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Cited by 3,162Lipoproteins and Cardiovascular HealthClinical practice guidelines implementationDiabetes, Cardiovascular Risks, and Lipoproteins

2016 ESC/EAS Guidelines for the Management of Dyslipidaemias

Open access
Catapano, Alberico L, Graham, Ian, De Backer, Guy, Wiklund, Olov, Chapman, M John, Drexel, Heinz, Hoes, Arno W, Jennings, Catriona S +112 more·2016·European Heart Journal
DOI 10.1093/eurheartj/ehw272
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Abstract

The Task Force for the Management of Dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) Developed with the special contribution of the European Assocciation for Cardiovascular Prevention & Rehabilitation (EACPR) ... Guidelines summarize and evaluate all available evidence on a particular issue at the time of the writing process, with the aim of assisting health professionals in selecting the best management strategies for an individual patient with a given condition, taking into account the impact on outcome as well as the risk–benefit ratio of particular diagnostic or therapeutic means. Guidelines and recommendations should help health professionals to make decisions in their daily practice. However, the final decisions concerning an individual patient must be made by the responsible health professional(s) in consultation with the patient and caregiver as appropriate. A great number of guidelines have been issued in recent years by the European Society of Cardiology (ESC) and by the European Atherosclerosis Society (EAS), as well as by other societies and organisations. Because of the impact on clinical practice, quality criteria for the development of guidelines have been established in order to make all decisions transparent to the user. The recommendations for formulating and issuing ESC Guidelines can be found on the ESC website (http://www.escardio.org/Guidelines-&-Education/Clinical-Practice-Guidelines/Guidelines-development/Writing-ESC-Guidelines). ESC Guidelines represent the official position of the ESC on a given topic and are regularly updated.

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  • Findingcitation
    § 3.3.6 Apolipoproteins · p. 19

    A recent meta-analysis indicates apolipoprotein B does not provide benefit beyond non-HDL-C or traditional lipid ratios.

    “Recent data from a meta-analysis 83,90 indicate that apoB does not provide any benefit beyond non-HDL-C or traditional lipid ratios. 101”
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    • cites [101] Ingelsson, 2007, Clinical utility of different lipid measures for prediction of coronary heart disease in men and women, JAMA source

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  • Findingcitation
    § 3.3.6 Apolipoproteins · p. 19

    In people with diabetes in the FIELD study, apolipoprotein B provided no benefit beyond traditional lipid markers.

    “Likewise, apoB provided no benefit beyond traditional lipid markers in people with diabetes in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. 102”
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    • cites [102] Taskinen, 2010, Ability of traditional lipid ratios and apolipoprotein ratios to predict cardiovascular risk in people with type 2 diabetes, Diabetologia source

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  • Findingcitation
    § 3.3.6 Apolipoproteins · p. 19

    In another meta-analysis, apolipoprotein B was superior to LDL-C and non-HDL-C as a marker of cardiovascular risk.

    “In contrast, in another meta-analysis of LDL-C, non-HDL-C and apoB, the latter was superior as a marker of CV risk. 103”
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    • cites [103] Sniderman, 2011, A meta-analysis of low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B as markers of cardiovascular risk, Circ Cardiovasc Qual Outcomes source

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  • Findingcitation
    § 3.3.7 Lipoprotein(a) · p. 19

    PCSK9 inhibitors and nicotinic acid reduce lipoprotein(a) by approximately 30%.

    “Proprotein convertase subtilisin/ kexin type 9 (PCSK9) inhibitors and nicotinic acid reduce Lp(a) by ≏ 30%. 115-117”
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    • 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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    • cites [117] Seed, 1993, The effect of nicotinic acid and acipimox on lipoprotein(a) concentration and turnover, Atherosclerosis source

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  • Findingcitation
    § 5.1 The influence of lifestyle on total cholesterol and low-density lipoprotein cholesterol levels · p. 24

    Experimental studies in humans show marked variability among individuals in effects of dietary cholesterol on cholesterol absorption and lipid metabolism.

    “Several experimental studies in humans have evaluated the effects of dietary cholesterol on cholesterol absorption and lipid metabolism and have revealed marked variability among individuals. 167,168”
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    • cites [167] Griffin, 2013, Dietary cholesterol and plasma lipoprotein profiles: randomized-controlled trials, Curr Nutr Rep source

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    • cites [168] Ordovas, 2009, Genetic influences on blood lipids and cardiovascular disease risk: tools for primary prevention, Am J Clin Nutr source

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    Findingcitation
    § Box 1 Key messages · p. 7

    A substantial proportion of patients receiving lipid-lowering or antihypertensive drugs do not 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”
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    • 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

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    • cites [29] Kotseva, 2010, EUROASPIRE III. 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

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

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    Findingown data
    § (1) Persons with · p. 9

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

    “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 + non-fatal) hard CVD endpoints; the multiplier is ≏ 4 in women and lower in older persons.”
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    Findingcitation
    § 5.1 The influence of lifestyle on total cholesterol and low-density lipoprotein cholesterol levels · p. 23

    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”
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    • cites [137] Estruch, 2013, Primary prevention of cardiovascular disease with a Mediterranean diet, N Engl J Med source

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    Findingcitation
    § 5.1 The influence of lifestyle on total cholesterol and low-density lipoprotein cholesterol levels · p. 23

    Replacing 1% of dietary energy from saturated fatty acids with n-6 polyunsaturated fatty acids decreases LDL-C by 0.051 mmol/L (2.0 mg/dL); replacing with monounsaturated fatty acids decreases by 0.041 mmol/L (1.6 mg/dL); replacing with carbohydrate decreases by 0.032 mmol/L (1.2 mg/dL).

    “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 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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    Findingcitation
    § 5.1 The influence of lifestyle on total cholesterol and low-density lipoprotein cholesterol levels · p. 23

    Partially hydrogenated fatty acids of industrial origin are the major source of trans fatty acids in the diet; average consumption ranges from 0.2% to 6.5% of total energy intake in different populations.

    “'Partially hydrogenated fatty acids' of industrial origin represent the major source of trans fatty acids in the diet; the average consumption of trans fatty acids ranges from 0.2% to 6.5% of the total energy intake in different populations. 166”
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    • cites [166] Micha, 2014, Global, regional, and national consumption levels of dietary fats and oils in 1990 and 2010: a systematic analysis including 266 country-specific nutrition surveys, BMJ source

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    Findingcitation
    § 5.1 The influence of lifestyle on total cholesterol and low-density lipoprotein cholesterol levels · p. 23

    n-3 polyunsaturated fatty acids have no hypocholesterolaemic effect; at high dosages (>3 g/day), their effect on LDL-C is neutral or a slight increase (particularly with DHA) with a concomitant decrease in 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”
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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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    Findingcitation
    § 5. Lifestyle modifications to improve the plasma lipid profile · p. 23

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

    “the dietary patterns that have been more extensively evaluated are the Dietary Approaches to Stop Hypertension (DASH) diet, particularly in relation to blood pressure control, and the Mediterranean diet; both have been proven to be effective in reducing CV risk factors and, possibly, to contribute to CVD prevention. 133”
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    • 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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    Findingcitation
    § 5. Lifestyle modifications to improve the plasma lipid profile · p. 22

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

    “Some interventions resulted in significant CVD prevention, whereas others did not.”
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    • cites [132] Dalen, 2014, Diets to prevent coronary heart disease 1957–2013: what have we learned, Am J Med source

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    Findingcitation
    § 5.1 The influence of lifestyle on total cholesterol and low-density lipoprotein cholesterol levels · p. 24

    Body weight reduction influences total cholesterol and LDL-C, but the effect is small; in grossly obese subjects, LDL-C decreases by about 0.2 mmol/L (8 mg/dL) for every 10 kg weight loss, with greater reduction if weight loss is achieved 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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    Findingcitation
    § 4. Treatment targets · p. 20

    Systematic reviews confirm a dose-dependent reduction in cardiovascular disease with LDL-C lowering; greater LDL-C reduction yields 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] Cholesterol Treatment Trialists' (CTT) Collaboration, 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] Cholesterol Treatment Trialists' (CTT) Collaborators, 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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    Premisecitation
    § 1.1 Definition and rationale · p. 6

    Removing 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”
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    • 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

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    • cites [4] Ezzati, 2004, Comparative quantification of health risks: global and regional burden of disease attributable to selected major risk factors

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    Premisenone given
    § Box 1 Key messages · p. 7

    Cost-effectiveness is influenced by baseline cardiovascular risk, intervention cost, reimbursement arrangements, and uptake of preventive measures.

