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Cited by 4,854Lipoproteins and Cardiovascular HealthDiabetes, Cardiovascular Risks, and LipoproteinsBlood Pressure and Hypertension Studies

2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk

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Mach, François, Baigent, Colin, Catapano, Alberico L., Koskinas, Konstantinos C., Casula, Manuela, Badimon, Lina, Chapman, M. John, De Backer, Guy G. +92 more·2019·Atherosclerosis
DOI 10.1016/j.atherosclerosis.2019.08.014
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Abstract

The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS).The disclosure forms of all experts involved in the development of these Guidelines are available on the ESC website www.escardio.org/guidelines.

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Crossref · 10.1016/j.atherosclerosis.2019.08.014

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Claims the paper makes

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  • Findingnone given
    § Box 3 · p. 12

    In some age categories, most people, especially males, have estimated 10-year cumulative CV death risks above 5-10% based on age alone, even when other risk factors are relatively low.

    “In some age categories, the majority of people, especially males, will have estimated 10 year cumulative CV death risks exceeding the 5-10% level, based on age only, even when other CV risk factor levels are relatively low.”
    Quote in the paperSubstantial claim
  • Findingnone given
    § 6. Treatment targets and goals · p. 18

    No LDL-C level below which benefit stops or harm occurs has been defined.

    “No level of LDL-C below which benefit ceases or harm occurs has been defined.”
    Quote in the paperSubstantial claim
  • Findingnone given
    § 6. Treatment targets and goals · p. 20

    No specific goals for HDL-C or triglyceride levels have been established in clinical trials.

    “To date, no specific goals for HDL-C or TG levels have been determined in clinical trials”
    Quote in the paperSubstantial claim
  • Findingcitation
    § 7.4.2. Dietary fat · p. 21

    Not enough data are available to recommend an optimal n-3:n-6 fatty acid ratio.

    “Not enough data are available to make a recommendation regarding the optimal n3:n-6 fatty acid ratio [177,178].”
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  • Findingnone given
    § 7.5.1. Phytosterols · p. 22

    No studies have yet examined the subsequent effect of phytosterols on CVD.

    “However, to date no studies have been performed on the subsequent effect on CVD.”
    Quote in the paperSubstantial claim
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  • May combine two claims. 189
  • The quote only partly states this claim. 2

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    Findingnone given
    § Box 3 · p. 11

    More women die from CVD than men.

    “Ultimately, more women die from CVD than men.”
    Quote in the paperNot a substantial claim

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    Findingown data
    § Box 3 · p. 11

    The multiplier from fatal to total CVD risk is higher in women and lower in older people.

    “the multiplier is higher in women and lower in older people.”
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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Findingnone given
    § Cost-effectiveness · p. 11

    Smoking cessation roughly halves cumulative risk within a fairly short time.

    “In general, people who stop smoking halve their cumulative risk over a relatively short period of time.”
    Quote in the paperNot a substantial claim

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    Findingnone given
    § Box 3 · p. 11

    Risk estimates are lower in women than in men.

    “Risk estimates are lower in women than in men.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Box 3 · p. 11

    In men, total CVD event risk is about three times the fatal CVD risk, so a SCORE risk of 5% corresponds to about 15% total CVD risk.

    “The SCORE data indicate that the total CVD event risk is about three times higher than the risk of fatal CVD for men, so a SCORE risk of 5% translates into a CVD risk of ∼15% of total (fatal + non-fatal) CVD endpoints”
    Quote in the paperNot a substantial claim

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    Findingnone given
    § 7.5. Dietary supplements and functional foods for the treatment of dyslipidaemias · p. 22

    The available evidence on functional foods in dyslipidaemia is incomplete, with the main gap being a lack of diet-based intervention trials of sufficient duration relevant to the natural history of dyslipidaemia and CVD.

    “Overall, the available evidence on functional foods so far identified in this field is incomplete; the major gap is an absence of diet-based intervention trials of enough duration to be relevant for the natural history of dyslipidaemia and CVD.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given
    § 2. Introduction · p. 5

    Research on the clinical safety of very low achieved LDL-C levels has been reassuring, though longer monitoring is still needed.

    “In addition, studies of the clinical safety of these very low achieved LDL-C values have proved reassuring, albeit monitoring for longer periods is required.”
    Quote in the paperSubstantial claim

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    Premisecitation
    § 2. Introduction · p. 5

    The lower the LDL-C level achieved, the lower the risk of later CV events, with no lower threshold for LDL-C and no J-curve effect.

    “Furthermore, these clinical trials have clearly indicated that the lower the achieved LDL-C values, the lower the risk of future cardiovascular (CV) events, with no lower limit for LDL-C values, or 'J'-curve effect.”
    Quote in the paperSubstantial claim

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    Premisecitation
    § 2. Introduction · p. 5

    Adding ezetimibe or PCSK9 monoclonal antibodies to statin treatment yields an additional decrease in ASCVD risk, and this decrease is directly and positively related to the absolute LDL-C reduction achieved incrementally.

    “Several recent placebo-controlled clinical studies have shown that the addition of either ezetimibe or antiproprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies (mAbs) to statin therapy provides a further reduction in atherosclerotic cardiovascular disease (ASCVD) risk, which is directly and positively correlated with the incrementally achieved absolute LDL-C reduction.”
    Quote in the paperSubstantial claim

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    Premisecitation
    § 2. Introduction · p. 5

    The ESC/EAS lipid guidelines that preceded the 2019 document were released in August 2016.

    “The previous ESC/EAS lipid Guidelines were published in August 2016 [1].”
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    Premisenone given
    § Cost-effectiveness · p. 11

    No threshold is universally applicable for risk-based advice.

    “While no threshold is universally applicable, the intensity of advice should increase with increasing risk.”
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    Premisenone given
    § Cost-effectiveness · p. 9

    Other risk estimation systems that use fatal and nonfatal events can also be recalibrated, but doing so is easier and more scientifically robust for mortality than for total events.

    “Other risk estimation systems-using both fatal and non-fatal events-can also be recalibrated, but the process is easier and scientifically more robust for mortality than for total events.”
    Quote in the paperNot a substantial claim

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    Premisereasoning
    § Cost-effectiveness · p. 10

    No risk estimation models are needed for persons with documented ASCVD, type 1 or type 2 DM, very high levels of individual risk factors, or chronic kidney disease; they all need active management of all risk factors.

    “Persons with documented ASCVD, type 1 or type 2 DM (T1DM and T2DM, respectively), very high levels of individual risk factors, or chronic kidney disease (CKD) are generally at very-high or high total CV risk. No risk estimation models are needed for such persons; they all need active management of all risk factors.”
    Quote in the paperSubstantial claim

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    Premisenone given
    § 4.2.1. Role of non-invasive cardiovascular imaging techniques in the assessment of total cardiovascular disease risk · p. 13

    Non-invasive imaging techniques can detect the presence, estimate the extent, and evaluate the clinical consequences of atherosclerotic vascular damage.

    “Non-invasive imaging techniques can detect the presence, estimate the extent, and evaluate the clinical consequences of atherosclerotic vascular damage.”
    Quote in the paperSubstantial claim

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    Premisenone given
    § Box 3 · p. 11

    Several factors modify SCORE-estimated risk, including social deprivation, obesity, physical inactivity, psychosocial stress, family history of premature CVD, chronic inflammatory disorders, major psychiatric disorders, HIV treatment, atrial fibrillation, left ventricular hypertrophy, chronic kidney disease, obstructive sleep apnoea, and non-alcoholic fatty liver disease.

    “Social deprivation: the origin of many of the causes of CVD. Obesity and central obesity as measured by the body mass index and waist circumference, respectively. Physical inactivity. Psychosocial stress including vital exhaustion.”
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    Premisenone given
    § Box 3 · p. 12

    All risk estimation systems are relatively crude and need attention to qualifying statements.

    “All risk estimation systems are relatively crude and require attention to qualifying statements.”
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    Study design and conductnone given
    § 1. Preamble · p. 3

    The Guidelines were produced after weighing the scientific and medical knowledge and evidence that existed at their date of publication.

    “The Guidelines were developed after careful consideration of the scientific and medical knowledge and the evidence available at the time of their dating.”
    Quote in the paperNot a substantial claim

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    Interpretationnone given
    § Cost-effectiveness · p. 11

    More prolonged and effective treatment produces greater risk reduction, though usually no more than about one-third of baseline risk.

    “The longer the treatment and the more effective it is, the greater the reduction in risk, but in general it will not be more than about one-third of the baseline risk.”
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    Premisecitation
    § 4.1.2. How to use the risk estimation charts · p. 13

    The cut-off for defining a country as low CVD risk is based on WHO data from the Global Burden of Disease Study.

    “in these Guidelines, the cut-off point for calling a country 'low CVD risk' is based on WHO data derived from the Global Burden of Disease Study.”
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    Premiseown data
    § Cost-effectiveness · p. 9

    The SCORE charts in these guidelines differ from the 2016 charts by extending age to 70, incorporating age interactions to reduce overestimation in older persons, and removing the 8 mmol/L cholesterol band.

    “age has been extended from age 65 to 70; (ii) the interaction between age and each of the other risk factors has been incorporated, thus reducing the overestimation of risk in older persons in the original Systematic Coronary Risk Estimation charts; and (iii) the cholesterol band of 8 mmoL/L has been removed”
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    Premisenone given
    § Cost-effectiveness · p. 9

    To convert fatal CVD risk to total CVD risk, multiply by 3 in men and by 4 in women, and slightly less in older people.

    “To convert the risk of fatal cardiovascular disease to risk of total (fatal + non-fatal) cardiovascular disease, multiply by 3 in men and by 4 in women, and slightly less in older people.”
    Quote in the paperNot a substantial claim

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    Premisecitation
    § 4.1.2. How to use the risk estimation charts · p. 13

    Social deprivation and psychosocial stress increase cardiovascular risk.

    “Social deprivation and psychosocial stress set the scene for increased risk [13].”
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    Study design and conductnone given
    § 1. Preamble · p. 3

    Diagnostic and therapeutic procedures underwent critical evaluation, including assessment of the risk-benefit ratio.

    “A critical evaluation of diagnostic and therapeutic procedures was performed, including assessment of the risk-benefit ratio.”
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    Study design and conductnone given
    § 1. Preamble · p. 3

    After suitable revisions, all experts involved in the Task Force approve the Guidelines.

    “After appropriate revisions the Guidelines are approved by all the experts involved in the Task Force.”
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    Interpretationnone given
    § Box 3 · p. 11

    Relative risks may be unexpectedly high in young persons even when absolute risk is low.

    “Relative risks may be unexpectedly high in young persons, even if absolute risk levels are low.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § 4.2.1. Role of non-invasive cardiovascular imaging techniques in the assessment of total cardiovascular disease risk · p. 13

    Detection of coronary artery calcification with noncontrast computed tomography gives a good estimate of atherosclerotic burden and is strongly associated with cardiovascular events.

    “Detection of coronary artery calcification with noncontrast computed tomography (CT) gives a good estimate of the atherosclerotic burden and is strongly associated with CV events [18].”
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    Premisenone given
    § Box 3 · p. 12

    Additional risk factors can be included in electronic risk estimation systems such as HeartScore.

    “Additional factors affecting risk can be accommodated in electronic risk estimation systems such as HeartScore (www.heartscore.org).”
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    Study design and conductnone given
    § 1. Preamble · p. 3

    The Task Force's entire financial support came from the ESC and EAS, with no involvement from the healthcare industry.

    “The Task Force received its entire financial support from the ESC and EAS without any involvement from the healthcare industry.”
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    Premisenone given
    § Box 3 · p. 11

    In apparently healthy persons, CVD risk usually results from multiple interacting risk factors.

    “In apparently healthy persons, CVD risk is most frequently the result of multiple, interacting risk factors.”
    Quote in the paperNot a substantial claim

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    Premisecitation
    § 4.1.2. How to use the risk estimation charts · p. 13

    High HDL-C up to 2.3 mmol/L or a family history of longevity can be associated with lower cardiovascular risk.

    “Some factors such as a high HDL-C up to 2.3 mmoL/L (90mg/dL) [17] or a family history of longevity can also be associated with lower risk.”
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    Interpretationcitation
    § Box 3 · p. 12

    Risk age is independent of the CV endpoint used, can be used in any population regardless of baseline risk or secular mortality changes, and therefore avoids recalibration.

    “Risk age has been shown to be independent of the CV endpoint used [6,8], can be used in any population regardless of baseline risk or secular changes in mortality, and therefore avoids the need for recalibration.”
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    Premisereasoning
    § 4.1.2. How to use the risk estimation charts · p. 13

    Use of low- or high-risk SCORE charts depends on the CVD mortality experience in each country.

    “Use of the low- or the high-risk SCORE charts will depend on the CVD mortality experience in each country.”
    Quote in the paperNot a substantial claim

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    Interpretationreasoning
    § Box 3 · p. 12

    A low absolute risk in young people may hide a very high relative risk that warrants at least intensive lifestyle advice.

    “A particular problem relates to young people with high levels of risk factors; a low absolute risk may conceal a very high relative risk requiring at least intensive lifestyle advice.”
    Quote in the paperSubstantial claim

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    Study design and conductnone given
    § 1. Preamble · p. 3

    Selected experts from both societies conducted a comprehensive review of published evidence for managing the condition, following ESC CPG policy.

    “Selected experts in the field from both societies undertook a comprehensive review of the published evidence for management of a given condition according to ESC Committee for Practice Guidelines (CPG) policy.”
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    Study design and conductnone given
    § 1. Preamble · p. 3

    The Task Force members were chosen by the ESC and EAS, with representation from relevant ESC sub-specialty groups, to represent professionals caring for patients with this condition.

