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Cited by 1,582Lipoproteins and Cardiovascular HealthDiabetes, Cardiovascular Risks, and LipoproteinsBlood Pressure and Hypertension Studies

2016 ESC/EAS Guidelines for the Management of Dyslipidaemias

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Catapano, Alberico L., Graham, Ian, De Backer, Guy, Wiklund, Olov, Chapman, M. John, Drexel, Heinz, Hoes, Arno W., Jennings, Catriona S. +10 more·2016·Atherosclerosis
DOI 10.1016/j.atherosclerosis.2016.08.018
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AI snapshot

Written from the paper’s full text.

TL;DR

This 2016 ESC/EAS guideline provides evidence-based recommendations for managing dyslipidaemias, emphasizing LDL-C as the primary treatment target with risk-stratified goals. It recommends lifestyle modification plus statins first-line, with ezetimibe, PCSK9 inhibitors, fibrates, and other agents in specific clinical settings.

Key findings

  • LDL-C goals are risk-stratified: very high risk <1.8 mmol/L (70 mg/dL) and ≥50% reduction from baseline if >1.8 mmol/L; high risk <2.6 mmol/L (100 mg/dL) and ≥50% reduction if >2.6 mmol/L; moderate risk <3.0 mmol/L (115 mg/dL). Secondary targets include non-HDL-C <2.6/3.4 mmol/L and apoB <80/100 mg/dL for very high/high risk.
  • In the CTT meta-analysis of >170,000 participants and 26 statin RCTs, each 1.0 mmol/L (40 mg/dL) LDL-C reduction gave a 10% proportional reduction in all-cause mortality, 20% reduction in CAD death, 23% reduction in major coronary events, and 17% reduction in stroke.
  • IMPROVE-IT randomized 18,144 patients after ACS; over 7 years, 170 fewer events occurred with simvastatin plus ezetimibe vs simvastatin alone (32.7% vs 34.7%, P=0.016), with average LDL-C 1.8 vs 1.4 mmol/L and a 21% reduction in ischaemic stroke (P=0.008). PCSK9 inhibitors lower LDL-C by ~50–70%.
  • Lifestyle evidence includes PREDIMED, where a Mediterranean diet supplemented with extra-virgin olive oil or nuts reduced major CV events by almost 30%; phytosterols at 2 g/day lower TC and LDL-C by 7–10%; and pharmacological n-3 fatty acids at 2–3 g/day reduce TGs up to 30%.

Methods

  • This is a joint ESC/EAS Task Force guideline, not a primary study. It used a comprehensive review of published evidence, critical evaluation of diagnostic and therapeutic procedures, and graded recommendations by class and level of evidence.
  • The evidence base includes RCTs, meta-analyses, observational studies, genetic data, and estimates of expected health outcomes for larger populations where data exist.
  • Recommendations were developed by selected experts, reviewed by the ESC Committee for Practice Guidelines and EAS-appointed experts, and approved by the Task Force.

Limitations

  • The Task Force states that RCTs have not systematically examined different LDL-C goals, so the choice of any target goal is open to debate; monitoring recommendations stem from consensus rather than evidence-based medicine.
  • The paper states that evidence for lowering elevated TGs is still modest and primarily derived from subgroup or post hoc analyses, and that evidence on functional foods is incomplete, with no diet-based intervention trials of sufficient duration.
  • Evident from the text: as a guideline, it synthesizes heterogeneous evidence and many recommendations rely on expert consensus and class grading rather than a single definitive trial.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.atherosclerosis.2016.08.018

Cites

498 of 499 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 375 cited sources checked · 0 supported · 0 flagged

  • Findingnone given
    § 3.3.3. Non-high-density lipoprotein cholesterol

    Non-HDL-C has strong predictive power.

    “Non-HDL-C has been shown to have a strong predictive power”
    Quote in the paperSubstantial claim
  • Findingnone given
    § 3.3.6. Apolipoproteins

    Several prospective studies show apoB is equal to LDL-C and non-HDL-C in risk prediction.

    “Several prospective studies have shown that apoB is equal to LDL-C and non-HDL-C in risk prediction.”
    Quote in the paperNot a substantial claim
  • Findingcitation
    § 3.3.4. High-density lipoprotein cholesterol

    The causative role of HDL-C for protection against CVD has been questioned in several Mendelian randomization studies.

    “The causative role of HDL-C for protection against CVD has been questioned in several studies utilizing Mendelian randomization.87,89,91,92”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [87] Sarwar, 2010, Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies, Lancet source

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    • cites [89] Holmes, 2015, Mendelian randomization of blood lipids for coronary heart disease, Eur Heart J source

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    • cites [91] Haase, 2010, Genetically elevated apolipoprotein A-I, high-density lipoprotein cholesterol levels, and risk of ischemic heart disease, J Clin Endocrinol Metab source

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    • cites [92] Voight, 2012, Plasma HDL cholesterol and risk of myocardial infarction: a Mendelian randomisation study, Lancet source

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  • Findingcitation
    § 3.3.5. Triglycerides

    Triglycerides have been shown to be an independent risk factor in meta-analyses.

    “In a number of meta-analyses, TGs has been shown to be an independent risk factor.96,97”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [96] Sarwar, 2007, Triglycerides and the risk of coronary heart disease: 10,158 incident cases among 262,525 participants in 29 Western prospective studies, Circulation source

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    • cites [97] Hokanson, 1996, Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a meta-analysis of population-based prospective studies, J Cardiovasc Risk source

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  • Findingcitation
    § 3.3.3. Non-high-density lipoprotein cholesterol

    Data comparing non-HDL-C and LDL-C in risk algorithms are inconclusive.

    “Several analyses have been published comparing these variables in risk algorithms, but data are inconclusive.”
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    • cites 83e85

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    § 3.3.5. Triglycerides

    High triglyceride levels are often associated with low HDL-C and high levels of small dense LDL particles.

    “High TG levels are often associated with low HDL-C and high levels of small dense LDL particles.”
    Quote in the paperNot a substantial claim

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    § 2.1.1. Rationale for assessing total cardiovascular disease risk

    SCORE data indicate that total cardiovascular disease event risk is about three times higher than fatal cardiovascular disease risk for men, so a SCORE risk of 5% corresponds to about 15% total hard cardiovascular endpoints; the multiplier is about 4 in women and lower in older persons.

    “The SCORE data indicate that the total CVD event risk is about three times higher than the risk of fatal CVD for men, so that a SCORE risk of 5% translates into a CVD risk of ~15% of total (fatal þ non-fatal) hard CVD endpoints; the multiplier is ~4 in women and lower in older persons.”
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    § 3.3.2. Low-density lipoprotein cholesterol

    Direct methods for LDL-C are unreliable in patients with hypertriglyceridaemia and may underestimate very low LDL-C values.

    “However, the direct methods have been found to be unreliable in patients with HTG and should be used with caution in these cases 72 ; also, they may underestimate very low values of LDL-C.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [72] Langlois, 2014, Clinical impact of direct HDLc and LDLc method bias in hypertriglyceridemia. A simulation study of the EAS-EFLM Collaborative Project Group, Atherosclerosis source

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    Findingnone given
    § 3.3.4. High-density lipoprotein cholesterol

    Low HDL-C is a strong and independent risk factor in several studies and is included in most risk estimation tools.

    “Low HDL-C has been shown to be a strong and independent risk factor in several studies and is included in most of the risk estimation tools available, including HeartScore.”
    Quote in the paperNot a substantial claim

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

    Findingnone given
    § 3.3.5. Triglycerides

    A rare error occurs in patients with hyperglycerolaemia, where falsely very high triglyceride values are detected.

    “A rare error occurs in patients with hyperglycerolaemia, where falsely very high values for TGs are detected.”
    Quote in the paperNot a substantial claim

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    Findingnone given
    § 3.3.4. High-density lipoprotein cholesterol

    Based on epidemiological data, HDL-C levels associated with increased risk are below 1.0 mmol/L for men and below 1.2 mmol/L for women.

    “Based on epidemiological data, levels of HDL-C associated with increased risk for men are <1.0 mmol/L (40 mg/dL) and for women are <1.2 mmol/L (48 mg/dL).”
    Quote in the paperNot a substantial claim

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    § Box 8

    Some dietary interventions resulted in significant cardiovascular disease prevention, whereas others did not.

    “Some interventions resulted in significant CVD prevention, whereas others did not.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [132] Dalen, 2014, Diets to prevent coronary heart disease 1957–2013: what have we learned?, Am J Med source

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    § 3.3.7. Lipoprotein(a)

    Lp(a) is an additional independent risk marker and genetic data show it is causal in atherosclerotic vascular disease and aortic stenosis.

    “Lp(a) has been found in several studies to be an additional independent risk marker; indeed, genetic data show it to be causal in the pathophysiology of atherosclerotic vascular disease and aortic stenosis.109e111”
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    • cites 109e111

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    § Apolipoprotein B:apolipoprotein A1 ratio, total

    Loss of function mutations in apoCIII are associated with low triglycerides and reduced cardiovascular disease risk.

    “Furthermore, loss of function mutations are associated with low TGs as well as with reduced risk for CVD.106,107”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [106] Crosby, 2014, Loss-of-function mutations in APOC3, triglycerides, and coronary disease, N Engl J Med source

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    • cites [107] Jorgensen, 2014, Loss-of-function mutations in APOC3 and risk of ischemic vascular disease, N Engl J Med source

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    § 4. Treatment targets

    Systematic reviews confirm a dose-dependent reduction in cardiovascular disease with LDL-C lowering; greater LDL-C reduction gives greater cardiovascular risk reduction.

    “Particular consideration was given to results from systematic reviews confirming the dose-dependent reduction in CVD with LDL-C lowering; the greater the LDL-C reduction, the greater the CV risk reduction.65,66”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [65] Fulcher, 2015, Efficacy and safety of LDL-lowering therapy among men and women: meta-analysis of individual data from 174,000 participants in 27 randomised trials, Lancet source

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    • cites [66] Mihaylova, 2012, The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials, Lancet source

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    Findingnone given
    § 4. Treatment targets

    Increases in HDL-C predict atherosclerosis regression.

    “although increases in HDL-C predict atherosclerosis regression”
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    § 5.1. The influence of lifestyle on total cholesterol and low-density lipoprotein cholesterol levels

    n-3 PUFAs have no hypocholesterolaemic effect; at high dosages (>3 g/day), they have a neutral or slightly increasing effect on LDL-C with concomitant decrease of triglycerides.

    “PUFAs of the n-3 series have no hypocholesterolaemic effect; conversely, when they are used at high dosages (>3 g/day), the effect on LDL-C levels is either neutral or a slight increase [particularly with docosahexaenoic acid (DHA)] with a concomitant decrease of TGs.165”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [165] Mensink, 2003, Effects of dietary fatty acids and carbohydrates on the ratio of serum total to HDL cholesterol and on serum lipids and apolipoproteins: a meta-analysis of 60 controlled trials, Am J Clin Nutr source

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    Findingnone given
    § 5.1. The influence of lifestyle on total cholesterol and low-density lipoprotein cholesterol levels

    Stearic acid does not increase total cholesterol levels, unlike other saturated fatty acids (lauric, myristic, palmitic).

    “Stearic acid, in contrast to other SFAs (lauric, myristic and palmitic), does not increase TC levels.”
    Quote in the paperNot a substantial claim

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    § 5.1. The influence of lifestyle on total cholesterol and low-density lipoprotein cholesterol levels

    Dietary trans fatty acids have a similar elevating effect on LDL-C to saturated fatty acids, but while saturated fatty acids increase HDL-C, trans fats decrease it.

    “Quantitatively, dietary trans fatty acids have a similar elevating effect on LDL-C to that of SFAs; however, while SFAs increase HDL-C levels, trans fats decrease them.137”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [137] Estruch, 2013, Primary prevention of cardiovascular disease with a Mediterranean diet, N Engl J Med source

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    § 5.3. The influence of lifestyle on high-density lipoprotein cholesterol levels

    Moderate alcohol consumption is associated with increased HDL-C levels compared with abstainers, with a dose-response relationship.

    “Moderate alcohol consumption is associated with increased HDL-C levels as compared with abstainers, with a dose-response relationship.”
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    Findingnone given
    § 5.3. The influence of lifestyle on high-density lipoprotein cholesterol levels

    MUFA consumption as replacement for saturated fatty acids has almost no effect on HDL-C, while n-6 PUFAs induce a slight decrease.

