Lipoprotein(a) in atherosclerosis: from pathophysiology to clinical relevance and treatment options

Figures & data

Figure 1. Molecular structure of apolipoprotein(a). Apolipoprotein(a) contains 10 subtypes of KIV repeats, as one copy of KIV₁, multiple copies of KIV₂ and one copy each of KIV₃ to KIV₁₀, KV and inactive protease-like (P) domain.

Figure 2. Role of lipoprotein(a) in the atherosclerotic process. The three defined roles of lipoprotein(a) in progression of the atherosclerotic process include its proatherogenic, prothrombotic, and pro-inflammatory effects. hsCRP, high sensitivity C-reactve protein; IL-6, interleukin 6; TNFα, tumour necrosis factor α.

Table 1. Overview of studies with lipid-lowering drugs and their effect on lipoprotein(a).

Treatment strategy	Outcome study	Changes in Lp(a) level	Study population (n)	Treatment intervention	Primary endpoint	Outcome	References
Fibrates	Meta-analysis of head-to-head randomized controlled trials of statins vs. fibrates	−2.70 mg/dL	Heterogenous study population	Fibrates	Lp(a) reduction in comparison to statins	Fibrates have greater effect on Lp(a) reduction than statins	[69]
Niacin	The Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE)	−31%	Patients with pre-existed atherosclerotic vascular disease on optimal hypolipemic therapy (n = 25,673)	Extended-release niacin/laropiprant	Nonfatal myocardial infarction or death from coronary causes, stroke of any type, or coronary or noncoronary revascularization	No impact on cardiovascular events	[70,71]
	Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglyceride and Impact on Global Health Outcomes (AIM-HIGH)	−21%	Patients with atherosclerotic cardiovascular disease and LDL cholesterol <70 mg/dL	Extended-release niacin	Death from coronary disease, nonfatal myocardial infarction, ischaemic stroke, hospitalization for acute coronary syndrome, coronary or cerebrovascular revascularization	No impact on cardiovascular events	[72,73]
Lipoprotein apheresis	Lipoprotein apheresis in patients with maximally tolerated lipid-lowering therapy, lipoprotein(a) hyperlipoproteinemia, and progressive cardiovascular disease: prospective observational multicentre study.	−70%; directly after treatment	Patients with hypolipoproteinemia (a) and progressive cardiovascular disease despite maximally tolerated lipid-lowering	Lipoprotein apheresis	Cardiovascular events	Decrease in cardiovascular events after regular treatment with lipoprotein apheresis	[74]
Statins	Meta-analysis and subanalysis of prospective trials	+0 to 20%	Heterogenous study population	Statins	Lp(a) reduction	No effects or even increase in Lp(a) levels; Lp(a) is an independent predictor of cardiovascular events despite statin therapy	[56,75,76]
Ezetimibe	Meta-analysis of randomised controlled trials	−7%	Patients with primary hypercholesterolaemia	Ezetimibe	Lp(a) reduction	Ezetimibe provide modest Lp(a) reduction	[77]
PCSK-9 inhibitors	Alirocumab and cardiovascular outcomes after acute coronary syndrome (ODDYSEY outcomes)	−20 to 29%	Patients with recent acute coronary syndrome and low-density lipoprotein cholesterol >70 mg/dL despite maximum tolerated statins (n = 18,924)	Alirocumab	Coronary heart disease deaths, non-fatal myocardial infarction, ischaemic stroke, hospitalization for unstable angina	Relative risk reduction of 0.6% per 1 mg/dL reduction, for CV events and non-fatal myocardial infarction, but not for the stroke; clinically meaningful reduction only for patients with higher baseline Lp(a) (>21.2 mg/dL)	[78,79]
	Further cardiovascular outcomes research with PCSK9 inhibition in subjects with elevated risk (FOURIER)	−25 to 30%	Patients with established cardiovascular disease on optimal hypolipidemic therapy (n = 25,096)	Evolocumab	Coronary heart disease death, myocardial infarction, stroke, urgent coronary revascularization	Overall 16% reduction of coronary heart disease death, myocardial infarction or urgent revascularization, and 23% reduction for Lp(a) >37 nmol/L	[80, 81]

Table 2. Overview of studies with nonlipid-lowering drugs and their effect on lipoprotein(a).

Treatment strategy	Outcome study	Changes in Lp(a) level	Study population (n)	Treatment intervention	Primary endpoints	Outcome	Reference
Aspirin	Polymorphism in the Apolipoprotein(a) Gene, Plasma Lipoprotein(a), Cardiovascular Disease, and Low-Dose Aspirin Therapy	−20%	Established atherosclerotic disease—coronary artery disease or cerebral infarction	81 mg/day	Lp(a) reduction, cardiovascular mortality	Effectively reduces Lp(a) levels, more than 2-fold reduction in cardiovascular events in carriers of rs3798220 allele	[82,83]
Hormone replacement therapy	The Heart and Oestrogen/Progestin Replacement Study (HERS)	−17%	Postmenopausal woman with coronary artery disease and an intact uterus (n = 2763)	Oestrogen; progestin	Non-fatal myocardial infarction and cardiovascular death	Significant reduction of myocardial infarction, but not coronary heart disease deaths in woman with >8/8 mg/dL reduction in Lp(a)	[84]

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