    “The Members of this Task Force were selected by the ESC and EAS, including representation from relevant ESC sub-specialty groups, in order to represent professionals involved with the medical care of patients with this pathology.”
    Quote in the paperNot a substantial claim

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    Interpretationreasoning
    § Box 3 · p. 11

    Risk is only deferred in women; a 60-year-old woman has a risk similar to that of a 50-year-old man.

    “However, risk is only deferred in women; the risk of a 60-year-old woman is similar to that of a 50-year-old man.”
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    Premisereasoning
    § 4.1.1. Rationale for assessing total cardiovascular disease risk · p. 6

    Calibrated country-specific SCORE versions exist for many European countries.

    “Calibrated country-specific versions are available for many European countries and can be found at http:// www.heartscore.org.”
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    Premisereasoning
    § Cost-effectiveness · p. 9

    The SCORE risk charts are for use in people without overt CVD, diabetes, chronic kidney disease, familial hypercholesterolaemia, or very high levels of individual risk factors.

    “the Systematic Coronary Risk Estimation chart is for use in people without overt cardiovascular disease, diabetes (type 1 and 2), chronic kidney disease, familial hypercholesterolaemia, or very high levels of individual risk factors”
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    Study design and conductnone given
    § 1. Preamble · p. 3

    ESC Guidelines receive extensive review by the CPG and external experts.

    “The ESC Guidelines undergo extensive review by the CPG and external experts.”
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    Study design and conductnone given
    § 1. Preamble · p. 3

    The ESC CPG oversees and coordinates the preparation of new Guidelines and is responsible for their endorsement.

    “The ESC CPG supervises and coordinates the preparation of new Guidelines. The Committee is also responsible for the endorsement process of these Guidelines.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given
    § Box 3 · p. 11

    Risk is overestimated in countries with decreasing CVD mortality and underestimated in countries with increasing mortality; recalibration addresses this.

    “Risk will be overestimated in countries with decreasing CVD mortality, and underestimated in countries in which mortality is increasing. This is dealt with by recalibration”
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    Premisecitation
    § Cost-effectiveness · p. 9

    The 2012 and 2016 European Guidelines on CVD prevention recommend SCORE because it rests on large representative European cohort data and is relatively easy to recalibrate for individual countries.

    “The European Guidelines on CVD prevention in clinical practice (both the 2012 [9] and 2016 [10] versions) recommend the use of the SCORE system because it is based on large, representative European cohort data sets and because it is relatively straightforward to recalibrate for individual countries.”
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    Interpretationnone given
    § Box 3 · p. 12

    A larger burden of risk factors corresponds to a higher lifetime risk.

    “The greater the burden of risk factors, the higher the lifetime risk.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given
    § 1. Preamble · p. 3

    The level of evidence and the strength of recommendations for particular management options were weighed and graded using predefined ESC scales.

    “The level of evidence and the strength of the recommendation of particular management options were weighed and graded according to predefined ESC scales, as outlined in the tables below.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisereasoning
    § Cost-effectiveness · p. 10

    For other apparently healthy people, SCORE is recommended to estimate total CV risk because many have several risk factors that in combination may result in high total CV risk.

    “For other, apparently healthy people, the use of a risk estimation system such as SCORE, which estimates the 10 year cumulative risk of a first fatal atherosclerotic event, is recommended to estimate total CV risk, since many people have several risk factors that, in combination, may result in high levels of total CV risk.”
    Quote in the paperSubstantial claim

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    Interpretationnone given
    § Box 3 · p. 12

    A risk estimation system such as SCORE can help make logical management decisions and may reduce under- and overtreatment.

    “A risk estimation system such as SCORE can assist in making logical management decisions, and may help to avoid both under- and overtreatment.”
    Quote in the paperNot a substantial claim

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    Premisecitation
    § Box 3 · p. 12

    Older people benefit from smoking cessation and from control of hypertension and hyperlipidaemia.

    “While older people benefit from smoking cessation, and control of hypertension and hyperlipidaemia (see section 9.3)”
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    Premisecitation
    § 4.2.1. Role of non-invasive cardiovascular imaging techniques in the assessment of total cardiovascular disease risk · p. 13

    A US Preventive Services Task Force meta-analysis found that although no randomized trials show that using coronary artery calcium reduces health outcomes, it improves discrimination and reclassification.

    “A recent meta-analysis from the US Preventive Services Task Force summarized the available evidence on the value of non-traditional risk factors for risk prediction, and found that, although there are no randomized trials showing that the use of CAC reduces health outcomes, nevertheless it improves both discrimination and reclassification [19].”
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    Premisenone given
    § 4.2. Risk levels · p. 13

    The cut-off points used to define high cardiovascular risk are partly arbitrary and partly based on risk levels at which benefit is evident in clinical trials.

    “The cut-off points that are used to define high-risk are, in part, both arbitrary and based on the risk levels at which benefit is evident in clinical trials.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given
    § Box 3 · p. 12

    The total risk approach is flexible; if one risk factor cannot be optimally controlled, greater effort on other factors can still lower risk.

    “The total risk approach allows flexibility; if optimal control cannot be achieved with one risk factor, trying harder with the other factors can still reduce risk.”
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    Study design and conductnone given
    § 1. Preamble · p. 3

    Experts on the writing and reviewing panels submitted declaration-of-interest forms covering all relationships that could be seen as real or potential conflicts of interest.

    “The experts of the writing and reviewing panels provided declaration of interest forms for all relationships that might be perceived as real or potential sources of conflicts of interest.”
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    Premisecitation
    § Cost-effectiveness · p. 10

    Risk estimates have been produced as charts for high- and low-risk regions in Europe.

    “Risk estimates have been produced as charts for high- and low-risk regions in Europe (Fig. 1 and 2) [11].”
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    Premisereasoning
    § Cost-effectiveness · p. 10

    Fatal-event SCORE is retained because nonfatal events depend on definition, diagnostic developments, and ascertainment methods, making multipliers variable, and total event charts are harder to recalibrate.

    “The reasons for retaining a system that estimates fatal as opposed to total fatal + non-fatal events are that nonfatal events are dependent on definition, developments in diagnostic tests, and methods of ascertainment, all of which can vary, resulting in very variable multipliers to convert fatal to total events.”
    Quote in the paperSubstantial claim

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    Premisecitation
    § 4.2.1. Role of non-invasive cardiovascular imaging techniques in the assessment of total cardiovascular disease risk · p. 13

    Carotid or femoral plaque burden assessed by ultrasound is predictive of cardiovascular events, comparable to coronary artery calcium.

    “Assessment of carotid or femoral plaque burden with ultrasound has also been demonstrated to be predictive of CV events, comparable to CAC [20-23]”
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    Premisenone given
    § Cost-effectiveness · p. 10

    SCORE estimates the 10-year cumulative risk of a first fatal atherosclerotic event.

    “the use of a risk estimation system such as SCORE, which estimates the 10 year cumulative risk of a first fatal atherosclerotic event, is recommended to estimate total CV risk”
    Quote in the paperSubstantial claim

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    Interpretationcitation
    § 5.3.1. Low-density lipoprotein cholesterol and risk of atherosclerosis · p. 14

    Clinical benefit of therapies that lower LDL-C by reducing LDL particle mass is proportional to the absolute reduction in LDL-C, because on average reductions in LDL-C and LDL particles are concordant.

    “Therefore, the clinical benefit of therapies that lower LDL-C by reducing LDL particle mass will be proportional to the absolute reduction in LDLC, because-on average-the reduction in LDL-C and LDL particles will be concordant [34,50,54,55].”
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    Premisenone given
    § 5.3.3. High-density lipoprotein cholesterol and risk of atherosclerosis · p. 15

    Most genetic variants associated with HDL-C are also associated with directionally opposite changes in triglycerides, LDL-C, or both, making Mendelian randomization estimates of HDL-C effects difficult.

    “However, this evidence must be interpreted with caution because most genetic variants associated with HDL-C are also associated with directionally opposite changes in TGs, LDL-C, or both, thus making estimates of the effect of HDL-C on the risk of ASCVD very difficult using the Mendelian randomization study design.”
    Quote in the paperSubstantial claim

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    Interpretationreasoning
    § 4.2.2. Risk-based intervention strategies · p. 13

    Because relative risk reduction is proportional to absolute LDL-C reduction and absolute LDL-C reduction from a drug regimen depends only on baseline LDL-C, at any given baseline risk the higher the initial LDL-C the greater the absolute risk reduction.

    “These data are consistent in showing that, since the relative risk reduction is proportional to the absolute reduction in LDL-C and the absolute reduction in LDL-C resulting from a particular drug regimen depends only on baseline LDL-C, at any given level of baseline risk the higher the initial LDL-C level the greater the absolute reduction in risk.”
    Quote in the paperSubstantial claim

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    Premisecitation
    § 5.3.2. Triglyceride-rich lipoproteins and risk of atherosclerosis · p. 15

    Lowering triglycerides with fibrates reduces cardiovascular event risk by the same amount as LDL-C-lowering therapies per unit change in non-HDL-C, suggesting that the effect of plasma triglycerides on atherosclerotic cardiovascular disease is mediated by changes in triglyceride-rich lipoprotein concentration as estimated by non-HDL-C.

    “Similarly, lowering TG with fibrates reduces the risk of CV events by the same amount as LDL-C-lowering therapies when measured per unit change of non-HDL-C [50], suggesting that the effect of plasma TGs on ASCVD is mediated by changes in the concentration of TG-rich lipoproteins as estimated by non-HDL-C.”
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    § 5.2. Role of lipids and lipoproteins in the pathophysiology of atherosclerosis · p. 14

    When atherosclerotic plaque burden increases and plaque composition changes, plaque disruption can occur, causing an overlying thrombus that acutely obstructs blood flow and results in unstable angina, myocardial infarction, or death.

    “Eventually, the increase of the atherosclerotic plaque burden along with changes in the composition of the plaque reaches a critical point at which disruption of a plaque can result, with the formation of an overlying thrombus that acutely obstructs blood flow resulting in unstable angina, myocardial infarction (MI), or death.”
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    § 5.3.2. Triglyceride-rich lipoproteins and risk of atherosclerosis · p. 15

    Triglyceride-lowering lipoprotein lipase variants and LDL-C-lowering LDL receptor variants have the same effect on atherosclerotic cardiovascular disease risk per unit change in ApoB, suggesting all ApoB-containing lipoproteins have the same effect on coronary heart disease risk.

    “A recent Mendelian randomization study demonstrated that TG-lowering lipoprotein lipase (LPL) variants and LDL-C-lowering LDL receptor variants had the same effect on the risk of ASCVD per unit change of ApoB, suggesting that all ApoB-containing lipoproteins have the same effect on the risk of CHD [53].”
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    § 5.3.2. Triglyceride-rich lipoproteins and risk of atherosclerosis · p. 15

    Mendelian randomization studies suggest the association between plasma triglycerides and coronary heart disease risk may be causal, but this evidence must be interpreted cautiously because nearly all triglyceride-associated variants are also associated with HDL-C, LDL-C, or Lp(a).

    “Mendelian randomization studies also suggest that the association between plasma TGs and the risk of CHD may be causal; however, this evidence must be interpreted with caution because nearly all variants associated with TGs are also associated with HDL-C, LDL-C, or Lp(a) [56-59].”
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    § 5.3.1. Low-density lipoprotein cholesterol and risk of atherosclerosis · p. 14

    LDL particles have both a causal and cumulative effect on atherosclerotic cardiovascular disease risk.

    “These data provide strong support for the concept that LDL particles have both a causal and cumulative effect on the risk of ASCVD.”
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    § 4.2.1. Role of non-invasive cardiovascular imaging techniques in the assessment of total cardiovascular disease risk · p. 13

    In the Multi-Ethnic Study of Atherosclerosis, 41-57% of statin-eligible individuals had a coronary artery calcium score of zero, and the 10-year atherosclerotic cardiovascular disease event rate was low at 1.5-4.9%.

    “Data from the Multi-Ethnic Study of Atherosclerosis (MESA) showed that 41-57% of individuals who would be eligible for statin therapy had a CAC score of zero and the rate of atherosclerotic CVD events in the 10 year follow-up period was low (1.5-4.9%) [26].”
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    § 5.2. Role of lipids and lipoproteins in the pathophysiology of atherosclerosis · p. 14

    Continued exposure to ApoB-containing lipoproteins leads to additional particle retention over time and to growth and progression of atherosclerotic plaques.

    “Continued exposure to ApoB-containing lipoproteins leads to additional particles being retained over time in the artery wall, and to the growth and progression of atherosclerotic plaques.”
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    § 5.3.4. Lipoprotein(a) and risk of atherosclerosis · p. 16

    Randomized trials lowering Lp(a) by 20-30% with niacin or CETP inhibitors have not shown that lowering Lp(a) reduces atherosclerotic cardiovascular disease risk beyond expected from ApoB reduction, but recent PCSK9 inhibitor data suggest a possible role for Lp(a) lowering in reducing cardiovascular risk.

    “While randomized trials evaluating therapies that lower Lp(a) by 20-30% (including niacin and CETP inhibitors) have not provided evidence that lowering Lp(a) reduces the risk of ASCVD beyond that which would be expected from the observed reduction in ApoB-containing lipoproteins, recent data with PCSK9 inhibitors have suggested a possible role for Lp(a) lowering in reducing CV risk [76].”
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    § 5.4.2. Lipid measurements · p. 16

    Lp(a) concentration is reported as molar or mass by various assays, and conversion between molar and mass concentrations is size- and concentration-dependent.

    “Furthermore, the concentration of Lp(a) is reported as either a molar concentration (nmol/L) or as a mass (mg/dL) by the various assays, and conversion between molar and mass concentrations has been found to be both size- and concentration-dependent [91-93].”
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    § 5.3.3. High-density lipoprotein cholesterol and risk of atherosclerosis · p. 15

    Several randomized trials show that directly infused HDL mimetics increase plasma HDL-C but do not reduce atherosclerosis progression measured by intravascular ultrasound.