    “MUFA consumption as a replacement for SFAs has almost no effect on HDL-C, while n-6 PUFAs induce a slight decrease.”
    Quote in the paperNot a substantial claim

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    Findingnone given
    § 5.2. The influence of lifestyle on triglyceride levels

    These effects are dose dependent; with 15-20% energy from fructose, plasma triglycerides increase as much as 30-40%.

    “These effects are dose dependent; with a habitual fructose consumption between 15 and 20% of the total energy intake, plasma TG increases as much as 30e40%.”
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    Findingcitation
    § Box 8

    Both DASH and Mediterranean diets have been proven effective in reducing cardiovascular risk factors and possibly contribute to cardiovascular disease prevention.

    “both have been proven to be effective in reducing CV risk factors and, possibly, to contribute to CVD prevention.133”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [133] Eckel, 2014, 2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, Circulation source

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    § 5.1. The influence of lifestyle on total cholesterol and low-density lipoprotein cholesterol levels

    Replacing 1% of dietary energy from saturated fatty acids with n-6 PUFAs decreases LDL-C by 0.051 mmol/L; with MUFAs by 0.041 mmol/L; with carbohydrate by 0.032 mmol/L.

    “If 1% of the dietary energy derived from SFAs is replaced by n-6 polyunsaturated fatty acids (PUFAs), LDL-C decreases by 0.051 mmol/L (2.0 mg/dL); if replaced by monounsaturated fatty acids (MUFAs), the decrease would be 0.041 mmol/L (1.6 mg/dL); and if replaced by carbohydrate, it would be 0.032 mmol/L (1.2 mg/dL).”
    Quote in the paperSubstantial claim

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    Findingnone given
    § 5.2. The influence of lifestyle on triglyceride levels

    Weight reduction improves insulin sensitivity and decreases triglyceride levels.

    “Weight reduction improves insulin sensitivity and decreases TG levels.”
    Quote in the paperSubstantial claim

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    Findingcitation
    § 5.3. The influence of lifestyle on high-density lipoprotein cholesterol levels

    Glycaemic index and fibre content do not seem to play a relevant role in this effect.

    “In this respect, both the glycaemic index and the fibre content do not seem to play a relevant role.178,179”
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    • cites [178] Goff, 2013, Low glycaemic index diets and blood lipids: a systematic review and meta-analysis of randomised controlled trials, Nutr Metab Cardiovasc Dis source

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    • cites [179] Bazzano, 2011, Non-soy legume consumption lowers cholesterol levels: a meta-analysis of randomized controlled trials, Nutr Metab Cardiovasc Dis source

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    § 5.2. The influence of lifestyle on triglyceride levels

    Detrimental effects of high carbohydrate diet on triglycerides occur mainly with refined carbohydrate-rich foods, less with fibre-rich, low glycaemic index foods.

    “In particular, 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 fibre-rich, low glycaemic index foods.”
    Quote in the paperNot a substantial claim

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    § 5.3. The influence of lifestyle on high-density lipoprotein cholesterol levels

    Saturated fatty acids increase HDL-C in parallel with LDL-C; trans fats decrease HDL-C.

    “SFAs increase HDL-C levels in parallel with LDL-C; in contrast, trans fats decrease them.137”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [137] Estruch, 2013, Primary prevention of cardiovascular disease with a Mediterranean diet, N Engl J Med source

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    § 5.2. The influence of lifestyle on triglyceride levels

    Glucose and lipid metabolism are strongly related, and high carbohydrate diet-induced perturbation of carbohydrate metabolism increases triglyceride concentrations.

    “Glucose and lipid metabolism are strongly related, and any perturbation of carbohydrate metabolism induced by a high carbohydrate diet will also lead to an increase in TG concentrations.148,165”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [148] Nordmann, 2006, Effects of low-carbohydrate vs low-fat diets on weight loss and cardiovascular risk factors: a meta-analysis of randomized controlled trials, Arch Intern Med source

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    • cites [165] Mensink, 2003, Effects of dietary fatty acids and carbohydrates on the ratio of serum total to HDL cholesterol and on serum lipids and apolipoproteins: a meta-analysis of 60 controlled trials, Am J Clin Nutr source

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    § 5.2. The influence of lifestyle on triglyceride levels

    In individuals with hypertriglyceridaemia, even small amounts of alcohol can further elevate triglycerides; in the general population, detrimental effects occur only with excessive intake.

    “While in individuals with HTG even a small amount of alcohol can induce a further elevation of TG concentrations, in the general population alcohol exerts detrimental effects on TG levels only if the intake is excessive.152,177”
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    • cites [152] Rimm, 1999, Moderate alcohol intake and lower risk of coronary heart disease: meta-analysis of effects on lipids and haemostatic factors, BMJ source

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    • cites [177] Brien, 2011, Effect of alcohol consumption on biological markers associated with risk of coronary heart disease: systematic review and meta-analysis of interventional studies, BMJ source

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    Findingcitation
    § 5.1. The influence of lifestyle on total cholesterol and low-density lipoprotein cholesterol levels

    Body weight reduction influences total cholesterol and LDL-C, with a decrease of about 0.2 mmol/L LDL-C per 10 kg weight loss in grossly obese subjects; reduction is greater with a low fat diet.

    “Body weight reduction also influences TC and LDL-C, but the magnitude of the effect is rather small; in grossly obese subjects, a decrease in LDL-C concentration of ~0.2 mmol/L (8 mg/dL) is observed for every 10 kg of weight loss; the reduction of LDL-C is greater if weight loss is achieved with a low fat diet.147,148”
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    • cites [147] Dattilo, 1992, Effects of weight reduction on blood lipids and lipoproteins: a meta-analysis, Am J Clin Nutr source

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    • cites [148] Nordmann, 2006, Effects of low-carbohydrate vs low-fat diets on weight loss and cardiovascular risk factors: a meta-analysis of randomized controlled trials, Arch Intern Med source

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    Findingnone given
    § 5.2. The influence of lifestyle on triglyceride levels

    In many studies, reduction of triglyceride levels due to weight reduction is between 20-30%, preserved as long as weight is not regained.

    “In many studies the reduction of TG levels due to weight reduction is between 20e30%; this effect is usually preserved as long as weight is not regained.”
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    § 5.4.2. Dietary fat

    Fat intakes above 35% of calories are generally associated with increased intakes of both saturated fat and calories.

    “However, fat intakes that >35% of calories are generally associated with increased intakes of both saturated fat and calories.”
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    § 5.4.2. Dietary fat

    A low intake of fats and oils increases risk of inadequate intakes of vitamin E and essential fatty acids, and may contribute to unfavourable changes in HDL-C.

    “Conversely, a low intake of fats and oils increases the risk of inadequate intakes of vitamin E and of essential fatty acids, and may contribute to unfavourable changes in HDL-C.165”
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    • cites [165] Mensink, 2003, Effects of dietary fatty acids and carbohydrates on the ratio of serum total to HDL cholesterol and on serum lipids and apolipoproteins: a meta-analysis of 60 controlled trials, Am J Clin Nutr source

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    § 9.11.1. Lower extremities arterial disease

    In critical limb ischaemia, statin therapy improved 1-year mortality and major adverse cardiovascular events and increased amputation-free survival.

    “Even in the most advanced stages of the disease (critical limb ischaemia), statin therapy improved rates of 1-year mortality and major adverse CV events and increased amputation-free survival.409”
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    • cites [409] Westin, 2014, Association between statin medications and mortality, major adverse cardiovascular event, and amputation-free survival in patients with critical limb ischemia, J Am Coll Cardiol source

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    § 9.11.3. Retinal vascular disease

    Atherosclerotic changes in retinal arteries correlate with total cholesterol, LDL-C, triglycerides and apolipoprotein B levels and also with coronary artery disease.

    “Atherosclerotic changes of retinal arteries correlate with TC, LDL-C, TG and apoB levels and also with CAD.412”
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    • cites [412] Tedeschi-Reiner, 2005, Relation of atherosclerotic changes in retinal arteries to the extent of coronary artery disease, Am J Cardiol source

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    § 9.14. Mental disorders

    In patients with first-episode schizophrenia spectrum disorders, cardiometabolic risk factors were present early in the illness, related to the underlying disorder, unhealthy lifestyle and antipsychotic medications, which interact with each other.

    “In patients with first-episode schizophrenia spectrum disorders, cardiometabolic risk factors were present early in the illness; this was related to the underlying disorder, unhealthy lifestyle and antipsychotic medications, which interact with each other.437”
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    • cites [437] Correll, 2014, Cardiometabolic risk in patients with first-episode schizophrenia spectrum disorders: baseline results from the RAISE-ETP study, JAMA Psychiatry source

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    § 9.14. Mental disorders

    There is a higher prevalence of obesity, metabolic syndrome, diabetes and dyslipidaemia in patients with these psychiatric diseases.

    “All this explains the higher prevalence of obesity, MetS, diabetes and dyslipidaemia in patients with these psychiatric diseases.438”
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    • cites [438] Andrade, 2013, Primary prevention of cardiovascular events in patients with major mental illness: a possible role for statins, Bipolar Disord source

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    § 9.12.1. Primary prevention of stroke

    A recent meta-analysis of randomized trials in subjects over 65 years of age at high cardiovascular risk without established cardiovascular disease showed that statins significantly reduce the incidence of myocardial infarction and stroke, but do not significantly prolong survival in the short term.

    “A recent meta-analysis of RCTs in subjects >65 years of age at high CV risk without established CV disease showed that statins significantly reduce the incidence of MI and stroke, but do not significantly prolong survival in the short-term.327”
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    • cites [327] Savarese, 2013, Benefits of statins in elderly subjects without established cardiovascular disease: a meta-analysis, J Am Coll Cardiol source

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    § 9.14. Mental disorders

    In patients with bipolar disorder there was a reduction in life expectancy of 12 to 14 years.

    “In patients with bipolar disorder there was a reduction in life expectancy of 12e14 years.440”
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    • cites [440] Laursen, 2011, Life expectancy among persons with schizophrenia or bipolar affective disorder, Schizophr Res source

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    § 9.14. Mental disorders

    In a Finnish cohort of patients with schizophrenia, life expectancy was about 2 decades less than in persons of similar age from the general population.

    “In a Finnish cohort of patients with schizophrenia, life expectancy was about 2 decades less than in persons of similar age from the general population.439”
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    • cites [439] Tiihonen, 2009, 11-year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study), Lancet source

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    § 9.12.1. Primary prevention of stroke

    Adding ezetimibe to simvastatin in post-acute coronary syndrome patients had an incremental beneficial effect for ischaemic stroke or all strokes, with marginal statistical significance for the latter.

    “The addition of ezetimibe to simvastatin in post-ACS patients had an incremental beneficial effect for ischaemic stroke or all strokes (marginal statistical significance for the latter).63”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [63] Cannon, 2015, Ezetimibe added to statin therapy after acute coronary syndromes, N Engl J Med source

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    § 9.12.2. Secondary prevention of stroke

    Secondary prevention with statins reduces the risk of recurrent stroke by 12%, myocardial infarction and vascular death.

    “Secondary prevention therapy with statins reduces the risk of recurrent stroke (by 12%), MI and vascular death.422,428”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [422] Amarenco, 2009, Lipid management in the prevention of stroke: review and updated meta-analysis of statins for stroke prevention, Lancet Neurol source

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    • cites [428] Amarenco, 2006, High-dose atorvastatin after stroke or transient ischemic attack, N Engl J Med source

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    § 9.14. Mental disorders

    Among 654 patients with bipolar disorder in the FACE-BD cohort, 18.5% met criteria for metabolic syndrome; only 11% and 28% of patients with hypercholesterolaemia and high fasting glycaemia, respectively, were treated for these conditions.

    “Among 654 patients with bipolar disorder in the Fondamental Advanced Centers of Expertise in Bipolar Disorders (FACE-BD) cohort, 18.5% met the criteria for MetS; only 11% and 28% of the patients with hypercholesterolaemia and high fasting glycaemia, respectively, were treated for these conditions.441”
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    • cites [441] Godin, 2014, Metabolic syndrome in a French cohort of patients with bipolar disorder: results from the FACE-BD cohort, J Clin Psychiatry source

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    § 9.13. Human immunodeficiency virus patients

    HIV-infected patients typically have low total cholesterol and LDL-C, low HDL-C and increased triglycerides.

