Coronary Artery Disease (Heart Arteries) and Lipoprotein(a) - clinical studies.
Antisense therapy targeting apolipoprotein(a): a randomised, double-blind, placebo-controlled phase 1 study.
Lancet. 2015 Oct 10;386(10002):1472-83. doi: 10.1016/S0140-6736(15)61252-1. Epub 2015 Jul 22.
Tsimikas S1, Viney NJ2, Hughes SG2, Singleton W2, Graham MJ2, Baker BF2, Burkey JL2, Yang Q2, Marcovina SM3, Geary RS2, Crooke RM2, Witztum JL4.
ISIS-APO(a)Rx results in potent, dose-dependent, selective reductions of plasma Lp(a). The safety and tolerability support continued clinical development of ISIS-APO(a)Rx as a potential therapeutic drug to reduce the risk of cardiovascular disease and calcific aortic valve stenosis in patients with elevated Lp(a) concentration.
Prediction of cardiovascular events in statin-treated stable coronary patients of the treating to new targets randomized controlled trial by lipid and non-lipid biomarkers.
PLoS One. 2014 Dec 22;9(12):e114519. doi: 10.1371/journal.pone.0114519. eCollection 2014.
Arsenault BJ1, Barter P2, DeMicco DA3, Bao W3, Preston GM3, LaRosa JC4, Grundy SM5, Deedwania P6, Greten H7, Wenger NK8, Shepherd J9, Waters DD10, Kastelein JJ1; Treating to New Targets (TNT) Investigators.
In conclusion, in patients with CHD treated with atorvastatin, plasma levels of Lp(a), neopterin, NT-proBNP, and sRAGE are associated with the risk of recurrent MCVEs.
Primary Prevention With Statins: ACC/AHA Risk-Based Approach Versus Trial-Based Approaches to Guide Statin Therapy.
J Am Coll Cardiol. 2015 Dec 22;66(24):2699-709. doi: 10.1016/j.jacc.2015.09.089.
The clinical performance of the ACC/AHA risk-based approach for primary prevention of ASCVD with statins was superior to the trial-based and hybrid approaches. Our results indicate that the ACC/AHA guidelines will prevent more ASCVD events than the trial-based and hybrid approaches, while treating fewer people compared with the trial-based approach.
In an audio commentary, JACC editor in chief Dr Valentin Fuster (Icahn School of Medicine at Mount Sinai, New York) summarizes: "This paper . . . is a good exercise for all of us to [contemplate] and perhaps not to disregard the 2013 ACC/AHA guidelines in part based on the risk calculator, which appears to be not so bad. In addition, let's begin to pay attention to Lp(a), since it may explain coronary artery disease events in patients who otherwise do not have a significant risk-factor profile." see link here: http://content.onlinejacc.org/article.aspx?articleid=2476062#tab1
Lipoprotein(a): resurrected by genetics
Kronenberg F1, Utermann G
J Intern Med. 2013 Jan;273(1):6-30. doi: 10.1111/j.1365-2796.2012.02592.x. Epub 2012 Nov 12.
Plasma lipoprotein(a) [Lp(a)] is a quantitative genetic trait with a very broad and skewed distribution, which is largely controlled by genetic variants at the LPA locus on chromosome 6q27. Based on genetic evidence provided by studies conducted over the last two decades, Lp(a) is currently considered to be the strongest genetic risk factor for coronary heart disease (CHD). The copy number variation of kringle IV in the LPA gene has been strongly associated with both Lp(a) levels in plasma and risk of CHD, thereby fulfilling the main criterion for causality in a Mendelian randomization approach. Alleles with a low kringle IV copy number that together have a population frequency of 25-35% are associated with a doubling of the relative risk for outcomes, which is exceptional in the field of complex genetic phenotypes. The recently identified binding of oxidized phospholipids to Lp(a) is considered as one of the possible mechanisms that may explain the pathogenicity of Lp(a). Drugs that have been shown to lower Lp(a) have pleiotropic effects on other CHD risk factors, and an improvement of cardiovascular endpoints is up to now lacking. However, it has been established in a proof of principle study that lowering of very high Lp(a) by apheresis in high-risk patients with already maximally reduced low-density lipoprotein cholesterol levels can dramatically reduce major coronary events.
Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality
Emerging Risk Factors Collaboration, Erqou S, Kaptoge S, Perry PL, Di Angelantonio E, Thompson A, White IR, Marcovina SM, Collins R, Thompson SG, Danesh J.
Under a wide range of circumstances, there are continuous, independent, and modest associations of Lp(a) concentration with risk of CHD and stroke that appear exclusive to vascular outcomes.
Mendelian Randomized Studies
Genetically elevated lipoprotein(a) and increased risk of myocardial infarction
Kamstrup PR1, Tybjaerg-Hansen A, Steffensen R, Nordestgaard BG.
These data are consistent with a causal association between elevated lipoprotein(a) levels and increased risk of MI.
Genetic Association Studies
Phenotypic Characterization of Genetically Lowered Human Lipoprotein(a) Levels
These data allow for several conclusions. First, using naturally occurring DNA sequence variation, a dose–response relationship between perturbation of Lp(a) and risk for CHD was provided. We examined the effects of both common and rare variants, as well as gain-of-function variants that increase Lp(a) levels and loss-of-function variants that decrease Lp(a) levels. The effects of these different variants on CHD were consistently proportional to their effect on Lp(a). Consistent with 2 recent reports (30,32), a low-frequency loss-of-function variant (rs41272114) and a burden of rare loss-of-function variants in LPA protected against CHD. In combination, these results suggest that greater pharmacological reductions in Lp(a) levels should produce proportionally greater reductions in CHD risk, thus supporting intensive Lp(a) lowering.
Second, these results suggest that Lp(a) inhibition may be a viable therapeutic strategy to prevent a range of diseases beyond CHD. This study extends previous research demonstrating that LPA variants are associated with cardiovascular disease (5,6,11,12,33,34). In a report of up to 12,716 individuals from 35 case-control studies, LPA variants were associated with peripheral arterial disease, ischemic stroke, and coronary artery disease (11). In contrast, in an analysis of 14,465 individuals in the Heart Protection Study, LPA variants were associated with PVD but not with stroke (12). Our results suggest that LPA variants are associated with PVD, stroke, and HF. Furthermore, our report of a significant association with aortic stenosis is consistent with recent analyses demonstrating a significant effect of LPA variants on aortic valve calcification and stenosis (9,10). Inclusion of these diseases in composite endpoints of trials of Lp(a)-reducing therapies (in addition to CHD) may increase the likelihood of a positive trial outcome, highlighting the potential benefits of genetic analyses for trial design and clinical drug development.
Third, a surprising finding of this study was that genetically lowered Lp(a) was associated with a modest but significant improvement in kidney function as assessed by 2 phenotypes—eGFR and prevalence of CKD. This lower risk of CKD may be mediated through a reduction in renal atherosclerotic burden. These findings are consistent with a recent GWAS of metabolites that revealed a strong association between LPA rs10455872 and creatinine levels (35). These results implicate Lp(a) metabolism in the development of CKD.
Genetically decreased Lp(a) was associated with a range of cardiometabolic disorders, including CHD, stroke, PVD, aortic stenosis, HF, and renal dysfunction. Pharmacological lowering of Lp(a) levels may reduce the risk of these disorders.
Genetic variants associated with Lp(a) lipoprotein level and coronary disease
Clarke R, Peden JF, Hopewell JC, Kyriakou T, Goel A, Heath SC, Parish S, Barlera S, Franzosi MG, Rust S, Bennett D, Silveira A, Malarstig A, Green FR, Lathrop M, Gigante B, Leander K, de Faire U, Seedorf U, Hamsten A, Collins R, Watkins H, Farrall M; PROCARDIS Consortium.
Three chromosomal regions (6q26-27, 9p21, and 1p13) were strongly associated with the risk of coronary disease. The LPA locus on 6q26-27 encoding Lp(a) lipoprotein had the strongest association. We identified a common variant (rs10455872) at the LPA locus with an odds ratio for coronary disease of 1.70 (95% confidence interval [CI], 1.49 to 1.95) and another independent variant (rs3798220) with an odds ratio of 1.92 (95% CI, 1.48 to 2.49). Both variants were strongly associated with an increased level of Lp(a) lipoprotein, a reduced copy number in LPA (which determines the number of kringle IV-type 2 repeats), and a small Lp(a) lipoprotein size. Replication studies confirmed the effects of both variants on the Lp(a) lipoprotein level and the risk of coronary disease. A meta-analysis showed that with a genotype score involving both LPA SNPs, the odds ratios for coronary disease were 1.51 (95% CI, 1.38 to 1.66) for one variant and 2.57 (95% CI, 1.80 to 3.67) for two or more variants. After adjustment for the Lp(a) lipoprotein level, the association between the LPA genotype score and the risk of coronary disease was abolished.