    “Furthermore, several randomized trials have shown that directly infused HDL mimetics increase plasma HDL-C concentrations, but do not reduce the progression of atherosclerosis as measured by intravascular ultrasound [68,69].”
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    § 5.3.4. Lipoprotein(a) and risk of atherosclerosis · p. 15

    Pro-atherogenic effects of Lp(a) are attributed to pro-coagulant effects due to its similarity to plasminogen and to pro-inflammatory effects related to its oxidized phospholipid load.

    “Pro-atherogenic effects of Lp(a) have also been attributed to pro-coagulant effects as Lp(a) has a similar structure to plasminogen, and it has pro-inflammatory effects most likely related to the oxidized phospholipid load carried by Lp(a) [71].”
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    § 5.5. Recommendations for measuring lipids and lipoproteins to estimate risk of atherosclerotic cardiovascular disease · p. 17

    Measurement of plasma total cholesterol is needed to calculate risk using SCORE, and inclusion of plasma HDL-C can improve risk estimation using the online SCORE calculator.

    “Measurement of plasma TC is needed to calculate risk using SCORE, while the inclusion of plasma HDL-C level can improve risk estimation using the online SCORE calculator.”
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    Interpretationcitation
    § 5.3.4. Lipoprotein(a) and risk of atherosclerosis · p. 16

    About 90% of a person's Lp(a) level is inherited, so extremely elevated Lp(a) may represent a new inherited lipid disorder associated with extremely high lifetime atherosclerotic cardiovascular disease risk and is two-fold more prevalent than heterozygous familial hypercholesterolaemia.

    “Because about 90% of a person's Lp(a) level is inherited, extremely elevated Lp(a) may represent a new inherited lipid disorder that is associated with extremely high lifetime risk of ASCVD and is two-fold more prevalent than HeFH [77].”
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    § 5.3.4. Lipoprotein(a) and risk of atherosclerosis · p. 16

    Higher plasma Lp(a) concentrations are associated with increased atherosclerotic cardiovascular disease risk, but Lp(a) appears to be a much weaker risk factor for most people than LDL-C.

    “Higher plasma Lp(a) concentrations are associated with an increased risk of ASCVD, but it appears to be a much weaker risk factor for most people than LDL-C [72,73].”
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    § 5.3.3. High-density lipoprotein cholesterol and risk of atherosclerosis · p. 15

    In ACCELERATE and REVEAL, CETP inhibitors more than doubled HDL-C but did not reduce atherosclerotic cardiovascular disease events beyond that expected from modest ApoB reductions.

    “Similarly, in the Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition with Evacetrapib in Patients at a High-Risk for Vascular Outcomes (ACCELERATE) and Randomized Evaluation of the Effects of Anacetrapib Through Lipid Modification (REVEAL) trials, treatment with CETP inhibitors more than doubled HDL-C levels, but did not appear to reduce the risk of ASCVD events beyond”
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    § 5.3.3. High-density lipoprotein cholesterol and risk of atherosclerosis · p. 15

    In the dal-OUTCOMES trial, dalcetrapib increased HDL-C without affecting LDL-C or ApoB but did not reduce major cardiovascular events.

    “In the Effects of Dalcetrapib in Patients with a Recent Acute Coronary Syndrome (dal-OUTCOMES) trial, treatment with the cholesteryl ester transfer protein (CETP) inhibitor dalcetrapib increased HDL-C without any effect on LDL-C or ApoB, but did not reduce the risk of major CV events [65].”
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    § 7.4.2. Dietary fat · p. 21

    Low intakes of fats and oils increase the risk of inadequate intakes of vitamin E and essential fatty acids and may contribute to a reduction in HDL-C.

    “low intakes of fats and oils increase the risk of inadequate intakes of vitamin E and of essential fatty acids, and may contribute to a reduction of HDL-C [164].”
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    § 7.4.2. Dietary fat · p. 21

    Trans fatty acids produced by partial hydrogenation of vegetable oils account for 80% of total trans fat intake.

    “The trans fatty acids produced in the partial hydrogenation of vegetable oils account for 80% of total intake.”
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    § 7.4.2. Dietary fat · p. 21

    Intake of trans fatty acids has decreased substantially over the past 10-15 years.

    “the intake of trans fatty acids has decreased substantially over the past 10-15 years.”
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    § 7.4.1. Body weight and physical activity · p. 21

    Combining diet and exercise leads to the greatest improvement in physical performance and quality of life and mitigates reductions in muscle and bone mass, particularly in older people.

    “this approach also leads to the greatest improvement in physical performance and quality of life, and mitigates reductions in muscle and bone mass, particularly in older people [176].”
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    § 7. Lifestyle modifications to improve the plasma lipid profile · p. 20

    The lack of concordance between diet studies is due to methodological problems such as inadequate sample sizes or short durations, and to difficulty evaluating a single dietary factor independently of other dietary changes.

    “The lack of concordance between studies is due both to methodological problems (particularly inadequate sample sizes or short study durations) and the difficulties of evaluating the impact of a single dietary factor independently of any other changes in the diet [130].”
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    § 7.3. Influence of lifestyle on high-density lipoprotein cholesterol levels · p. 21

    Weight reduction increases HDL-C levels; a 0.01 mmol/L increase is observed for every kilogram decrease in body weight once weight reduction has stabilized.

    “Weight reduction increases HDL-C levels; a 0.01 mmoL/L (0.4 mg/ dL) increase is observed for every kilogram decrease in body weight when weight reduction has stabilized.”
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    § 7.4.3. Dietary carbohydrate and fibre · p. 21

    Dietary carbohydrate has a neutral effect on LDL-C, but excessive consumption has adverse effects on plasma triglycerides and HDL-C.

    “Dietary carbohydrate has a 'neutral' effect on LDL-C, although excessive consumption is represented by untoward effects on plasma TGs and HDL-C levels [164].”
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    § 7.2. Influence of lifestyle on triglyceride levels · p. 21

    The effect of fructose on plasma triglycerides is dose-dependent; at habitual intake of 15-20% of total energy, plasma triglycerides increase by as much as 30-40%.

    “These effects are dose-dependent; with a habitual fructose consumption between 15 and 20% of total energy intake, plasma TG increases by as much as 30-40%.”
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    § 7.4.3. Dietary carbohydrate and fibre · p. 21

    Dietary fibre, especially soluble fibre, has a cholesterol-lowering effect and is a good substitute for saturated fat to maximize dietary effects on LDL-C and minimize adverse effects of a high-carbohydrate diet on other lipoproteins.

    “Dietary fibre (particularly of the soluble type)-which is present in legumes, fruits, vegetables, and wholegrain cereals (e.g. oats and barley)-has a hypocholesterolaemic effect and represents a good dietary substitute for saturated fat to maximize the effects of the diet on LDL-C levels, and to minimize the untoward effects of a high-carbohydrate diet on other lipoproteins [140,179].”
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    § 7.2. Influence of lifestyle on triglyceride levels · p. 21

    Weight reduction improves insulin sensitivity and lowers triglyceride levels.

    “Weight reduction improves insulin sensitivity and decreases TG levels.”
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    § 7.2. Influence of lifestyle on triglyceride levels · p. 21

    The adverse effects of a high-carbohydrate diet on triglycerides occur mainly with refined carbohydrate-rich foods and are much less prominent with fibre-rich, low-glycaemic-index foods, especially in people with diabetes or metabolic syndrome.

    “The detrimental effects of a high-carbohydrate diet on TGs occur mainly when refined carbohydrate-rich foods are consumed, while they are much less prominent if the diet is based largely on fibrerich, low-glycaemic index foods. This applies particularly to people with DM or MetS [171,172].”
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    § 8.1.2. Effects on lipids · p. 23

    In a meta-analysis, statin-induced HDL-C elevations varied with dose and ranged from 1% to 10%.

    “In a meta-analysis [201], elevations in HDL-C levels varied with dose among the respective statins; such elevations ranged from 1 to 10%.”
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    § 8.1.2. Effects on lipids · p. 23

    More potent statins such as atorvastatin, rosuvastatin, and pitavastatin produce robust triglyceride lowering, especially at high doses and in patients with elevated triglycerides, in whom absolute risk reduction is larger.

    “More potent statins (atorvastatin, rosuvastatin, and pitavastatin) demonstrate robust lowering of TG levels, especially at high doses and in patients with elevated TGs (HTG), in whom the absolute risk, and therefore the absolute risk reduction, is larger.”
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    § 8.1.2. Effects on lipids · p. 23

    Statins only marginally affect Lp(a) plasma levels, with previous studies reporting either no effect or an increase after treatment.

    “Statins only marginally affect Lp(a) plasma levels. Previous studies have reported either no effect on or an increase of Lp(a) levels after statin treatment [202,203].”
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    § 7.5.2. Monacolin and red yeast rice · p. 22

    The long-term safety of regular red yeast rice consumption is not fully documented, and safety concerns about contaminants in some preparations have been raised.

    “Moreover, the long-term safety of the regular consumption of these products has not been fully documented and safety issues due to the possible presence of contaminants in some preparations have been raised.”
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    § 7.5.4. Soy · p. 22

    Soy's cholesterol-lowering effect is generally attributed to isoflavones and phytoestrogens, whose content falls with increasing soybean processing.

    “The cholesterol-lowering effect of soy is generally attributed to its isoflavone and phytoestrogen content, which decreases progressively with the increasing degree of soybean processing.”
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    § 7.4.3. Dietary carbohydrate and fibre · p. 21

    In the PURE cohort, total fat and fat types showed no association with CVD, MI, or CVD mortality, while saturated fat was inversely associated with stroke.

    “Total fat and types of fat were not associated with CVD, MI, or CVD mortality, whereas saturated fat had an inverse association with stroke [181].”
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    § 7.5.4. Soy · p. 22

    Soy protein has been suggested to modestly lower LDL-C when replacing animal protein, but this was not confirmed after accounting for changes in other dietary components.

    “Soy protein has also been indicated as being able to induce a modest LDL-C-lowering effect when replacing animal protein foods. However, this was not confirmed when changes in other dietary components were taken into account [187,188].”
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    § 7.5.6. n-3 unsaturated fatty acids · p. 22

    Observational evidence associates eating fish at least twice weekly and vegetable foods rich in n-3 fatty acids with lower risk of cardiovascular death and stroke, but without major effects on plasma lipoprotein metabolism.

    “Observational evidence indicates that consumption of fish (at least twice a week) and vegetable foods rich in n-3 fatty acids (α-linoleic acid is present in walnuts, some vegetables, and some seed oils) is associated with lower risk of CV death and stroke, but has no major effects on plasma lipoprotein metabolism [178,192].”
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    § 7.5.2. Monacolin and red yeast rice · p. 22

    Commercial red yeast rice preparations vary in monacolin content and in their LDL-C and total cholesterol lowering effects, and consumers cannot distinguish among them.

    “Different commercial preparations of RYR have different concentrations of monacolins, and lower TC and LDL-C levels to variable extents, but the consumer is not able to make that distinction [144,185].”
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    § 8.1.2. Effects on lipids · p. 22

    The degree of LDL-C reduction by statins is dose-dependent and differs among statins.

    “The degree of LDL-C reduction is dose-dependent and varies between the different statins.”
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    § 7.5.1. Phytosterols · p. 22

    Daily intake of 2 g phytosterols lowers total cholesterol and LDL-C by 7-10% in humans, with interindividual heterogeneity, and has little or no effect on HDL-C or triglycerides.

    “Daily consumption of 2 g of phytosterols can effectively lower TC and LDL-C levels by 7-10% in humans (with a certain degree of heterogeneity among individuals), while it has little or no effect on HDL-C and TG levels [143].”
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    • Rests on an assumption: Phytosterols compete with cholesterol for intestinal absorption and thereby modulate total cholesterol levels.

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    § 7.5.5. Policosanol and berberine · p. 22

    Because high-quality randomized trials are lacking, berberine's efficacy for dyslipidaemia requires further validation, and the bioavailability of different berberine preparations is debated.

    “However, due to the lack of highquality randomized clinical trials, the efficacy of berberine for treating dyslipidaemia needs to be further validated.”
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    § 8.1.2. Effects on lipids · p. 23

    The mechanism of statin triglyceride lowering is not fully elucidated but appears partly independent of the LDL receptor and may involve increased hepatic VLDL uptake and reduced VLDL production, depending on pre-treatment VLDL concentrations.

    “The mechanism of the TG-lowering effect has not been fully elucidated, but it seems to be partly independent of the LDLR pathway. It may involve the upregulation of VLDL uptake by hepatocytes, as well as a reduction of the production rate of VLDLs; these effects seem to be dependent on pre-treatment VLDL concentrations [200].”
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    § 7.4.3. Dietary carbohydrate and fibre · p. 21

    A fat-modified diet providing 25-40 g per day of total dietary fibre, including at least 7-13 g of soluble fibre, is well tolerated and effective for plasma lipid control.

    “A fat-modified diet that provides 25-40 g per day of total dietary fibre, including ≥7-13 g of soluble fibre, is well tolerated, effective, and recommended for plasma lipid control”
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    § 7.5.3. Dietary fibre · p. 22

    Foods enriched with beta-glucan or related fibre supplements are well tolerated and effective for LDL-C lowering.

    “Foods enriched with these fibres or supplements are well tolerated, effective, and recommended for LDL-C lowering [186].”
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    § 8.1.3. Other effects of statins · p. 23

    The proportional effects of statins per mmol/L LDL-C reduction on major vascular events were similar across examined subgroups, so absolute risk reduction was proportional to baseline absolute risk.