    “HIV-infected patients typically have low TC and LDL-C, as well as low HDL-C and increased TGs.430,431”
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    • cites [430] Riddler, 2003, Impact of HIV infection and HAART on serum lipids in men, JAMA source

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    • cites [431] Hemkens, 2014, HIV infection and cardiovascular disease, Eur Heart J source

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    § 9.14. Mental disorders

    A systematic review found that the incidence of drug-induced hepatotoxicity in patients taking statins is unknown, with very few cases occurring in large-scale randomized controlled trials.

    “A systematic review found that the incidence of drug-induced hepatotoxicity in patients taking statins is unknown, with very few cases occurring in large-scale RCTs.212,214”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [212] Law, 2006, Statin safety: a systematic review, Am J Cardiol source

      Not checked in the free run.

    • cites [214] Naci, 2013, Comparative tolerability and harms of individual statins: a study-level network meta-analysis of 246 955 participants from 135 randomized, controlled trials, Circ Cardiovasc Qual Outcomes source

      Not checked in the free run.

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

    Findingcitation
    § 462

    Various empirical models of health behaviour and behaviour change theory have been shown to predict adherence, including the Theory of Planned Behaviour and the Health Belief Model.

    “Various empirical models of health behaviour and behaviour change theory have been shown to predict adherence, including the Theory of Planned Behaviour 466 and the Health Belief Model.467”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [466] Ajzen, 1991, The Theory of Planned Behaviour, Organ Behav Hum Decis Process source

      Not checked in the free run.

    • cites [467] Becker, 1974, The Health Belief Model and personal health behaviour, Health Educ Monogr source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation
    § 462

    Predictors of non-adherence with statins include use in primary prevention rather than in patients with disease or multiple risk factors, lower income, being elderly, complex polypharmacy, cost, forgetfulness due to a lack of symptoms and psychological co-morbidities.

    “Predictors of non-adherence with statins have been identified 450,472e474 and include their use in individuals for primary prevention as compared with their use in patients with disease or with multiple risk factors, lower income, being elderly, complex polypharmacy, cost and forgetfulness due to a lack of symptoms and psychological co-morbidities.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [450] Benner, 2002, Long-term persistence in use of statin therapy in elderly patients, JAMA source

      Not checked in the free run.

    • cites 472e474

      Not checked in the free run.

  • May combine two claims.

    Findingcitation
    § 11.2. Adhering to medications

    Adherence declines over the duration of treatment, and this is truer in patients treated for primary compared with secondary prevention of cardiovascular disease, with reported rates of up to 77% discontinuing statins within 2 years.

    “Adherence declines over the duration of treatment 450e454 ; however, this is truer in patients treated for primary compared with secondary prevention of CVD, with reported rates of up to 77% discontinuing their statins within 2 years.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites 450e454

      Not checked in the free run.

  • May combine two claims.

    Findingcitation
    § 11.2. Adhering to medications

    Non-adherence has an impact on healthcare costs, morbidity, hospital readmissions and mortality.

    “Not surprisingly, this non-adherence has an impact on healthcare costs, morbidity, hospital readmissions and mortality.457e461”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites 457e461

      Not checked in the free run.

  • May combine two claims.

    Findingcitation
    § 11.2. Adhering to medications

    Despite a wealth of evidence on the efficacy and effectiveness of statins in primary and secondary prevention, adherence remains a consistent barrier, with rates below 50% demonstrated in several studies.

    “Despite a wealth of evidence on the efficacy and effectiveness of statins in both primary and secondary prevention, adherence remains a consistent barrier, with rates of <50% demonstrated in several studies.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites 450e454

      Not checked in the free run.

  • May combine two claims.

    Findingcitation
    § 462

    Studies of adherence to medications in long-term conditions identified high susceptibility, severity of the condition, strong intentions and high self-efficacy as associated with good adherence, while poor lifestyle habits and low perceived behavioural control were associated with poor adherence.

    “Studies that investigated adherence to medications in long-term conditions identified factors such as high susceptibility, severity of the condition, strong intentions and high self-efficacy as being associated with good adherence, while poor lifestyle habits and low perceived behavioural control were associated with poor adherence.468,469”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [468] Rich, 2015, Theory of planned behavior and adherence in chronic illness: a meta-analysis, J Behav Med source

      Not checked in the free run.

    • cites [469] Kamran, 2014, Determinants of patient's adherence to hypertension medications: application of health belief model among rural patients, Ann Med Health Sci Res source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation
    § 462

    The same Cochrane overview found that self-management or self-monitoring programmes, as well as regular pharmacy review of prescribed medications with a view to removing unnecessary medications, were helpful.

    “This overview also found that the use of self-management or self-monitoring programmes, as well as a regular pharmacy review of prescribed medications with a view to taking out unnecessary medications, was helpful.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [484] Ryan, 2014, Interventions to improve safe and effective medicines use by consumers: an overview of systematic reviews, Cochrane Database Syst Rev

      Not checked in the free run.

  • May combine two claims.

    Findingcitation
    § 462

    At 15 months, statistically significant differences between the intervention and usual care were seen in self-reported adherence and changes in systolic blood pressure and LDL-C.

    “At 15 months, statistically significant differences between intervention and usual care were seen in self-reported adherence and changes in systolic blood pressure and LDL-C.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [482] Thom, 2013, Effects of a fixed-dose combination strategy on adherence and risk factors in patients with or at high risk of CVD: the UMPIRE randomized clinical trial, JAMA source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation
    § 462

    In phase 1 of FOCUS, factors associated with non-adherence were younger age, depression, complex regimen, poorer health insurance coverage and low social support.

    “In phase 1, factors associated with non-adherence were younger age, depression, complex regimen, poorer health insurance coverage and low social support.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [483] Castellano, 2014, A polypill strategy to improve adherence: results from the FOCUS project, J Am Coll Cardiol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 1.3. Cost-effectiveness of prevention

    A sizable portion of patients on hypolipidaemic or antihypertensive drug treatment fail to take treatment adequately or reach therapeutic goals, with clinical and economic consequences.

    “Importantly, a sizable portion of patients on hypolipidaemic or antihypertensive drug treatment fail to take their treatment adequately or to reach their therapeutic goals, 28,29 with clinical and economic consequences.30”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [28] Banegas, 2011, Achievement of treatment goals for primary prevention of cardiovascular disease in clinical practice across Europe: the EURIKA study, Eur Heart J source

      Not checked in the free run.

    • cites [29] Kotseva, 2010, Management of cardiovascular risk factors in asymptomatic high-risk patients in general practice: cross-sectional survey in 12 European countries, Eur J Cardiovasc Prev Rehabil source

      Not checked in the free run.

    • cites [30] Cherry, 2009, The clinical and economic burden of nonadherence with antihypertensive and lipid-lowering therapy in hypertensive patients, Value Health source

      Not checked in the free run.

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

    Premisecitation
    § Box 1 Key messages.

    Coronary artery disease mortality rates could be halved by only modest risk factor reduction.

    “Coronary artery disease (CAD) mortality rates could be halved by only modest risk factor reduction, 39”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] Capewell, 2010, Cardiovascular risk factor trends and potential for reducing coronary heart disease mortality in the United States of America, Bull World Health Org source

      Not checked in the free run.

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

    Interpretationreasoning
    § 2.1.1. Rationale for assessing total cardiovascular disease risk

    Patients who have had a clinical event such as acute coronary syndrome or stroke are at very high risk of a further event and automatically qualify for risk factor evaluation and management.

    “Patients who have had a clinical event such as acute coronary syndrome (ACS) or a stroke are at very high risk of a further event and automatically qualify for risk factor evaluation and management (Table 6).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Table 6

      Not checked in the free run.

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

    Premisereasoning
    § 2.1.1. Rationale for assessing total cardiovascular disease risk

    All current guidelines on cardiovascular disease prevention in clinical practice recommend assessment of total coronary artery disease or cardiovascular risk, because atherosclerotic cardiovascular disease is usually the product of multiple risk factors, and prevention should be adapted to total cardiovascular risk.

    “All current guidelines on the prevention of CVD in clinical practice recommend the assessment of total CAD or CV risk, because atherosclerotic CVD is usually the product of a number of risk factors, and prevention of CVD in a given person should be adapted to his/her total CV risk: the higher the risk, the more intense the action should be.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Atherosclerotic cardiovascular disease is usually the product of a number of risk factors.

  • May combine two claims.

    Interpretationcitation
    § Box 1 Key messages.

    Targeting lower levels of the health impact pyramid would address the socio-economic divide in cardiovascular health, which has not diminished despite major improvements in cardiovascular disease treatment.

    “Targeting lower levels in the health impact pyramid will also address the socio-economic divide in CV health, which has not diminished despite major improvements in the treatment of CVD in recent decades.9,10”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [9] Heidenreich, 2011, Forecasting the future of cardiovascular disease in the United States: a policy statement from the American Heart Association, Circulation source

      Not checked in the free run.

    • cites [10] McConnachie, 2014, Long-term impact on healthcare resource utilization of statin treatment, and its cost effectiveness in the primary prevention of cardiovascular disease: a record linkage study, Eur Heart J source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 1.1. Definition and rationale

    Eliminating health risk behaviours could prevent at least 80% of cardiovascular disease and 40% of cancers.

    “the elimination of health risk behaviours would make it possible to prevent at least 80% of CVD and even 40% of cancers, thus providing added value for other chronic diseases.3,4”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [3] Liu, 2012, Healthy lifestyle through young adulthood and the presence of low cardiovascular disease risk profile in middle age: the Coronary Artery Risk Development in (Young) Adults (CARDIA) study, Circulation source

      Not checked in the free run.

    • cites [4] Ezzati, 2004

      Not checked in the free run.

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

    Premisecitation
    § Box 1 Key messages.

    A National Institute for Health and Care Excellence report estimated that a UK national programme reducing population cardiovascular risk by 1% would prevent 25,000 cardiovascular disease cases and generate savings of 40 million euros per year.

    “A report from the National Institute for Health and Care Excellence (NICE) estimated that a UK national programme reducing population CV risk by 1% would prevent 25 000 CVD cases and generate savings of V40 million per year.38”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [38] National Institute for Health and Care Excellence, 2010

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 1.3. Cost-effectiveness of prevention

    Most cost-effectiveness studies of cardiovascular disease prevention combine clinical research evidence with simulation, and randomized controlled trial data are relatively scarce.

    “Most studies assessing the cost-effectiveness of prevention of CVD combine evidence from clinical research with simulation approaches, while data from randomized controlled trials (RCTs) are relatively scarce.7,10,11”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [7] Mistry, 2012, Cost-effectiveness of a European preventive cardiology programme in primary care: a Markov modelling approach, BMJ Open

      Not checked in the free run.

    • cites [10] McConnachie, 2014, Long-term impact on healthcare resource utilization of statin treatment, and its cost effectiveness in the primary prevention of cardiovascular disease: a record linkage study, Eur Heart J source

      Not checked in the free run.

    • cites [11] Ward, 2007, A systematic review and economic evaluation of statins for the prevention of coronary events, Health Technol Assess source

      Not checked in the free run.

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

    Premisecitation
    § 2.1.1. Rationale for assessing total cardiovascular disease risk

    The 2012 European Guidelines on cardiovascular disease prevention recommend SCORE because it is based on large, representative European cohort datasets.

    “The European Guidelines on CVD prevention in clinical practice (version 2012) 6 recommend use of the SCORE system because it is based on large, representative European cohort datasets.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] Perk, 2012, Eur Heart J source

      Not checked in the free run.

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

    Premisecitation
    § Box 1 Key messages.

    According to the World Health Organization, policy and environmental changes could reduce cardiovascular disease in all countries for less than US$1 per person per year, while individual-level interventions are considerably more expensive.

    “According to the WHO, policy and environmental changes could reduce CVD in all countries for <US$1 per person per year, while interventions at the individual level are considerably more expensive.37”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] Brown, 2011, Medication adherence: WHO cares?, Mayo Clin Proc source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § 1.3. Cost-effectiveness of prevention

    Cost-effectiveness results depend strongly on target population age, population cardiovascular risk, and intervention cost, so results from one country may not apply in another.

    “Cost-effectiveness results strongly depend on parameters such as the target population's age, the overall population risk of CVD and the cost of interventions.Hence, results obtained in one country might not be valid in another.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § 1.3. Cost-effectiveness of prevention

    Lowering blood cholesterol with statins and improving blood pressure control are cost effective.