We identified two LPA variants that were strongly associated with both an increased level of Lp(a) lipoprotein and an increased risk of coronary disease. Our findings provide support for a causal role of Lp(a) lipoprotein in coronary disease.
|PREVALENCE OF LPA SINGLE NUCLEOTIDE POLYMORPHISMS AND ISOFORMS IN PATIENTS ENROLLED IN A PHASE 2 IONIS-APO(a)Rx CLINICAL TRIAL
Elevated Lp(a) is an independent predictor of CVD and aortic stenosis. Lp(a) levels are genetically determined by apo(a) isoforms, and by single nucleotide polymorphisms (snps) rs10455872 and rs3798220 in European communities (prevalence ~7-15% and ~3%, respectively). The distribution in patients eligible for clinical trials of Lp(a) lowering is unknown
A phase 2 study (n=64) randomizing patients with Lp(a) 125-438 nmol/L (≥~50-175 mg/dL) or ≥438 nmol/L (≥~175 mg/dL), representing the 80th and >99th percentile of Lp(a), was conducted with IONIS-APO(a)Rx [previously called ISIS-APO(a)Rx], an antisense oligonucleotide to apo(a). The size of the major apo(a) isoform was available in 63 patients and rs3798220 and rs10455872 in 60 patients
Patients were recruited from high-risk lipid clinics in Canada and Europe. Average age was 55, 48.4% female, 96.9% white, and 36.9% had history of CVD. Mean (range) LDL-C was 122 (49-238) mg/dL, median (range) Lp(a) was 276 (140-803) nmol/L and mean size (range) of apo(a) isoforms was 16.7 (12-20) KIV repeats. 46/60 (76.7%) of patients had risk alleles of rs3798220 and/or rs10455872: 20 (33.3%) rs3798220 and 18 (30.0%) s10455872 heterozygotes, 4 (6.7%) compound heterozygotes, and 1 (1.7%) s3798220 and 3 (5.0%) rs10455872 homozygotes, respectively. 10/11 (90.9%) patients with Lp(a) ≥438 nmol/L had snps rs3798220 and/or rs10455872. The highest Lp(a) levels were present in homozygotes/compound heterozygotes or 12-16 KIV repeats
Patients with elevated Lp(a) (≥125 nmol/L or ≥~50 mg/dL) generally had ≤20 KIV repeats and were more likely to be carriers of rs10455872 and rs3798220 relative to historical community controls
| E.S. Stroes 1, F.M. van der Valk 1, D. Gaudet 2, I. Gouni-Berthold 3, N.P. Riksen 4, E. Steinhagen-Thiessen 5, B. Isermann 6, B. Nordestgaard 7, N.J. Viney 8, S. Marcovina 9, S.G. Hughes 8, J. Tami 10, S. Xia 11, J.L. Witztum 12, S. Tsimikas 13
1Academic Medical Center- Amsterdam, Medicine, Amsterdam, Netherlands
2Universite de Montreal and Ecogene-21 Clinical Reserach centre, Medicine, Chicoutimi, Canada
3University of Cologne, Medicine, Cologne, Germany
4Rabdoud University Medical Centre, Medicine, Nijmegen, Netherlands
5Lipid Ambulatory clinic- Charite-Universitaetsm edizin, Medicine, Berlin, Germany
66Institut für klinische chemie und Biochemie- Lipidambulanz- Germany, Medicine, Magdeburg, Germany
7Herlev Hospital- Copenhagen University Hospital- University of Copenhagen- Denmark, Medicine, Copenhagen, Denmark
8Ionis Pharmaceuticals- Carlsbad- CA, Pharmaceuticals, Carlsbad, USA
9University of Washington- Seattle- WA, Medicine, Seattle, USA
10Ionis Pharmaceuticals, Pharmaceuticals, Carlesbad, USA
11Ionis Pharmaceuticals, Pharmaceuticals, Carlsbad, USA
12UCSD, Medicine/endocrinology, LA JOLLA, USA