    “The proportional effects (per mmol/L reduction in LDL-C) on major vascular events were similar in all subgroups examined, so the absolute risk reduction was proportional to the absolute baseline risk.”
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    § 7.4.5. Smoking · p. 21

    Smoking cessation has clear benefits for overall cardiovascular risk and specifically for HDL-C levels.

    “Smoking cessation has clear benefits regarding overall CV risk, and specifically on HDL-C levels [163].”
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    § 8.1.3. Other effects of statins · p. 23

    Anti-inflammatory and antioxidant effects of statins have been shown in vitro and in experimental systems, but their clinical relevance remains unproven.

    “These effects have been shown in vitro and in experimental systems, but their clinical relevance remains unproven [18,206].”
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    § 7.5.6. n-3 unsaturated fatty acids · p. 22

    Pharmacological doses of long-chain n-3 fatty acids of 2-3 g/day reduce triglycerides by about 30% and reduce post-prandial lipaemia, but higher doses may raise LDL-C.

    “Pharmacological doses of long-chain n-3 fatty acids (2-3 g/day) reduce TG levels by about 30% and also reduce the post-prandial lipaemic response, but a higher dosage may increase LDL-C levels.”
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    § 8.1.3. Other effects of statins · p. 23

    In the CTT individual-participant meta-analysis, each 1 mmol/L LDL-C reduction with statin or more intensive statin reduced major vascular events by about 22%, major coronary events by 23%, CAD death by 20%, total stroke by 17%, and total mortality by 10% over 5 years.

    “for each 1 mmoL/L reduction in LDL-C, statin/more statin reduced major vascular events (MI, CAD death, or any stroke or coronary revascularization) by ∼22%, major coronary events by 23%, CAD death by 20%, total stroke by 17%, and total mortality by 10% over 5 years.”
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    § 8.1.2. Effects on lipids · p. 22

    Poor statin responses in clinical studies are partly due to poor compliance and may also be explained by genetic background.

    “Poor responses to statin treatment in clinical studies are to some extent caused by poor compliance, but may also be explained by genetic backgrounds [195,196].”
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    § 8.1.4. Adverse effects and interactions of statins · p. 24

    Mild ALT elevation has not been shown to be associated with true hepatotoxicity or changes in liver function.

    “Mild elevation of ALT has not been shown to be associated with true hepatotoxicity or changes in liver function.”
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    § 8.1.4. Adverse effects and interactions of statins · p. 24

    Mild ALT elevation occurs in 0.5-2.0% of patients on statin treatment, more commonly with potent statins or high doses.

    “Mild elevation of ALT occurs in 0.5-2.0% of patients on statin treatment, more commonly with potent statins or high doses.”
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    § 8.1.3. Other effects of statins · p. 23

    For dementia, hepatic steatosis, venous thromboembolism, atrial fibrillation, and polycystic ovary syndrome, no effect of statins has been reliably demonstrated.

    “Other conditions, such as dementia [224], hepatic steatosis [225], venous thromboembolism [226], atrial fibrillation [227,228], and polycystic ovary syndrome [229] have also been studied, and no effect of statins on these conditions has been reliably demonstrated.”
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    § 8.1.4. Adverse effects and interactions of statins · p. 23

    The ASCOT-LLA investigators concluded that a nocebo effect may partly explain the higher frequency of statin-associated muscle symptoms in observational studies compared with trials.

    “They concluded that a nocebo effect (i.e. one caused by negative expectations) may partly explain the higher frequency of SAMS in observational studies compared with in trials.”
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    § 8.1.3. Other effects of statins · p. 23

    Current meta-analytic evidence suggests that the clinical benefit of statin treatment is largely a class effect driven by absolute LDL-C reduction, so the choice of statin should reflect treatment goals.

    “Current available evidence from meta-analyses suggests that the clinical benefit of statin treatment is largely a class effect, driven by the absolute LDL-C reduction; therefore, the type of statin used should reflect the treatment goals for a given patient.”
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    § 8.1.4. Adverse effects and interactions of statins · p. 24

    Patients on statin treatment have an increased risk of dysglycaemia and type 2 diabetes mellitus, and this is a consistent, dose-related effect.

    “Patients on statin treatment have been shown to exhibit an increased risk of dysglycaemia and development of type 2 diabetes mellitus (T2DM). Several studies have shown that this is a consistent, dose-related effect [232].”
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    § 8.1.4. Adverse effects and interactions of statins · p. 23

    Statins are generally well tolerated but have specific adverse effects on muscle, glucose haemostasis, and haemorrhagic stroke, and there is widespread misinformation about their potential adverse effects.

    “Although statins are generally very well tolerated, they do have some specific adverse effects on muscle, glucose haemostasis, and haemorrhagic stroke. However, there is also widespread misinformation about potential adverse effects, as reviewed recently [232,233].”
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    § 8.1.3. Other effects of statins · p. 23

    A Cochrane analysis reported no conclusive effect of statins on Alzheimer's disease.

    “The suggested effect on Alzheimer's disease was recently reviewed in a Cochrane analysis reporting no conclusive effect from statins [230].”
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    § 8.1.4. Adverse effects and interactions of statins · p. 23

    In rhabdomyolysis, creatine kinase levels are elevated by at least 10 times and often at least 40 times the upper limit of normal.

    “In rhabdomyolysis, creatine kinase (CK) levels are elevated by ≥ 10 times, and often ≥40 times, the upper limit of normal (ULN) [234].”
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    § 8.1.4. Adverse effects and interactions of statins · p. 24

    Statin-induced proteinuria is of tubular origin, usually transitory, and believed due to reduced tubular reabsorption rather than glomerular dysfunction.

    “The proteinuria induced by statins is of tubular origin, usually transitory, and is believed to be due to reduced tubular reabsorption and not to glomerular dysfunction [254,255].”
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    § 8.1.4. Adverse effects and interactions of statins · p. 24

    The diabetes effect is probably related to statin mechanism, as Mendelian randomization studies have confirmed increased diabetes risk in individuals with HMG-CoA reductase polymorphisms that reduce cholesterol synthesis.

    “This effect is probably related to the mechanism of action of statins, as Mendelian randomization studies have confirmed the increased risk of DM in individuals with HMG-CoA reductase polymorphisms that reduce cholesterol synthesis [250].”
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    § 8.1.4. Adverse effects and interactions of statins · p. 23

    The frequency of rhabdomyolysis has been estimated at 1-3 cases per 100,000 patient-years.

    “The frequency of rhabdomyolysis has been estimated to represent 1-3 cases/100 000 patient-years [235].”
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    § 8.1.4. Adverse effects and interactions of statins · p. 24

    The risk of new-onset diabetes is higher with more potent statins at high doses, in the elderly, and in the presence of other diabetes risk factors such as overweight or insulin resistance.

    “However, the risk is higher with the more potent statins at high doses [248], and is also higher in the elderly, and in the presence of other risk factors for diabetes such as overweight or insulin resistance [249].”
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    § 8.1.4. Adverse effects and interactions of statins · p. 23

    Myopathy is the most clinically relevant adverse effect of statins, and interaction with concomitant drug therapy is an important risk factor.

    “Myopathy is the most clinically relevant adverse effect of statins. Among the risk factors for myopathy, it is particularly important that interaction with concomitant drug therapy is considered (see below).”
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    § 8.4.1. Mechanism of action · p. 25

    Statin treatment increases circulating PCSK9 serum levels, and the best effect of PCSK9 monoclonal antibodies has been demonstrated in combination with statins.

    “Statin treatment increases circulating PCSK9 serum levels [282], and thus the best effect of these mAbs has been demonstrated in combination with statins.”
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    § 8.4.2. Effects on lipids · p. 26

    Given their mechanism, PCSK9 inhibitors effectively reduce LDL-C in all patients capable of expressing hepatic LDL receptors, including most HeFH and some HoFH with residual receptor expression, but receptor-deficient HoFH responds poorly.

    “Given the mechanism of action, these drugs are effective at reducing LDL-C in all patients capable of expressing LDLR in the liver. Therefore, this pharmacological approach is effective in the vast majority of patients, including those with HeFH and, albeit to a lower level, those with HoFH with residual LDLR expression. Receptor-deficient HoFH responds poorly to the therapy [285].”
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    § 8.2.3. Effect on cardiovascular morbidity and mortality · p. 25

    In IMPROVE-IT, there was no evidence of harm from ezetimibe or from further LDL-C reduction.

    “There was no evidence of harm caused by ezetimibe or the further LDL-C reduction.”
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    § 8.3.4. Adverse effects and interactions · p. 25

    Colesevelam is better tolerated and has fewer drug interactions than other bile acid sequestrants, and can be taken together with statins and several other drugs.

    “Colesevelam is better tolerated and has fewer interactions with other drugs, and can be taken together with statins and several other drugs [279].”
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    § 8.2.2. Effects on lipids · p. 25

    A meta-analysis of randomized trials including over 2700 people showed ezetimibe reduced LDL-C by 18.5% versus placebo, increased HDL-C by 3%, reduced triglycerides by 8%, and reduced total cholesterol by 13%.

    “A meta-analysis of RCTs that included over 2700 people showed an 18.5% reduction in LDL-C as compared with placebo [262]. In addition, there was a significant 3% increase in HDL-C, a significant 8% reduction in TGs, and a 13% reduction in TC with ezetimibe as compared with placebo.”
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    § 8.3.4. Adverse effects and interactions · p. 25

    Bile acid sequestrants have major drug interactions with several commonly prescribed drugs and must be administered either 4 hours before or 1 hour after other drugs.

    “Bile acid sequestrants have major drug interactions with several commonly prescribed drugs, and must therefore be administered either 4 h before or 1 h after other drugs.”
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    § 8.2.4. Adverse effects and interactions · p. 25

    Age, sex, and race have no clinically significant effects on ezetimibe pharmacokinetics, and no dosage adjustment is needed in mild hepatic impairment or mild-to-severe renal insufficiency.

    “There are no clinically significant effects of age, sex, or race on ezetimibe pharmacokinetics, and no dosage adjustment is necessary in patients with mild hepatic impairment or mild-to-severe renal insufficiency.”
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    § 8.4.2. Effects on lipids · p. 26

    Both alirocumab and evolocumab effectively lower LDL-C in high cardiovascular risk patients, including those with diabetes mellitus.

    “Both alirocumab and evolocumab have also been shown to effectively lower LDL-C levels in patients who are at high CV risk, including those with DM [284].”
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    § 8.1.4. Adverse effects and interactions of statins · p. 24

    In clinical trials, proteinuria frequency is generally low and in most cases not higher than with placebo.

    “In clinical trials, the frequency of proteinuria is generally low and, in most cases, is not higher than for placebo [256].”
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    Interpretationown data
    § 8.2.3. Effect on cardiovascular morbidity and mortality · p. 25

    IMPROVE-IT supports the proposition that lowering LDL-C by means other than statins is beneficial and safe.

    “Therefore, the study supports the proposition that LDL-C lowering by means other than statins is beneficial and safe.”
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    § 8.2.3. Effect on cardiovascular morbidity and mortality · p. 25

    In IMPROVE-IT, 18,144 patients were randomized to statin or statin plus ezetimibe; over 7 years, 5314 had a cardiovascular event, with 170 fewer events in the simvastatin plus ezetimibe group (32.7% vs 34.7%, P=0.016).

    “A total of 18 144 patients were randomized to statin or statin plus ezetimibe, and 5314 patients over 7 years experienced a CV event; 170 fewer events (32.7 vs. 34.7%) were recorded in the group taking simvastatin plus ezetimibe ( P =0.016).”
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    § 8.1.4. Adverse effects and interactions of statins · p. 24

    Combining statins with gemfibrozil increases myopathy risk and must be avoided.

    “Combination of statins with gemfibrozil enhances the risk of myopathy, and its association with statins must be avoided.”
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    Premisecitation
    § 8.3.4. Adverse effects and interactions · p. 25

    Bile acid sequestrants have been reported to reduce absorption of fat-soluble vitamins and may increase circulating triglycerides in certain patients.

    “Reduced absorption of fat-soluble vitamins has been reported. Furthermore, these drugs may increase circulating TG levels in certain patients.”
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    § 8.4.2. Effects on lipids · p. 26

    With high-intensity or maximally tolerated statins, alirocumab and evolocumab reduced LDL-C by 46-73% more than placebo and by 30% more than ezetimibe.

    “In combination with high-intensity or maximally tolerated statins, alirocumab and evolocumab reduced LDL-C by 46-73% more than placebo, and by 30% more than ezetimibe.”
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    § 8.4.1. Mechanism of action · p. 25

    Elevated PCSK9 concentration or function reduces LDL receptor expression by promoting LDL receptor lysosomal catabolism and increasing plasma LDL, while lower PCSK9 concentration or function is related to lower plasma LDL-C.

    “Elevated concentration or function of this protein in plasma reduces LDLR expression by promoting, upon binding, LDLR lysosomal catabolism and a subsequent increase in plasma LDL concentrations, while lower concentration or function of PCSK9 is related to lower plasma LDL-C levels [281].”
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    § 8.3.2. Effects on lipids · p. 25

    Bile acid sequestrants have no major effect on HDL-C, but triglycerides may increase in some predisposed patients.

    “No major effect on HDL-C has been reported, while TGs may increase in some predisposed patients [274].”
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    § 8.4.1. Mechanism of action · p. 25

    Because PCSK9 binding triggers intracellular LDL receptor degradation, lower circulating PCSK9 increases LDL receptor expression at the cell surface and reduces circulating LDL-C.

    “Since this interaction triggers the intracellular degradation of the LDLR, lower levels of circulating PCSK9 will result in increased expression of LDLRs at the cell surface and therefore in a reduction of circulating LDL-C levels [281].”
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    § 8.2.2. Effects on lipids · p. 25

    Ezetimibe plus statin improved LDL-C reductions compared with doubling the statin dose by 13-20%, and after switching from statin monotherapy to combination therapy by 11-15%.