    “Lowering blood cholesterol levels using statins 10,11,23e25 and improving blood pressure control are also cost effective.26,27”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites 10,11,23e25

      Not checked in the free run.

    • cites [26] Stevanovic, 2014, Economic evaluation of primary prevention of cardiovascular diseases in mild hypertension: a scenario analysis for the Netherlands, Clin Ther source

      Not checked in the free run.

    • cites [27] Wisloff, 2012, Choice of generic antihypertensive drugs for the primary prevention of cardiovascular disease—a cost-effectiveness analysis, BMC Cardiovasc Disord source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given
    § Gaps in evidence.

    In young people with high levels of risk factors, a low absolute risk may conceal a very high relative risk requiring 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 intensive lifestyle advice.”
    Quote in the paperNot a substantial claim

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

    Premisenone given
    § 2.2. Risk levels

    Cut-off points used to define high risk are in part arbitrary and 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 arbitrary and based on the risk levels at which benefit is evident in clinical trials.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given
    § 3.3.3. Non-high-density lipoprotein cholesterol

    Non-HDL-C estimates the total amount of atherogenic lipoproteins in plasma and relates well to apoB levels.

    “Non-HDL-C is used as an estimation of the total amount of atherogenic lipoproteins in plasma (VLDL, VLDL remnants, intermediate-density lipoprotein (IDL), LDL, Lp(a)) and relates well to apoB levels.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § Box 4 Qualifiers.

    Social deprivation and psychosocial stress set the scene for increased risk.

    “Social deprivation and psychosocial stress set the scene for increased risk.57”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [57] Mortensen, 2015, The high-density lipoprotein-adjusted SCORE model worsens SCORE-based risk classification in a contemporary population of 30,824 Europeans: the Copenhagen General Population Study, Eur Heart J source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Gaps in evidence.

    HDL-C modifies risk at all levels estimated from SCORE cholesterol charts, in both genders and all age groups including older women.

    “For example, HDL-C modifies risk at all levels of risk as estimated from the SCORE cholesterol charts.55 Furthermore, this effect is seen in both genders and in all age groups, including older women.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [55] Cooney, 2009, HDL cholesterol protects against cardiovascular disease in both genders, at all ages and at all levels of risk, Atherosclerosis source

      Not checked in the free run.

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

    Premisenone given
    § 3.3.4. High-density lipoprotein cholesterol

    Most available HDL-C assays are of high quality.

    “Most available assays are of high quality”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given
    § 3.3.6. Apolipoproteins

    ApoB is the major apolipoprotein of atherogenic lipoprotein families (VLDL, IDL, LDL) and estimates the number of these particles.

    “ApoB is the major apolipoprotein of the atherogenic lipoprotein families (VLDL, IDL and LDL).ApoB is a good estimate of the number of these particles in plasma.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisereasoning
    § 3.3.3. Non-high-density lipoprotein cholesterol

    Non-HDL-C includes atherogenic triglyceride-rich lipoproteins (VLDL, IDL and remnants).

    “Non-HDL-C also includes the atherogenic TG-rich lipoproteins (VLDL, IDL and remnants)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning
    § 2.1.2. How to use the risk estimation charts

    Some countries are at very high risk, and the high-risk chart may underestimate risk in these countries.

    “Of these, some are at very high risk, and the high-risk chart may underestimate risk in these countries.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning
    § Gaps in evidence.

    Risk age can be used in any population regardless of baseline risk or secular changes in mortality, and avoids the need for recalibration.

    “Risk age can be used in any population regardless of baseline risk or secular changes in mortality, and therefore avoids the need for recalibration.”
    Quote in the paperNot a substantial claim

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

    Interpretationnone given
    § 2.1.1. Rationale for assessing total cardiovascular disease risk

    Persons with documented cardiovascular disease, type 1 or type 2 diabetes, very high levels of individual risk factors, or chronic kidney disease are automatically at very high or high total cardiovascular risk and need active management of all risk factors without risk estimation models.

    “Persons with documented CVD type 1 or type 2 diabetes very high levels of individual risk factors chronic kidney disease (CKD) (refer to section 9.9) are automatically at very high or high total CV risk.No risk estimation models are needed for them; they all need active management of all risk factors.”
    Quote in the paperSubstantial claim

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

    Interpretationnone given
    § 3.3.2. Low-density lipoprotein cholesterol

    The Friedewald formula may be unreliable when blood is obtained under non-fasting conditions.

    “The Friedewald formula may be unreliable when blood is obtained under non-fasting conditions.”
    Quote in the paperNot a substantial claim

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

    Premisecitation
    § 3.3.3. Non-high-density lipoprotein cholesterol

    Some recent guidelines recommend non-HDL-C as a better risk indicator than LDL-C.

    “Some recent guidelines recommend non-HDL-C as a better risk indicator than LDL-C.82”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [82] National Institute for Health and Care Excellence, 2014

      Not checked in the free run.

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

    Interpretationnone given
    § 3.3.4. High-density lipoprotein cholesterol

    Hypertriglyceridaemia might interfere with direct HDL-C assays.

    “It should also be considered that HTG might interfere with the direct HDL-C assays.”
    Quote in the paperNot a substantial claim

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

    Premisenone given
    § 3.3.6. Apolipoproteins

    The analytical performance of apoB and apoA1 assays is good, and they do not require fasting and are not sensitive to elevated triglyceride levels.

    “The analytical performance is good and the assays do not require fasting conditions and are not sensitive to markedly elevated TG levels.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § Gaps in evidence.

    HDL-C has a modest but useful effect in refining risk estimation, but this may not be universal, as it may not be seen in some low-risk populations with relatively high mean HDL-C.

    “Overall, HDL-C has a modest but useful effect in refining risk estimation, 56 but this may not be universal, as its effect may not be seen in some low-risk populations, particularly with a relatively high mean HDL-C level.57”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [56] Cooney, 2009, How much does HDL cholesterol add to risk estimation? A report from the SCORE Investigators, Eur J Cardiovasc Prev Rehabil source

      Not checked in the free run.

    • cites [57] Mortensen, 2015, The high-density lipoprotein-adjusted SCORE model worsens SCORE-based risk classification in a contemporary population of 30,824 Europeans: the Copenhagen General Population Study, Eur Heart J source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 2.2.1. Risk-based intervention strategies

    These trials consistently show that the higher the initial LDL-C, the greater the absolute risk reduction, while relative risk reduction remains constant at any given baseline LDL-C.

    “These trials are consistent in showing that the higher the initial LDL-C level, the greater the absolute reduction in risk, while the relative risk reduction remains constant at any given baseline LDL-C level.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites 61e71

      Not checked in the free run.

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

    Premisenone given
    § 3.3.6. Apolipoproteins

    Good immunochemical methods for apoB and apoA1 are available and easily run in conventional autoanalysers.

    “Good immunochemical methods are available and easily run in conventional autoanalysers.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given
    § 3.3.1. Total cholesterol

    Patients with familial hyperlipidaemia or total cholesterol above 7.5 mmol/L are always at high cardiovascular risk.

    “These patients are always at high risk and should receive special attention.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § Gaps in evidence.

    Recent work shows that b-coefficients are not constant with ageing and that SCORE overestimates risk in older people.

    “Recent work has shown that b-coefficients are not constant with ageing and that SCORE overestimates risk in older people.54”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [54] Cooney, 2016, Cardiovascular risk estimation in older persons: SCORE O.P, Eur J Prev Cardiol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 3.3.7. Lipoprotein(a)

    Several methods for Lp(a) determination are available, but standardization between assays is needed.

    “Several methods for determination of Lp(a) are available, but standardization between assays is needed.112”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [112] Marcovina, 2003, Report of the National Heart, Lung, and Blood Institute Workshop on Lipoprotein(a) and Cardiovascular Disease: recent advances and future directions, Clin Chem source

      Not checked in the free run.

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

    Premisenone given
    § 3.3.7. Lipoprotein(a)

    Lp(a) contains a unique protein, apo(a), structurally homologous to plasminogen.

    “Lp(a) has properties in common with LDL, but it contains a unique protein, apolipoprotein(a) [apo(a)], that is structurally homologous to plasminogen.”
    Quote in the paperNot a substantial claim

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

    Premisenone given
    § 3.3.6. Apolipoproteins

    Each HDL particle may carry from one to five apoA1 molecules.

    “However, each HDL particle may carry from one to five apoA1 molecules.”
    Quote in the paperNot a substantial claim

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

    Premisenone given
    § 3.3.9. Genotyping

    ApoE is present in three isoforms (apoE2, apoE3, apoE4).

    “ApoE is present in three isoforms (apoE2, apoE3 and apoE4).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning
    § 4. Treatment targets

    Secondary targets for non-HDL-C and apoB have been defined by inference and receive a moderate grading because they have not been extensively studied in RCTs.

    “Secondary targets have also been defined by inference for non-HDL-C and for apoB; they receive a moderate grading, as they have not been extensively studied in RCTs.”
    Quote in the paperSubstantial claim

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

    Premisereasoning
    § 3.3.6. Apolipoproteins

    Plasma apoA1 levels below 120 mg/dL for men and below 140 mg/dL for women correspond approximately to low HDL-C.

    “Plasma apoA1 levels <120 mg/dL for men and <140 mg/dL for women correspond approximately to what is considered as low for HDL-C.”
    Quote in the paperNot a substantial claim

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

    Premisenone given
    § 3.3.6. Apolipoproteins

    ApoA1 is the major protein of HDL-C and provides a satisfactory estimate of HDL-C concentration.

    “ApoA1 is the major protein of HDL-C and provides a satisfactory estimate of HDL-C concentration.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § Apolipoprotein B:apolipoprotein A1 ratio, total

    ApoCIII is a key regulator of triglyceride metabolism, and high apoCIII levels are associated with high VLDL and triglycerides.

    “ApoCIII is a key regulator of TG metabolism, and high apoCIII plasma levels are associated with high plasma VLDL and plasma TGs.”
    Quote in the paperNot a substantial claim

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

    Interpretationcitation
    § 3.3.9. Genotyping

    In familial hypercholesterolaemia, genetic diagnosis is important for family screening, establishing diagnosis in borderline LDL-C, and improving adherence.

    “In FH, a genetic diagnosis is important for family screening, to establish the diagnosis in patients with borderline LDL-C and to improve patient adherence to therapy.121”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [121] Nordestgaard, 2013, Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society, Eur Heart J source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationcitation
    § 3.3.7. Lipoprotein(a)

    The risk is regarded as significant when Lp(a) is above the 80th percentile (50 mg/dL).

    “The risk is regarded as significant when Lp(a) is above the 80th percentile (50 mg/dL).109”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [109] Nordestgaard, 2010, Lipoprotein(a) as a cardiovascular risk factor: current status, Eur Heart J source

      Not checked in the free run.

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

    Premisenone given
    § 3.3.9. Genotyping

    ApoE genotyping is used primarily for diagnosis of dysbetalipoproteinaemia (apoE2 homozygosity) and is indicated in severe combined hyperlipidaemia.

    “ApoE genotyping is used primarily for the diagnosis of dysbetalipoproteinaemia (apoE2 homozygosity) and is indicated in cases with severe combined hyperlipidaemia.”
    Quote in the paperNot a substantial claim

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

    Interpretationcitation
    § 3.3.8. Lipoprotein particle size

    Small dense LDL may be an emerging risk factor but is not currently recommended for risk estimation.

    “Determination of small dense LDL may be regarded as an emerging risk factor and may be used in the future, but it is not currently recommended for risk estimation.119”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [119] Mora, 2007, LDL particle subclasses, LDL particle size, and carotid atherosclerosis in the Multi-Ethnic Study of Atherosclerosis (MESA), Atherosclerosis source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation
    § 3.3.9. Genotyping

    Known risk loci account for only a small proportion of risk, so genotyping is not recommended for risk estimation.

    “At present, the use of genotyping for risk estimation is not recommended since known risk loci account for only a small proportion of risk.120”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [120] Whitfield, 2014, Genetic insights into cardiometabolic risk factors, Clin Biochem Rev

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

    Interpretationcitation
    § Apolipoprotein B:apolipoprotein A1 ratio, total

    ApoCIII is a potential therapeutic target currently being studied, but its role in clinical practice is unknown.