    “Cost-effectiveness depends on several factors, including baseline CV risk, cost of drugs or other interventions, reimbursement procedures, and uptake of preventive strategies.”
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    Premisecitation
    § Box 1 Key messages · p. 7

    According to the WHO, policy and environmental changes could reduce cardiovascular disease in all countries for less than US$1 per person per year, whereas 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”
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    • cites [37] Brown, 2011, Medication adherence: WHO cares?, Mayo Clin Proc source

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    Premisecitation
    § Box 1 Key messages · p. 7

    A NICE report estimated that a UK national programme reducing population cardiovascular risk by 1% would prevent 25,000 cardiovascular disease cases and save €40 million 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 E 40 million per year. 38”
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    • cites [38] National Institute for Health and Care Excellence

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    Premisecitation
    § Box 1 Key messages · p. 7

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

    “Lowering blood cholesterol levels using statins 10,11,23-25 and improving blood pressure control are also cost effective. 26,27”
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    • 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

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

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    • cites [23] Neyt, 2009, Cost-effectiveness of statins in the primary prevention of cardiovascular disease: a systematic review and economic analysis for Belgium, Acta Cardiol source

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    • cites [24] Peura, 2008, Cost-effectiveness of statins in the prevention of coronary heart disease events in middle-aged Finnish men, Curr Med Res Opin source

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    • cites [25] Ito, 2011, Statins for cardiovascular prevention according to different strategies: a cost analysis, Am J Cardiovasc Drugs source

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

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

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    Premisecitation
    § Box 1 Key messages · p. 7

    Most cost-effectiveness studies of cardiovascular prevention combine clinical 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”
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    • cites [7] Mistry, 2012 11, Cost-effectiveness of a European preventive cardiology programme in primary care: a Markov modelling approach, BMJ Open source

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    • 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

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

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    Premisecitation
    § Box 1 Key messages · p. 7

    Coronary artery disease mortality 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”
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    • 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

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    Interpretationreasoning
    § Box 1 Key messages · p. 7

    Cost-effectiveness findings depend strongly on target population age, population cardiovascular risk, and intervention cost, so results from one country may not hold 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 paperSubstantial claim

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    Premisecitation
    § 2.1.1 Rationale for assessing total cardiovascular disease risk · p. 8

    Many cardiovascular risk assessment systems are available and have been comprehensively reviewed, including Framingham models, SCORE, ASSIGN, Q-Risk, PROCAM, Reynolds, CUORE, the Pooled Cohort equations, and Globorisk.

    “Many risk assessment systems are available and have been comprehensively reviewed, including different Framingham models, 41 Systemic Coronary Risk Estimation (SCORE), 42 ASSIGN (CV risk estimation model from the Scottish Intercollegiate Guidelines Network), 43 Q-Risk, 44 Prospective Cardiovascular Munster Study (PROCAM), 45 Reynolds, 46,47 CUORE, 48 the Pooled Cohort equations 49 and Globorisk. 5”
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    • cites [41] D'Agostino, 2008, General cardiovascular risk profile for use in primary care: the Framingham Heart Study, Circulation source

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    • cites [42] Conroy, 2003, Estimation of ten-year risk of fatal cardiovascular disease in Europe: the SCORE project, Eur Heart J source

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    • cites [43] Woodward, 2007, Adding social deprivation and family history to cardiovascular risk assessment: the ASSIGN score from the Scottish Heart Health Extended Cohort (SHHEC), Heart source

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    • cites [44] Hippisley-Cox, 2008, Predicting cardiovascular risk in England and Wales: prospective derivation and validation of QRISK2, BMJ source

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    • cites [45] Assmann, 2002, Simple scoring scheme for calculating the risk of acute coronary events based on the 10-year follow-up of the prospective cardiovascular Munster (PROCAM) study, Circulation source

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    • cites [46] Ridker, 2008, C-reactive protein and parental history improve global cardiovascular risk prediction: the Reynolds Risk Score for men, Circulation source

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    • cites [47] Ridker, 2007, Development and validation of improved algorithms for the assessment of global cardiovascular risk in women: the Reynolds Risk Score, JAMA source

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    • cites [48] Ferrario, 2005, Prediction of coronary events in a low incidence population. Assessing accuracy of the CUORE Cohort Study prediction equation, Int J Epidemiol source

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    • cites [49] Goff, 2014, 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, Circulation

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    • cites [50] Hajifathalian, 2015, A novel risk score to predict cardiovascular disease risk in national populations (Globorisk): a pooled analysis of prospective cohorts and health examination surveys, Lancet Diabetes Endocrinol source

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    Premisereasoning
    § (1) Persons with · p. 8

    Non-fatal events depend on definitions, diagnostic test developments, and ascertainment methods, which vary and produce highly variable multipliers for converting fatal to total events.

    “The reasons for retaining a system that estimates fatal as opposed to total fatal + non-fatal events are that non-fatal events are dependent on definition, developments in diagnostic tests and methods of ascertainment, all of which can vary, resulting in very variable multipliers to convert fatal to total events.”
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    Interpretationreasoning
    § (1) Persons with · p. 10

    Risk is continuous and there is no threshold at which a drug is automatically indicated.

    “This is problematic since risk is a continuum and there is no threshold at which, for example, a drug is automatically indicated.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Risk is continuous and no threshold exists at which a drug is automatically indicated.

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    Interpretationnone given
    § (1) Persons with · p. 11

    Risk age can be used in any population regardless of baseline risk or secular mortality changes, and therefore 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

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    Premisecitation
    § 2.2.1 Risk-based intervention strategies · p. 15

    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.

    “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 10 sources checked
    • cites [61] Boekholdt, 2014, Very low levels of atherogenic lipoproteins and the risk for cardiovascular events: a meta-analysis of statin trials, J Am Coll Cardiol source

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    • cites [62] Brugts, 2009, The benefits of statins in people without established cardiovascular disease but with cardiovascular risk factors: meta-analysis of randomised controlled trials, BMJ source

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    • cites [63] Cannon, 2015, Ezetimibe added to statin therapy after acute coronary syndromes, N Engl J Med source

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    • cites [64] Cholesterol Treatment Trialists' (CTT) Collaboration, 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

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    • cites [65] Cholesterol Treatment Trialists' (CTT) Collaboration, 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] Cholesterol Treatment Trialists' (CTT) Collaborators, 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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    • cites [67] Hegele, 2014, The polygenic nature of hypertriglyceridaemia: implications for definition, diagnosis, and management, Lancet Diabetes Endocrinol source

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    • cites [68] Mills, 2008, Primary prevention of cardiovascular mortality and events with statin treatments: a network meta-analysis involving more than 65,000 patients, J Am Coll Cardiol source

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    • cites [69] Pedersen, 2005, High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial, JAMA source

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    • cites [70] SPRINT Research Group, 2015, A randomized trial of intensive versus standard blood-pressure control, N Engl J Med source

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    Premisecitation
    § 2.2.1 Risk-based intervention strategies · p. 15

    This graded approach is based on evidence from multiple meta-analyses and individual RCTs, which show a consistent and graded reduction in CVD risk in response to reductions in TC and LDL-C levels.

    “This graded approach is based on evidence from multiple meta-analyses and individual RCTs, which show a consistent and graded reduction in CVD risk in response to reductions in TC and LDL-C levels. 61-71”
    Quote in the paperSubstantial claim0 of 10 sources checked
    • cites [61] Boekholdt, 2014, Very low levels of atherogenic lipoproteins and the risk for cardiovascular events: a meta-analysis of statin trials, J Am Coll Cardiol source

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    • cites [62] Brugts, 2009, The benefits of statins in people without established cardiovascular disease but with cardiovascular risk factors: meta-analysis of randomised controlled trials, BMJ source

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    • cites [63] Cannon, 2015, Ezetimibe added to statin therapy after acute coronary syndromes, N Engl J Med source

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    • cites [64] Cholesterol Treatment Trialists' (CTT) Collaboration, 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.

    • cites [65] Cholesterol Treatment Trialists' (CTT) Collaboration, 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

      Not checked in the free run.

    • cites [66] Cholesterol Treatment Trialists' (CTT) Collaborators, 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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    • cites [67] Hegele, 2014, The polygenic nature of hypertriglyceridaemia: implications for definition, diagnosis, and management, Lancet Diabetes Endocrinol source

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    • cites [68] Mills, 2008, Primary prevention of cardiovascular mortality and events with statin treatments: a network meta-analysis involving more than 65,000 patients, J Am Coll Cardiol source

      Not checked in the free run.

    • cites [69] Pedersen, 2005, High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial, JAMA source

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    • cites [70] SPRINT Research Group, 2015, A randomized trial of intensive versus standard blood-pressure control, N Engl J Med source

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  • May combine two claims.

    Interpretationcitation
    § (1) Persons with · p. 12

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

    “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 paperSubstantial 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

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    • 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

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    Premiseown data
    § (1) Persons with · p. 8

    SCORE risk estimates are presented as charts for high-risk and low-risk regions in Europe.

