Genetic Studies Can Help Determine How Low LDL Should Go With Treatment

Florian Kronenberg

Dr. Kronenberg Interview with:
Florian Kronenberg, MD
Division of Genetic Epidemiology
Department of Medical Genetics, Molecular and Clinical Pharmacology
Medical University of Innsbruck, Innsbruck, Austria What is the background for this study?

Response: Lp(a) is one of the most prevalent lipoprotein risk factors for cardiovascular disease. Roughly 20% of the general Caucasian population have concentrations above 50 mg/dL and the 10% with the highest concentrations have a 2 to 3-fold increased risk for myocardial infarction.

There is strong evidence from genetic studies that high Lp(a) concentrations are causally related to cardiovascular outcomes. Until recently there was no drug available which lowers Lp(a) without any effects on other lipoproteins. This has recently changed by the development of drugs that block the production of Lp(a) in an impressive way. These drugs have to be studied in randomized controlled trials whether they not only lower Lp(a) concentrations but also cardiovascular outcomes. For the planning of such studies it is crucial to estimate the amount of Lp(a) lowering required to show a clinical benefit. What are the main findings?

Response: We used the genetic effect estimates of 27 single-nucleotide polymorphisms on Lp(a) concentrations from a genome-wide association study (GWAS) we had recently performed in almost 14000 individuals. At the same time we evaluated which effect these polymorphisms have on the cardiovascular risk.

Using these data, we estimated that the required reduction in Lp(a) would have to be roughly 65 mg/dL to reach the same potential effect on clinical outcomes that can be reached by lowering LDL-C by 38.67mg/dL. The lowering of LDL-C is used as a kind of benchmark for comparison. These data can now be used for the planning of trials and imply that an Lp(a)-lowering substance has to have a pronounced Lp(a)-lowering capacity and that first trials better include patients with Lp(a) concentrations above 100 mg/dL. Previous calculations using a similar approach might have overestimated the required Lp(a)-lowering effect size which might be explained by standardization issues of the previously used Lp(a) assays. What should readers take away from your report?

Response: The many genetic epidemiological studies from the past have created a solid basis to assume that Lp(a) is a causal risk factor for cardiovascular disease. A similar approach was now used by us and others to estimate the required Lp(a)-lowering potential for future clinical trials. There is a strong hope for the many patients with very high Lp(a) concentrations that in 6-7 years the final proof will be available that lowering Lp(a) is also effective in lowering clinical events. What recommendations do you have for future research as a result of this work?

Response:  Perform the first randomized controlled trials based on the above recommendations. Is there anything else you would like to add?

Response: The question is what should a patient with high Lp(a) concentrations do in the meanwhile: put major efforts on the management of classical cardiovascular risk factors such as body mass index, diet, physical activity, smoking, hypertension, diabetes and cholesterol levels. An earlier observational long-term study by Perrot et al. (Atherosclerosis 256:47-52, 2017) revealed that individuals with Lp(a) concentrations above 50 mg/dL and who belonged to the third of the group who had the lowest number of these seven risk factors had only a third of the risk to develop a cardiovascular event during the upcoming 11.5 years compared to the reference group which had also Lp(a) concentrations above 50 mg/dL and who belonged to the third of the individuals with the highest number of these risk factors. Although these data are of observational nature, they can support the motivation of patients to contribute to their risk management. 


Lamina C, Kronenberg F, for the Lp(a)-GWAS-Consortium. Estimation of the Required Lipoprotein(a)-Lowering Therapeutic Effect Size for Reduction in Coronary Heart Disease OutcomesA Mendelian Randomization AnalysisJAMA Cardiol. Published online April 24, 2019. doi:10.1001/jamacardio.2019.1041 


Apr 25, 2019 @ 11:44 am




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