    “ApoCIII has been identified as a new potential therapeutic target that is currently being studied, but whether it has a role in clinical practice is unknown and its measurements on a routine basis are not encouraged.108”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [108] Graham, 2013, Antisense oligonucleotide inhibition of apolipoprotein C-III reduces plasma triglycerides in rodents, nonhuman primates, and humans, Circ Res source

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

    Premisenone given
    § 3.3.9. Genotyping

    Several genes have been associated with cardiovascular disease.

    “Several genes have been associated with CVD.”
    Quote in the paperNot a substantial claim

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

    Interpretationnone given
    § Apolipoprotein B:apolipoprotein A1 ratio, total

    Ratios between atherogenic lipoproteins and HDL-C or apoA1 are useful for risk estimation but not for diagnosis or as treatment targets.

    “Ratios between atherogenic lipoproteins and HDL-C or apoA1 (TC:HDL-C, non-HDL-C:HDL-C, apoB:apoA1) are useful for risk estimation, but not for diagnosis or as treatment targets.”
    Quote in the paperSubstantial claim

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

    Premisenone given
    § 3.3.9. Genotyping

    Large GWASs have been published for coronary heart disease and associated biomarkers and risk factors.

    “Large GWASs have been published for coronary heart disease (CHD), as well as for associated biomarkers and risk factors.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given
    § 3.3.6. Apolipoproteins

    ApoB is not included in global risk algorithms and has not been a predefined treatment target in controlled trials.

    “A major disadvantage of apoB is that it is not included in algorithms for calculation of global risk, and it has not been a predefined treatment target in controlled trials.”
    Quote in the paperNot a substantial claim

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

    Premisenone given
    § 3.3.7. Lipoprotein(a)

    The measurement of Lp(a) is particularly stable over time.

    “The measurement of Lp(a) is particularly stable over time.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning
    § Box 8

    Inconsistencies in meta-analyses are due to methodological problems and difficulty of evaluating single dietary factors independently.

    “This is due not only to methodological problems, particularly inadequate sample size or the short duration of many trials included in the systematic revision, but also to the difficulty of evaluating the impact of a single dietary factor independently of any other changes in the diet.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given
    § 5.6. Other features of a healthy diet contributing to cardiovascular disease prevention

    Previous randomized controlled trials in which omega-3 supplementation was beneficial were not blinded or had low use of standard cardiovascular medications such as statins.

    “Previous RCTs where omega-3 supplementation was beneficial were not blinded or had low use of standard CV medications (such as statins).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given
    § 5.5. Dietary supplements and functional foods for the treatment of dyslipidaemias

    The available evidence on functional foods for dyslipidaemia is incomplete, and the main gap is the lack of diet-based intervention trials of sufficient duration to be relevant to the natural history of dyslipidaemia and cardiovascular disease.

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

  • May combine two claims.

    Premisecitation
    § 5.5.1. Phytosterols

    Daily consumption of 2 g of phytosterols can lower total cholesterol and LDL cholesterol by 7-10% in humans, with heterogeneity among individuals, and has little or no effect on HDL cholesterol and triglycerides.

    “The daily consumption of 2 g of phytosterols can effectively lower TC and LDL-C by 7e10% in humans (with a certain degree of heterogeneity among individuals), while it has little or no effect on HDL-C and TG levels. 143”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [143] Musa-Veloso, 2011, A comparison of the LDL-cholesterol lowering efficacy of plant stanols and plant sterols over a continuous dose range: results of a meta-analysis of randomized, placebo-controlled trials, Prostaglandins Leukot Essent Fatty Acids source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 5.5.2. Monacolin and red yeast rice

    Different commercial red yeast rice preparations have different monacolin concentrations and lower total cholesterol and LDL cholesterol to a variable extent.

    “Different commercial preparations of RYR have different concentrations of monacolins, and lower TC and LDL-C to a variable extent, 145”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [145] Gordon, 2010, Marked variability of monacolin levels in commercial red yeast rice products: buyer beware, Arch Intern Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § . Mechanism of action

    The degree of LDL cholesterol reduction by statins is dose dependent and varies between different statins.

    “The degree of LDL-C reduction is dose dependent and varies between the different statins (supplementary Figure A and supplementary Table A).191”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [191] Weng, 2010, A systematic review and meta-analysis on the therapeutic equivalence of statins, J Clin Pharm Ther source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Meta-analyses.

    Per 1.0 mmol/L (40 mg/dL) LDL cholesterol reduction, all-cause mortality is reduced by 10% and coronary artery disease death by 20%.

    “A 10% proportional reduction in all-cause mortality and 20% proportional reduction in CAD death per 1.0 mmol/L (40 mg/dL) LDL-C reduction was reported.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [64] Baigent, 2010, Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials, Lancet source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 5.5.5. Policosanol and berberine

    A meta-analysis of berberine included six trials, with 229 patients in the berberine group and 222 in the control group.

    “six trials were available for this purpose: the berberine group contained 229 patients and the control group contained 222 patients.190”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [190] Lan, 2015, Meta-analysis of the effect and safety of berberine in the treatment of type 2 diabetes mellitus, hyperlipemia and hypertension, J Ethnopharmacol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § . Mechanism of action

    Poor response to statin treatment in clinical studies is partly caused by poor compliance, but may also be explained by genetic variation in cholesterol metabolism and statin uptake and metabolism in the liver.

    “Poor response to statin treatment in clinical studies is to some extent caused by poor compliance, but may also be explained by a genetic background involving variations in genes of both cholesterol metabolism and of statin uptake and metabolism in the liver.192,193”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [192] Chasman, 2012, Genetic determinants of statin-induced low-density lipoprotein cholesterol reduction: the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial, Circ Cardiovasc Genet source

      Not checked in the free run.

    • cites [193] Reiner, 2014, Resistance and intolerance to statins, Nutr Metab Cardiovasc Dis source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Meta-analyses.

    Per 1 mmol/L (40 mg/dL) LDL cholesterol reduction, the risk of major coronary events is reduced by 23% and the risk of stroke by 17%.

    “The risk of major coronary events was reduced by 23% and the risk of stroke was reduced by 17% per 1 mmol/L (40 mg/dL) LDL-C reduction.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [64] Baigent, 2010, Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials, Lancet source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 5.5.3. Dietary fibre

    Foods enriched with oat or barley beta-glucan are well tolerated and effective for LDL cholesterol lowering at a daily dose of at least 3 g.

    “Foods enriched with these fibres are well tolerated, effective and recommended for LDL-C lowering at a daily dose of at least 3 g/day.186,187”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [186] AbuMweis, 2010, β-glucan from barley and its lipid-lowering capacity: a meta-analysis of randomized, controlled trials, Eur J Clin Nutr source

      Not checked in the free run.

    • cites [187] Wolever, 2010, Physicochemical properties of oat beta-glucan influence its ability to reduce serum LDL cholesterol in humans: a randomized clinical trial, Am J Clin Nutr source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 5.5.5. Policosanol and berberine

    The berberine studies showed statistically significant heterogeneity and were all performed in China in people of Asian ethnicity.

    “The studies, showing a statistically significant heterogeneity, were all performed in China in people of Asian ethnicity.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [190] Lan, 2015, Meta-analysis of the effect and safety of berberine in the treatment of type 2 diabetes mellitus, hyperlipemia and hypertension, J Ethnopharmacol source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation
    § 5.4.1. Body weight and physical activity

    Bariatric surgery seems to induce beneficial effects on overall risk factor profile and cardiovascular events.

    “This treatment seems to induce beneficial effects not only on the overall risk factor profile, but also on CV events.181”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [181] Puzziferri, 2014, Long-term follow-up after bariatric surgery: a systematic review, JAMA source

      Not checked in the free run.

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

    Interpretationnone given
    § 5.4.2. Dietary fat

    For most individuals, a wide range of total fat intakes is acceptable and depends on individual preferences and characteristics.

    “For most individuals, a wide range of total fat intakes is acceptable and will depend upon individual preferences and characteristics.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § 5.4.5. Smoking

    Smoking cessation has clear benefits on overall cardiovascular risk and specifically on HDL cholesterol.

    “Smoking cessation has clear benefits on the overall CV risk, and specifically on HDL-C, but special attention should be paid in order to prevent weight gain in people who stop smoking.163”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [163] Maeda, 2003, The effects of cessation from cigarette smoking on the lipid and lipoprotein profiles: a meta-analysis, Prev Med source

      Not checked in the free run.

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    Premisecitation
    § 5.5.6. n-3 unsaturated fatty acids

    Observational evidence supports that intake of fish at least twice weekly and low-dose long-chain n-3 fatty acid supplements may reduce the risk of cardiovascular death and stroke in primary prevention, but have no major effects on plasma lipoprotein metabolism.

    “Observational evidence supports the recommendation that the intake of fish (at least twice a week) and long chain n-3 fatty acids supplements at low dosage may reduce the risk of CV death and stroke in primary prevention, but have no major effects on plasma lipoprotein metabolism.183”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [183] Mozaffarian, 2013, Plasma phospholipid long-chain omega-3 fatty acids and total and cause-specific mortality in older adults: a cohort study, Ann Intern Med source

      Not checked in the free run.

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    Premisecitation
    § 6.1.4. Interactions

    The increased risk of myopathy with nicotinic acid has been debated, but recent reviews found no increased risk with this agent.

    “The increased risk for myopathy with nicotinic acid has been debated, but in recent reviews no increased risk of myopathy was found with this agent.236,237”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [236] Guyton, 2007, Safety considerations with niacin therapy, Am J Cardiol source

      Not checked in the free run.

    • cites [237] Cziraky, 2006, Statin safety: an assessment using an administrative claims database, Am J Cardiol source

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    Premisecitation
    § 6.1.3. Adverse effects of statins

    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 1e3 cases/100√000 patient-years.212”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [212] Law, 2006, Statin safety: a systematic review, Am J Cardiol source

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  • May combine two claims.

    Premisecitation
    § 6.1.3. Adverse effects of statins

    Proteinuria induced by statins is of tubular origin and is supposed to be due to reduced tubular reabsorption rather than glomerular dysfunction.

    “The proteinuria induced by statins is of tubular origin and is supposed to be due to reduced tubular reabsorption and not to glomerular dysfunction.229”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [229] Vidt, 2005, Statins and proteinuria, Curr Atheroscler Rep source

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  • May combine two claims.

    Premisecitation
    § 6.1.3. Adverse effects of statins

    Patients with mild ALT elevation due to steatosis have been studied during statin treatment, and there is no indication that statins worsen liver disease.

    “Patients with mild ALT elevation due to steatosis have been studied during statin treatment and there is no indication that statins cause any worsening of liver disease.222e224”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [222] Chalasani, 2004, Patients with elevated liver enzymes are not at higher risk for statin hepatotoxicity, Gastroenterology source

      Not checked in the free run.

    • cites [223] Vuppalanchi, 2005, Patients with elevated baseline liver enzymes do not have higher frequency of hepatotoxicity from lovastatin than those with normal baseline liver enzymes, Am J Med Sci source

      Not checked in the free run.

    • cites [224] Dongiovanni, 2015, Statin use and non-alcoholic steatohepatitis in at risk individuals, J Hepatol source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given
    § Meta-analyses.

    Current evidence from meta-analyses suggests that the clinical benefit of statins is largely independent of the type of statin but depends on the extent of LDL cholesterol lowering.

    “Current available evidence from meta-analyses suggests that the clinical benefit is largely independent of the type of statin but depends on the extent of LDL-C lowering, therefore the type of statin used should reflect the LDL-C goal in a given patient.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § 6.1.3. Adverse effects of statins

    The risk for diabetes is higher in the elderly and in the presence of other risk factors such as overweight or insulin resistance.

    “and the risk for diabetes is higher in the elderly and in the presence of other risk factors for diabetes such as overweight or insulin resistance.227”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [227] Waters, 2013, Cardiovascular event reduction versus new-onset diabetes during atorvastatin therapy: effect of baseline risk factors for diabetes, J Am Coll Cardiol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Meta-analyses.

    The benefits of statins were significant within the first year but were greater in subsequent years.

    “The benefits were significant within the first year, but were greater in subsequent years.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [64] Baigent, 2010, Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials, Lancet source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 2.1. Mechanism of action

    A recent Cochrane review found that colesevelam added to other antidiabetic agents showed significant effects on glycaemic control, but more research on cardiovascular risk is required.

    “A recent Cochrane review found that colesevelam, when added to other antidiabetic agents, showed significant effects on glycaemic control; however, more research on the impact of CV risk is required.238”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [238] Ooi, 2014, Colesevelam for type 2 diabetes mellitus: an abridged Cochrane review, Diabet Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Meta-analyses.

