Lipoprotein(a) Elevation (Hyperlipoproteinemia): Drug Therapy

Therapeutic Targets

  • Reduction of severely elevated lipoprotein levels in the future possible by antisense therapy).
  • Treatment of concomitant hyperlipoproteinemias (lipid metabolic disorders).

Therapy recommendations

Therapy of hyperlipoproteinemia (in this case: Lipoprotein(a) elevation) is based on the following pillars:

  • Secondary prevention, that is, reduction of risk factors [no effect on lipoprotein(a) elevation].
  • Micronutrient therapy (vital substances; see below Therapy with micronutrients).
  • Patients with severely elevated Lp(a) levels: lipoprotein apheresis (see below “Further therapy“).
  • See also “Possible future therapeutic measures in case of lipoprotein(a) elevation “
  • See also under “Further therapy” (lifestyle modification, etc.). – Lipoprotein(a) serum concentrations are practically not to influence by lifestyle measures; lifestyle changes in the sense of a dietary influence of elevated triglycerides and LDL cholesterol are, however, useful.

Intervention strategy according to overall cardiovascular risk and LDL cholesterol levels.

Total cardiovascular risk LDL level
<70 mg/dL< 1.8 mmol/dL 70 to < 100 mg/dL1.8 to < 2.5 mmol/dL 100 to < 155 mg/dL2.5 to < 4.0 mmol/dL 155 to 190 mg/dL4.0 to 4.9 mmol/dL > 190 mg/dL> 4.9 mmol/dL
<1% (low risk) No lipid lowering No lipid lowering Lifestyle intervention Lifestyle Intervention Lifestyle intervention;if uncontrolled, consider medication
Evidence class/level I/C I/C I/C I/C IIa/C
≥ 1 to < 5% (or moderate risk). Lifestyle intervention Lifestyle Intervention Lifestyle intervention;if uncontrolled, consider medication Lifestyle intervention;if uncontrolled, consider medication Lifestyle intervention;if uncontrolled, consider medication
Evidence class/level I/C I/C IIa/A IIa/A I/A
≥ 5 to < 10 % (or high) Lifestyle intervention,consider medications* Lifestyle intervention,consider medication* Lifestyle modification and immediate drug intervention. Lifestyle modification and immediate drug intervention Lifestyle modification and immediate drug intervention
Evidence class/level IIa/A IIa/A IIa/A I/A I/A
≥ 10 % (or very high risk) Lifestyle intervention,consider medications* Lifestyle modification and immediate drug intervention. Lifestyle modification and immediate drug intervention Lifestyle modification and immediate drug intervention Lifestyle modification and immediate drug intervention
Evidence class/level IIa/A I/A I/A I/A

* In patients with myocardial infarction (heart attack), statin therapy should be considered regardless of LDL cholesterol level. The current European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) guidelines on dyslipidemia recommend even lower low-density lipoprotein cholesterol (LDL-C) target levels [guidelines: see below 2019 ESC/EAS Guidelines]:

Total cardiovascular risk Target LDL cholesterol Comments
<1% (low risk) <3 mmol/l < 116 mg/dl
≥ 1 to < 5% (or moderate risk). < 2.6 mmol/l < 100 mg/dl
≥ 5 to < 10 % (or high) < 1.8 mmol/l < 70 mg/dl Or at least 50% LDL-C reduction; this group includes, among others, patients with familial hypercholesterolemia and diabetics
≥ 10% (or very high risk). < 1.4 mmol/l < 55 mg/dl Or at least 50% reduction in LDL-C.

No current statin use: this likely requires high-intensity LDL-lowering therapy.Current LDL-lowering treatment: increased treatment intensity is required.

