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News: EAS Academy - Lecture of the week

New lipid drugs: Is LDL done, ready for new targets?

Monday 22 June 2020   (1 Comments)
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About the presenter: Professor Erik S. Stroes

Erik Stroes is Professor and Chair of the Department of Vascular Medicine, Academic Medical Center, University of Amsterdam,
The Netherlands. Professor Stroes received his medical degree from the University of Rotterdam in 1991, and subsequently trained in internal medicine at the University Medical Center of Utrecht.

His major research interest over the last two decades has been the role of the vessel wall in atherogenesis, especially the contributions of lipid disorders and inflammation. Recent research has focused on targeting epigenetic changes in innate immune cells in atherosclerosis that may offer future potential for imaging, biomarkers and therapies.Professor Stroes is a member of the Council for Basic Science, the American Heart Association, the International Atherosclerosis Society and Chair of the Dutch Society of Atherosclerosis. He has authored more than 300 scientific publications associated with his research interests.

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About the topic

Much of the emphasis on novel treatments in atherosclerosis has been on apolipoprotein (apo)B-containing lipoproteins, especially in view of the indisputable causality of low-density lipoprotein (LDL) for atherosclerotic cardiovascular disease. Cardiovascular outcomes studies with proprotein convertase subtilisin kexin type 9 (PCSK9) monoclonal antibody therapy represent the pinnacle of this avenue, showing that lowering LDL cholesterol levels, beyond those attained on intensive statin therapy, reduced cardiovascular events in very high risk patients. Moreover, there was no evidence to suggest any threshold in LDL cholesterol lowering for associated clinical benefit.

Yet despite the availability of these highly efficacious LDL cholesterol lowering treatments, very high risk patients continue to experience cardiovascular events. This implies the need to address other targets that contribute to this residual cardiovascular risk. Lipoprotein(a) [Lp(a)] is a key contender, given evidence from epidemiologic and genetic studies for a causal role in atherosclerotic cardiovascular disease. Insights from cardiovascular outcomes studies with the PCSK9 inhibitors add further support, showing that patients with higher baseline Lp(a) levels gained greater cardiovascular benefit from PCSK9 inhibition.

Other lipid targets also merit attention. Recently, the REDUCE-It trial demonstrated reduction in cardiovascular events with high dose (4-g daily) of the omega-3 oil eicosapentaenoic acid in very high risk patients with elevated triglycerides. While the magnitude of benefit (25% relative risk reduction) implies the involvement of mechanisms beyond lipid-lowering, the study is pivotal in supporting the importance of targeting elevated triglycerides, a characteristic of the atherogenic dyslipidaemia associated with type 2 diabetes. Beyond lipids, findings from the CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) provide proof of principle for targeting inflammatory risk to reduce cardiovascular events.
The search for other novel targets will undoubtedly continue. In the future, this will undoubtedly include the opportunity to ‘re-programme’ aberrant changes in the control of gene expression with epigenetic treatments for cardiovascular disease prevention.

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Key references

O’Donoghue ML, Fazio S, Giugliano RP, Stroes ESG, Kanevsky E, Gouni-Berthold I, Im K, Lira Pineda A, Wasserman SM, Češka R, Ezhov MV, Jukema JW, Jensen HK, Tokgözoğlu SL, Mach F, Huber K, Sever PS, Keech AC, Pedersen TR, Sabatine MS. Lipoprotein(a), PCSK9 Inhibition, and cardiovascular risk. Circulation 2019;139:1483-92.
Stiekema LCA, Stroes ESG, Verweij SL, Kassahun H, Chen L, Wasserman SM, Sabatine MS, Mani V, Fayad ZA. Persistent arterial wall inflammation in patients with elevated lipoprotein(a) despite strong low-density lipoprotein cholesterol reduction by proprotein convertase subtilisin/kexin type 9 antibody treatment. Eur Heart J 2018 Dec 18. doi: 10.1093/eurheartj/ehy862. [Epub ahead of print]
Kastelein JJP, Stroes ESG. FISHing for the miracle of eicosapentaenoic acid. N Engl J Med 2019;380:89-90.
Nicorescu I, Dallinga GM, de Winther MPJ, Stroes ESG, Bahjat M. Potential epigenetic therapeutics for atherosclerosis treatment. Atherosclerosis 2019;281:189-97.

Comments...

William E. Feeman, Jr says...
Posted Wednesday 24 June 2020
The prediction of the population at risk of atherothrombotic disease (ATD) doesn't have to be this hard. Use the ratio between LDL- and HDL-cholesterol (and I prefer the Cholesterol Retention Fraction, or CRF, defined a s [LDL-HDL]/LDL) and systolic blood pressure (SBP), and stratifying by cigarette smoking status, on can create a graph with CRF on the ordinate and SBP on the abcissa. CRF-SBP cohorts can be created, which (when stratified by cigarette smoking status) can show the individuals at risk of ATD and simultaneously give a measure of intensity of the risk. This approach is published in EC Cardiology7.3 (2020): 01-19. Using this approach, my patients have done very well. The last treated male patient to sustain an AMI did so about 8 years ago and the last non-smoking female patient was a 95 year old who was forced to walk on an (unrecognized) fractured hip at the local hospital.

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