    In the Cochrane primary prevention analysis, per 1 mmol/L (40 mg/dL) LDL cholesterol reduction, all-cause mortality was reduced by 14%, cardiovascular disease events by 27%, fatal and non-fatal coronary events by 27%, and stroke by 22%.

    “In this analysis, all-cause mortality was reduced by 14%, CVD events by 27%, fatal and non-fatal coronary events by 27% and stroke by 22% per 1 mmol/L (40 mg/ dL) LDL-C reduction.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [200] Taylor, 2013, Statins for the primary prevention of cardiovascular disease, Cochrane Database Syst Rev

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Meta-analyses.

    The 2013 Cochrane review included 19 studies with different statins and somewhat varying inclusion criteria.

    “The analysis included 19 studies with different statins and with somewhat varying inclusion criteria.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [200] Taylor, 2013, Statins for the primary prevention of cardiovascular disease, Cochrane Database Syst Rev

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 6.1.3. Adverse effects of statins

    A recent Cochrane analysis could not find support for beneficial effects of statins on renal function based on studies where creatinine clearance was available, and no deleterious effects were observed.

    “A recent Cochrane analysis could not find support for beneficial effects on renal function based on studies where creatinine clearance was available, and no deleterious effects were observed.228”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [228] Palmer, 2014, HMG CoA reductase inhibitors (statins) for kidney transplant recipients, Cochrane Database Syst Rev

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

    Premisecitation
    § 6.1.3. Adverse effects of statins

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

    “In rhabdomyolysis, creatine kinase (CK) levels are elevated at least 10 times, often up to 40 times the upper limit of normal.211”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [211] Stroes, 2015, Ginsberg HN;, European Atherosclerosis Society Consensus Panel. Statin-associated muscle symptoms: impact on statin therapy—European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management, Eur Heart J source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 6.1.3. Adverse effects of statins

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

    “In clinical trials the frequency of proteinuria is in general low and in most cases is not higher than for placebo.231”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [231] Davidson, 2004, Rosuvastatin safety: lessons from the FDA review and post-approval surveillance, Expert Opin Drug Saf source

      Not checked in the free run.

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

    Premisecitation
    § 6.1.3. Adverse effects of statins

    Statin-induced reduced pinocytosis is directly related to inhibition of cholesterol synthesis.

    “The statin-induced reduced pinocytosis is directly related to the inhibition of cholesterol synthesis.230”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [230] Sidaway, 2004, Inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase reduce receptor-mediated endocytosis in opossum kidney cells, J Am Soc Nephrol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 7.5.3. Adverse effects and interactions

    In the FIELD study, small but significant increases in pancreatitis and pulmonary embolism, and a nonsignificant trend toward increased deep vein thrombosis, were seen with fenofibrate compared with placebo.

    “In the FIELD study, small but significant increases in the incidence of pancreatitis (0.8% vs. 0.5%) and pulmonary embolism (1.1% vs. 0.7%) and a nonsignificant trend toward an increase in deep vein thrombosis (1.4% vs. 1.0%) were seen in those taking fenofibrate compared with placebo; this is in line with data from other fibrate studies.261”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [261] Keech, 2005, d'Emden M, Whiting M, Ehnholm C, Laakso M. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial, Lancet source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 6.3.2. Efficacy in clinical studies

    In IMPROVE-IT, 18,144 patients were randomized; 5,314 over 7 years experienced a cardiovascular disease event, with 170 fewer events (32.7% vs 34.7%) in the simvastatin plus ezetimibe group (P=0.016).

    “A total of 18 144 patients were randomized and 5314 patients over 7 years experienced a CVD event; 170 fewer events (32.7 vs. 34.7%)were recorded in the group taking simvastatin plus ezetimibe (P ¼ 0.016).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [63] Cannon, 2015, Ezetimibe added to statin therapy after acute coronary syndromes, N Engl J Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 6.5. Nicotinic acid

    After two large studies with nicotinic acid, one with extended-release niacin and one with niacin plus laropiprant, showed no beneficial effect but an increased frequency of serious adverse effects, no medication containing nicotinic acid is currently approved in Europe.

    “After two large studies with nicotinic acid, one with extended-release niacin 251 and one with niacin plus laropiprant, 252 showed no beneficial effect, but rather an increased frequency of serious adverse effects, no medication containing nicotinic acid is currently approved in Europe.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [251] Boden, 2011, Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy, N Engl J Med source

      Not checked in the free run.

    • cites [252] GroupLandray, 2014, Effects of extended-release niacin with laropiprant in high-risk patients, N Engl J Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 7.6.2. Efficacy in clinical trials

    The AIM-HIGH and HPS2-THRIVE trials failed to show positive benefits on cardiovascular outcomes and challenged the position and benefits of niacin in lipid management.

    “Two large randomized clinical trials [the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH) and the Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE)] using, respectively, extended release (ER) nicotinic acid vs. placebo in addition to simvastatin, and ER nicotinic acid/l”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [251] Boden, 2011, Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy, N Engl J Med source

      Not checked in the free run.

    • cites [252] GroupLandray, 2014, Effects of extended-release niacin with laropiprant in high-risk patients, N Engl J Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 6.6.3. Other combinations

    Functional foods containing phytosterols and plant sterol-containing tablets additionally reduce LDL cholesterol by up to 5-10% in patients taking a stable dose of a statin, and this combination is well tolerated and safe.

    “Functional foods containing phytosterols as well as plant sterolecontaining tablets additionally reduce LDL-C levels by up to 5e10% in patients taking a stable dose of a statin, and this combination is also well tolerated and safe.142,255”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [142] Gylling, 2014, Plant sterols and plant stanols in the management of dyslipidaemia and prevention of cardiovascular disease, Atherosclerosis source

      Not checked in the free run.

    • cites [255] Abumweis, 2008, Plant sterols/stanols as cholesterol lowering agents: a meta-analysis of randomized controlled trials, Food Nutr Res

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given
    § 7.3. Strategies to control plasma triglycerides

    The evidence on the benefits of lowering elevated triglyceride levels is modest and primarily derived from subgroup or post hoc analyses.

    “As compared with the overwhelming evidence for the benefits of LDL-C reduction, the evidence on the benefits of lowering elevated TG levels is still modest, and is primarily derived from subgroup or post hoc analyses.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation
    § 6.3.2. Efficacy in clinical studies

    IMPROVE-IT supports the proposition that LDL cholesterol lowering by means other than statins is beneficial and can be performed without adverse effects.

    “However, the study supports the proposition that LDL-C lowering by means other than statins is beneficial and can be performed without adverse effects.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [63] Cannon, 2015, Ezetimibe added to statin therapy after acute coronary syndromes, N Engl J Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 6.3.2. Efficacy in clinical studies

    Naturally occurring mutations that inactivate NPC1L1 are associated with reduced plasma LDL cholesterol and reduced risk for coronary artery disease.

    “Naturally occurring mutations that inactivate the protein were found to be associated with reduced plasma LDL-C and reduced risk for CAD.245”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [245] Won, 2014, Inactivating mutations in NPC1L1 and protection from coronary heart disease, N Engl J Med source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § 6.4.2. Efficacy in clinical studies

    PCSK9 inhibitors are effective in the vast majority of patients, including those with heterozygous familial hypercholesterolaemia and, to a lower level, those with homozygous familial hypercholesterolaemia with residual LDL receptor expression.

    “Therefore this pharmacological approach is effective in the vast majority of patients, including those with heterozygous FH (HeFH) and, albeit to a lower level, those with homozygous FH (HoFH) with residual LDLR expression.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § 6.3.2. Efficacy in clinical studies

    In IMPROVE-IT, the average LDL cholesterol during the study was 1.8 mmol/L in the simvastatin group and 1.4 mmol/L in patients taking ezetimibe plus simvastatin.

    “The average LDL-C during the study was 1.8 mmol/L in the simvastatin group and 1.4 mmol/ L in patients taking ezetimibe plus simvastatin.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [63] Cannon, 2015, Ezetimibe added to statin therapy after acute coronary syndromes, N Engl J Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 6.4.2. Efficacy in clinical studies

    The efficacy of PCSK9 inhibitors at reducing LDL cholesterol is in the range of 50-70%, independent of background therapy, and preliminary phase 3 data suggest a reduction of cardiovascular events in line with the LDL cholesterol reduction achieved.

    “The efficacy at reducing LDL-C is in the range of 50e70%, independent of the presence of a background therapy (statins, ezetimibe, etc.); preliminary data from phase 3 trials suggest a reduction of CV events in line with the LDL-C reduction achieved.115,116”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [115] Robinson, 2015, Efficacy and safety of alirocumab in reducing lipids and cardiovascular events, N Engl J Med source

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    • cites [116] Sabatine, 2015, Efficacy and safety of evolocumab in reducing lipids and cardiovascular events, N Engl J Med source

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  • May combine two claims.

    Premisecitation
    § 7.6.2. Efficacy in clinical trials

    At a daily dose of 2 g, nicotinic acid reduces triglycerides by 20-40% and LDL-C by 15-18%, and increases HDL-C by 15-35%.

    “At a daily dose of 2 g it reduces TGs by 20e40% and LDL-C by 15e18% and increases HDL-C by 15e35%.257,277,278”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [257] Canner, 1986, Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin, J Am Coll Cardiol source

      Not checked in the free run.

    • cites [277] Kamanna, 2008, Mechanism of action of niacin, Am J Cardiol source

      Not checked in the free run.

    • cites [278] Bruckert, 2010, Meta-analysis of the effect of nicotinic acid alone or in combination on cardiovascular events and atherosclerosis, Atherosclerosis source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 7.5.2. Efficacy in clinical trials

    Other meta-analyses suggest reduced major cardiovascular disease events in patients with high triglycerides and low HDL-C treated with fibrates, but no decrease in cardiovascular disease 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.270e272”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites 270e272

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 6.4.3. Adverse effects and interactions

    In some studies, an increase in patient-reported neurocognitive effects with anti-PCSK9 monoclonal antibodies was described, and this finding requires further scrutiny.

    “In some studies an increase of patient-reported neurocognitive effects was described.This finding requires further scrutiny.250”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [250] Zhang, 2016, Comparative efficacy and safety of everolimus-eluting bioresorbable scaffold versus everolimus-eluting metallic stents: a systematic review and meta-analysis, Ann Intern Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 7.5.3. Adverse effects and interactions

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

    “Fibrates are generally well tolerated with mild adverse effects, gastrointestinal disturbances being reported in <5% of patients and skin rashes in 2%.273”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [273] Davidson, 2007, Safety considerations with fibrate therapy, Am J Cardiol source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § 9.4. Older persons

    Although relative risk reduction is seen in the oldest subjects, the absolute number of coronary artery disease cases associated with cholesterol is highest in this group because coronary artery disease is more frequent.

    “although a relative risk reduction is seen in the oldest subjects, the increased frequency of CAD means that the absolute number of cases associated with cholesterol is highest in this group.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § 9.4.2. Secondary prevention

    In the Heart Protection Study, after 5 years simvastatin reduced coronary death by 18% and coronary events by 25%, with similar reduction in age groups younger than 65, 65-70, and older than 70 years.

    “In the Heart Protection Study (HPS), 20 536 individuals were allocated to simvastatin or placebo.After 5 years the relative risk reduction was 18% for coronary death and 25% for coronary events.The reduction was similar in age groups <65, 65e70 and >70 years.333”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [333] 2002, MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial, Lancet source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 9.4.2. Secondary prevention

    The PROSPER study in patients 70-82 years of age with cardiovascular disease or high risk found that pravastatin 40 mg reduced a combined coronary artery disease endpoint by 15%, with no reduction in stroke.

    “The Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) study included patients 70e82 years of age with CVD or at high risk for CVD.330 Patients were treated with pravastatin 40 mg daily or placebo.The relative risk reduction for a combined CAD endpoint was reduced by 15%, whereas no reduction was shown for stroke.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [330] Shepherd, 2002, Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial, Lancet source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 9.3.4. Hormone therapy

    Oestrogen replacement therapy has not been demonstrated to reduce cardiovascular risk despite some favourable effects on the lipid profile.

    “Oestrogen replacement therapy, despite some favourable effects on the lipid profile, has not been demonstrated to reduce CV risk and cannot be recommended for CVD prevention in women.318”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [318] Manson, 2003, Estrogen plus progestin and the risk of coronary heart disease, N Engl J Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 9.4. Older persons

    High total cholesterol is a significant risk factor for coronary artery disease mortality at all ages, but this association is attenuated in older adults.