<1.0 mmol/l < 40 mg/dl High-risk patients who have had a 2nd vascular event within 2 years despite maximal lipid-lowering therapy

Other treatment targets

  • Non-HDL-C: Non-HDL-C secondary targets are <2.2, 2.6, and 3.4 mmol/l (<85, 100, and 130 mg/dl) for individuals at very high, high, and intermediate risk, respectively.
  • ApoB: ApoB secondary targets are < 65, 80, and 100 mg/dl for individuals at very high, high, and intermediate risk, respectively.
  • Triglycerides: no target, but < 1.7 mmol/l.
  • Diabetes HbA1c: < 7%

Determination of total cardiovascular risk by priority:

Very high risk
  • Cardiovascular disease/cardiovascular disease (CVD).
  • Type 2 diabetes or type 1 diabetes with target organ damage.
  • Score ≥ 10
High risk
  • Pronounced individual risk factors such as:
    • Familial dyslipidemia (lipid metabolism disorder).
    • Severe hypertension (high blood pressure)
  • Score ≥ 5 and < 10
Moderate risk
  • Family history: coronary heart disease (CHD) – before age 55 (men) or 65 (women).
  • Abdominal obesity (waist circumference).
    • Women: ≥ 88 cm
    • Men: ≥ 102 cm
  • Lack of physical activity (lack of exercise).
  • Elevated triglycerides and hs-CRP
  • Score ≥ 1 to < 5
Low risk
  • Score <1

See also under: HeartScore or Euro Score

Note: Risk may be higher than that calculated by the SCORE risk estimation system: The following factors contribute to the increase in risk:

  • Socially disadvantaged
  • Sedentary patients and those with central obesity.
  • Patients with diabetes mellitus
  • Patients with low HDL cholesterol or apolipoprotein A1, apolipoprotein B as well as elevated triglycerides, fibrinogen, homocysteine, Lp(a) levels, hs-CRP; familial hypercholesterolemia; impaired glucose tolerance (inadequate regulation of blood glucose after oral glucose intake).
  • Asymptomatic subjects with preclinical evidence of atherosclerosis (arteriosclerosis; hardening of the arteries), for example, presence of plaques or increased intima-media thickness of the common carotid artery.
  • Patients with impaired renal function
  • Patients with a family history of premature coronary artery disease (CAD; coronary artery disease).
  • Patients with obesity and physical inactivity

In contrast, risk may be lower in those with very high HDL cholesterol or a family history of longevity. Targets defined according to SCORE risk categories:

Very high risk < 1.8 mmol/L (= 70 mg/dL) and/or an LDL reduction of at least 50% if the baseline value is in the range between 70 mg/dl and 135 mg/dl (1.8 mmol/L and 3.5 mmol/L) (class 1/B instead of previously 1/A recommendation)
High risk <2.5 mmol/L (= 100 mg/dL), alternatively lower LDL cholesterol by at least 50% if baseline is in the range of 100 mg/dl to 200 mg/dl (2.6 – 5.1 mmol/L) (1/B recommendation)
Moderate risk <3.0 mmol/L (= 115 mg/dL)

Medication:

  • Lowering LDL cholesterol (see hypercholesterolemia below).
  • Furthermore, the highest possible HDL level is also important for the prevention of severe cardiovascular disease. It should be > 1.0 mmol/l (> 46 mg/dl).
  • Triglyceride levels should be in the following range: < 1.7 mmol/l (< 150 mg/dl).

Possible future therapy for lipoprotein (a) elevation.

  • An antisense oligonucleotide (targeting apo(a) mRNA) that blocks the production of lipoprotein(a) in the liver significantly reduced serum concentrations in initial clinical trials: Lp(a) levels decreased by 67-72% under weekly injections of “IONIS-APO(a)Rx”.
  • Phase II study: antisense therapy (AKCEA-APO(a)-LRx) in study participants who had Lp(a) levels of at least 60 mg/dl (150 nmol/L) and cardiovascular disease (coronary artery disease (CAD), myocardial infarction, peripheral arterial disease (PAVD), or apoplexy/TIA) showed a dose-dependent effect of the drug after 6 months of exposure:
    • Placebo group: Lp(a) levels decreased by a mean of 6%.
    • 20 mg dose every 4 weeks: decreased Lp(a) by a mean of 35% (p = 0.003)
    • 40 mg dose every 4 weeks by 56% (p ˂ 0.001).
    • 20 mg dose every 2 weeks by 58% (p ˂ 0.001)
    • 60 mg dose every 4 weeks by 72% (p ˂ 0.001)
    • 20 mg dose every 2 weeks by 80% (p ˂ 0.001)

    Side effects: Injection site reactions (27%); treatment group: 90% versus placebo group 83%.An endpoint study is next to prove efficacy on risk of serious cardiovascular events.