Participants with Elevated Lp (a) Had Greater than Average Benefit from Evolocumab in FOURIER

Kevin C Maki, PhD, CLS, FNLA and Mary R Dicklin, PhD

It has been known for decades that an elevated level of lipoprotein (a) or Lp (a) is associated with increased cardiovascular disease (CVD) risk.  The Lp (a) particle consists of a low-density lipoprotein (LDL) particle that has an apoprotein (a) glycoprotein linked to the apolipoprotein B via a single disulfide bond.

Lp (a) is mainly genetically determined and shows a right skewed distribution in most populations, with approximately 80% having values below 50 mg/dL, when measured by mass, and 100 nmol/L, when measured by particle concentration.1,2  Some individuals have extremely elevated levels, as high as 300 mg/dL in mass in some instances.  Lp (a) shares homology with the plasminogen molecule, and may interfere with fibrinolysis.  It can also enter the arterial endothelial space and participate, like other LDL particles, in initiation and promotion of atherosclerotic plaques.  In addition, oxidized phospholipids appear to bind to Lp (a); levels of Lp (a) and oxidized phospholipids are highly correlated.  Both elevated oxidized phospholipid and Lp (a) concentrations are associated with increased CVD risk.2,3

Mendelian randomization studies have shown that genetic variants associated with Lp (a) level are associated with CVD risk.  Smaller apolipoprotein (a) isoforms are associated with higher levels of Lp (a) in circulation, and both Lp (a) level (mass or particle concentration) and genetic variants associated with smaller isoforms have been associated with higher CVD risk in a dose-dependent manner (i.e., more alleles associated with higher CVD risk).  Thus, both traditional observational studies and studies of genetic variants that affect Lp (a) levels have been associated with CVD risk, which provides strong support for a causal relationship between Lp (a) level and CVD risk.

Statin therapy has little effect on the Lp (a) concentration.4  However, several interventions are known to affect the circulating Lp (a) concentration, but evidence has been lacking for a benefit of lowering Lp (a) level per se as an intervention to reduce CVD risk.  Among the interventions known to lower Lp (a) are niacin, estrogen, LDL apheresis, cholesterol ester transfer protein inhibition, and two drugs used to treat familial hypercholesterolemia (mipomersen and lomitapide).4  In addition, the proprotein convertase subtilisin kexin type 9 (PCKS9) inhibitor class of lipid-altering medications is known to lower Lp (a) by 25% or more.5-7

Because of the ability of PCSK9 inhibitors to lower Lp (a) mass and particle concentration, as well as LDL cholesterol and LDL particle concentration, it would be expected that if Lp (a) lowering produced CVD benefit, that the risk reduction associated with PCSK9 inhibitor therapy would be expected to be greater among those with elevated Lp (a) concentrations.

The Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) was a CVD outcomes trial that tested the effects of treatment with maximally tolerated statin therapy plus the PCSK9 inhibitor evolocumab or placebo on CVD event risk in patients with stable atherosclerotic CVD at the time of randomization.  The main results showed a 15% reduction in the primary composite event outcome and a 20% reduction in a key secondary composite measure over a median treatment period of 22 months.8

A pre-planned subgroup analysis was presented at the 86th Annual Congress of the European Atherosclerosis Society in Lisbon, Spain in early May 2018.  At baseline, the median Lp (a) level was 37 nmol/L and the 25th and 75th percentiles were 13 and 165 nmol/L, respectively.  A higher baseline Lp (a) particle concentration was associated with greater risk for a CVD event in the placebo group, with the fourth quartile having 26% higher (95% confidence interval 2% to 56%) risk of coronary heart disease death or myocardial infarction compared with the first quartile.9

Evolocumab treatment lowered the Lp (a) concentration and the degree of lowering was related to the baseline level.  Median absolute (nmol/L) changes in Lp (a) were -1, -9, -24 and -36 nmol/L in the first through fourth quartiles, respectively.  An analysis of the results for those with baseline Lp (a) above and below the median baseline level showed a larger risk reduction in those with values above the median than below (24% vs. 15%) for the outcome of CV death, myocardial infarction or stroke.  The number needed to treat (NNT) to prevent one event was lower in those with Lp (a) above the median (NNT = 36) than those below the median (NNT = 79).  In addition, cumulative CVD event incidence was lowest in those who achieved both Lp (a) and LDL cholesterol levels at or below the median (6.57%), was intermediate in those who achieved only one value at or below the median (7.88-8.45%) and was highest in those who had both levels above the median value (9.43%).9,10

These findings add to the body of evidence supporting a causal role for Lp (a) in CVD risk.  They also provide support for the view that lowering Lp (a) reduces CVD event risk, and therefore is a promising therapeutic target.  Thus, PCSK9 inhibitor therapy may be a reasonable consideration for high risk patients who have elevated Lp (a).  These results also confer enhanced optimism regarding the potential efficacy of therapies in development that target Lp (a), such as monoclonal antibodies and an antisense oligonucleotide for apolipoprotein (a).11

References

  1. Nordestgaard BG, Chapman MJ, Ray K, et al. Lipoprotein (a) as a cardiovascular risk factor: current status. Eur Heart J. 2010;31:2844-2853.
  2. Kronenberg F. Human genetics and the causal role of lipoprotein(a) for various diseases. Cardiovasc Drugs Ther. 2016;30:87-100.
  3. Tsimikas S, Witztum JL. The role of oxidized phospholipids in mediating lipoprotein(a) atherogenicity. Curr Opin Lipidol. 2008;19:369-377.
  4. Van Capelleveen JC, van der Valk FM, Stroes ESG. Current therapies for lowering lipoprotein (a). J Lipid Res. 2016;57:1612-1618.
  5. Raal F, Giugliano RP, Sabatine MS, et al. Reduction in Lp(a) with PCSK9 monoclonal antibody evolocumab (AMG 145): a pooled analysis of more than 1,300 patients in 4 phase II trials. J Am Coll Cardiol. 2014;63:1278-1288.
  6. Raal FJ, Giugliano RP, Sabatine MS, et al. PCSK9 inhibition-mediated reduction in Lp(a) with evolocumab: an analysis of 10 clinical trials and the LDL receptor’s role. J Lipid Res. 2016;57:1086-1096.
  7. Gaudet D, Watts GF, Robinson JG, et al. Effect of alirocumab on lipoprotein(a) over ≥1.5 years (from the phase 3 ODYSSEY program). Am J Cardiol. 2017;119:40-46.
  8. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376:1713-1722.
  9. Davenport L. Lp(a) levels may modulate CV benefits of evolocumab: FOURIER – Medscape – May 09, 2018. Accessed at file:///Users/Mary/Downloads/FOURIER%20Lp(a)%20Level%20Influences%20Benefit%20from%20Evolocumab%2010May18.pdf.
  10. Maxwell YL. Unlocking Lp(a): baseline levels matter, but so too does absolute reduction. tctMD/the heart beat. May 08, 2018. Accessed at https://www.tctmd.com/news/unlocking-lpa-baseline-levels-matter-so-too-does-absolute-reduction.

    11.  Vuorio A, Watts GF, Kovanen PT. Depicting new pharmacological strategies for familial hypercholesterolaemia involving lipoprotein(a). Eur

Photo by Joel Filipe

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