John J.P. Kastelein

Amsterdam, The Netherlands

John J.P. Kastelein is Emeritus Professor of Medicine at the Department of Vascular Medicine at the Academic Medical Center (AMC) of the University of Amsterdam, where he held the Strategic Chair of Genetics of Cardiovascular Disease. After completing his medical studies in Amsterdam, he trained in medical genetics, lipidology and molecular biology at the University of British Columbia, Vancouver (1986-1988). Upon his return to the Netherlands, he was awarded a doctorate (Cum Laude) and in 1989 he founded the Lipid Research Clinic at AMC, which has become part of the Department of Vascular Medicine. The most important concept in Dr. Kastelein’s research career is the “extreme genetics” approach, in which the study of rare human disorders that are associated with premature coronary disease have broader relevance for the understanding of the etiology of heart disease. This approach has been very successful, most notably in familial hypercholesterolemia (FH), now recognized as the paradigm for the relationship between low-density lipoprotein cholesterol and heart disease. In 1995, Dr. Kastelein initiated a foundation for the active identification of patients with classical FH in the Netherlands (StoeH). Dr. Kastelein was president of the Dutch Atherosclerosis Society, is a member of the Royal Dutch Society for Medicine & Physics, the Council for Basic Science of the American Heart Association and the European Atherosclerosis Society, a Fellow of the European Society of Cardiology, and a board member of the International Task Force for CHD Prevention. Among his many awards, Professor Kastelein received the Anitschkow Prize from the European Atherosclerosis Society in 2014. He is ranked among the top 100 of the most influential clinical researchers globally.

Wednesday 03 June 10:00

New therapeutic approaches

Technological advances, especially in genomics, have provided critical insights into novel therapeutic targets, guiding drug development in the lipoprotein field. Low-density lipoprotein cholesterol (LDL-C) has been the primary focus, given overwhelming evidence that has irrefutably established LDL as causal for atherosclerotic cardiovascular disease.  The discovery of PCSK9 (proprotein convertase subtilisin/kexin type 9) and elucidation of its role in the regulation of LDL particle clearance prompted the development of PCSK9 monoclonal antibody therapies. Robust LDL-C lowering (by 50% to 60%) translated to reduction in cardiovascular events in major outcomes studies in very high risk patients. Subsequent development using RNA interference resulted in inclisiran, a small interfering RNA that targets intracellular PCSK9 production. This latter approach provides similarly robust lipid lowering compared with the PCSK9 monoclonal antibodies but with the advantage of less frequent dosing; a major cardiovascular outcomes study is ongoing. Other novel approaches to PCSK9 inhibition include active immunization and gene editing. Beyond PCSK9, genetic studies have provide the foundation for development of ETC-1002 (bempedoic acid), an orally and once daily administered drug that both inhibits ACL (ATP-citrate lyase) and activates AMpK (AMP-activated protein kinase), thereby reducing hepatic cholesterol synthesis and increasing LDL receptor expression.

Attention has also focused on other lipoprotein targets, notably lipoprotein(a) and triglyceride-rich lipoproteins and their remnants, largely driven by evidence from genetic studies. Current clinical trials are investigating novel therapies directed to. The development of antisense oligonucleotides targeting apolipoprotein(a) synthesis provides an opportunity to test the ‘lipoprotein(a) hypothesis’ in major outcome studies. Fish oils (omega-3 fatty acids) have been the focus of renewed clinical development. The REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial) showed significant reduction in major cardiovascular events associated with treatment with eicosapentaenoic acid in high risk patients with mixed dyslipidemia, although the extent of cardiovascular event reduction was not explained by the magnitude of triglyceride-lowering in this trial, implying the involvement of other mechanisms. Other novel approaches targeting triglyceride-rich lipoproteins and their remnants include the selective peroxisome proliferator-activated receptor alpha modulator pemafibrate, currently being tested in the PROMINENT cardiovascular outcomes study, as well as a monoclonal antibody to angiopoietin-like 3 (evinacumab) and an antisense oligonucleotide to apolipoprotein C-III.  

The future holds promise for novel therapeutic approaches to dyslipidemia management with the ultimate aim of reducing major cardiovascular events in high risk patients in both primary and secondary prevention settings.

Key references

Ray KK, Stoekenbroek RM, Kallend D, Nishikido T, Leiter LA, Landmesser U, Wright RS, Wijngaard PLJ, Kastelein JJP. Effect of 1 or 2 doses of inclisiran on low-density lipoprotein cholesterol levels: one-year follow-up of the ORION-1 randomized clinical trial. JAMA Cardiol 2019. doi: 10.1001/jamacardio.2019.3502.

Ference BA, Kastelein JJP, Ray KK, Ginsberg HN, Chapman MJ, Packard CJ, Laufs U, Oliver-Williams C, Wood AM, Butterworth AS, Di Angelantonio E, Danesh J, Nicholls SJ, Bhatt DL, Sabatine MS, Catapano AL. Association of triglyceride-lowering LPL variants and LDL-C-lowering LDLR variants with risk of coronary heart disease. JAMA 2019;321:364-73.

Larsen LE, Stoekenbroek RM, Kastelein JJP, Holleboom AG. Moving targets: recent advances in lipid-lowering therapies. Arterioscler Thromb Vasc Biol 2019;39:349-59.