    “Risk estimates have been produced as charts for high- and low-risk regions in Europe ( Figures 2 and 3 ).”
    Quote in the paperNot a substantial claim

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

    Premisenone given
    § (1) Persons with · p. 8

    Some other risk estimation systems estimate coronary artery disease risk only.

    “Some other systems estimate CAD risk only.”
    Quote in the paperNot a substantial claim

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

    Interpretationnone given
    § 2.1.1 Rationale for assessing total cardiovascular disease risk · p. 8

    Other risk estimation systems can also be recalibrated, but recalibration is easier for mortality than for total events.

    “Other risk estimation systems can also be recalibrated, but the process is easier for mortality than for total events.”
    Quote in the paperNot a substantial claim

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

    Premisenone given
    § 2.1.1 Rationale for assessing total cardiovascular disease risk · p. 8

    Calibrated country-specific SCORE versions exist for Belgium, Cyprus, Czech Republic, Germany, Greece, Poland, Slovakia, Spain, Switzerland, and Sweden, and electronic versions exist for Bosnia and Herzegovina, Croatia, Estonia, France, Romania, Russian Federation, and Turkey.

    “Calibrated country-specific versions exist for Belgium, Cyprus, Czech Republic, Germany, Greece, Poland, Slovakia, Spain, Switzerland and Sweden, and country-specific electronic versions for Bosnia and Herzegovina, Croatia, Estonia, France, Romania, Russian Federation and Turkey can be found at http://www.heartscore.org.”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning
    § Box 5 Factors modifying SCORE risks · p. 14

    Recalibrated charts are likely to represent current risk levels better.

    “Such charts are likely to represent current risk levels better.”
    Quote in the paperNot a substantial claim

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

    Premisenone given
    § (1) Persons with · p. 8

    SCORE includes all International Classification of Diseases codes related to deaths from vascular origin caused by atherosclerosis.

    “All International Classification of Diseases (ICD) codes that are related to deaths from vascular origin caused by atherosclerosis are included.”
    Quote in the paperNot a substantial claim

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

    Premisenone given
    § (1) Persons with · p. 8

    SCORE estimates the 10-year cumulative risk of a first fatal atherosclerotic event, including heart attack, stroke, other occlusive arterial disease, and sudden cardiac death.

    “The SCORE system estimates the 10-year cumulative risk of a first fatal atherosclerotic event, whether heart attack, stroke or other occlusive arterial disease, including sudden cardiac death.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § (1) Persons with · p. 11

    SCORE overestimates risk in older people because beta-coefficients are not constant with ageing.

    “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.

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    Premisecitation
    § 2.1.1 Rationale for assessing total cardiovascular disease risk · p. 8

    The 2012 European Guidelines 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, European Guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts), Eur Heart J

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    Premisecitation
    § 2.1.1 Rationale for assessing total cardiovascular disease risk · p. 8

    Most guidelines use one of the available risk estimation systems.

    “Most guidelines use one of these risk estimation systems. 50-52”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [50] Hajifathalian, 2015, A novel risk score to predict cardiovascular disease risk in national populations (Globorisk): a pooled analysis of prospective cohorts and health examination surveys, Lancet Diabetes Endocrinol source

      Not checked in the free run.

    • cites [51] Cooney, 2009, Value and limitations of existing scores for the assessment of cardiovascular risk: a review for clinicians, J Am Coll Cardiol source

      Not checked in the free run.

    • cites [52] Cooney, 2010, Cardiovascular risk-estimation systems in primary prevention: do they differ? Do they make a difference? Can we see the future?, Circulation source

      Not checked in the free run.

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

    Interpretationnone given
    § 2.1.1 Rationale for assessing total cardiovascular disease risk · p. 8

    Patients who have had a clinical event such as acute coronary syndrome or stroke are at very high risk of another 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 claim

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

    Interpretationcitation
    § 3.3.6 Apolipoproteins · p. 19

    Apolipoprotein CIII is a new potential therapeutic target currently being studied, but whether it has a 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

      Not checked in the free run.

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    Premisecitation
    § 3.3.3 Non-high-density lipoprotein cholesterol · p. 18

    In some reports non-HDL-C is superior, but in others, LDL-C and non-HDL-C give similar information.

    “In some reports non-HDL-C is superior, but in others, LDL-C and non-HDL-C are reported to give similar information. 83-85”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [83] Emerging Risk Factors Collaboration, 2012, Thompson SG, Boekholdt SM, Sattar N, Packard C, Gudnason V, Danesh J. Lipid-related markers and cardiovascular disease prediction, JAMA

      Not checked in the free run.

    • cites [84] Boekholdt, 2012, Association of LDL cholesterol, non-HDL cholesterol, and apolipoprotein B levels with risk of cardiovascular events among patients treated with statins: a meta-analysis, JAMA source

      Not checked in the free run.

    • cites [85] Robinson, 2012, Meta-analysis of comparison of effectiveness of lowering apolipoprotein B versus low-density lipoprotein cholesterol and nonhigh-density lipoprotein cholesterol for cardiovascular risk reduction in randomized trials, Am J Cardiol source

      Not checked in the free run.

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    Premisereasoning
    § 3.3.4 High-density lipoprotein cholesterol · p. 18

    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

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

    Premisecitation
    § 3.3.4 High-density lipoprotein cholesterol · p. 18

    Hypertriglyceridaemia might interfere with direct HDL-C assays.

    “It should also be considered that HTG might interfere with the direct HDL-C assays. 72”
    Quote in the paperNot a substantial 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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    Interpretationreasoning
    § 2.2 Risk levels · p. 15

    This raises the issue that most older people in high-risk countries who smoke would be candidates for lipid-lowering drug treatment even if they have satisfactory blood pressure levels.

    “This raises the issue that most older people in high-risk countries who smoke would be candidates for lipid-lowering drug treatment even if they have satisfactory blood pressure levels.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The strongest driver of total CV risk is age, which can be considered as 'exposure time' to risk factors.

  • May combine two claims.

    Premisecitation
    § 3.1 Fasting or non-fasting? · p. 17

    For risk estimation, non-fasting has a prediction strength similar to fasting, and non-fasting lipid levels can be used in screening and general risk estimation.

    “For risk estimation, non-fasting has a prediction strength similar to fasting, and non-fasting lipid levels can be used in screening and in general risk estimation. 73-76”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [73] Kolovou, 2011, Assessment and clinical relevance of non-fasting and postprandial triglycerides: an expert panel statement, Curr Vasc Pharmacol source

      Not checked in the free run.

    • cites [74] Mihas, 2011, Diagnostic value of postprandial triglyceride testing in healthy subjects: a meta-analysis, Curr Vasc Pharmacol source

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    • cites [75] Nordestgaard, 2014, Triglycerides and cardiovascular disease, Lancet source

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    • cites [76] Jorgensen, 2013, Genetically elevated non-fasting triglycerides and calculated remnant cholesterol as causal risk factors for myocardial infarction, Eur Heart J source

      Not checked in the free run.

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    Premisecitation
    § 3.3.3 Non-high-density lipoprotein cholesterol · p. 18

    Non-HDL-C includes atherogenic TG-rich lipoproteins, which is essential considering recent information from GWAS and Mendelian randomization supporting TGs and remnant particles as causative factors in atherogenesis.

    “Non-HDL-C also includes the atherogenic TG-rich lipoproteins (VLDL, IDL and remnants), which is essential considering the recent information from genome-wide association studies (GWASs) and Mendelian randomization 76,86 - 89 supporting TGs and remnant particles as causative factors in atherogenesis.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [76] Jorgensen, 2013, Genetically elevated non-fasting triglycerides and calculated remnant cholesterol as causal risk factors for myocardial infarction, Eur Heart J source

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    • cites [86] Varbo, 2013, Remnant cholesterol as a causal risk factor for ischemic heart disease, J Am Coll Cardiol source

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    • cites [87] Triglyceride Coronary Disease Genetics, Consortium and Emerging Risk Factors Collaboration, 2010, Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies, Lancet source

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    • cites [88] Do, 2013, Common variants associated with plasma triglycerides and risk for coronary artery disease, Nat Genet source

      Not checked in the free run.

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

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  • May combine two claims.

    Premisecitation
    § 3.1 Fasting or non-fasting? · p. 17

    Risk may be underestimated in patients with diabetes, because in one study, patients with diabetes had up to 0.6 mmol/L lower LDL-C in non-fasting samples.