    “Results from a meta-analysis on blood cholesterol and vascular mortality indicates that high TC is a significant risk factor for CAD mortality at all ages, but this association is attenuated in older adults”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [321] Lewington, 2007, Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths, Lancet source

      Not checked in the free run.

    • cites [322] Prevention of coronary heart disease in clinical practice, 1998, Recommendations of the Second Joint Task Force of European and other societies on coronary prevention, Eur Heart J source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given
    § 9.5. Diabetes and metabolic syndrome

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

    “Diabetes itself is an independent risk factor for CVD and is associated with a higher risk of CVD, even more so in women.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § 9.5. Diabetes and metabolic syndrome

    Data from recent meta-analyses indicate that people with metabolic syndrome have a two-fold increase in cardiovascular outcomes and a 1.5-fold increase in all-cause mortality.

    “Data from recent meta-analyses indicate that people with MetS have a two-fold increase in CV outcomes and a 1.5fold increase in all-cause mortality.348”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [348] Mottillo, 2010, The metabolic syndrome and cardiovascular risk a systematic review and meta-analysis, J Am Coll Cardiol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 9.6.1. Specific lipid management issues in acute coronary syndrome

    Ezetimibe further reduced LDL-C and offered additional benefit, a 6.4% relative risk reduction in the composite clinical endpoint, in association with simvastatin in post-acute coronary syndrome patients.

    “Ezetimibe further reduced LDL-C and offered additional benefit (6.4% relative risk reduction in composite clinical endpoint) in association with simvastatin in post-ACS patients. 63”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [63] Cannon, 2015, Ezetimibe added to statin therapy after acute coronary syndromes, N Engl J Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 9.4.2. Secondary prevention

    In the SAGE trial of 893 patients 65-83 years of age with stable coronary artery disease, atorvastatin 80 mg was associated with lower all-cause mortality (HR 0.33) and a non-significant trend toward reduction in major coronary artery disease events compared with pravastatin 40 mg.

    “In the Studies Assessing Goals in the Elderly (SAGE) trial, 893 patients 65e83 years of age with stable CAD were recruited to treatment with atorvastatin 80 mg or pravastatin 40 mg.331 The atorvastatin group had a lower all-cause mortality (HR 0.33) and a non-significant trend towards reduction in major CAD events.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [331] Deedwania, 2007, Effects of intensive versus moderate lipid-lowering therapy on myocardial ischemia in older patients with coronary heart disease: results of the Study Assessing Goals in the Elderly (SAGE), Circulation source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 9.3.2. Secondary prevention

    A meta-analysis by Walsh and Pignone of 8272 women with previous cardiovascular disease, mainly treated with statins, found 26% lower cardiovascular mortality, 29% lower myocardial infarction, and 20% lower total coronary artery disease events.

    “The meta-analysis of Walsh and Pignone 314 reported a 26% reduction of CV mortality, a 29% reduction of MI and a 20% reduction of total CAD events in a cohort of 8272 females with previous CVD mainly treated with statins.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [314] Walsh, 2004, Drug treatment of hyperlipidemia in women, JAMA source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 9.3.3. Non-statin lipid-lowering drugs

    In the IMPROVE-IT trial of patients at least 50 years old hospitalized within the preceding 10 days for acute coronary syndrome, 24% of whom were women, simvastatin-ezetimibe compared with simvastatin monotherapy lowered the composite endpoint of cardiovascular death, myocardial infarction, or stroke by 1.8 percentage points, and the benefit was consistent for women.

    “The rate of the composite endpoint of death from CV causes, MI or stroke was significantly lower, by 1.8 percentage points, in the combination group and the benefit of simvastatineezetimibe was consistent for women.63”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [63] Cannon, 2015, Ezetimibe added to statin therapy after acute coronary syndromes, N Engl J Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 9.5.2.2. Triglycerides and high-density lipoprotein cholesterol.

    A meta-analysis of fibrates in 11,590 people with type 2 diabetes showed that fibrates significantly reduced the risk of non-fatal myocardial infarction by 21%, but had no effect on overall or coronary mortality.

    “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.353”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [353] Saha, 2010, Fibrates in the prevention of cardiovascular disease in patients with type 2 diabetes mellitus—a pooled meta-analysis of randomized placebo-controlled clinical trials, Int J Cardiol source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning
    § 9.5.4. Type 1 diabetes

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

    “The lipid profile in type 1 diabetic subjects with good glycaemic control is 'supernormal' and characterized by subnormal TGs and LDL-C, whereas HDL-C is usually within the upper normal range or slightly elevated.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § 9.5. Diabetes and metabolic syndrome

    Recent data indicate that diabetes per se increases cardiovascular disease risk about two-fold on average, with wide variation depending on the population.

    “Recent data indicate that diabetes per se increases CVD risk about two-fold on average, but the risk is subject to wide variation depending on the population.342”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [342] Sattar, 2013, Revisiting the links between glycaemia, diabetes and cardiovascular disease, Diabetologia source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 9.5.4. Type 1 diabetes

    Type 1 diabetes is associated with high cardiovascular disease risk, particularly in patients with microalbuminuria and renal disease.

    “Type 1 diabetes is associated with high CVD risk, in particular in patients with microalbuminuria and renal disease.355”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [355] Laing, 2003, Mortality from heart disease in a cohort of 23,000 patients with insulin-treated diabetes, Diabetologia source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation
    § 9.3.2. Secondary prevention

    In women with previous cardiovascular disease, lipid-lowering therapy substantially lowers cardiovascular events, but no reduction in total mortality has been demonstrated.

    “The results of these trials concordantly show that lipid-lowering therapy substantially reduces CV events in these patients, although no reduction in total mortality risk could be demonstrated.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § 9.4.1. Primary prevention

    In a recent meta-analysis of subjects older than 65 years (n=24,674) from eight studies, statin treatment reduced myocardial infarction (RR 0.61) and stroke (RR 0.76).

    “In a recent meta-analysis, subjects >65 years of age (n ¼ 24 674) from eight studies were included.327 Statin treatment reduced MI (RR 0.61) and stroke (RR 0.76).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [327] Savarese, 2013, Benefits of statins in elderly subjects without established cardiovascular disease: a meta-analysis, J Am Coll Cardiol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 9.6.1. Specific lipid management issues in acute coronary syndrome

    Supplementation with highly purified n-3 PUFAs reduced mortality in myocardial infarction survivors in the GISSI study, but failed to affect clinical outcomes in two more recent trials using modern evidence-based prevention therapies.

    “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 (GISSI)], but failed to affect clinical outcomes in two more recent trials using modern evidence-based prevention therapies (most patients were on statins), and therefore cannot be recommended in routine practice.361”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [361] Rizos, 2012, Association between omega-3 fatty acid supplementation and risk of major cardiovascular disease events: a systematic review and meta-analysis, JAMA source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 9.5.2.2. Triglycerides and high-density lipoprotein cholesterol.

    In a post hoc analysis of the FIELD study, fenofibrate reduced cardiovascular disease events by 27% in those with elevated triglycerides above 2.3 mmol/L and reduced HDL-C, with a number needed to treat of 23.

    “In a post hoc analysis of the FIELD study, fenofibrate reduced CVD events by 27% in those with elevated TGs [>2.3 mmol/L (~204 mg/dL)] and reduced HDL-C (NNT ¼ 23).351”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [351] Scott, 2009, Effects of fenofibrate treatment on cardiovascular disease risk in 9,795 individuals with type 2 diabetes and various components of the metabolic syndrome: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, Diabetes Care source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Management of dyslipidaemia in women.

    A Swedish myocardial infarction registry study found that statin treatment is associated with lower cardiovascular mortality in very old post-myocardial infarction patients without increasing cancer risk.

    “Results from an MI registry study in Sweden demonstrate that statin treatment is associated with lower CV mortality in very old post-MI patients without (which is important to stress) increasing the risk of cancer.337”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [337] Gränsbo, 2010, Cardiovascular and cancer mortality in very elderly post-myocardial infarction patients receiving statin treatment, J Am Coll Cardiol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 9.8. Autoimmune diseases

    Statins are effective in reducing disease activity, cardiovascular events, and mortality, particularly in primary prevention, in autoimmune diseases, while their discontinuation increases myocardial infarction and mortality.

    “Statins are effective in reducing disease activity, CV events and mortality (particularly in primary prevention) in this setting, while their discontinuation increases MI and mortality.386”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [386] De Vera, 2011, Statin discontinuation and risk of acute myocardial infarction in patients with rheumatoid arthritis: a population-based cohort study, Ann Rheum Dis source

      Not checked in the free run.

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

    Premisenone given
    § . Prevention of incident heart failure in coronary artery disease patients

    The onset of heart failure increases the risk of mortality and morbidity three to four times compared with patients without heart failure.

    “The onset of heart failure (HF) increases the risk of mortality and morbidity three to four times compared with patients without HF.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation
    § 9.11.2. Carotid artery disease

    The predictive value of carotid intima-media thickness, but not of carotid plaque, is somewhat compromised by recent data.

    “yet the predictive role of this biomarker (but not of carotid plaque) is somewhat compromised in light of recent data.60”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [60] Vlachopoulos, 2015, Atherosclerosis source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given
    § 9.9.4. Recommendations of lipid management for patients with chronic kidney disease

    Lipid abnormalities are common in solid organ transplant recipients and predispose them to atherosclerotic disease and transplant arterial vasculopathy, resulting in major vascular events.

    “Lipid abnormalities are common in patients who have undergone solid organ transplantation and predispose patients to the development of both atherosclerotic disease and transplant arterial vasculopathy, resulting in major vascular events.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § 9.9.2. Evidence for lipid management in patients with chronic kidney disease

    In patients with chronic kidney disease not on dialysis, statins reduced all-cause mortality by 34%, cardiovascular mortality by 31%, cardiovascular events by 45%, and stroke by 34%.

    “In patients with CKD not on dialysis, treatment with statins reduced all-cause mortality by 34%, CV mortality by 31%, CV events by 45% and stroke by 34%.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [394] Barylski, 2013, Statins decrease all-cause mortality only in CKD patients not requiring dialysis therapy–a meta-analysis of 11 randomized controlled trials involving 21,295 participants, Pharmacol Res source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 9.9.4. Recommendations of lipid management for patients with chronic kidney disease

    Randomized trial data show that statins have the potential to improve outcomes in heart transplant and renal transplant patients, but the amount of outcome data is not extensive.

    “Although randomized trial data have shown that statins have the potential to improve outcomes in heart transplant patients 400e402 and renal transplant patients, 403 the amounts of outcome data are not extensive.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites 400e402

      Not checked in the free run.

    • cites [403] Navaneethan, 2009, HMG CoA reductase inhibitors (statins) for kidney transplant recipients, Cochrane Database Syst Rev

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 9.9.2. Evidence for lipid management in patients with chronic kidney disease

    In patients receiving dialysis, statins had no effect on all-cause mortality and stroke, but reduced cardiovascular mortality by 21% and cardiovascular events by 19%.

    “In patients receiving dialysis, treatment with statins had no effect on all-cause mortality and stroke, but reduced CV mortality by 21% and CV events by 19%.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [394] Barylski, 2013, Statins decrease all-cause mortality only in CKD patients not requiring dialysis therapy–a meta-analysis of 11 randomized controlled trials involving 21,295 participants, Pharmacol Res source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 9.9.2. Evidence for lipid management in patients with chronic kidney disease

    In AURORA, involving 2776 patients on haemodialysis, rosuvastatin lowered LDL-C as expected but had no significant effect on the composite cardiovascular disease endpoint.

    “The results from AURORA (A study to evaluate the Use of Rosuvastatin in subjects On Regular haemodialysis: an Assessment of survival and cardiovascular events), involving 2776 patients on haemodialysis, show that rosuvastatin lowered LDL-C as expected but had no significant effect on the composite CVD endpoint.396”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [396] Fellström, 2009, Rosuvastatin and cardiovascular events in patients undergoing hemodialysis, N Engl J Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § . Secondary prevention in patients with aortic abdominal aneurysm

    Abdominal aortic aneurysm is a risk-equivalent condition and is associated with age, male sex, personal history of atherosclerotic cardiovascular disease, smoking, hypertension and dyslipidaemia, while diabetic patients are at decreased risk.