    “In other studies, this combination has also significantly improved reductions in LDL-C levels when compared with doubling of the statin dose (13-20%), and after switching from statin monotherapy to ezetimibe and statin combination therapy (11-15%) [263].”
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    § 8.2.4. Adverse effects and interactions · p. 25

    Ezetimibe is rapidly absorbed and extensively metabolized to pharmacologically active ezetimibe glucuronide.

    “Ezetimibe is rapidly absorbed and extensively metabolized to pharmacologically active ezetimibe glucuronide.”
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    § 8.2.2. Effects on lipids · p. 25

    Ezetimibe monotherapy at 10 mg/day reduces LDL-C in hypercholesterolaemic patients by 15-22%, with relatively high interindividual variation.

    “In clinical studies, ezetimibe in monotherapy at 10 mg/day reduces LDL-C in hypercholesterolaemic patients by 15-22% with relatively high interindividual variation [261].”
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    § 8.7.1. Mechanism of action · p. 27

    Fibrates are PPAR-alpha agonists that act through transcription factors regulating lipid and lipoprotein metabolism.

    “Fibrates are agonists of peroxisome proliferator-activated receptorα (PPAR-α), acting via transcription factors regulating, among other things, various steps in lipid and lipoprotein metabolism.”
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    Premisecitation
    § 8.4.4. Adverse effects and interactions · p. 26

    Bococizumab development was discontinued because neutralizing antibodies increased, attenuating LDL-C lowering over time and causing more injection site reactions.

    “Indeed, the development programme for a third PCSK9 inhibitor, bococizumab, a humanized antibody, was discontinued because of an increase of neutralizing antibodies, which resulted in the attenuation of the LDL-C-lowering effect over time, as well as a higher rate of injection site reactions [300].”
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    § 8.4.3. Effect on cardiovascular morbidity and mortality · p. 26

    In FOURIER, evolocumab did not reduce cardiovascular mortality (HR 1.05, 95% CI 0.88-1.25) or all-cause mortality.

    “In the FOURIER trial, allocation to evolocumab did not reduce the risk of CV mortality (HR 1.05, 95% CI 0.88-1.25) or allcause mortality.”
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    § 8.4.2. Effects on lipids · p. 26

    PCSK9 inhibition with monoclonal antibodies reduces Lp(a) plasma levels, with pooled phase II trial results showing about a 30-40% reduction.

    “In contrast to statins, inhibiting PCSK9 with mAbs also reduces Lp(a) plasma levels. Pooled results of phase II trials have shown that treatment leads to an Lp(a) reduction of about 30-40% [288,289].”
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    § 8.5. Lomitapide · p. 27

    Lomitapide is associated with increased aminotransferase levels, likely reflecting increased liver fat, and with poor gastrointestinal tolerability.

    “As a consequence of its mechanism of action, lomitapide has been shown to be associated with increased aminotransferase levels, which most likely reflects the increased fat in the liver, as well as poor GI tolerability [301,302].”
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    Interpretationreasoning
    § 8.7.1. Mechanism of action · p. 27

    Fibrates effectively lower fasting triglycerides, post-prandial triglycerides, and triglyceride-rich lipoprotein remnant particles.

    “As a consequence, fibrates have good efficacy in lowering fasting TG levels, as well as post-prandial TGs and TG-rich lipoprotein (TRL) remnant particles.”
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    Premisecitation
    § 8.6. Mipomersen · p. 27

    After subcutaneous injection, mipomersen is preferentially transported to the liver, binds ApoB mRNA, prevents ApoB translation, and reduces production of atherogenic lipids and lipoproteins including LDL and Lp(a).

    “After subcutaneous injection, the oligonucleotide is preferentially transported to the liver, where it binds to a specific mRNA preventing the translation of ApoB protein and, consequently, reducing the production of atherogenic lipids and lipoproteins, including LDL and Lp(a) [303].”
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    § 8.4.2. Effects on lipids · p. 26

    The mechanism of Lp(a) reduction by PCSK9 inhibition remains unclear and appears distinct from statins, which enhance LDL receptor function but do not lower circulating Lp(a) in humans.

    “While recent investigations have attempted to unravel the mechanism, it remains unclear. However, it appears to be distinct from that of statins, which also enhance LDLR function but do not lower circulating Lp(a) levels in humans.”
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    § 8.4.3. Effect on cardiovascular morbidity and mortality · p. 26

    In FOURIER, time-to-benefit analysis showed lower benefit in the first year than in subsequent years, consistent with statin effects in the CTT meta-analysis.

    “An analysis of the time to benefit also showed that there was a lower benefit in the first year than in subsequent years, consistent with the effects of statins observed within the CTT metaanalysis [268].”
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    § 8.4.3. Effect on cardiovascular morbidity and mortality · p. 26

    Because both PCSK9 outcome trials had relatively short follow-up and statin trials indicate clinical benefits of LDL-lowering may emerge only after about 1 year, these trials may have underestimated the impact of longer-term treatment.

    “Both studies had relatively short follow-up periods and the evidence from statin trials indicates that the clinical benefits of LDL-lowering may only emerge after about 1 year [51], so these trials may have underestimated the potential impact of longer-term treatment [120,290].”
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    § 8.4.4. Adverse effects and interactions · p. 26

    The EBBINGHAUS trial, designed to detect neurocognitive changes, was reassuring, as were safety reports from FOURIER and ODYSSEY.

    “However, the EBBINGHAUS trial [231], which was specifically designed to detect neurocognitive function changes, was reassuring, as were the safety reports in both the FOURIER and ODYSSEY trials.”
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    § 8.7.3. Effect on cardiovascular morbidity and mortality · p. 27

    Neither the FIELD nor the ACCORD studies with fenofibrate showed a reduction in total cardiovascular disease outcomes.

    “Although the HHS reported a significant reduction in CVD outcomes with gemfibrozil, neither the FIELD nor the ACCORD studies involving fenofibrate showed a reduction in total CVD outcomes.”
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    § 8.4.2. Effects on lipids · p. 26

    In phase II trials, evolocumab lowered triglycerides by 26% and raised HDL-C and ApoA-I by 9% and 4%, respectively, with similar findings for alirocumab.

    “In phase II trials, evolocumab lowered TG levels by 26%, and raised HDL-C and ApoA-I by 9 and 4%, respectively; similar findings have been reported for alirocumab [286,287].”
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    § 8.4.3. Effect on cardiovascular morbidity and mortality · p. 26

    FOURIER and ODYSSEY Outcomes had similar secondary prevention and background therapy designs, but enrolled populations with stable CHD, peripheral arterial disease, or stroke, or a recent acute coronary syndrome, respectively.

    “The designs of the trials were similar with regard to the settings of secondary prevention and background therapy; however, the populations enrolled had either stable CHD, peripheral arterial disease (PAD), or stroke; or a recent (median 2.6 months) ACS, respectively.”
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    § 8.7.3. Effect on cardiovascular morbidity and mortality · p. 27

    Other meta-analyses suggest reduced major cardiovascular events in patients with high triglycerides and low HDL cholesterol treated with fibrates, but no decrease in cardiovascular or total mortality.

    “Results from other meta-analyses suggest reduced major CVD events in patients with high TGs and low HDL-C in fibrate-treated patients, but no decrease in CVD or total mortality [314-316].”
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    § 8.7.4. Adverse effects and interactions · p. 27

    A fibrate-induced increase in homocysteine may blunt HDL cholesterol and ApoA1 elevation and may contribute to smaller than estimated benefits of fenofibrate on cardiovascular outcomes.

    “However, a fibrate-induced increase in homocysteine may blunt elevation of both HDL-C and ApoA1 levels, and this effect may contribute to the smaller than estimated benefits of fenofibrate in CV outcome parameters [322].”
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    § 8.7.4. Adverse effects and interactions · p. 27

    The risk of myopathy is 5.5-fold greater with fibrate monotherapy, mainly gemfibrozil, than with a statin, and varies with different fibrates and statins used in combination.

    “The risk of myopathy has been reported to be 5.5-fold greater with fibrate monotherapy (mainly with gemfibrozil) compared with a statin, and it varies with different fibrates and statins used in combination.”
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    § 8.8.3. Effect on cardiovascular morbidity and mortality · p. 28

    Data on omega-3 clinical efficacy remain inconclusive, and efficacy appears related to non-lipid effects.

    “The data remain inconclusive and the clinical efficacy of omega-3 fatty acids appears to be related to non-lipid effects [330,331].”
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    § 8.8.3. Effect on cardiovascular morbidity and mortality · p. 28

    A Cochrane meta-analysis of 112,059 people from 79 trials reported no overall effect of omega-3 PUFAs on total mortality or cardiovascular events, with only a suggestion of reduced CHD events.

    “A Cochrane meta-analysis, including 112 059 people from 79 trials, reported no overall effect of omega-3 PUFAs on total mortality (relative risk 0.98, 95% CI 0.90-1.03) or CV events (relative risk 0.99, 95% Cl 0.94-1.04), with only a suggestion that omega-3 fatty acids reduced CHD events (relative risk 0.93, 95% Cl 0.88-0.97) [328].”
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    § 8.7.4. Adverse effects and interactions · p. 27

    Myopathy, liver enzyme elevations, and cholelithiasis are the most well-known adverse effects associated with fibrate therapy.

    “In general, myopathy, liver enzyme elevations, and cholelithiasis represent the most well-known adverse effects associated with fibrate therapy [319].”
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    § 8.7.4. Adverse effects and interactions · p. 27

    Fibrates are generally well tolerated with mild adverse effects; gastrointestinal disturbances are reported in less than 5% of patients and skin rashes in 2%.

    “Fibrates are generally well tolerated with mild adverse effects, GI disturbances being reported in < 5% of patients, and skin rashes in 2% [319].”
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    § 8.11.2. New approaches to reduce triglyceride-rich lipoproteins and their remnants · p. 29

    Genetic studies indicate that ANGPTL3 deficiency protects against atherosclerotic disease and that this relationship is causal.

    “As genetic studies indicate that angiopoietin-like protein 3 (ANGPTL3) deficiency protects against atherosclerotic disease and that this relationship is causal [343]”
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    § 8.8.4. Safety and interactions · p. 28

    Data from one study associated high dietary intake of n-3 PUFAs with risk of prostate cancer.

    “Recently, data from one study have associated a risk of prostate cancer with high dietary intake of n-3 PUFAs [334].”
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    § 9.1.2. Familial hypercholesterolaemia · p. 32

    The prevalence of heterozygous familial hypercholesterolaemia is estimated at 1 in 200-250, translating to 14-34 million cases worldwide.

    “The prevalence of HeFH in the population is estimated to be 1/ 200-250, 361 translating to a total number of cases between 14 and 34 million worldwide [362,363].”
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    • cites [361] L.E. Akioyamen, J. Genest, S.D. Shan, R.L. Reel, J.M. Albaum, A. Chu, J.V. Tu, Estimating the prevalence of heterozygous familial hypercholesterolaemia: a systematic review and meta-analysis, BMJ Open 7 (2017) e016461. http://refhub.elsevier.com/S0021-9150(1931459-5/sref361) source

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    § 8.10. Cholesteryl ester transfer protein inhibitors · p. 28

    Torcetrapib was studied in the ILLUMINATE trial, which was stopped early due to increased mortality.

    “Torcetrapib was studied in the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) trial, which was stopped early due to increased mortality [336].”
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    § 8.10. Cholesteryl ester transfer protein inhibitors · p. 28

    Evacetrapib raises HDL cholesterol by 130% and lowers LDL cholesterol by 37%, and the ACCELERATE trial was terminated due to futility.

    “Evacetrapib, which raises HDL-C levels by 130% and lowers LDL-C by 37%, was studied in the ACCELERATE trial [63], which was terminated due to futility.”
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    § 8.9. Nicotinic acid · p. 28

    Nicotinic acid inhibits diacylglycerol acyltransferase 2 in the liver, decreasing VLDL secretion and reducing IDL and LDL particles.

    “In the liver, nicotinic acid inhibits diacylglycerol acyltransferase2 resulting in decreased secretion of VLDL particles, which is also reflected in reductions of plasma levels of both IDL and LDL particles [335].”
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    § 8.11.1. New approaches to reduce low-density lipoprotein cholesterol · p. 28

    Inclisiran inhibits PCSK9 synthesis and reduced LDL cholesterol by up to 50% dose-dependently, with reductions in PCSK9 and LDL cholesterol maintained for up to 6 months.

    “In a phase I and a phase II trial, the small interfering RNA (siRNA) molecule inclisiran-which inhibits the synthesis of PCSK9-reduced LDL-C by up to 50% and the reduction was dose-dependent. Reductions in PCSK9 and LDL-C levels were maintained for ≤6 months [338,339].”
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    § 8.9. Nicotinic acid · p. 28

    Two large randomized trials of nicotinic acid, one with extended-release niacin and one with niacin plus laropiprant, showed no beneficial effect and an increased frequency of serious adverse effects.

    “Two large randomized trials with nicotinic acid-one with extended-release niacin [66] and one with niacin plus laropiprant [67]-have shown no beneficial effect and an increased frequency of serious adverse effects.”
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    § 8.11.3. New approaches to increase high-density lipoprotein cholesterol · p. 29

    An antisense oligonucleotide to ApoC-III leads to a reduction in triglycerides of about 70% and a marked elevation in HDL cholesterol of about 40% in hypertriglyceridaemia.

