Role of Lipoproteina in Coronary Disease An Emerging

Role of Lipoprotein(a) in Coronary Disease: An Emerging Novel Target Steven E. Nissen MD MACC Chief Academic Officer, Heart and Vascular Institute Cleveland Clinic Disclosure Consulting: Many pharmaceutical companies Clinical Trials: Abbvie, Amgen, Astra. Zeneca, Eli Lilly, Novartis, Novo Nordisk, The Medicines Company, Cerenis, Orexigen, Takeda and Pfizer. Companies are directed to pay any honoraria, speaking or consulting fees directly to charity so that neither income nor tax deduction is received.

Lipoprotein(a) and Plasminogen Structure Lp(a) isoforms Apo(a) Adapted from J Am Coll Cardiol 2017; 69: 692– 711 Apo(a)

Distribution of Lp(a) in the General Population Fraction of Population Men Women 20% 0 50 100 20% 150 Lipoprotein(a) (mg/d. L) Nordestgaard B G et al. Eur Heart J 2010; 31: 2844 -2853 200 0 50 100 150 Lipoprotein(a) (mg/d. L) 200

Dallas Heart Study: Lp(a) Levels by Race/Ethnicity 90% 75% Circulation. 2009; 119: 1711 -1719

Prevalence of Elevated Lp(a): US and Globally Prevalence Top 20% Top 10% Top 5% Top 1% Lp(a) Level 60 mg/d. L 90 mg/d. L 116 mg/d. L 180 mg/d. L Number (USA) 64 million 30 million 16 million 3. 2 million Number (EU) 150 million 75 million 37. 5 million Number Globally 1. 4 billion 700 million 350 million 7 million Arterioscler Thromb Vasc Biol. 2016; 36: 2239 -2245 and adapted from Tsimikas

LDL-C and Lp(a): A Key Insight • Lipoprotein(a) is an Apo. B containing particle that cross reacts with LDL-C in most assays. • The LDL obtained in a standard lipid panel reflects BOTH Lp(a) and LDL. • In patients whose LDL does not fall appropriately with statins/ezetimibe (so-called statin resistance), consider the possibility of a very high Lp(a). • Formulae for adjusting LDL-C for Lp(a) mass are feasible, but not standardized.

How Does Lipoprotein(a) Contribute to Atherosclerosis?

Lp(a) Components: Dual Mechanisms Of Harm European Heart Journal (2017) 38, 1553– 1560

Lipoprotein(a) Levels are Genetically Determined Diet and Lifestyle Have No Effect

Odds Ratio: SNPs Associated with Elevated Lp(a) New Engl J Med 2009; 361: 2518 -28

What are Abnormal (Risky) Levels of Lipoprotein(a)?

Risk of Elevated Lp(a) in General Population* JAMA. 2009; 301(22): 2331 -2339 *Data from Copenhagen City Heart Study

Prevention Clinic: Mortality for Lp(a) for >58 mg/d. L Lp(a) <58 mg/d. L Adjusted odds ratio = 1. 28 N=11, 614

Lipoprotein(a) and Aortic Stenosis

Lipoprotein(a) Levels and Risk of Aortic Stenosis J Am Coll Cardiol 2014; 63: 470– 7

Effect of Statins on Lipoprotein(a) Levels

Effect of Rosuvastatin on Lipoprotein(a) Levels J Am Coll Cardiol 2017; 69: 692– 711

Limited Current Treatments for Elevated Lipoprotein(a)

Apheresis: Effect on Major Cardiovascular Events Circulation. 2013; 128: 2567 -2576

Can elevated Lp(a) be pharmacologically addressed?

Alternative Approaches to Gene Silencing

Lp(a) Anti-Sense Oligonucleotide Therapy RNase H 1’ Degrades Apo(a) m. RNA LPA Gene Anti-Sense Oligonucleotide (single stranded, DNA-like Lancet 2015; 386: 1472– 83 No apo(a) produced

Phase II: Effect of ASO on Lp(a) Levels (n=286) Presented by Tsmikas et al (AHA 2018)

Pivotal Phase 3 Trial: Lp(a)HORIZON • Approximately 8000 patients with established CAD in two strata (Lp(a) levels either >70 mg/d. L or >90 mg/d. L). • Optimal background therapies including statins. • Randomized to 80 mg TQJ 230 monthly or placebo for 4 years. • Primary endpoint: 4 component MACE (CV death, nonfatal MI, stroke or hospitalization for urgent coronary revascularization A trial with enormous public health implications, but we must find the patients and enroll them! We need your help!