Elevated Lipoprotein A, are we ready to intervene?

Lipid abnormalities can be classified into four clinical groups:1) elevated triglycerides, 2) low high-density lipoprotein cholesterol (HDL-C),3) elevated low-density lipoprotein cholesterol (LDL-C), and 4) elevated lipoprotein A.  Lipoprotein A disorder has been the least lipid abnormality studied from a clinical standpoint. Although many mendelian and genome-wide association studies have shown an association between elevated lipoprotein A and risk of incident atherosclerotic cardiovascular disease (ASCVD), the causality relationship still lacks the final corroboration of a randomized Lp(a) lowering intervention clinical trial1.

In 1963, for the first time, Kare Berg described the existence of Lp(a). Lp(a) consisted of apolipoprotein (a) bound to apolipoprotein B-100, an apolipoprotein also found on LDL-C particles. Distinct from other lipoproteins greatly affected by diet and genetics, Lp (a) is determined by more than 90% by individuals’ genetics. Lp(a) is synthesized in hepatocytes and is released into blood circulation. Plasma concentrations of Lp(a) are inversely associated with the size of apolipoprotein(a). It is postulated that small isoforms can be synthesized faster than large ones, and apolipoprotein(a) size can account for up to 70% influence on Lp(a) blood concentration. Other known factors include single nucleotide polymorphisms, sex hormones, inflammatory mediators, and dietary factors2.

Many medications have been tested to lower Lp(a) concentration. A large-scale meta-analysis of 5,256 patients (1,371 on placebo and 3,885 on statin) enrolled in a randomized clinical trial showed that most statins significantly increase Lp(a) concentration by 8-24%3. Niacin may lower Lp(a) concentration by 20-30%. However, studies did not show any significant reduction in risk of ASCVD event, once niacin was added to the medication list of patients already receiving a statin. Estrogen can also lower Lp(a) concentration by 20%; however, the usage is limited due to concern about increasing the risk of thrombotic events. Proprotein convertase subtilisin Kexin type 9 inhibitors (PCSK9 inhibitors) have been shown to lower Lp(a) concentrations. In 2 major PCSK-9 inhibitors clinical trials- FOURIER and ODYSSEY OUTCOME- the fourth quartile of Lp(a) in the treatment arm was associated with a 25% increase risk of major adverse cardiovascular events. This implies the presence of residual risk of ASCVD despite very low LDL-C4. In a recent sub-analysis of ODYSSEY OUTCOME trial, alirocumab reduced Lp(a) concentration. Each 5mg/dl decrease in Lp(a) by alirocumab resulted in a 2.5% reduction in risk of cardiovascular events5. It should be noted that none of the above medications have primarily been initially designed to test the hypotheses of the beneficial effect of medication on Lp(a) concentration.

Genetic studies have shed light on the role of each allele on Lp(a) concentrations and have provided a base for pharmacological intervention. Antisense oligonucleotides (ASO) have revolutionized the treatment of Lp(a). ASOs are short DNA fragments designed complementary for a target messenger RNA. LPA gene transcribes the two alleles of apolipoprotein(a) mRNA. ASO like Pelacarsen binds to the mRNA and generates the mRNA-ASO complex. Hepatocytes recognized this complex as foreign objects, and RNase H1 cleaves the sense strand. Four clinical trials have been conducted to assess the efficacy of ASOs to lower Lp(a) concentrations. All the clinical trials have shown promising results, from 40% to up to 90% reduction in Lp(a) depending on the type of ASO, dosage, and frequency of administrations6.

Currently, the pivotal phase 3 of Lp(a)HORIZON7 (ClinicalTrials.gov Identifier: NCT04023552) randomized controlled trial is enrolling up to 8280 individuals, aged >18 years with Lp(a) ≥ 70 mg/dl and with a history of myocardial infarction, ischemic stroke, or symptomatic peripheral artery disease. Participants are double blindly randomized to receive TQJ230 80 mg injected monthly subcutaneously or placebo and will be followed for the primary outcome of MACE (CV death, non-fatal MI, non-fatal stroke, and urgent coronary revascularization). The estimated primary completion date is May 29, 2025. So, we need to be patient and wait to see if the causal relationship between Lp(a) and ASCVD will be established by 2025.

 

References:

  1. Miksenas H, Januzzi JL, Jr. and Natarajan P. Lipoprotein(a) and Cardiovascular Diseases. JAMA. 2021;326:352-353.
  2. Tsimikas S. A Test in Context: Lipoprotein(a): Diagnosis, Prognosis, Controversies, and Emerging Therapies. J Am Coll Cardiol. 2017;69:692-711.
  3. Tsimikas S, Gordts P, Nora C, Yeang C and Witztum JL. Statin therapy increases lipoprotein(a) levels. Eur Heart J. 2020;41:2275-2284.
  4. Ruscica M, Greco MF, Ferri N and Corsini A. Lipoprotein(a) and PCSK9 inhibition: clinical evidence. Eur Heart J Suppl. 2020;22:L53-L56.
  5. Szarek M, Bittner VA, Aylward P, Baccara-Dinet M, Bhatt DL, Diaz R, Fras Z, Goodman SG, Halvorsen S, Harrington RA, Jukema JW, Moriarty PM, Pordy R, Ray KK, Sinnaeve P, Tsimikas S, Vogel R, White HD, Zahger D, Zeiher AM, Steg PG, Schwartz GG and Investigators OO. Lipoprotein(a) lowering by alirocumab reduces the total burden of cardiovascular events independent of low-density lipoprotein cholesterol lowering: ODYSSEY OUTCOMES trial. Eur Heart J. 2020;41:4245-4255.
  6. Tsimikas S, Moriarty PM and Stroes ES. Emerging RNA Therapeutics to Lower Blood Levels of Lp(a): JACC Focus Seminar 2/4. J Am Coll Cardiol. 2021;77:1576-1589.
  7. Assessing the Impact of Lipoprotein (a) Lowering With TQJ230 on Major Cardiovascular Events in Patients With CVD (Lp(a)HORIZON). https://clinicaltrialsgov/ct2/show/NCT04023552. 2019.

“The views, opinions and positions expressed within this blog are those of the author(s) alone and do not represent those of the American Heart Association. The accuracy, completeness and validity of any statements made within this article are not guaranteed. We accept no liability for any errors, omissions or representations. The copyright of this content belongs to the author and any liability with regards to infringement of intellectual property rights remains with them. The Early Career Voice blog is not intended to provide medical advice or treatment. Only your healthcare provider can provide that. The American Heart Association recommends that you consult your healthcare provider regarding your personal health matters. If you think you are having a heart attack, stroke or another emergency, please call 911 immediately.”