Definition of dyslipidemia

  • the previously used term hyperlipidemia is now replaced by the broader term dyslipoproteinemia or dyslipidemia (DLP), which better reflects the fact that the pathology may not be limited to elevated blood lipid levels
  • metabolic disease with increased concentration of:
    • total cholesterol (>5 mmol/l) and/or
    • LDL-cholesterol (>3 mmol/l) and/or
    • Lp(a) (risk value >430 nmol/L)
    • triacylglycerols (TAG > 2 mmol/L)
  • there may be a concomitant decrease (<1 mmol/L) or increase (>1.6 mmol/L) in HDL cholesterol
  • the cause: increased lipid synthesis and/or decreased lipid catabolism
  • the most serious clinical consequence of prolonged dyslipidemia is the premature manifestation of atherosclerotic cardiovascular disease (ASCVD), especially CAD, PAD, and stroke (mainly TOAST type 1 or 3)
  • deposition of LDL-C and apolipoprotein B (ApoB) in the arterial wall is the key initiating event in atherogenesis
  • another important risk factor for atherogenesis is lipoprotein (a) – Lp(a) (risk level > 430 nmol/L)
    • structural similarity to plasminogen causes competition for its activator, resulting in impaired fibrinolysis and endothelial dysfunction

Notes on dyslipidemia therapy

  • treatment reduces the risk of stroke and mortality by ~21-26%
    • meta-analysis of 42 studies (n=121,285) – RR 0.84
    • SPARCL (atorvastatin) – RR 0.85/5 years, Heart Protection Study (HPS) (simvastatin), ASCOTT-LLA (simvastatin), JUPITER (rosuvastatin)
    • the effect of statin treatment is directly related to the degree of LDL-c reduction (a 10% decrease in LDL-c reduces the risk of stroke by 13.2%)
      • according to the data analysis of the SPARCL trial, a 39 mg/dl (1 mmol/l) reduction in LDL-C led to a 20% reduction in stroke risk [Amarenco, 2020]
      • there is no lower limit for LDL-C values or ‘J’-curve effect
    • effective in stroke prevention in patients with manifest cardiovascular disease (CVD), after a TIA/stroke, but also in people with increased overall CV risk without a history of CVD
    • the effect is also seen in patients with other than pure atherosclerotic stroke etiology ⇒ treatment should be started ASAP after the stroke
    • intensive therapy does not increase the risk of hemorrhagic stroke, according to meta-analyses [Masson, 2021]
  • randomized trials have shown a further reduction in ASCVD risk with the addition of ezetimibe and anti-PCSK9 antibodies to statins (correlating with a decrease in LDL-C)
  • fibrates or ethyl-icosapent can be added to the medication when triglyceridemia is significant
  • the clinical effect of HDL-raising drugs (niacin, CETP inhibitors) has not been demonstrated [Keene, 2014]

SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels)

  • 80 mg atorvastatin vs placebo were randomly assigned to 4731 patients with a history of stroke or TIA within one to six months before study entry
  • statin treatment achieved a mean LDL-C level of 1.9 mmol/l (73mg/dL)
    • mean LDL on placebo was 3.3 mmol/l (129 mg/dL)
  • a median follow-up of 4.9 years
  • fatal/nonfatal stroke 11.2% vs 13.1%  (ARR/5 let 2.2%, RRR 15%)
  • the 5-year absolute reduction in the risk of major cardiovascular events was 3.5%
  • the SPARCL trial clearly documented the beneficial effect of high-dose statin therapy in secondary stroke prevention