    “agents that enhance catabolism of TG-rich lipoproteins, such as the antisense oligonucleotide to ApoC-III, and which lead to a concomitant reduction in TGs (∼70%) and a marked elevation in HDL-C (∼40%) in hypertriglyceridemia, are under development [351].”
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    § 8.11.2. New approaches to reduce triglyceride-rich lipoproteins and their remnants · p. 29

    Volanesorsen reduced plasma triglycerides by about 70% and ApoC-III by 80-90%.

    “Volanesorsen reduced plasma TGs by ∼70% and ApoC-III by 80-90% [349].”
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    § 9.1.4. Genetic causes of hypertriglyceridaemia · p. 34

    Heterozygous carriers of mutations causing severe hypertriglyceridaemia commonly have moderate serum triglyceride elevations and increased cardiovascular disease risk.

    “Heterozygous carriers of these same gene mutations commonly express moderate elevations of serum TG levels that expose them to increased CVD risk [378].”
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    § 9.1.1. Familial combined hyperlipidaemia · p. 32

    Familial combined hyperlipidaemia has no monogenic component and is not linked to a single genetic cause, but its phenotype is high LDL cholesterol and/or high triglycerides.

    “FCH has no monogenic component and is not linked to a single genetic cause, but the phenotype is high LDL-C and/or high TGs [358,359].”
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    § 9.3.1. Effects of statins in primary and secondary prevention · p. 36

    The relative reduction in major vascular events was similar irrespective of age among patients with pre-existing vascular disease, but appeared smaller among older individuals without known vascular disease.

    “The relative reduction in major vascular events was similar, irrespective of age, among patients with pre-existing vascular disease, but appeared smaller among older individuals not known to have vascular disease.”
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    § 9.3.2. Adverse effects, interactions, and adherence · p. 36

    Fatal cardiovascular disease outcomes declined significantly in both type 1 and type 2 diabetes between 1998 and 2014.

    “The good news is that fatal CVD outcomes have declined significantly in both T1DM and T2DM between 1998 and 2014 [400].”
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    § 9.3.2. Adverse effects, interactions, and adherence · p. 36

    In type 2 diabetes, ASCVD risk is strongly determined by target organ damage including nephropathy, neuropathy, or retinopathy, with risk increasing with the number of conditions present.

    “In T2DM, the risk of ASCVD is strongly determined by the presence of target organ damage-including nephropathy (microalbuminuria), neuropathy, or retinopathy-with the risks increasing in relation to the number of conditions present [405].”
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    § 9.3.2. Adverse effects, interactions, and adherence · p. 36

    Recent data indicate that diabetes itself increases cardiovascular disease risk about two-fold on average, but the risk varies widely by population and current prophylactic therapy.

    “Recent data indicate that DM per se increases CVD risk about two-fold on average, but the risk is subject to wide variation depending on the population and current aggressive prophylactic therapy [401,404].”
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    § 9.3.2. Adverse effects, interactions, and adherence · p. 36

    The difference in cardiovascular disease risk between individuals with and without diabetes has narrowed substantially over the last few decades.

    “The difference in CVD risk between individuals with and without DM has narrowed substantially over the last few decades [401]”
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    § 9.1.4. Genetic causes of hypertriglyceridaemia · p. 34

    Hypertriglyceridaemia accounts for about 10% of all pancreatitis cases, and pancreatitis can occur at triglyceride levels of 5-10 mmol/L.

    “Notably, HTG is the cause of ∼10% of all cases with pancreatitis, and patients can develop pancreatitis even when their TG concentration is 5-10 mmoL/L (440-880 mg/dL).”
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    § 9.3. Older people · p. 36

    Because absolute coronary artery disease risk is higher in older persons, the absolute increase in risk for a given increment in total cholesterol is larger with increasing age.

    “However, since the absolute risk of CAD is higher in older persons, the associated absolute increase in risk for a given increment in TC is larger with increasing age [217].”
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    § 9.3.2. Adverse effects, interactions, and adherence · p. 36

    Hypertension, dyslipidaemia, abdominal obesity, and non-alcoholic fatty liver disease commonly coexist with type 2 diabetes and further aggravate risk, which is highest in those with multiple cardiometabolic risk factors.

    “Hypertension, dyslipidaemia, abdominal obesity, and non-alcoholic fatty liver disease (NAFLD) commonly coexist with T2DM and further aggravate the risk, which is highest in people with T2DM and multiple cardiometabolic risk factors [406-408].”
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    § 9.4. Diabetes and metabolic syndrome · p. 36

    Elevation of triglycerides or low HDL-C in the fasting or post-prandial state is seen in about one-half of all people with type 2 diabetes, and is often present in abdominal adiposity, insulin resistance, or impaired glucose tolerance.

    “Elevation of TGs or low HDL-C levels in the fasting or post-prandial state is seen in about one-half of all people with T2DM [416,417], and is also often present in people with abdominal adiposity, insulin resistance or impaired glucose tolerance [413].”
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    § 9.2. Women · p. 35

    Few randomized statin trials have shown independently significant cardiovascular benefits in women, largely because women were underrepresented in those trials.

    “Few randomized trials of statin therapy have reported independently significant CV benefits in women [387,389], chiefly because women have not been adequately represented in statin trials.”
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    § 9.2.1. Effects of statins in primary and secondary prevention · p. 35

    A 2013 Cochrane analysis found that statin therapy reduced all-cause mortality, vascular events, and revascularizations in primary prevention, with proportional effects in women similar to men.

    “Using published data, a 2013 Cochrane analysis showed that statin therapy reduced all-cause mortality, vascular events, and revascularizations in primary prevention, and the proportional effects in women were similar to those in men [213].”
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    § 9.4.2. Evidence for lipid-lowering therapy · p. 37

    The overall cardiovascular benefit of statin treatment remains and greatly outweighs the increased incidence of diabetes.

    “These observations should not lessen our attention to the treatment of patients, as the overall benefits in CV event reduction remain and greatly outweigh the increased incidence of DM.”
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    § 9.4.2. Evidence for lipid-lowering therapy · p. 37

    The relative reduction in major vascular events is proportional to the absolute amount of LDL-C lowering and matches the relationship observed for statins.

    “The relative risk reduction in major vascular events is proportional to the absolute degree of LDL-C lowering and consistent with the relationship seen for statins.”
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    § 9.4.2. Evidence for lipid-lowering therapy · p. 37

    A meta-analysis of fibrates in 11,590 people with type 2 diabetes showed a significant 21% reduction in non-fatal myocardial infarction, but no effect on overall or coronary mortality.

    “Consistent with these findings, a metaanalysis of fibrates in the prevention of CVD in 11 590 people with T2DM showed that fibrates significantly reduced the risk of non-fatal MI by 21%, but had no effect on the risk of overall mortality or coronary mortality [422].”
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    § 9.5. Patients with acute coronary syndromes and patients undergoing percutaneous coronary intervention · p. 38

    Cardiac rehabilitation programmes enhance control of lipid levels and improve overall survival following acute coronary syndrome.

    “Ideally, patients should be signed up to cardiac rehabilitation programmes to enhance the control of lipid levels [434] and improve overall survival following ACS [435].”
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    § 9.4.2. Evidence for lipid-lowering therapy · p. 37

    In REDUCE-IT, icosapent ethyl 2 g twice daily in 8,179 high-risk patients with hypertriglyceridaemia taking a statin yielded a significant 25% lower risk of the composite primary endpoint over a median 4.9 years, with an absolute decrease of 4.8%, offset by a 1% absolute increase in hospitalization for atrial fibrillation or flutter.

    “The REDUCE-IT trial examined the effects of icosapent ethyl 2 g b.i.d. on CV events in 8179 high-risk patients with HTG who were taking a statin. Over a median of 4.9 years, there was a significant ( P < 0.001) 25% reduction in the composite primary outcome of CV death, non-fatal MI, non-fatal stroke, coronary revascularization, or unstable angina, corresponding with an absolute reduction of 4.”
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    § 9.4.2. Evidence for lipid-lowering therapy · p. 37

    The clinical benefits of treating high triglyceride and low HDL-C levels remain debated; fenofibrate effects on major adverse cardiovascular events were negative in FIELD and ACCORD in type 2 diabetes cohorts.

    “The clinical benefits achieved by the treatment of high TG and low HDL-C levels (frequently seen with DM) are still a matter of debate, as the effects of fenofibrate therapy on the major outcome (MACE) remained negative in both the FIELD and the ACCORD studies performed in T2DM cohorts [306,307].”
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    § 9.4.2. Evidence for lipid-lowering therapy · p. 37

    The increased diabetes incidence with statins has been seen in Mendelian randomization studies and clinical trials, with the largest effect in patients already at high diabetes risk (e.g., pre-diabetes).

    “These observations have been seen in Mendelian randomization studies and in clinical trials, although the effect appears greatest in patients already at high risk for DM (e.g. those with pre-diabetes).”
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    § 9.5.1. Lipid-lowering therapy in patients with acute coronary syndromes · p. 38

    Patients do not have to be fasting for lipid profiling because fasting has little impact on LDL-C levels.

    “Patients do not have to be fasting as this has little impact on LDL-C levels [100].”
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    § 9.4.3. Type 1 diabetes mellitus · p. 38

    A meta-analysis including 18,686 patients with diabetes demonstrated that statin-induced LDL-C reduction yielded a 9% reduction in all-cause mortality and a 21% reduction in major cardiovascular events per 1.0 mmol/L lower LDL-C.

    “A meta-analysis including 18 686 patients with DM demonstrated that a statin-induced reduction of LDL-C yielded a 9% reduction in all-cause mortality and a 21% reduction in the incidence of major CV events per 1.0 mmoL/L (40mg/dL) lower LDL cholesterol [418].”
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    § 9.4.3. Type 1 diabetes mellitus · p. 38

    Consistent data demonstrate that statins prevent cardiovascular events and reduce cardiovascular mortality in patients with diabetes, with no evidence of sex differences.

    “Consistent data have demonstrated the efficacy of statins in preventing CV events and reducing CV mortality in patients with DM, with no evidence of sex differences [430,431].”
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    § 9.5. Patients with acute coronary syndromes and patients undergoing percutaneous coronary intervention · p. 38

    Although lowering LDL-C benefits ACS patients, many still do not reach target LDL-C levels in this very high-risk group.

    “Despite the acknowledged clinical benefits of lowering LDLC in patients with ACS [436], attainment of LDL-C target values remains suboptimal in this very high-risk setting [437].”
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    § 9.4.3. Type 1 diabetes mellitus · p. 37

    In type 1 diabetes with good glycaemic control, the lipid profile is 'supernormal', with subnormal triglycerides and LDL-C and HDL-C usually in the upper normal range or slightly elevated.

    “The lipid profile in T1DM patients with good glycaemic control is 'supernormal', and is characterized by subnormal TG and LDL-C levels, whereas HDL-C levels are usually within the upper normal range or slightly elevated.”
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    § 9.4.2. Evidence for lipid-lowering therapy · p. 37

    Available evidence supports reducing saturated fat intake and replacing it with unsaturated fat, and replacing refined starchy foods and simple sugars with fibre-rich foods.

    “In relation to diet composition, besides the need to eliminate trans fat, the available evidence supports the reduction of saturated fat intake and its substitution with unsaturated fat, as well as the replacement of a major proportion of refined starchy foods and simple sugars with fibrerich foods like fruits, vegetables, and wholegrains [179].”
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    § 9.4.3. Type 1 diabetes mellitus · p. 37

    Subcutaneous insulin administration increases lipoprotein lipase activity in adipose tissue and skeletal muscle, increasing VLDL turnover, which explains the supernormal lipid profile in type 1 diabetes.

    “This is explained by subcutaneous administration of insulin that increases LPL activity in adipose tissue and skeletal muscle, and consequently the turnover rate of VLDL particles [429].”
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    § 9.4.2. Evidence for lipid-lowering therapy · p. 37

    In randomized controlled trials, neither ezetimibe nor PCSK9 inhibitors have been reported to increase diabetes risk.

    “In RCTs, neither ezetimibe nor the PCSK9 inhibitors have been reported to increase the risk of DM [297].”
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    § 9.4.3. Type 1 diabetes mellitus · p. 38

    In diabetic patients with acute coronary syndrome, intensive statin treatment reduced all-cause mortality and cardiovascular death, and contributed to reduced atheroma progression.

    “In diabetic patients with ACS, intensive statin treatment led to a reduction in all-cause mortality and CV death, and contributed to a reduction in atheroma progression [432].”
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    § 9.4.3. Type 1 diabetes mellitus · p. 37

    Emerging evidence highlights frequent coexistence of metabolic syndrome with type 1 diabetes, resulting in double diabetes that increases cardiovascular risk.

    “Emerging evidence highlights the frequent coexistence of MetS with T1DM, resulting in the so-called double diabetes increasing CVD risk [428].”
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    § 9.7.1. Prevention of incident heart failure in coronary artery disease patients · p. 40

    Cholesterol lowering with statins reduces the incidence of heart failure in patients with coronary artery disease (stable CAD or history of ACS) without previous heart failure; this has been shown in RCTs comparing statin vs no statin and more-intensive vs less-intensive statin therapy.

    “Cholesterol lowering with statins reduces the incidence of HF in patients with CAD (stable CAD or a history of ACS) without previous HF; this has been shown consistently in RCTs that have compared statin vs. no statin treatment [463,464] as well as more-intensive vs. lessintensive statin therapy [465-468].”
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    § 9.5.1. Lipid-lowering therapy in patients with acute coronary syndromes · p. 38

    The clinical benefit of adding ezetimibe was consistent across patient subgroups and led to reductions in total cardiovascular events, stroke, and rehospitalizations.