    “It should be emphasized, however, that the risk may be underestimated in patients with diabetes, because in one study, patients with diabetes had up to 0.6 mmol/L lower LDL-C in non-fasting samples. 77”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [77] Langsted, 2011, Nonfasting lipids, lipoproteins, and apolipoproteins in individuals with and without diabetes: 58 434 individuals from the Copenhagen General Population Study, Clin Chem source

      Not checked in the free run.

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    Premisenone given
    § 3.3.4 High-density lipoprotein cholesterol · p. 18

    Low HDL-C is a strong independent risk factor for cardiovascular disease and is included in most risk estimation tools, including HeartScore.

    “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

  • May combine two claims.

    Premisecitation
    § 3.3.6 Apolipoproteins · p. 19

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

    “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] TG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute, 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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    Premisecitation
    § 3.3. Lipid and lipoprotein analyses · p. 18

    Non-HDL-C has recently been proposed by locally developed guidelines such as NICE using the QRISK2 risk calculator.

    “Non-HDL-C has recently been proposed by locally developed guidelines such as NICE using the QRISK2 risk calculator. 79,80”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [79] Rabar, 2014, Lipid modification and cardiovascular risk assessment for the primary and secondary prevention of cardiovascular disease: summary of updated NICE guidance, BMJ source

      Not checked in the free run.

    • cites [80] JBS3, 2014, Joint British Societies' consensus recommendations for the prevention of cardiovascular disease (JBS3), Heart source

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    Premisecitation
    § 3. Evaluation of laboratory lipid and apolipoprotein parameters · p. 17

    The direct methods for HDL-C and LDL-C analysis are currently widely used and are reliable in patients with normal lipid levels.

    “The direct methods for HDL-C and LDL-C analysis are currently widely used and are reliable in patients with normal lipid levels. 72”
    Quote in the paperNot a substantial 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

      Not checked in the free run.

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    Premisecitation
    § 3.3.4 High-density lipoprotein cholesterol · p. 18

    Recent studies suggest HDL has a complex role in atherogenesis and dysfunctional HDL may be more relevant to atherosclerosis than the HDL-C level.

    “Recent studies suggest that HDL has a complex role in atherogenesis and that the presence of dysfunctional HDL may be more relevant to the development of atherosclerosis than the HDL-C level. 93-95”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [93] Khera, 2011, Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis, N Engl J Med source

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    • cites [94] Li, 2013, Paradoxical association of enhanced cholesterol efflux with increased incident cardiovascular risks, Arterioscler Thromb Vasc Biol source

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    • cites [95] Rohatgi, 2014, HDL cholesterol efflux capacity and incident cardiovascular events, N Engl J Med source

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    Premisecitation
    § 3.2 Intra-individual variation · p. 18

    This variation is due to analytical variation, environmental factors, and seasonal variation, with higher TC and HDL-C in winter.

    “This is to some extent due to analytical variation, but is also due to environmental factors such as diet and physical activity, and a seasonal variation, with higher levels of TC and HDL-C during the winter. 78”
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    • cites [78] Marti-Soler, 2014, Seasonality of cardiovascular risk factors: an analysis including over 230 000 participants in 15 countries, Heart source

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    Premisecitation
    § 3.3.3 Non-high-density lipoprotein cholesterol · p. 18

    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, Lipid modification: cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation
    § 3.3.7 Lipoprotein(a) · p. 19

    Risk is regarded as significant when lipoprotein(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

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    Premisecitation
    § 3.3.9 Genotyping · p. 20

    With increasing knowledge, the importance of a polygenic background to familial hyperlipidaemias is emphasized.

    “With increasing knowledge about common polymorphisms and lipoproteins, the importance of a polygenic background to familial hyperlipidaemias is emphasized. 67,122”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [67] Hegele, 2014, The polygenic nature of hypertriglyceridaemia: implications for definition, diagnosis, and management, Lancet Diabetes Endocrinol source

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    • cites [122] Futema, 2015, Refinement of variant selection for the LDL cholesterol genetic risk score in the diagnosis of the polygenic form of clinical familial hypercholesterolemia and replication in samples from 6 countries, Clin Chem source

      Not checked in the free run.

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    Premisecitation
    § 5.2 The influence of lifestyle on triglyceride levels · p. 24

    Glucose and lipid metabolism are strongly related, and any perturbation of carbohydrate metabolism caused by a high-carbohydrate diet 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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    Interpretationcitation
    § 3.3.8 Lipoprotein particle size · p. 19

    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.

    “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

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    Interpretationreasoning
    § 5. Lifestyle modifications to improve the plasma lipid profile · p. 22

    Inconsistencies in meta-analyses of dietary modifications are due to methodological problems, inadequate sample size, short duration of trials, and difficulty evaluating a single dietary factor independently of other diet changes.

    “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

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

    Premisecitation
    § 3.3.7 Lipoprotein(a) · p. 19

    Several methods for lipoprotein(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

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    Premisecitation
    § 4. Treatment targets · p. 20

    The 2011 EAS/ESC and AHA/ACC guidelines strongly emphasize the importance of LDL-C lowering to prevent cardiovascular disease.

    “In both the 2011 EAS/ESC guidelines for the management of dyslipidaemias 125 and the American Heart Association/American College of Cardiology (AHA/ACC) guidelines on the treatment of blood cholesterol to reduce atherosclerotic CV risk in adults, 71 the importance of LDL-C lowering to prevent CVD is strongly emphasized.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [125] European Association for Cardiovascular Prevention & Rehabilitation, 2011, ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS), Eur Heart J source

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    • cites [71] Stone, 2014, 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, Circulation

      Not checked in the free run.

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

    Interpretationcitation
    § 3.3.9 Genotyping · p. 20

    In familial hypercholesterolaemia, genetic diagnosis is important for family screening, to establish diagnosis in patients with borderline LDL-C, and to improve patient adherence to therapy.

    “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.

  • May combine two claims.

    Study design and conductreasoning
    § 4. Treatment targets · p. 22

    Secondary targets for non-HDL-C and apolipoprotein B have been defined by inference and receive a moderate grading because they have not been extensively studied in randomized controlled trials.

    “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

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    Premisecitation
    § 5.4.3 Dietary carbohydrate and fibre · p. 25

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

    “A fat-modified diet that provides 25-40 g of total dietary fibre, including at least 7-13 g of soluble fibre, is well tolerated, effective and recommended for plasma lipid control; conversely, there is no justification for the recommendation of very low carbohydrate diets. 164”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [164] Poli, 2008, Non-pharmacological control of plasma cholesterol levels, Nutr Metab Cardiovasc Dis source

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    Premisereasoning
    § 5.2 The influence of lifestyle on triglyceride levels · p. 24

    The harmful effects of a high-carbohydrate diet on triglycerides occur mainly with refined carbohydrate-rich foods and are much less prominent when the diet is based largely on 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 claim0 of 2 sources checked
    • cites [173] Liu, 2001, Dietary glycemic load assessed by food-frequency questionnaire in relation to plasma high-density-lipoprotein cholesterol and fasting plasma triacylglycerols in postmenopausal women, Am J Clin Nutr source

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    • cites [174] De Natale, 2009, Effects of a plant-based high-carbohydrate/high-fiber diet versus high-monounsaturated fat/low-carbohydrate diet on postprandial lipids in type 2 diabetic patients, Diabetes Care source

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    Premisecitation
    § 5.4.1 Body weight and physical activity · p. 25

    Bariatric surgery seems to induce beneficial effects not only on the overall risk factor profile but also on 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

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    Interpretationnone given
    § 5.4 Lifestyle recommendations to improve the plasma lipid profile · p. 25

    Dietary components, other lifestyle factors and weight loss also reduce overall cardiovascular risk through their influence on other risk factors such as hypertension, subclinical inflammation or impaired insulin sensitivity.

    “It has to be kept in mind that dietary components, other lifestyle factors and weight loss also contribute to reducing the overall CV risk through their influence on other risk factors, e.g. hypertension, subclinical inflammation or impaired insulin sensitivity.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § 5.4.1 Body weight and physical activity · p. 25

    Waist circumference thresholds of more than 80 cm for women of any ethnicity, more than 94 cm for men of European ancestry, and more than 90 cm for men of Asian origin indicate abdominal adiposity even in people of normal weight.

    “Measurements of waist circumference . 80 cm for women of any ethnicity and . 94 cm for men of European ancestry or . 90 cm for men of Asian origin indicate the presence of abdominal adiposity, even in people of normal weight ( Table 14 ). 180”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [180] Alberti, 2009, Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity, Circulation source

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    Premisecitation
    § 5.4.2 Dietary fat · p. 25

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

    “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”
    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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    Interpretationnone given
    § 5.5 Dietary supplements and functional foods for the treatment of dyslipidaemias · p. 26

    The available evidence on functional foods identified in this field is incomplete, and the major gap is the absence of diet-based intervention trials of sufficient duration to be relevant for 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

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    Premisecitation
    § 5.4.1 Body weight and physical activity · p. 25

    Modest weight reduction and regular moderate-intensity physical exercise are very effective in preventing type 2 diabetes and improving metabolic abnormalities and cardiovascular risk factors clustering with insulin resistance, which are often associated with abdominal adiposity.

