Sotirios Tsimikas

La Jolla, USA

Sotirios (Sam) Tsimikas is Professor of Medicine and Director of Vascular Medicine at the University of California San Diego – School of Medicine. After completing his MD degree in 1988 at the University of Massachusetts Medical School, Dr. Tsimikas undertook Internal Medicine training at the University of Massachusetts Medical Center. He completed separate fellowships in Cardiovascular Disease, Atherosclerosis, and Interventional Cardiology at the University of California, San Diego, from 1992-1997. Dr. Tsimikas’ clinical interests are focused in his role as Director of the Vascular Medicine Program in treating a wide variety of patients across the continuum of high-risk primary prevention to endovascular intervention. Dr. Tsimikas is a Fellow of the American College of Cardiology, the American Heart Association, and the Society for Cardiac Angiography and Interventions.

Tuesday 02 June 08:30

The lipoprotein(a) story - from risk factor to causality to clinical trials

Lipoprotein(a) [Lp(a)] has been considered a cardiovascular risk factor for many years. In the last decade, there has been accumulating and substantial evidence from epidemiologic and Mendelian randomization studies, as well as genome-wide association studies, to support a likely causal role for elevated Lp(a) levels in cardiovascular disease. Until recently, however, the main obstacle to confirmation of causality has been the lack of treatments that specifically lower Lp(a) for testing in large-scale cardiovascular outcomes studies.

A new frontier in Lp(a) research has emerged with antisense-oligonucleotide therapy, which targets Lp(a) production at the level of mRNA translation. Antisense oligonucleotides targeting apolipoprotein(a) have shown promise in early trials. Subsequent development led to an antisense oligonucleotide containing an N-acetyl-galactosamine (GalNac3)−conjugated molecule, which was shown to be highly and selectively taken up by hepatocytes. These properties allowed the use of lower doses and longer dose intervals for this agent compared with other antisense oligonucleotides. In early clinical trials, treatment with this novel therapy was associated with dose dependent reduction in plasma Lp(a) of up to 90% or more in some patients. These advances provide the opportunity to finally test whether pharmacologically lowering elevated Lp(a) levels reduces the risk of cardiovascular events against a background of current best evidence-based therapy.

Key references

Hegele RA, Tsimikas S. Lipid-lowering agents. Circ Res 2019;124:386-404.

Tsimikas S, Gordts PLSM, Nora C, Yeang C, Witztum JL. Statin therapy increases lipoprotein(a) levels. Eur Heart J 2019. pii: ehz310.

Tsimikas S. In search of patients with elevated Lp(a): Seek and ye shall find. J Am Coll Cardiol 2019;73:1040-2.

Willeit P, Ridker PM, Nestel PJ, Simes J, Tonkin AM, Pedersen TR, Schwartz GG, Olsson AG, Colhoun HM, Kronenberg F, Drechsler C, Wanner C, Mora S, Lesogor A, Tsimikas S. Baseline and on-statin treatment lipoprotein(a) levels for prediction of cardiovascular events: individual patient-data meta-analysis of statin outcome trials. Lancet 2018;392;1311-20.