    “The presence of an abdominal aortic aneurysm represents a riskequivalent condition and is associated with age, male gender, personal history of atherosclerotic CVD, smoking, hypertension and dyslipidaemia, 415 while, in contrast, diabetic patients are at decreased risk.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [415] Golledge, 2006, Abdominal aortic aneurysm: pathogenesis and implications for management, Arterioscler Thromb Vasc Biol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 9.11. Peripheral arterial disease

    Peripheral arterial disease 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.405,406”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [405] Tendera, 2011, Eur Heart J source

      Not checked in the free run.

    • cites [406] McDermott, 2003, Knowledge and attitudes regarding cardiovascular disease risk and prevention in patients with coronary or peripheral arterial disease, Arch Intern Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 9.9. Chronic kidney disease

    Cardiovascular mortality in patients with stage 3 and stage 4 chronic kidney disease is two-fold and three-fold higher, respectively, compared with patients with normal renal function.

    “The CV mortality in patients with stage 3 and stage 4 CKD is two-fold and three-fold higher, respectively, when compared with patients with normal renal function.391”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [391] Matsushita, 2010, Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis, Lancet source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 9.8. Autoimmune diseases

    Autoimmune diseases including rheumatoid arthritis, SLE, psoriasis, and anti-phospholipid syndrome are characterized by enhanced atherosclerosis and consequently higher cardiovascular morbidity and mortality rates compared with the general population.

    “Autoimmune diseases, including rheumatoid arthritis, SLE, psoriasis and anti-phospholipid syndrome, are characterized by enhanced atherosclerosis and consequently higher CV morbidity and mortality rates compared with the general population.383e385”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites 383e385

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § . Prevention of incident heart failure in coronary artery disease patients

    In two large randomized controlled trials, statins had no benefit on hard endpoints such as cardiovascular mortality, non-fatal myocardial infarction, and stroke in mainly systolic heart failure, despite a decrease in hospitalizations and marked reduction in LDL-C and hs-CRP.

    “In two large RCTs 373,374 there was no benefit on hard endpoints, such as CV mortality and non-fatal MI and stroke, in spite of a decrease in hospitalizations 373,375 and a marked reduction of LDL-C and hs-CRP in patients with mainly systolic heart failure.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [373] Kjekshus, 2007, Rosuvastatin in older patients with systolic heart failure, N Engl J Med source

      Not checked in the free run.

    • cites [374] GISSI-HF InvestigatorsTavazzi L, 2008, Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial, Lancet source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation
    § 9.12.2. Secondary prevention of stroke

    The aetiology of stroke may influence the response to statins, with patients whose cerebrovascular events are underlain by atherothrombosis appearing to benefit most, while those with haemorrhagic stroke may not benefit.

    “However, the aetiology of stroke may influence the response to statins, and those patients with evidence of atherothrombosis underlying their cerebrovascular events appear to benefit most, while those with haemorrhagic stroke may not benefit.422”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [422] Amarenco, 2009, Lipid management in the prevention of stroke: review and updated meta-analysis of statins for stroke prevention, Lancet Neurol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given
    § 9.13. Human immunodeficiency virus patients

    There are no data on the effects of statins, ezetimibe or fibrates on cardiovascular events in dyslipidaemic HIV-infected patients.

    “There are no data on the effects of statins, ezetimibe or fibrates on CV events in dyslipidaemic HIV-infected patients.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: In HIV-infected patients, lowering LDL-C with statins will reduce cardiovascular events even though outcome data for statins, ezetimibe or fibrates in this population are absent.

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

    Interpretationcitation
    § 462

    Given the benefits for adherence demonstrated with simplified dosing in a Cochrane overview, it makes sense that a pill containing multiple medications in one tablet will enhance adherence.

    “Given the benefits for adherence demonstrated with simplified dosing reported in a Cochrane overview of interventions to improve safe and effective medicines use by consumers, 484 it makes sense that a pill that contains multiple medications in one tablet will enhance adherence.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [484] Ryan, 2014, Interventions to improve safe and effective medicines use by consumers: an overview of systematic reviews, Cochrane Database Syst Rev

      Not checked in the free run.

182 of 182

  • The paper relies on this without support.

    Atherosclerotic cardiovascular disease is usually the product of a number of risk factors.

    “because atherosclerotic CVD is usually the product of a number of risk factors”

  • The paper relies on this without support.

    Many people have several risk factors that in combination may result in unexpectedly high total cardiovascular risk.

    “since many people have several risk factors that, in combination, may result in unexpectedly high levels of total CV risk.”

  • The paper relies on this without support.

    The strongest driver of total cardiovascular risk is age.

    “The strongest driver of total CV risk is age”

  • The paper relies on this without support.

    Women often have higher HDL-C levels.

    “This is especially so in women, who often have higher HDL-C levels”

  • The paper relies on this without support.

    Subjects with diabetes or high triglycerides often have low HDL-C levels.

    “and in subjects with diabetes or with high TGs, who often have low HDL-C levels”

  • The paper relies on this without support.

    The Friedewald formula cannot be used with high triglyceride values (>4.5 mmol/L or >400 mg/dL).

    “With high TG values (>4.5 mmol/L or >400 mg/dL), the formula cannot be used.”

  • The paper relies on this without support.

    Patients with familial hyperlipidaemia or total cholesterol above 7.5 mmol/L are always at high cardiovascular risk.

    “These patients are always at high risk and should receive special attention.”

  • 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.

    The hypocholesterolaemic effects of red yeast rice are related to a statin-like mechanism, inhibition of HMG-CoA reductase, by monacolins.

    “Hypocholesterolaemic effects of RYR are related to a statinlike mechanism, inhibition of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase, of monacolins, which represent the bioactive ingredient.”

  • The paper relies on this without support.

    Statins reduce cholesterol synthesis in the liver by competitively inhibiting HMG-CoA reductase activity.

    “Statins reduce the synthesis of cholesterol in the liver by competitively inhibiting HMG-CoA reductase activity.”

  • The paper relies on this without support.

    A reduction in intracellular cholesterol concentration induces increased LDL receptor expression on hepatocytes, which increases uptake of LDL cholesterol from the blood and decreases plasma LDL cholesterol and other apoB-containing lipoproteins, including triglyceride-rich particles.

    “The reduction in intracellular cholesterol concentration induces an increased expression of LDLR on the surface of the hepatocytes, which results in increased uptake of LDL-C from the blood and a decreased plasma concentration of LDL-C and other apoB-containing lipoproteins, including TG-rich particles.”

  • The paper relies on this without support.

    Bile acids are synthesized in the liver from cholesterol and released into the intestinal lumen, but most bile acid is returned to the liver from the terminal ileum via active absorption.

    “Bile acids are synthesized in the liver from cholesterol and are released into the intestinal lumen, but most of the bile acid is returned to the liver from the terminal ileum via active absorption.”

  • The paper relies on this without support.

    Ezetimibe inhibits intestinal uptake of dietary and biliary cholesterol without affecting the absorption of fat-soluble nutrients.

    “Ezetimibe is the first lipid-lowering drug that inhibits intestinal uptake of dietary and biliary cholesterol without affecting the absorption of fat-soluble nutrients.”

  • The paper relies on this without support.

    The risk of pancreatitis is clinically significant if triglycerides exceed 10 mmol/L.

    “The risk of pancreatitis is clinically significant if TGs exceed 10 mmol/L (880 mg/dL), and actions to prevent acute pancreatitis are mandatory.”

  • The paper relies on this without support.

    Statins have significant effects on mortality as well as most cardiovascular disease outcome parameters.

    “Since statins have significant effects on mortality as well as most CVD outcome parameters, these drugs are the first choice to reduce both total CVD risk and moderately elevated TG levels.”

  • The paper relies on this without support.

    Fibrates are agonists of peroxisome proliferator-activated receptor-alpha.

    “Fibrates are agonists of peroxisome proliferator-activated receptor-a (PPAR-a), acting via transcription factors regulating various steps in lipid and lipoprotein metabolism.”

  • The paper relies on this without support.

    In HIV-infected patients, lowering LDL-C with statins will reduce cardiovascular events even though outcome data for statins, ezetimibe or fibrates in this population are absent.

    “There are no data on the effects of statins, ezetimibe or fibrates on CV events in dyslipidaemic HIV-infected patients.”
17 of 17

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?

  • Phytosterols have well-documented LDL-C lowering at Level A and absence of adverse signals according to the 2016 ESC/EAS lipid guidelines.

    “phytosterols have well-documented LDL-C lowering (Level of Recommendation: A) and the absence of adverse signals”

    From The Role of Nutraceuticals in Statin Intolerant Patients (2018) · cites this paper as [7]

  • ESC/EAS lipid guidelines state that purified RYR can be considered for hypercholesterolemic people not eligible for statin treatment after overall CV risk assessment.

    “For example, the current ESC/EAS lipid guidelines state that the use of purified RYR products can be considered in people with hypercholesterolemia who are not qualified for statin treatment after considering the overall CV risk(7).”

    From The Role of Nutraceuticals in Statin Intolerant Patients (2018) · cites this paper as [7]

  • ESC/EAS guidelines state plant sterols/stanols can be considered for high cholesterol with low-to-intermediate CV risk not qualifying for drugs, with pharmacotherapy in high/very-high risk statin-intolerant or not-at-target patients, and in adults and children over 6 with familial hypercholesterolemia.

    “The current ESC/EAS lipid guidelines state that, based on the reduction of LDL-C and the absence of adverse events, the use of plant sterols/stanols can be considered: 1) in subjects with high cholesterol levels with low to intermediate CV risk who do not qualify for pharmacological treatment; 2) in combination with pharmacotherapy in high-risk or very-high-risk patients who have been statin-intol”

    From The Role of Nutraceuticals in Statin Intolerant Patients (2018) · cites this paper as [7]

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.

  • CK-elevation guidance points to the mental-disorders table

    Minor

    The text directs readers to Table 35 for managing CK elevations, but Table 35 is identified as recommendations for patients with mental disorders, not CK monitoring.

  • ACS LDL-C recommendation changes "and" to "or"

    Minor

    The general very-high-risk recommendation requires both an LDL-C below 1.8 mmol/L and, when baseline LDL-C exceeds 1.8 mmol/L, at least a 50% reduction. The ACS recommendation instead permits either result while saying it follows Table 11; a 50% reduction alone need not reach 1.8 mmol/L.

2 of 2

Cites

1 retracted

Flagged first, then by citations

2 of the 501 references couldn’t be matched to a known paper.

Research works printed but not linked: 2

  1. Hinchcliffe, 2011, Patient Adherence to Treatment with Statins for the Prevention of Cardiovascular Disease, Cardiff: Public Health Wales NHS Trust
  2. Jackson, 2014, Applying COM-B to medication adherence, Eur Health Psychol, 16, 7

Cited by

Sorted by citations

Related

Authors
Catapano, A. L., Graham, I., De Backer, G., Wiklund, O., Chapman, M. J., Drexel, H., Hoes, A. W., Jennings, C. S., Landmesser, U., Pedersen, T. R., Reiner, Ž., Riccardi, G., Taskinen, M.-R., Tokgozoglu, L., Verschuren, W. M. M., Vlachopoulos, C., Wood, D. A., & Zamorano, J. L.
ORCID
Venue
Atherosclerosis
Publisher
Elsevier BV
Published
2016-10
Volume
253
Pages
281-344
ISSN
0021-9150 (ISSN-L)
DOI
10.1016/j.atherosclerosis.2016.08.018
OpenAlex
W2509676484
Semantic Scholar
b1dcd574e6b384735f3de7ecc8fb2020e40c3483
Cited by
1,582
References
501
Citations by year
2026: 6 · 2025: 45 · 2024: 104 · 2023: 116 · 2022: 155 · 2021: 124 · 2020: 182 · 2019: 298 · 2018: 280 · 2017: 234 · 2016: 33 · 2015: 2
FWCI
312.02
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Atherosclerosis (publishedVersion)
  • PubMed (publishedVersion)
  • Työväentutkimus Vuosikirja (submittedVersion, other-oa)
  • Utrecht University Repository (Utrecht University) (submittedVersion)
Funders
  • National Institute for Health and Care Research (NF-SI-0508-10312)
  • European Society of Cardiology
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, dyslipidemia management, cardiovascular risk, lipid-lowering therapy, cardiovascular disease prevention, ESC/EAS guidelines
MeSH terms
Cardiology, Humans, Dyslipidemias, Atherosclerosis

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 2026-10-08.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-08.

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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