    “Modest weight reduction and regular physical exercise of moderate intensity are very effective in preventing type 2 diabetes and improving all the metabolic abnormalities and CV risk factors clustering with insulin resistance, which are often associated with abdominal adiposity.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [169] Huffman, 2012, Exercise effects on lipids in persons with varying dietary patterns-does diet matter if they exercise? Responses in Studies of a Targeted Risk Reduction Intervention through Defined Exercise I, Am Heart J source

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    Premisecitation
    § 5.2 The influence of lifestyle on triglyceride levels · p. 24

    The effects of fructose on triglycerides are dose dependent; with habitual fructose intake between 15% and 20% of total energy, plasma triglycerides increase by as much as 30-40%.

    “These effects are dose dependent; with a habitual fructose consumption between 15 and 20% of the total energy intake, plasma TG increases as much as 30-40%.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [158] Stanhope, 2009, Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans, J Clin Invest source

      Not checked in the free run.

    • cites [175] Stanhope, 2015, A dose-response study of consuming high-fructose corn syrup-sweetened beverages on lipid/lipoprotein risk factors for cardiovascular disease in young adults, Am J Clin Nutr source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 5.2 The influence of lifestyle on triglyceride levels · p. 24

    Weight reduction improves insulin sensitivity and lowers triglyceride levels.

    “Weight reduction improves insulin sensitivity and decreases TG levels.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [150] Shaw, 2006, Exercise for overweight or obesity, Cochrane Database Syst Rev

      Not checked in the free run.

    • cites [169] Huffman, 2012, Exercise effects on lipids in persons with varying dietary patterns-does diet matter if they exercise? Responses in Studies of a Targeted Risk Reduction Intervention through Defined Exercise I, Am Heart J source

      Not checked in the free run.

    • cites [176] Kraus, 2002, Effects of the amount and intensity of exercise on plasma lipoproteins, N Engl J Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 5.5.2 Monacolin and red yeast rice · p. 26

    Different commercial preparations of red yeast rice have different concentrations of monacolins 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 but the long-term safety of the regular consumption of these products is not fully documented.”
    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
    § 5.2 The influence of lifestyle on triglyceride levels · p. 24

    In many studies, weight reduction lowers triglycerides by 20-30%, and this effect is usually preserved as long as weight is not regained.

    “In many studies the reduction of TG levels due to weight reduction is between 20-30%; this effect is usually preserved as long as weight is not regained.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [150] Shaw, 2006, Exercise for overweight or obesity, Cochrane Database Syst Rev

      Not checked in the free run.

    • cites [169] Huffman, 2012, Exercise effects on lipids in persons with varying dietary patterns-does diet matter if they exercise? Responses in Studies of a Targeted Risk Reduction Intervention through Defined Exercise I, Am Heart J source

      Not checked in the free run.

    • cites [176] Kraus, 2002, Effects of the amount and intensity of exercise on plasma lipoproteins, N Engl J Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 5.5.1 Phytosterols · p. 26

    Daily consumption of 2 g of phytosterols can effectively lower total cholesterol and LDL cholesterol by 7-10% in humans, with some heterogeneity among individuals, while it 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 7-10% in humans (with a certain degree of heterogeneity among individuals), while it has little or no effect on HDL-C and TG levels. 143”
    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
    § 5.3 The influence of lifestyle on high-density lipoprotein cholesterol levels · p. 24

    Smoking cessation may contribute to HDL cholesterol elevation, provided that weight gain is prevented; this is often observed soon after quitting smoking.

    “Smoking cessation may also contribute to HDL-C elevation, provided that weight gain is prevented; this is often observed soon after quitting 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.

  • May combine two claims.

    Premisecitation
    § 5.4.5 Smoking · p. 26

    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.

  • May combine two claims.

    Premisecitation
    § 5.3 The influence of lifestyle on high-density lipoprotein cholesterol levels · p. 24

    Saturated fatty acids increase HDL cholesterol in parallel with LDL cholesterol, whereas trans fats decrease HDL cholesterol.

    “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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 5.5.5 Policosanol and berberine · p. 26

    A recent meta-analysis evaluated berberine effects on plasma lipids in humans; six trials were available, with 229 patients in the berberine group and 222 in the control group.

    “As for berberine, a recent meta-analysis has evaluated its effects on plasma lipids in humans; 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
    § 6.1.3 Adverse effects of statins · p. 29

    Patients with mild alanine aminotransferase elevation due to steatosis have been studied during statin treatment, and there is no indication that statins cause any worsening of 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. 222-224”
    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.

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

    Premisecitation
    § 6.1.3 Adverse effects of statins · p. 29

    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, 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.

    Premisenone given
    § 6.1.2 Efficacy of cardiovascular disease prevention in clinical studies · p. 29

    Statins reduce triglycerides by 30-50% and may increase HDL cholesterol by 5-10%.

    “Statins also reduce TGs by 30-50% and may increase HDL-C by 5-10%.”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Premisecitation
    § 5.5.6 n-3 unsaturated fatty acids · p. 27

    Alpha-linolenic acid is less effective on triglyceride levels than long-chain n-3 polyunsaturated fatty acids.

    “Alfa-linolenic acid (a medium chain n-3 fatty acid present in chestnuts, some vegetables and some seed oils) is less effective on TG levels.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [156] Rivellese, 2003, Effects of dietary saturated, monounsaturated and n-3 fatty acids on fasting lipoproteins, LDL size and post-prandial lipid metabolism in healthy subjects, Atherosclerosis source

      Not checked in the free run.

    • cites [172] Jacobson, 2012, Effects of eicosapentaenoic acid and docosahexaenoic acid on low-density lipoprotein cholesterol and other lipids: a review, J Clin Lipidol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 5.5.6 n-3 unsaturated fatty acids · p. 27

    Observational evidence supports that intake of fish at least twice a week 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.

  • May combine two claims.

    Interpretationcitation
    § 6.1.2 Efficacy of cardiovascular disease prevention in clinical studies · p. 29

    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
    § 6.1.2 Efficacy of cardiovascular disease prevention in clinical studies · p. 29

    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] Cholesterol Treatment Trialists' (CTT) Collaboration, 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.

    Premisenone given
    § 6.1.3 Adverse effects of statins · p. 29

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

    “Mild elevation of ALT occurs in 0.5-2.0% of patients on statin treatment, more commonly with potent statins or high doses.”
    Quote in the paperNot a substantial claim

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

    Premisecitation
    § 6.1.3 Adverse effects of statins · p. 29

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

    “The frequency of rhabdomyolysis has been estimated to represent 1-3 cases/100 p 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

      Not checked in the free run.

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

    Interpretationnone given
    § 5.6 Other features of a healthy diet contributing to cardiovascular disease prevention · p. 27

    New evidence is accumulating on possible beneficial effects of compounds such as polyphenols on subclinical inflammation and endothelial function, as well as their beneficial influence on plasma triglycerides at fasting and particularly in the postprandial period.

    “New evidence is accumulating on the possible beneficial effects of these compounds, which are also present in olive oil, red wine, coffee, tea and cocoa, on subclinical inflammation and endothelial function, as well as their beneficial influence on plasma TGs at fasting and particularly in the postprandial period.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § 6.1.3 Adverse effects of statins · p. 29

    Progression to liver failure is exceedingly rare, and therefore routine monitoring of alanine aminotransferase during statin treatment is no longer recommended.

    “Progression to liver failure is exceedingly rare, therefore routine monitoring of ALT during statin treatment is no longer recommended. 221”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [221] Marcum, 2012, FDA drug safety communications: a narrative review and clinical considerations for older adults, Am J Geriatr Pharmacother source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 6.1.2 Efficacy of cardiovascular disease prevention in clinical studies · p. 29

    In the 2013 Cochrane review, all-cause mortality was reduced by 14%, cardiovascular disease events by 27%, fatal and non-fatal coronary events by 27%, and stroke by 22% per 1 mmol/L (40 mg/dL) LDL cholesterol reduction.

    “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
    § 5.5.3 Dietary fibre · p. 26

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

    “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.

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

    Premisenone given
    § 6.1.3 Adverse effects of statins · p. 29

    Rhabdomyolysis is the most severe form of statin-induced myopathy, characterized by severe muscular pain, muscle necrosis and myoglobinuria potentially leading to renal failure and death.

