An Update on Lipoprotein(a): The Latest on Testing, Treatment, and Guideline Recommendations

Expert Analysis

Pamela L Alebna, MB CHB; Anurag Mehta, MD, FACC

November 22, 2023

Quick Takes

Lipoprotein(a) (Lp[a]) is an independent risk factor for atherosclerotic cardiovascular disease (CVD) and calcific valvular aortic stenosis.
Lp(a) exhibits significant race/ethnic variations, with levels highest among persons of African ancestry.
Lp(a) levels typically do not change after 5 years of age except during times of significant inflammation, liver disease, or kidney disease; hence, levels should be interpreted cautiously during these times.
Current guidelines support once-in-a-lifetime measurement in most individuals with increased risk of atherosclerotic CVD.
Emerging data appear to show a strong correlation with high-sensitivity C-reactive protein levels for predicting CVD risk.
New lines of therapy targeting lipoprotein(a) (LPA) gene translation are being developed.

Lipoprotein(a) (Lp[a]) is a low-density lipoprotein–like molecule with an apolipoprotein (b) moiety that is covalently attached to apolipoprotein (a) (Apo[a]), a plasminogen-like protein that confers several pathologic features to Lp(a). Produced mainly in the liver, Lp(a) has a wide spectrum of characteristics, including atherogenicity, thrombogenicity, and proinflammatory properties; hence, it may have pathologic effects on multiple systems. Its physiologic function has been a topic of debate, and it is thought to have a role in wound healing. However, many individuals have undetectable Lp(a) levels, which raises the relevance of its function. An estimated 20-25% of the world's population is believed to have elevated levels.

Table 1: Phase 2 and 3 Trials of Novel Therapies Targeting *LPA* Gene Transcription Rate Using siRNAs and Gene Translation With ASOs
Study Name, Phase (Therapy)	Therapy Mechanism	Therapy Formulation	Population	Outcome
OCEAN(a) DOSE,^a phase 2 (olpasiran [AMG 890])	siRNA that reduces Lp(a) synthesis in the liver	SC injection of 10, 75, or 225 mg every 12 weeks, or 225 mg every 24 weeks	281 participants 18-80 years of age Lp(a) >150 nmol/L Evidence of ASCVD	Percent change in Lp(a) level at 36 weeks Preliminary results: percent reduction of 70.5% to 110.5%
SLN360,^b phase 2 (SLN360)	Double-stranded siRNA targeting LPA mRNA	SC injection of 30, 100, 300, or 600 mg vs. placebo	BMI 18-32 kg/m2 Lp(a) level >125 nmol/L At high risk of ASCVD events	Change of Lp(a) level from baseline
ORION-11,^c phase 3 (inclisiran)	siRNA that inhibits PCSK9 synthesis	SC injection of 300 mg on day 1 and day 90, then every 6 months vs. placebo	≥18 years of age LDL-C level ≥70 mg/dL History of ASCVD	Secondary outcome evaluating effect of inclisiran on Lp(a) level Preliminary results: percent reduction of Lp(a) level by 28.5%
Lp(a)HORIZON,^d phase 3 (pelacarsen [TQJ230])	ASO against Apo(a)	SC injection of 80 mg monthly vs. placebo	8,323 participants 18-90 years of age Lp(a) level ≥70 mg/dL Established CVD	Time to occurrence of MACE in 4 years
AKCEA-APO(a)-LRx,^e phase 2 (pelacarsen [ISIS 681257])	ASO against Apo(a)	SC injection of 20, 40, or 60 mg every 4 weeks; 20 mg every 2 weeks; or 20 mg every week vs. placebo for 6-12 months	286 participants 18-10 years of age Lp(a) level ≥60 mg/dL Diagnosed CVD Must be on standard-of-care preventive therapy for CVD risk factors other than elevated Lp(a) levels	Percent change from baseline Lp(a) level Preliminary results: dose-dependent reduction ranging 35-80%
TQJ230,^f phase 3 (pelacarsen [TQJ230])	ASO against Apo(a)	SC injection of 80 mg monthly vs. placebo	60 participants Established ASCVD Currently undergoing lipoprotein apheresis for isolated Lp(a)	Superiority of pelacarsen over placebo in reducing the rate of lipoprotein apheresis sessions
KRAKEN,^g phase 2 (LY3473329)	siRNA-based approach targeting Apo(a)	Daily oral dose vs. placebo	233 participants Lp(a) level ≥175 nmol/L At high risk of ASCVD	Percent change from baseline Lp(a) level to week 12
LY3819469,^h phase 2 (LY3819469)	siRNA-based approach targeting Apo(a)	SC injections in four different doses vs. placebo	254 participants >40 years of age Lp(a) level ≥175 nmol/L at screening	Percent change from baseline in time-averaged Lp(a) level

Table 1: Phase 2 and 3 Trials of Novel Therapies Targeting LPA Gene Transcription Rate Using siRNAs and Gene Translation With ASOs Courtesy of Alebna PL, Mehta A.

^aa OCEAN(a) DOSE (Olpasiran Trials of Cardiovascular Events and LipoproteiN(a) Reduction–Dose Finding Study)

^b SLN360 (Evaluate SLN360 in Participants With Elevated Lipoprotein(a) at High Risk of Atherosclerotic Cardiovascular Disease Events)

^c ORION-11 (Impact of Inclisiran on LDL-C Over 18 months in Patients With ASCVD or Risk-Equivalent)

^d Lp(a) HORIZON (Assessing the Impact of Lipoprotein (a) Lowering With Pelacarsen (TQJ230) on Major Cardiovascular Events in Patients With CVD)

^e AKCEA-APO(a)-LRx (Phase 2 Study of ISIS 681257 [AKCEA-APO(a)-LRx] in Participants With Hyperlipoproteinemia[a] and Cardiovascular Disease)

^f TQJ230 (A Multicenter Trial Assessing the Impact of Lipoprotein(a) Lowering With Pelacarsen [TQJ230] on the Rate of Weekly Lipoprotein Apheresis Sessions in Patients With Hyperlipoproteinemia[a] and Established Cardiovascular Disease in Germany)

^g KRAKEN (A Study of LY3473329 in Adult Participants With Elevated Lipoprotein(a) at High Risk for Cardiovascular Events)

^h LY3819469 (A Study of LY3819469 in Participants With Elevated Lipoprotein[a])

Apo(a) = apolipoprotein(a); ASCVD = atherosclerotic cardiovascular disease; ASO = antisense oligonucleotide; BMI = body mass index; CVD = cardiovascular disease; LDL-C = low-density lipoprotein cholesterol; Lp(a) = lipoprotein(a); LPA = lipoprotein(a) gene; MACE = major adverse cardiovascular events; mRNA = messenger RNA; PCSK9 = proprotein convertase subtilisin/kexin 9; SC = subcutaneous; siRNA = small interfering RNA.

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