials. See pages 1172--1180).

HDL-cholesterol may be protective, but can also be detrimental, particularly in patients with coronary disease[18,19] and renal failure.[20–22] Pre-clinical evidence has indicated that HDL may play an important role in the immune system;[23] however, very little is known about its role in the human immune system. This has been addressed by Børge Nordestgaard and colleagues from Herlev University Hospital in Denmark in their manuscript entitled 'U-shaped relationship of high-density lipoprotein and risk of infectious disease: two prospective population-based cohort studies'.[24] They investigated whether low and high concentrations of HDL-cholesterol are associated with risk of infectious disease in 97 166 individuals from the Copenhagen General Population Study and 9387 from the Copenhagen City Heart Study. Using restricted cubic splines, there was a U-shaped association between concentrations of HDL-cholesterol and risk of any infection. Following adjustment, individuals with HDL-cholesterol <0.8mmol/L and >2.6mmol/L had hazard ratios for any infection of 1.75 and 1.43, compared with those with HDL-cholesterol of 2.2–2.3 mmol/L. In the Copenhagen City Heart Study, hazard ratios for any infection were 2.00 and 1.13 (Figure 2). Thus, low and high HDL-cholesterol levels are associated with higher risk of infectious disease. The potential causality and clinical relevance of these findings are critically discussed in an Editorial by Thimoteus Speer from the Saarland University Hospital in Homburg, Germany.[25]

Figure 2.

HDL-cholesterol, apolipoprotein A1, triglycerides, and LDL-cholesterol on a continuous scale and risk of any infectious disease in 97 166 individuals from the Copenhagen General Population Study. Analyses were conducted using restricted cubic splines, with hazard ratios and 95% confidence intervals from multiple event Cox proportional hazards regression. The values of HDL-cholesterol, apolipoprotein A1, triglycerides, and LDL-cholesterol with the lowest hazard ratio were chosen as reference. The light green, blue, yellow, and purple areas indicate the distribution of concentrations of HDL cholesterol, apolipoprotein A1, triglycerides, and LDL-cholesterol, respectively (from Madsen CM, Varbo A, Tybjærg-Hansen A, Frikke-Schmidt R, Nordestgaard BG. U-shaped relationship of HDL and risk of infectious disease: two prospective population-based cohort studies. See pages 1181--1190).

The biogenesis of HDL particles by cholesterol-laden foam cells in atherosclerotic lesions is crucial for the removal of excess cholesterol from the vessel wall.[26,27] Impairment in the HDL biogenic process contributes to the progression of atherosclerosis. In a Basic Science article entitled 'Desmocollin 1 is abundantly expressed in atherosclerosis and impairshigh-density lipoproteinbiogenesis', Hong Y. Choi and colleagues from the Research Institute of the McGill University Health Centre in Montreal, Quebec, Canada aimed to identify novel cellular factors regulating HDL biogenesis.[28] HDL biogenesis is a process of apolipoprotein-mediated solubilization of specific plasma membrane microdomains generated in cells which have accumulated cholesterol . Using a new method to isolate plasma membrane microdomains interacting with the major HDL protein constituent, apolipoprotein A-I, lipidomic and proteomic analyses of an isolated plasma membrane microdomain revealed that apolipoprotein A-I binds to cholesterol-rich and desmocollin 1-containing microdomains. In this novel apolipoprotein A-I-binding microdomain, desmocollin 1 binds to and prevents apolipoprotein A-I from interacting with another plasma membrane microdomain created by ATP-binding cassette transporter A1 or ABCA1 for the formation of HDL. Inhibition of apolipoprotein A-I desmocollin 1 binding by silencing desmocollin 1 expression or using desmocollin 1-blocking antibodies increases apolipoprotein A-I accessibility to ABCA1-created microdomains and thus enhances HDL biogenesis. Importantly, desmocollin 1 is abundantly expressed in macrophages and human atherosclerotic lesions, suggesting that desmocollin 1 may contribute to cholesterol accumulation in atherosclerotic lesions by sequestering apolipoprotein A-I and impairing HDL biogenesis. Thus, this suggests that HDL biogenesis and plasma membrane cholesterol levels may be regulated by the relative abundance of ABCA1 and desmocollin 1 domains, and that novel HDL biogenic therapies may be developed by targeting desmocollin 1. The translationability of these findings is outlined in an Editorial by Jean-Claude Tardif from the Montreal Heart Institute in Canada.[29]

The editors hope that readers of this issue of the European Heart Journal will find it of interest.

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