TST (Treat Stroke To Target 

  • comparison of intensive and conservative hypolipidemic intervention in patients after stroke (within the previous 3 months) or TIA (within the previous 15 days)
  • n= 2860 (1463 each group), median follow-up 3.5 years
  • mean baseline LDL cholesterol  was 135 mg/dL (3.5 mmol/L)
  • target LDL
    • lower-target LDL: < 70 mg/dL (1.8 mmol/L)
    • higher-target LDL:  90-110 mg/dL (2.3-2.8 mmol/L)
  • intensive treatment (mean LDL 1.8 mmol) vs conservative treatment (mean LDL 2.4 mmol/l)
  • the composite primary endpoint of major cardiovascular events included ischemic stroke, myocardial infarction, new symptoms leading to urgent coronary or carotid revascularization, or death from cardiovascular causes
  • combined endpoint 8.5% (lower target) vs. 10.9% (⇒ 22% decrease of RR in the intensive treatment group with comparable risk of hemorrhage)


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  • frequency of major congenital DLP in the population approx 2% of the adult population
  • lipid metabolism disorder is present in > 50% of the population
    • inappropriate diet, obesity, lack of physical activity, and smoking are involved

Clinical presentation

  • long latent period
  • less severe symptoms (at older ages or in severe, mostly congenital, forms):
    • xanthelasma (yellow bump on or near eyelid skinXanthelasma
    • arcus lipoides cornae  Arcus lipoides corneae
    • tendon and skin xanthomas  Xantoma tendinosum
  • atherosclerotic cardiovascular disease (ASCVD) is caused by plaque buildup in arterial walls and include
    • cerebrovascular disease, such as a  TIA, ischemic stroke, and pre-cerebral and cerebral artery stenosis
    • coronary artery disease (CAD) – such as myocardial infarction, angina, and coronary artery stenosis
    • peripheral artery disease (PAD) – claudications, limb ischemia
    • aortic atherosclerotic disease – such as abdominal aortic aneurysm and descending thoracic aneurysm

Diagnostic evaluation

Indication for testing

  • in adults > 18 years of age, test total cholesterol every 5 years (primary prevention)
  • complete lipid spectrum should be tested in:
    • adults >18 years of age with elevated total cholesterol concentrations
    • patients with manifest CVD (CAD, stroke, PAD)
      • the effect of therapy is also seen in patients without a clear atherosclerotic etiology of stroke
    • people without CVD (primary prevention) with additional risk factors (QRISK calculator):
      • type 1 and type 2 diabetes mellitus
      • evidence of subclinical atherosclerosis (IMT, ABI)
      • arterial hypertension
      • abdominal obesity
      • clinical signs of DLP (xanthelasma, xanthomas, arcus lipoides corneae)
      • CHRI
      • positive family history of premature clinical manifestation of atherosclerosis (first-degree relatives in men < 55 years, in women < 65 years)
  • repeat lipid panel testing in 4-8 weeks if DLP is newly detected in primary prevention
    • during this period, maintain a normal lifestyle (no change in diet or weight loss)
    • if the result of two consecutive lipid tests is significantly different in any parameter, perform a third critical test
  • exclude from screening patients for whom treatment would not be indicated (e.g. for life-limiting disease)

Further evaluation of a patient diagnosed with hyperlipidemia

  • family history (manifestation of ACVD in relatives)
  • general physical examination, BMI, BP + pulse, ECG
    • look for signs of DLP – xanthelasma, tendon or skin xanthomas, arcus corneae
    • exclude murmur over large arteries
  • basic metabolic panel to rule out the most common causes of secondary DLP
  • screening for possible subclinical atherosclerosis
    • stress ECG
    • neurosonology (Doppler ultrasound), including IMT measurement
      • arterial (carotid and/or femoral) plaque burden on arterial ultrasonography should be considered as a risk modifier in individuals at low or moderate risk
    • echocardiography
    • ABI (Ankle-Brachial Index)
    • Coronary Artery Calcium (CAC) Scoring
      • CAC score assessment with CT should be considered as a risk modifier in CV risk assessment of asymptomatic individuals at low or moderate risk
  • determine 10-year total cardiovascular risk (in primary prevention)
  • the Ankle-Brachial Pressure Index (ABPI) is a quick, non-invasive way to check for peripheral artery disease (PAD)
    • the disease occurs when narrowed arteries reduce blood flow to the limbs
    • an abnormal ABPI may be an independent predictor of mortality, as it reflects the burden of atherosclerosis
  • it is a ratio of the blood pressure at the ankle to the blood pressure in the upper arm (brachial BP)
    • the patient must be in the supine position, without the head or any extremities dangling over the edge of the table
    • the brachial BP is measured in both arms, and the higher value is used
  • a low ABPI index indicates narrowing or occlusion of peripheral arteries in the legs