    “Rhabdomyolysis is the most severe form of statin-induced myopathy, characterized by severe muscular pain, muscle necrosis and myoglobinuria potentially leading to renal failure and death.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given
    § 6.1.2 Efficacy of cardiovascular disease prevention in clinical studies · p. 28

    A number of large-scale trials have demonstrated that statins substantially reduce cardiovascular morbidity and mortality in both primary and secondary prevention, in both genders and in all age groups.

    “A number of large-scale trials have demonstrated that statins substantially reduce CV morbidity and mortality in both primary and secondary prevention, in both genders and in all age groups.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § 6.1.2 Efficacy of cardiovascular disease prevention in clinical studies · p. 28

    A 10% proportional reduction in all-cause mortality and a 20% proportional reduction in coronary artery disease death per 1.0 mmol/L (40 mg/dL) LDL cholesterol reduction was reported.

    “A 10% proportional reduction in allcause 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] Cholesterol Treatment Trialists' (CTT) Collaboration, 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.

    Premisenone given
    § 5.6 Other features of a healthy diet contributing to cardiovascular disease prevention · p. 27

    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 paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § 6.1.1 Mechanism of action · p. 27

    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
    § 5.5.6 n-3 unsaturated fatty acids · p. 27

    Pharmacological doses of n-3 fatty acids, 2-3 g/day, reduce triglyceride levels by up to 30%, but a higher dosage may increase LDL cholesterol.

    “Pharmacological doses of n-3 fatty acids (2-3 g/day) reduce TG levels up to 30%, but a higher dosage may increase LDL-C.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [156] Rivellese, 2003, Effects of dietary saturated, monounsaturated and n-3 fatty acids on fasting lipoproteins, LDL size and post-prandial lipid metabolism in healthy subjects, Atherosclerosis source

      Not checked in the free run.

    • cites [172] Jacobson, 2012, Effects of eicosapentaenoic acid and docosahexaenoic acid on low-density lipoprotein cholesterol and other lipids: a review, J Clin Lipidol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 6.4.1 Mechanism of action · p. 31

    Elevated PCSK9 levels/functions reduce LDL receptor expression by promoting lysosomal catabolism of LDLR, increasing plasma LDL-C; lower PCSK9 levels/functions are associated with lower plasma LDL-C.

    “Elevated levels/functions of this protein in plasma reduce LDLR expression by promoting, upon binding, the LDLR lysosomal catabolism and increase plasma LDL-C concentration, while lower levels/functions of PCSK9 are related to lower plasma LDL-C levels.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [248] Norata, 2014, Targeting PCSK9 for hypercholesterolemia, Annu Rev Pharmacol Toxicol source

      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
    § 6.3.3 Adverse effects and interactions · p. 31

    No major adverse effects of ezetimibe have been reported; the most frequent are moderate liver enzyme elevations and muscle pain.

    “No major adverse effects have been reported; the most frequent adverse effects are moderate elevations of liver enzymes and muscle pain.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given
    § 6.3.1 Mechanism of action · p. 31

    Ezetimibe inhibits intestinal uptake of dietary and biliary cholesterol without affecting 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.”
    Quote in the paperNot a substantial claim

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

    Premisecitation
    § 6.1.3 Adverse effects of statins · p. 30

    The statin-induced reduced pinocytosis is directly related to the 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
    § 6.1.3 Adverse effects of statins · p. 30

    In clinical trials the frequency of proteinuria is in general low and in most cases is not higher than for 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.

  • May combine two claims.

    Premisecitation
    § 6.1.4 Interactions · p. 30

    Combining statins with fibrates may increase the risk of myopathy, with the highest risk for gemfibrozil.

    “Combinations of statins with fibrates may enhance the risk for myopathy. This risk is highest for gemfibrozil, and the association of gemfibrozil with statins should be avoided.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [234] Holoshitz, 2008, Relative safety of gemfibrozil and fenofibrate in the absence of concomitant cerivastatin use, Am J Cardiol source

      Not checked in the free run.

    • cites [235] Franssen, 2009, Combination statin-fibrate therapy: safety aspects, Diabetes Obes Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given
    § 6.2.2 Efficacy in clinical studies · p. 30

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

    “No major effect on HDL-C has been reported, while TGs may increase in some predisposed patients.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation
    § 6.3.2 Efficacy in clinical studies · p. 31

    IMPROVE-IT supports that LDL-C 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
    § 6.1.3 Adverse effects of statins · p. 30

    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.

    “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.

    Premisenone given
    § 6.3.1 Mechanism of action · p. 31

    Ezetimibe inhibits cholesterol absorption at the intestinal brush border by interacting with NPC1L1, reducing cholesterol delivery to the liver.

    “By inhibiting cholesterol absorption at the level of the brush border of the intestine [by interaction with the Niemann-Pick C1-like protein 1 (NPC1L1)], ezetimibe reduces the amount of cholesterol delivered to the liver.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisereasoning
    § 6.1.3 Adverse effects of statins · p. 30

    With approved doses up to 40 mg, the frequency of proteinuria is much lower and in line with the frequency for other statins.

    “With the approved doses up to 40 mg, the frequency is much lower and in line with the frequency for other statins.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning
    § 6.1.3 Adverse effects of statins · p. 30

    An increased frequency of proteinuria has been reported for all statins, but has been analysed in more detail for rosuvastatin, probably due to the high frequency of proteinuria observed with a higher dose of 80 mg.

    “An increased frequency of proteinuria has been reported for all statins, but has been analysed in more detail for rosuvastatin, probably due to the high frequency of proteinuria observed with a higher dose (80 mg).”
    Quote in the paperNot a substantial claim

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

    Premisenone given
    § 6.2.3 Adverse effects and interactions · p. 31

    Bile acid sequestrants reduce absorption of fat-soluble vitamins.

    “Reduced absorption of fat-soluble vitamins has been reported.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § 6.3.2 Efficacy in clinical studies · p. 31

    Naturally occurring mutations that inactivate NPC1L1 are associated with reduced plasma LDL-C and reduced risk of CAD.

    “Naturally occurring mutations that inactivate the protein were found to be associated with reduced plasma LDL-C and reduced risk for CAD.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [245] Myocardial Infarction Genetics Consortium Investigators, 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.

    Premisenone given
    § 6.2.3 Adverse effects and interactions · p. 31

    Gastrointestinal adverse effects (flatulence, constipation, dyspepsia, nausea) are common with bile acid sequestrants even at low doses, limiting their practical use.

    “Gastrointestinal adverse effects (most commonly flatulence, constipation, dyspepsia and nausea) are often present with these drugs, even at low doses, which limits their practical use.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § 6.4.2 Efficacy in clinical studies · p. 31

    A recent meta-analysis confirmed the LDL-C reduction and CV event findings for PCSK9 inhibitors.

    “A recent meta-analysis confirmed these findings.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [249] Navarese, 2016, Proprotein convertase subtilisin/kexin type 9 monoclonal antibodies for acute coronary syndrome: a narrative review, Ann Intern Med source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning
    § 6.3.1 Mechanism of action · p. 31

    Reduced cholesterol delivery to the liver upregulates LDL receptor expression, increasing LDL-C clearance from blood.

    “In response to reduced cholesterol delivery, the liver reacts by upregulating LDLR expression, which in turn leads to increased clearance of LDL-C from the blood.”
    Quote in the paperSubstantial claim

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

    Premisenone given
    § 6.3.3 Adverse effects and interactions · p. 31

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

    “Ezetimibe is rapidly absorbed and extensively metabolized to pharmacologically active ezetimibe glucuronide.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § 6.1.3 Adverse effects of statins · p. 30

    The proteinuria induced by statins is of tubular origin and is supposed to be due to reduced tubular reabsorption and not to 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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 6.1.4 Interactions · p. 30

    Pravastatin is not metabolized by cytochrome P450 enzymes but is metabolized by sulfation and conjugation.

    “Pravastatin does not undergo metabolism through the CYP system, but is metabolized by sulfation and conjugation.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [232] Egan, 2011, Weighing the benefits of high-dose simvastatin against the risk of myopathy, N Engl J Med source

      Not checked in the free run.

    • cites [233] Wiklund, 2013, Monitoring of lipids, enzymes, and creatine kinase in patients on lipid-lowering drug therapy, Curr Cardiol Rep source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 6.4.1 Mechanism of action · p. 31

    PCSK9 inhibitors work by reducing plasma PCSK9, preventing it from binding LDLR, which reduces intracellular degradation of LDLR, leading to higher LDLR expression and lower circulating LDL-C.