    “The clinical benefit of adding ezetimibe was consistent across patient subgroups [299,444] and also led to a reduction of total CV events [445], stroke [446], and rehospitalizations [447].”
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    § 9.5.1. Lipid-lowering therapy in patients with acute coronary syndromes · p. 39

    In the REVEAL study, anacetrapib in more than 30,000 patients with atherosclerotic vascular disease resulted in a lower incidence of MACE compared with placebo after 4 years, with no safety concerns.

    “More recently, the REVEAL study investigated anacetrapib in > 30 000 patients with atherosclerotic vascular disease and resulted in a lower incidence of MACE compared with placebo after 4 years, with no safety concerns [64].”
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    § 9.6. Stroke · p. 40

    Secondary prevention therapy with statins reduces the risk of recurrent stroke (by 12% per mmol/L reduction in LDL cholesterol), myocardial infarction, and vascular death.

    “Secondary prevention therapy with statins reduces the risk of recurrent stroke (by 12% per mmol/L reduction in LDL cholesterol), MI, and vascular death [459,460].”
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    § 9.5.1. Lipid-lowering therapy in patients with acute coronary syndromes · p. 39

    In ODYSSEY Outcomes, which included 18,924 patients with recent acute coronary syndrome, adding alirocumab to statin therapy (89% high-intensity) resulted in a 15% relative risk reduction in the primary composite endpoint and a 15% relative reduction in all-cause mortality over 2.8 years.

    “In the ODYSSEY Outcomes trial, which included 18 924 patients with recent ACS (1-12 months prior to enrolment, median 2.6 months), alirocumab added to statin therapy (89% high-intensity therapy) also resulted in a 15% relative risk reduction in the primary composite endpoint and was associated with a 15% relative reduction in all-cause mortality throughout a 2.8 year follow-up [120].”
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    Premisecitation
    § 9.6. Stroke · p. 40

    Statin therapy may yield a small increase in the risk of haemorrhagic stroke, but the evidence regarding this risk is uncertain.

    “Statin therapy may yield a small increase in the risk of haemorrhagic stroke, but the evidence regarding this risk is uncertain [34,36,251,252].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [34] source

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    • cites [36] source

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  • May combine two claims.

    Premisecitation
    § 9.7.2. Chronic heart failure · p. 40

    A reduction in heart failure hospitalizations and a small reduction in myocardial infarction were observed in a pooled analysis of the CORONA and GISSI-HF trials.

    “a reduction in HF hospitalizations [218,471], as well as a small reduction in MI, was observed in a pooled analysis of the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA) and GISSI-HF trials [472].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [218] source

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    • cites [471] source

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    Premisecitation
    § 9.7.1. Prevention of incident heart failure in coronary artery disease patients · p. 40

    A large-scale meta-analysis of primary and secondary prevention RCTs with statins showed a modest 10% reduction in first non-fatal heart failure hospitalizations, with no effect on heart failure death within the limited RCT period.

    “A large-scale meta-analysis of primary and secondary prevention RCTs with statins showed a modest (10%) reduction in first non-fatal HF hospitalizations with statin treatment, with no effect on HF death within the limited RCT period [469].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [469] source

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  • May combine two claims.

    Premisenone given
    § 9.5.1. Lipid-lowering therapy in patients with acute coronary syndromes · p. 39

    In GISSI-P, oral supplementation with highly purified n-3 PUFAs reduced mortality in survivors of myocardial infarction, but subsequent trials using contemporary secondary prevention therapies failed to affect clinical outcomes.

    “Oral supplementation with highly purified n-3 PUFAs reduced mortality in survivors of MI in one study [Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico-Prevenzione (GISSI-P)] but failed to affect clinical outcomes in subsequent trials using contemporary secondary prevention therapies.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § 9.5.1. Lipid-lowering therapy in patients with acute coronary syndromes · p. 39

    In 2007, a large prospective study using the CETP inhibitor torcetrapib failed to show any clinical benefit in more than 15,000 high-risk patients and was potentially harmful.

    “In 2007, a large prospective study using the CETP inhibitor torcetrapib failed to show any clinical benefit in more than 15 000 high-risk patients, and was potentially harmful [336].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [336] source

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  • May combine two claims.

    Premisecitation
    § 9.8. Chronic kidney disease · p. 41

    Chronic kidney disease is associated with increased risk of both atherosclerotic vascular disease and structural heart disease.

    “There is an increased risk of both atherosclerotic vascular disease and structural heart disease [492].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [492] source

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  • May combine two claims.

    Interpretationreasoning
    § 9.8. Chronic kidney disease · p. 41

    Patients with chronic kidney disease are considered to be at high (stage 3 CKD) or very-high risk (stage 4-5 CKD or on dialysis) of cardiovascular disease, and risk estimation models are not needed in these patients.

    “Therefore, patients with CKD are considered to be at high (stage 3 CKD) or very-high risk (stage 4-5 CKD or on dialysis) of CVD, and there is no need to use risk estimation models in these patients.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § 9.8.3. Safety of lipid management in patients with chronic kidney disease · p. 41

    Although no specific safety concerns were raised by the 4D, AURORA, or SHARP trials, statins metabolized via CYP3A4 may result in adverse effects due to drug-drug interactions and caution is required.

    “Although there were no specific safety concerns raised by the 4D, AURORA, or SHARP trials, statins metabolized via CYP3A4 may result in adverse effects due to drug-drug interactions and caution is required.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [220] source

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  • May combine two claims.

    Premisecitation
    § 9.8.2. Evidence for risk reduction through statin-based therapy in patients with chronic kidney disease · p. 41

    Statin-based therapy is clearly effective in mild-to-moderate chronic kidney disease, but whether statin therapy is effective in more advanced CKD, particularly dialysis patients, remained controversial after 4D, AURORA, and SHARP.

    “Although statin-based therapy is clearly effective in mild-to-moderate CKD, a major controversy that remained after the publication of the 4D, AURORA, and SHARP studies was whether statin therapy is effective in more advanced CKD, particularly dialysis patients.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [214]

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § 9.9. Transplantation · p. 42

    That systematic review also suggested that additional studies are needed.

    “A systematic review of the benefits and harms of statins in patients with a functioning kidney transplant included 3465 patients, free of CHD, from 22 studies. Although the authors concluded that statins may reduce CV events, they also suggested a need for additional studies [253].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [253] source

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  • May combine two claims.

    Premisecitation
    § 9.8.2. Evidence for risk reduction through statin-based therapy in patients with chronic kidney disease · p. 41

    The CTT investigators found that, after adjusting for smaller LDL-C reductions in more advanced CKD and for differences in outcome definitions between dialysis trials, there was a trend towards smaller relative reductions per mmol/L reduction in LDL-C in major atherosclerotic events as estimated GFR declines, with little evidence of benefit among dialysis patients.

    “By combining data from the three CKD trials with other trials in the existing database, the CTT investigators found that, even after adjusting for the smaller LDL-C reductions achieved among patients with more advanced CKD and for differences in outcome definitions between dialysis trials, there was a trend towards smaller relative reductions per mmol/L reduction in LDL- C in major atherosclerotic”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [214]

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  • May combine two claims.

    Premisecitation
    § 9.9. Transplantation · p. 42

    Fluvastatin, pravastatin, pitavastatin, and rosuvastatin are metabolized by different CYP enzymes than other statins and have less potential for interaction.

    “Fluvastatin, pravastatin, pitavastatin, and rosuvastatin are metabolized through different CYP enzymes than the others and have less potential for interaction [507].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [507] source

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  • May combine two claims.

    Premisecitation
    § 9.10. Peripheral arterial disease · p. 42

    PAD is an independent risk factor for myocardial infarction and cardiovascular death.

    “PAD is a common manifestation of atherosclerosis and such patients are at elevated risk of coronary events, with PAD representing an independent risk factor for MI and CV death [510,511].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [510] source

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  • Classified as probably not a substantial claim.

    Premisecitation
    § 9.9. Transplantation · p. 42

    A systematic review of 22 studies including 3465 patients with functioning kidney transplants and no CHD concluded that statins may reduce cardiovascular events.

    “A systematic review of the benefits and harms of statins in patients with a functioning kidney transplant included 3465 patients, free of CHD, from 22 studies. Although the authors concluded that statins may reduce CV events, they also suggested a need for additional studies [253].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [253] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 9.9. Transplantation · p. 41

    These dyslipidaemias increase the risk of atherosclerotic cardiovascular disease and transplant arterial vasculopathy in transplant recipients.

    “Dyslipidaemias are very common in patients who have undergone heart, lung, liver, kidney, or allogenic haematopoietic stem cell transplantation, and predispose such patients to an increased risk of developing ASCVD and transplant arterial vasculopathy [497-501].”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [497] source

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    • cites [498] source

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    • cites [499] source

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    • cites [500] source

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    • cites [501] source

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  • May combine two claims.

    Premisecitation
    § 9.10.4. Secondary prevention in patients with abdominal aortic aneurysm · p. 42

    Abdominal aortic aneurysm is linked to older age, male sex, prior atherosclerotic CVD, smoking, hypertension, and dyslipidaemia.

    “The presence of an abdominal aortic aneurysm represents a riskequivalent condition for CAD and is associated with age, male gender, personal history of atherosclerotic CVD, smoking, hypertension, and dyslipidaemia [519]; in contrast, diabetic patients are at decreased risk.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [519] source

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  • May combine two claims.

    Premisecitation
    § 9.10.1. Lower extremity arterial disease · p. 42

    Evolocumab lowered major adverse limb event risk by 42%, with similar effects regardless of known PAD.

    “Evolocumab also reduced the risk of major adverse limb events by 42% in patients, with consistent effects in those with and without known PAD.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [514]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 9.10.1. Lower extremity arterial disease · p. 42

    Lowering LDL-C levels reduces the risk of ischaemic cardiovascular events and worsening of claudication.

    “Lowering LDL-C levels reduces the risk of ischaemic CV events and worsening of claudication, while it also improves walking performance.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [512] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 9.10.3. Retinal vascular disease · p. 42

    Atherosclerotic changes of retinal arteries correlate with total cholesterol, LDL-C, triglycerides, and apoB levels and also with CAD.

    “Atherosclerotic changes of retinal arteries correlate with TC, LDL-C, TG, and apoB levels and also with CAD [516].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [516] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 9.10.1. Lower extremity arterial disease · p. 42

    The FIELD trial found fenofibrate lowered amputation risk, especially minor amputations in patients without known large-vessel disease, likely via non-lipid pathways.

    “In the FIELD trial, fenofibrate reduced the risk of amputations, particularly minor amputations without known large-vessel disease, probably through non-lipid mechanisms [515].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [515] source

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226 of 226

  • The paper relies on this without support.

    Applying clinical recommendations thoroughly can favourably affect disease outcomes.

    “Implementation programmes are needed because it has been shown that the outcome of disease may be favourably influenced by the thorough application of clinical recommendations.”

  • The paper relies on this without support.

    Country-specific cohort data for risk charts are not available for most countries.

    “These are not available for most countries.”

  • The paper relies on this without support.

    The SCORE system can be recalibrated for use in different populations by adjusting for secular changes in CVD mortality and risk factor prevalence.

    “The SCORE (Systematic Coronary Risk Estimation) system can be recalibrated for use in different populations by adjusting for secular changes in CVD mortality and risk factor prevalence.”

  • The paper relies on this without support.

    At extremely high HDL-C values above ∼2.3 mmol/L (90 mg/dL), there appears to be an increased risk of ASCVD.

    “at extremely high values [above ∼2.3 mmoL/L (90 mg/dL)] of HDL-C there appears to be an increased risk of ASCVD”

  • The paper relies on this without support.

    The relative strengths of risk factors vary with age.

    “The relative strengths of risk factors vary with age”

  • The paper relies on this without support.

    The strongest driver of total cardiovascular risk is age, which can be considered as exposure time to risk factors.

    “The strongest driver of total CV risk is age, which can be considered as 'exposure time' to risk factors.”

  • The paper relies on this without support.

    Coronary artery calcium score is often very low and has low specificity in patients younger than 45 years with severe familial hypercholesterolaemia, including homozygous familial hypercholesterolaemia.

    “Note that CAC score is often very low in patients younger than 45 years of age with severe familial hypercholesterolaemia (FH), including homozygous FH (HoFH), and has low specificity in this population.”

  • The paper relies on this without support.

    Coronary artery calcium score is increased following statin treatment.

    “Of note, CAC score is increased following statin treatment; therefore, the CAC scores of statin-treated patients should be interpreted with caution.”

  • The paper relies on this without support.

    Standardized, automated, accurate, and inexpensive methods to measure ApoB are available.

    “Standardized, automated, accurate, and inexpensive methods to measure ApoB are available.”

  • The paper relies on this without support.

    ApoB provides an accurate estimate of the total concentration of atherogenic particles under all circumstances.

    “Because ApoB provides an accurate estimate of the total concentration of atherogenic particles under all circumstances”

  • The authors state this as an assumption.

    A goal approach may facilitate adherence to treatment.

    “It is judged that a goal approach may facilitate adherence to treatment, although this consensus opinion has not been fully tested.”

  • The authors state this as an assumption.

    Limiting current knowledge on cardiovascular prevention only to results from randomized controlled trials reduces the exploitation of the potential available for preventing ASCVD.

    “The European Task Force felt that limiting the current knowledge on CV prevention only to results from RCTs reduces the exploitation of the potential that is available for the prevention of ASCVD.”

  • The authors state this as an assumption.

    The concordance of conclusions from many different approaches contributes to understanding the causes of ASCVD.

    “It is the concordance of the conclusions from many different approaches (from basic science, clinical observations, genetics, epidemiology, RCTs, etc.) that contributes to the understanding of the causes of ASCVD”

  • The paper relies on this without support.

    Phytosterols compete with cholesterol for intestinal absorption and thereby modulate total cholesterol levels.

    “Phytosterols compete with cholesterol for intestinal absorption, thereby modulating TC levels.”