   ankle BP

ABPI = ———————————

brachial BP

Interpretation of ABPI
> 1.3 abnormal  (vessel hardening due to calcifications)
1-1.2 normal
0.8-0.89 mild PAD
 0.8 – 0.5 moderate PAD
< 0.5 severe PAD

Therapeutic target levels

Secondary prevention / very-high risk FH
  • LDL-C reduction ≥ 50% from baseline  +  LDL-C goal < 1.4 mmol/L (< 55mg/dL)
For patients with ASCVD who experience a second vascular event within 2 years (not necessarily of the same type as the first event) while taking maximally tolerated statin therapy
  • consider LDL-C  < 1.0 mmol/L (< 40mg/dl)
Primary prevention
  • very-high risk without FH –  LDL-C reduction ≥ 50% from baseline  +  LDL-C <1.4 mmol/L (<55mg/dL)
  • high risk – LDL-C reduction of  ≥ 50% from baseline and an LDL-C goal of <1.8 mmol/L (<70 mg/dL)
  • moderate risk – LDL-C goal  <2.6 mmol/L (<100mg/dl)
  • low risk – LDL-C goal <3 mmol/L (<116 mg/dL)
  • TAG <1.7 mmol/L (<150 mg/dL) indicates lower risk, and higher levels indicate a need to look for other risk factors
  • ApoB secondary goals are <65, 80, and 100 mg/dL for very-high-, high-, and moderate-risk people, respectively

Very high-risk FH (familial hypercholesterolemia):  FH + ASCVD or major risk factors
High-risk FH: FH without major risk factors

  •  documented ASCVD (either clinical or clear on imaging)
    • CAD
      • acute coronary syndrome (ACS) – MI or unstable angina
      • stable AP
      • coronary revascularization (PCI, CABG) or other arterial revascularization procedures
    • stroke/TIA
    • peripheral arterial disease (PAD)
    • significant atherosclerosis on carotid ultrasound, coronary CTA, etc.
  • diabetes with organ damage (proteinuria, retinopathy, polyneuropathy) or ≥ 3 major risk factors and/or T1DM with long duration (> 20 years)
  • severe CKD (eGFR: <30 mL/min/1.73 m2 (0.5 mL/s)
  • a calculated SCORE ≥ 10% for a 10-year risk of fatal CVD
  • FH + ASCVD or with another major risk factor
High-risk (elevated single risk factors)
  • total cholesterol > 8 mmol/L (> 310 mg/dL)
  • LDL-C >4.9 mmol/L (>190 mg/dL)
  • BP ≥  180/110 mmHg
  • patients with FH without other major risk factors
  • diabetes without organ damage with a duration ≥ 10 years or any other additional risk factor
  • moderate CKD – eGFR  30-59 mL/min/1.73 m2 ( 0.5-0.99 mL/s)
  • calculated SCORE ≥ 5% and <10% for a 10-year risk of fatal CVD
  • T1DM (age < 35y) or T2DM (age < 50y)  with diabetes duration <10 years without other risk factors
  • calculated SCORE  1 % and  <5% for a 10-year risk of fatal CVD
  • calculated SCORE <1% for a 10-year risk of fatal CVD


Lifestyle modification and treatment of other vascular risk factors

Pharmacotherapy of dyslipidemia

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