    “The mechanism of action relates to the reduction of plasma levels of PCSK9, which in turn is not available to bind the LDLR. Since this interaction triggers the intracellular degradation of the LDLR, lower levels of circulating PCSK9 will result in a higher expression of LDLRs at the cell surface and therefore in a reduction of circulating LDL-C levels.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [248] Norata, 2014, Targeting PCSK9 for hypercholesterolemia, Annu Rev Pharmacol Toxicol source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning
    § 6.2.1 Mechanism of action · p. 30

    Bile acid sequestrants are not systemically absorbed or altered by digestive enzymes, so their beneficial clinical effects are indirect.

    “The bile acid sequestrants are not systemically absorbed or altered by digestive enzymes, therefore the beneficial clinical effects are indirect.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § 6.4.2 Efficacy in clinical studies · p. 31

    PCSK9 inhibitors reduce LDL-C by 50-70%, independent of background therapy; preliminary phase 3 data suggest CV event reduction in line with LDL-C reduction.

    “The efficacy at reducing LDL-C is in the range of 50-70%, 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.”
    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

      Not checked in the free run.

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

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning
    § 6.2.1 Mechanism of action · p. 30

    By binding bile acids, bile acid sequestrants prevent their entry into the blood and remove a large portion from the enterohepatic circulation.

    “By binding the bile acids, the drugs prevent the entry of bile acids into the blood and thereby remove a large portion of the bile acids from the enterohepatic circulation.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Premisenone given
    § 6.1.3 Adverse effects of statins · p. 30

    With a dose of 80 mg rosuvastatin, a frequency of proteinuria of 12% was reported.

    “With a dose of 80 mg, a frequency of 12% was reported.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § 6.2.3 Adverse effects and interactions · p. 31

    Colesevelam may be better tolerated than cholestyramine and has fewer drug interactions, allowing co-administration with statins and several other drugs.

    “Colesevelam represents a newer formulation of the bile acid sequestrant, which may be better tolerated than cholestyramine. Colesevelam has fewer interactions with other drugs and can be taken together with statins and several other drugs.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [242] He, 2014, Lack of effect of colesevelam HCl on the single-dose pharmacokinetics of aspirin, atenolol, enalapril, phenytoin, rosiglitazone, and sitagliptin, Diabetes Res Clin Pract source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given
    § 6.3.3 Adverse effects and interactions · p. 31

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

    “There are no clinically significant effects of age, sex or race on ezetimibe pharmacokinetics, and no dosage adjustment is necessary in patients with mild hepatic impairment or mild to severe renal insufficiency.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § 6.2.2 Efficacy in clinical studies · p. 31

    Clinical trials of bile acid sequestrants demonstrated that LDL-C lowering reduces CV events in hypercholesterolaemic subjects, with benefit proportional to LDL-C reduction.

    “In clinical trials, bile acid sequestrants have contributed greatly to the demonstration of the efficacy of LDL-C lowering in reducing CV events in hypercholesterolaemic subjects, with a benefit proportional to the degree of LDL-C lowering.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [239] 1984, The Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in incidence of coronary heart disease, JAMA source

      Not checked in the free run.

    • cites [240] 1983, Pre-entry characteristics of participants in the Lipid Research Clinics' Coronary Primary Prevention Trial, J Chronic Dis source

      Not checked in the free run.

    • cites [241] The Lipid Research Clinics Coronary Primary Prevention Trial, 1992, Results of 6 years of post-trial follow-up. The Lipid Research Clinics Investigators, Arch Intern Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 6.1.3 Adverse effects of statins · p. 30

    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

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § 6.4.2 Efficacy in clinical studies · p. 32

    PCSK9 inhibitors are effective at reducing LDL-C in all patients who can express LDL receptors in the liver, including those with HeFH and, to a lower extent, HoFH with residual LDLR expression.

    “Given the mechanism of action, these drugs are effective at reducing LDL-C in all patients with the capability of expressing LDLRs in the liver. 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

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    Premisecitation
    § 6.3.2 Efficacy in clinical studies · p. 31

    In IMPROVE-IT, average LDL-C was 1.8 mmol/L with simvastatin alone and 1.4 mmol/L with simvastatin plus ezetimibe.

    “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
    § 7.3 Strategies to control plasma triglycerides · p. 33

    CVD risk is increased if fasting TGs > 1.7 mmol/L; drug treatment to lower TGs may be considered in high-risk subjects when TGs > 2.3 mmol/L and not lowered by lifestyle.

    “Although the CVD risk is increased if fasting TGs are . 1.7 mmol/ L (150 mg/dL), 87 the use of drugs to lower TGs may only be considered in high-risk subjects when TGs are . 2.3 mmol/L (200 mg/dL) and cannot be lowered by lifestyle measures.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [87] Triglyceride Coronary Disease Genetics, Consortium and Emerging Risk Factors Collaboration, 2010, Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies, Lancet source

      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
    § 7.2 Definition of hypertriglyceridaemia · p. 33

    Severe hypertriglyceridaemia is rare and typically associated with monogenic mutations.

    “Severe HTG is rare and is typically associated with monogenic mutations.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning
    § 7.6.1 Mechanism of action · p. 34

    Nicotinic acid decreases fatty acid influx to the liver and VLDL secretion by the liver.

    “Nicotinic acid has been reported to decrease fatty acid influx to the liver and the secretion of VLDL by the liver.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § 7.6.2 Efficacy in clinical trials · p. 34

    AIM-HIGH and HPS2-THRIVE failed to show positive benefits of nicotinic acid therapies on CV outcomes, challenging the position and benefits of niacin in lipid management.

    “Twolarge 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] AIM-HIGH Investigators, 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] HPS2-THRIVE Collaborative Group, 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.

    Premisereasoning
    § 7.5.1 Mechanism of action · p. 34

    Fibrates effectively lower fasting TG levels, post-prandial TGs, and TG-rich lipoprotein remnant particles.

    “As a consequence, fibrates have good efficacy in lowering fasting TG levels as well as post-prandial TGs and TG-rich lipoprotein (TRL) remnant particles.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § 7.5.2 Efficacy in clinical trials · p. 34

    The Helsinki Heart Study reported significant reduction in CVD outcomes with gemfibrozil, but FIELD and ACCORD did not show reduction in total CVD outcomes.

    “Although the Helsinki Heart Study reported a significant reduction in CVD outcomes with gemfibrozil, neither the FIELD nor the ACCORD study showed a reduction in total CVD outcomes.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [261] Keech, 2005, 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.

    • cites [262] ACCORD Study Group, 2010, Effects of combination lipid therapy in type 2 diabetes mellitus, N Engl J Med source

      Not checked in the free run.

    • cites [265] Frick, 1987, Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease, N Engl J Med source

      Not checked in the free run.

    • cites [266] Rubins, 1999, Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group, N Engl J Med source

      Not checked in the free run.

    • cites [267] Lipids and lipoproteins in symptomatic coronary heart disease, 1992, Distribution, intercorrelations, and significance for risk classification in 6,700 men and 1,500 women. The Bezafibrate Infarction Prevention (BIP) Study Group, Israel, Circulation source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 7.6.2 Efficacy in clinical trials · p. 34

    At 2 g/day, nicotinic acid reduces TGs by 20-40%, LDL-C by 15-18%, and increases HDL-C by 15-35%.

    “At a daily dose of 2 g it reduces TGs by 20-40% and LDL-C by 15-18% and increases HDL-C by 15-35%.”
    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 · p. 34

    Other meta-analyses suggest reduced major CVD events in patients with high TGs and low HDL-C treated with fibrates, but no decrease in CVD 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.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [270] Jun, 2010, Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis, Lancet source

      Not checked in the free run.

    • cites [271] Lee, 2011, Efficacy of fibrates for cardiovascular risk reduction in persons with atherogenic dyslipidemia: a meta-analysis, Atherosclerosis source

      Not checked in the free run.

    • cites [272] Bruckert, 2011, Fibrates effect on cardiovascular risk is greater in patients with high triglyceride levels or atherogenic dyslipidemia profile: a systematic review and meta-analysis, J Cardiovasc Pharmacol source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given
    § 7.1 Triglycerides and cardiovascular disease risk · p. 33

    Hypertriglyceridaemia has multiple causes, with polygenic nature being most important for CVD prevention.

    “HTG can have different causes ( Table 17 ), among which its polygenic nature is most important in relation to CVD prevention.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § 6.5 Nicotinic acid · p. 32

    Two large studies of extended-release niacin and niacin plus laropiprant showed no beneficial effect but increased serious adverse effects; consequently, no nicotinic acid medication 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] AIM-HIGH Investigators, 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] HPS2-THRIVE Collaborative Group, 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
    § 7.6.1 Mechanism of action · p. 34

    In the liver, nicotinic acid inhibits DGAT-2, decreasing VLDL secretion, reflected in reductions of IDL and LDL particles.