  • The paper relies on this without support.

    Statins reduce hepatic cholesterol synthesis by competitively inhibiting HMG-CoA reductase, the rate-limiting step in cholesterol biosynthesis; the resulting fall in intracellular cholesterol increases LDL receptor expression, increases LDL uptake, and lowers plasma LDL and other ApoB-containing lipoproteins.

    “Statins reduce the synthesis of cholesterol in the liver by competitively inhibiting the enzyme HMG-CoA reductase, the rate-limiting step in cholesterol biosynthesis. The reduction in intracellular cholesterol promotes increased LDL receptor (LDLR) expression at the surface of the hepatocytes, which in turn results in increased uptake of LDL from the blood, and decreased plasma concentrations of L”

  • The paper relies on this without support.

    Ezetimibe inhibits intestinal uptake of dietary and biliary cholesterol at the brush border by interacting with NPC1L1 without affecting fat-soluble nutrient absorption; this reduces cholesterol delivery to the liver, upregulates LDL receptors, and increases LDL clearance.

    “Ezetimibe inhibits intestinal uptake of dietary and biliary cholesterol at the level of the brush border of the intestine [by interacting with the Niemann-Pick C1-like protein 1 (NPC1L1)] without affecting the absorption of fat-soluble nutrients. By inhibiting cholesterol absorption, ezetimibe reduces the amount of cholesterol delivered to the liver. In response to reduced cholesterol delivery, t”

  • The paper relies on this without support.

    Bile acid sequestrants are not systemically absorbed or altered by digestive enzymes; by binding bile acids they prevent reabsorption of bile acids and cholesterol, increase hepatic cholesterol demand and LDL receptor expression, and decrease circulating LDL.

    “As bile acid sequestrants are not systemically absorbed or altered by digestive enzymes, the beneficial clinical effects are indirect. By binding the bile acids, the drugs prevent the reabsorption of both the drug and cholesterol into the blood, and thereby remove a large portion of the bile acids from the enterohepatic circulation. The liver, depleted of bile, synthesizes more from hepatic”

  • The paper relies on this without support.

    All currently available statins except pravastatin, rosuvastatin, and pitavastatin undergo major hepatic metabolism via cytochrome P450 isoenzymes, which are mainly expressed in liver and intestine, and other substrates of these enzymes may interfere with statin metabolism.

    “All currently available statins-except pravastatin, rosuvastatin, and pitavastatin-undergo major hepatic metabolism via the CYPs. These isoenzymes are mainly expressed in the liver and intestine.”

  • The paper relies on this without support.

    PCSK9 inhibitors lower LDL-C by up to 60% when added to statins.

    “PCSK9 inhibitors lower LDL-C levels by up to 60% on top of statins.”

  • The paper relies on this without support.

    Homozygous familial hypercholesterolaemia is a rare and life-threatening disease.

    “HoFH is a rare and life-threatening disease.”

  • The paper relies on this without support.

    Most patients with homozygous familial hypercholesterolaemia develop coronary artery disease and aortic stenosis before age 20 and die before age 30.

    “Most patients develop CAD and aortic stenosis before the age of 20 years and die before 30 years of age.”

  • The paper relies on this without support.

    Lipoprotein apheresis performed every 1-2 weeks can decrease plasma LDL-C levels by 55-70%.

    “This treatment (every 1-2 weeks) can decrease plasma LDL-C levels by 55-70%.”

  • The paper relies on this without support.

    Familial dysbetalipoproteinaemia is rare and generally inherited as an autosomal recessive disorder with variable penetrance.

    “Familial dysbetalipoproteinaemia (i.e. type III hyperlipoproteinaemia; remnant removal disease) is rare and is generally inherited as an autosomal recessive disorder with variable penetrance.”

  • The paper relies on this without support.

    Any factor that increases VLDL production can aggravate the risk of pancreatitis, with alcohol consumption being the most common contributing factor.

    “Any factor that increases VLDL production can aggravate the risk of pancreatitis, with alcohol consumption being the most common contributing factor.”

  • The paper relies on this without support.

    In general, a sharp decrease of triglyceride values is seen within 2-5 days.

    “In general, a sharp decrease of TG values is seen within 2-5 days.”

  • The paper relies on this without support.

    Volanesorsen has been approved by the EMA as an adjunct to diet in adult patients with genetically confirmed familial chylomicronaemia syndrome who are at high risk for pancreatitis.

    “Volanesorsen has been recently approved by the EMA as an adjunct to diet in adult patients with genetically confirmed FCS who are at high-risk for pancreatitis.”

  • The paper relies on this without support.

    Diabetes itself is an independent risk factor for cardiovascular disease and is associated with a higher risk of cardiovascular disease, even more so in women.

    “DM itself is an independent risk factor for CVD and is associated with a higher risk of CVD, even more so in women.”

  • The paper relies on this without support.

    In CKD patients receiving a renal transplant, ASCVD risk may be partly attributable to CKD itself.

    “In patients with CKD undergoing renal transplantation, the risk of ASCVD may be determined, at least in part, by the increased risk resulting from CKD itself.”

  • The paper relies on this without support.

    Ciclosporin is metabolized via CYP3A4 and may raise systemic statin exposure and myopathy risk.

    “Several potential drug interactions must also be considered, especially with ciclosporin, which is metabolized through CYP3A4, and may increase systemic statin exposure and the risk of myopathy.”

  • The paper relies on this without support.

    Ciclosporin raises blood levels of all statins.

    “Ciclosporin increases the blood levels of all statins.”

  • The paper relies on this without support.

    Tacrolimus is also metabolized by CYP3A4 but appears less likely than ciclosporin to cause harmful statin interactions.

    “Tacrolimus is also metabolized by CYP3A4, but appears to have less potential for harmful interaction with statins than ciclosporin.”

  • The paper relies on this without support.

    Ciclosporin can raise ezetimibe levels 2- to 12-fold.

    “Ciclosporin can induce a 2-12-fold increase in the ezetimibe level.”

  • The paper relies on this without support.

    Fibrates can lower ciclosporin levels and may cause myopathy.

    “Care is required with the use of fibrates, as they can decrease ciclosporin levels and have the potential to cause myopathy.”

  • The paper relies on this without support.

    Cholestyramine is ineffective as monotherapy in heart transplant patients and can reduce absorption of immunosuppressants; giving it separately minimizes this effect.

    “Cholestyramine is not effective as monotherapy in heart transplant patients and has the potential to reduce absorption of immunosuppressants; this potential is minimized by separate administration.”

  • The paper relies on this without support.

    An ABI of 0.90 or lower diagnoses lower extremity arterial disease (LEAD).

    “A low ABI (0.90) is diagnostic for lower extremity arterial disease (LEAD).”

  • The paper relies on this without support.

    Either a low (0.90) or high (1.40) ABI predicts cardiovascular morbidity and mortality.

    “Either a low (0.90) or high (1.40, related to stiffened arteries) ABI is predictive of CV morbidity and mortality.”

  • The paper relies on this without support.

    Lowering LDL-C improves walking performance.

    “Lowering LDL-C levels reduces the risk of ischaemic CV events and worsening of claudication, while it also improves walking performance.”
37 of 37

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Four large trials recruiting different types of patients with chronic kidney disease have confirmed the safety of intensive LDL-C lowering with statins alone or combining a moderate dose of simvastatin with ezetimibe.

    “Four large trials recruiting different types of patients with CKD have confirmed the safety of intensive LDL-C lowering with statins alone (atorvastatin, rosuvastatin, fluvastatin), or combining a moderate dose of simvastatin with ezetimibe.698,[701][702][703][704]”

    From 2023 ESC guidelines for the management of cardiovascular disease in patients with diabetes. (2023) · cites this paper as [702]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • REDUCE-IT triglyceride range differs between sections

    Minor

    The REDUCE-IT description gives the 135-499 mg/dL range as 1.52-1.63 mmol/L, whereas the treatment recommendation gives essentially the same mg/dL range as 1.5-5.6 mmol/L. The two upper bounds cannot both represent 499 mg/dL.

  • ACCORD HDL-C threshold has mismatched units

    Minor

    Using the paper's cholesterol conversion of 1 mmol/L = 38.67 mg/dL, 0.4 mmol/L is about 15.5 mg/dL, not 34 mg/dL.

    Reported 34 · recomputed 15.468

2 of 2

Cites

1 retracted

Flagged first, then by citations

Research works printed but not linked: 4

  1. Global Lipids Genetics Consortium, 2013, Discovery and refinement of loci associated with lipid levels, Nat. Genet., 45, 1274, 10.1038/ng.2797 · DOI
  2. World Health Organization, 1999, Human genetics programme. Familial hypercholesterolemia: report of a second WHO consultation. WHO/HGN/FH/Cons/99.2. Geneva, World Health Organization
  3. Landmesser, 2017, Eur. Heart J., 38, 2245
  4. Tavazzi, 2008, Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial, Lancet, 372, 1231, 10.1016/S0140-6736(08)61240-4 · DOI · Paper page

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Authors
Mach, F., Baigent, C., Catapano, A. L., Koskinas, K. C., Casula, M., Badimon, L., Chapman, M. J., De Backer, G. G., Delgado, V., Ference, B. A., Graham, I. M., Halliday, A., Landmesser, U., Mihaylova, B., Pedersen, T. R., Riccardi, G., Richter, D. J., Sabatine, M. S., Taskinen, M.-R., Tokgozoglu, L., Wiklund, O., Windecker, S., Aboyans, V., Baigent, C., Collet, J.-P., Dean, V., Delgado, V., Fitzsimons, D., Gale, C. P., Grobbee, D., Halvorsen, S., Hindricks, G., Iung, B., Jüni, P., Katus, H. A., Landmesser, U., Leclercq, C., Lettino, M., Lewis, B. S., Merkely, B., Mueller, C., Petersen, S., Petronio, A. S., Richter, D. J., Roffi, M., Shlyakhto, E., Simpson, I. A., Sousa-Uva, M., Touyz, R. M., Nibouche, D., Zelveian, P. H., Siostrzonek, P., Najafov, R., van de Borne, P., Pojskic, B., Postadzhiyan, A., Kypris, L., Špinar, J., Larsen, M. L., Eldin, H. S., Viigimaa, M., Strandberg, T. E., Ferrières, J., Agladze, R., Laufs, U., Rallidis, L., Bajnok, L., Gudjónsson, T., Maher, V., Henkin, Y., Gulizia, M. M., Mussagaliyeva, A., Bajraktari, G., Kerimkulova, A., Latkovskis, G., Hamoui, O., Slapikas, R., Visser, L., Dingli, P., Ivanov, V., Boskovic, A., Nazzi, M., Visseren, F., Mitevska, I., Retterstøl, K., Jankowski, P., Fontes-Carvalho, R., Gaita, D., Ezhov, M., Foscoli, M., Giga, V., Pella, D., Fras, Z., Perez de Isla, L., Hagström, E., Lehmann, R., Abid, L., Ozdogan, O., Mitchenko, O., & Patel, R. S.
Affiliations
  • University Hospital of Geneva (CH)
  • University of Milan (IT)
  • University Hospital of Bern (CH)
  • Inserm (FR)
  • University of Cambridge (GB)
  • Trinity College Dublin (IE)
  • University of Oxford (GB)
  • Queen Mary University of London (GB)
  • Oslo University Hospital (NO)
  • Federico II University Hospital (IT)
  • Brigham and Women's Hospital (US)
  • University of Helsinki (FI)
  • Hacettepe University (TR)
  • University of Gothenburg (SE)
  • Austrian Society of Cardiology (AT)
  • Danish Society of Cardiology (DK)
  • Egyptian Society of Cardiology (EG)
  • Suomen Kardiologinen Seura (FI)
  • Société Française de Cardiologie (FR)
  • German Cardiac Society (DE)
  • Hellenic Cardiological Society (GR)
  • Netherlands Haemophilia Society (NL)
  • Polish Cardiac Society (PL)
  • Taiwan Society of Cardiology (TW)
  • Slovak Society of Cardiology (SK)
  • Ural Institute of Cardiology (RU)
  • British Cardiovascular Society (GB)
ORCID
Venue
Atherosclerosis
Publisher
Elsevier BV
Published
2019-11
Volume
290
Pages
140-205
ISSN
0021-9150 (ISSN-L)
DOI
10.1016/j.atherosclerosis.2019.08.014
OpenAlex
W2953804067
Semantic Scholar
05e5a4032d1f663b44c97a4e2f904dc1df29c5f8
Cited by
4,854
References
623
Citations by year
2026: 91 · 2025: 402 · 2024: 811 · 2023: 932 · 2022: 859 · 2021: 951 · 2020: 722 · 2019: 79 · 2018: 1 · 2017: 1 · 2013: 1
FWCI
623.77
Type
journal article
Language
en
Update notices
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Atherosclerosis (publishedVersion)
  • PubMed (publishedVersion)
  • Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
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  • HAL (submittedVersion)
  • Leiden Repository (Leiden University) (submittedVersion)
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  • Työväentutkimus Vuosikirja (submittedVersion, other-oa)
  • Research Portal (Queen's University Belfast) (submittedVersion)
  • Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
  • Utrecht University Repository (Utrecht University) (submittedVersion)
Funders
Medical Research Council (MC_UU_00017/4)
Topics
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Blood Pressure and Hypertension Studies
Keywords
dyslipidemia, lipid modification, cardiovascular risk reduction, dyslipidemia management, ESC/EAS guidelines
MeSH terms
Adult, Aged, Hypolipidemic Agents, Cardiovascular Diseases, Drug Therapy, Combination, Female, Humans, Lipids, Male, Middle Aged, Risk Factors, Biomarkers, Treatment Outcome, Risk Assessment, Consensus, Risk Reduction Behavior, Dyslipidemias

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-04.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-04.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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