    “In the liver, nicotinic acid inhibits diacylglycerol acyltransferase-2 (DGAT-2), resulting in decreased secretion of VLDL particles from the liver, which is also reflected in reductions of both IDL and LDL particles.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [277] Kamanna, 2008, Mechanism of action of niacin, Am J Cardiol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 6.6.3 Other combinations · p. 32

    Phytosterol-containing functional foods and plant sterol tablets reduce LDL-C by an additional 5-10% in patients on stable statin therapy, and the combination is well tolerated and safe.

    “Functional foods containing phytosterols as well as plant sterolcontaining tablets additionally reduce LDL-C levels by up to 5-10% in patients taking a stable dose of a statin, and this combination is also well tolerated and safe.”
    Quote in the paperSubstantial 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 source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning
    § 6.6.3 Other combinations · p. 32

    It is unknown whether phytosterols or plant sterols reduce CVD risk because no trials with these in combination with other lipid-lowering drugs are available for CVD outcomes.

    “However, it is still not known whether this could reduce the risk of CVD since no trials with plant sterols or stanols in combination with other lipid-lowering drugs are available for CVD outcomes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given
    § 7.3 Strategies to control plasma triglycerides · p. 33

    Evidence for benefits of lowering elevated TG levels is modest and primarily from subgroup or post hoc analyses, compared to strong evidence for LDL-C reduction.

    “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

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

    Premisecitation
    § 7.5.3 Adverse effects and interactions · p. 34

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

    “In general, myopathy, liver enzyme elevations and cholelithiasis represent the most well-known adverse effects associated with fibrate therapy.”
    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.

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

    Premisecitation
    § 7.1 Triglycerides and cardiovascular disease risk · p. 33

    About one-third of adult individuals have triglyceride levels > 1.7 mmol/L (150 mg/dL).

    “The burden of HTG as a CVD risk factor is highlighted by the fact that about one-third of adult individuals have TG levels . 1.7 mmol/L (150 mg/dL).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [258] Kotseva, 2009, EUROASPIRE III: a survey on the lifestyle, risk factors and use of cardioprotective drug therapies in coronary patients from 22 European countries, Eur J Cardiovasc Prev Rehabil source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 7.5.3 Adverse effects and interactions · p. 34

    In FIELD, fenofibrate compared to placebo showed small but significant increases in pancreatitis (0.8% vs 0.5%) and pulmonary embolism (1.1% vs 0.7%), and a nonsignificant trend for deep vein thrombosis (1.4% vs 1.0%).

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [261] Keech, 2005, 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.

    Interpretationcitation
    § 7.5.3 Adverse effects and interactions · p. 34

    Fibrate-induced homocysteine increase may blunt HDL-C and apoA1 increases, possibly contributing to smaller than estimated benefits of fenofibrate.

    “However, the fibrate-induced increase in homocysteine may blunt the increases in both HDL-C and apoA1, and this may contribute to the smaller than estimated benefits of fenofibrate in the outcome parameters.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [275] Taskinen, 2009, Relationships of HDL cholesterol, ApoA-I, and ApoA-II with homocysteine and creatinine in patients with type 2 diabetes treated with fenofibrate, Arterioscler Thromb Vasc Biol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 7.5.3 Adverse effects and interactions · p. 34

    Fibrates are generally well tolerated; gastrointestinal disturbances occur in <5% and skin rashes in 2% of patients.

    “Fibrates are generally well tolerated with mild adverse effects, gastrointestinal disturbances being reported in , 5% of patients and skin rashes in 2%.”
    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
    § 7.5.3 Adverse effects and interactions · p. 34

    Because fenofibrate does not share the same pharmacokinetic pathways as gemfibrozil, the risk of myopathy is much less with fenofibrate-statin combination.

    “As fenofibrate does not share the same pharmacokinetic pathways as gemfibrozil, the risk of myopathy is much less with this combination therapy.”
    Quote in the paperSubstantial 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.

    Premisecitation
    § 6.6.3 Other combinations · p. 32

    Co-administering ezetimibe with bile acid sequestrants (colesevelam, colestipol, or cholestyramine) produces additional LDL-C reduction without additional adverse effects compared to bile acid sequestrant alone.

    “Co-administration of ezetimibe and bile acid sequestrants (colesevelam, colestipol or cholestyramine) resulted in an additional reduction of LDL-C levels without any additional adverse effects when compared with the stable bile acid sequestrant regimen alone.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [254] Jones, 2013, Role of colesevelam in combination lipid-lowering therapy, Am J Cardiovasc Drugs source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning
    § 7.4 Statins · p. 33

    Statins have significant effects on mortality and most CVD outcomes, making them first choice for reducing total CVD risk and moderately elevated TG levels.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given
    § 7.5.1 Mechanism of action · p. 34

    Fibrates are PPARα agonists that act via transcription factors to regulate lipid and lipoprotein metabolism.

    “Fibrates are agonists of peroxisome proliferator-activated receptora (PPARa ), acting via transcription factors regulating various steps in lipid and lipoprotein metabolism.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § 9.2 Children · p. 40

    Carotid ultrasound evidence shows that increased CIMT in children with HeFH compared with unaffected siblings can be detected from age 6, and that progression of CIMT can be ameliorated with statin therapy and/or apheresis.

    “There is evidence from carotid ultrasound measurements that increased CIMT in children with HeFH compared with siblings who have not inherited HeFH can be detected from the age of 6 years onwards, and that the progression of increasing CIMT can be ameliorated with statin therapy and/ or apheresis. 311”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [311] Reiner, 2014, Impact of early evidence of atherosclerotic changes on early treatment in children with familial hypercholesterolemia, Circ Res source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 9.3.2 Secondary prevention · p. 40

    The Walsh and Pignone meta-analysis reported a 26% reduction in CV mortality, a 29% reduction in MI, and a 20% reduction in total CAD events in 8272 women with previous CVD mainly treated with statins.

    “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 CVDmainly 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 · p. 40

    In IMPROVE-IT, the composite endpoint of CV death, MI, or stroke was significantly lower by 1.8 percentage points with simvastatin-ezetimibe than with simvastatin alone, and the benefit was consistent in 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 simvastatin-ezetimibe 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
    § 9.3.1 Primary prevention · p. 40

    The 2013 Cochrane analysis showed that statins reduce all-cause mortality, vascular events, and revascularisations in primary prevention, with similar effects in women and men.

    “The 2013 Cochrane analysis showed reductions of all-cause mortality, vascular events and revascularisations with statins in primary prevention. Effects in women were similar to those in men. 200”
    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
    § 9.3 Women · p. 40

    Among studies of lipid-lowering therapy for CAD prevention, only a few included women, usually in small numbers, and results were often not reported separately by gender.

    “Among several studies that have evaluated the impact of lipid-lowering therapy on primary and secondary prevention of CAD, only a few have included women, usually in small numbers, and the results have often not been separately reported by gender. 312”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [312] Jonsdottir, 2002, Do lipids, blood pressure, diabetes, and smoking confer equal risk of myocardial infarction in women as in men? The Reykjavik Study, J Cardiovasc Risk source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 9.3.1 Primary prevention · p. 40

    All-cause mortality reductions with statins were seen in both women and men, indicating similar effectiveness.

    “All-cause mortality reductions were seen in both women and men, showing that statin therapy is of similar effectiveness.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [65] Cholesterol Treatment Trialists' (CTT) Collaboration, 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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 8. Drugs affecting high-density lipoprotein cholesterol ( Table 20 ) · p. 36

    Recent studies testing whether raising HDL-C prevents CVD (ILLUMINATE, dal-OUTCOMES, ACCELERATE, HPS2-THRIVE, AIM-HIGH) failed to show any beneficial effect, though population selection in the last two may not have been optimal.

    “Recent studies aimed at testing this hypothesis have failed to show any beneficial effect [ILLUMINATE (torcetrapib), Dalcetrapib Outcomes (dal-OUTCOMES), ACCELERATE (evacetrapib), HPS2-THRIVE (nicotinic acid plus statin), AIM-HIGH (nicotinic acid on background statin)], although the population selection in the last two studies may not have been optimal.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § 9.3.1 Primary prevention · p. 40

    In postmenopausal women, plaque rupture is a more common cause of ACS than plaque erosion and is correlated with TC levels.

    “In postmenopausal women, plaque rupture was found to be a more common cause of ACS than plaque erosion and is correlated with TC levels. 313”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [313] Falk, 2013, Update on acute coronary syndromes: the pathologists' view, Eur Heart J source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 9.1.4.1 Action to prevent acute pancreatitis in severe hypertriglyceridaemia · p. 39

    A prospective cohort study of 33,346 people found that acute pancreatitis risk increased significantly across serum TG quartiles, suggesting that serum TGs as a risk factor may have been underestimated.

    “Recent data from a prospective cohort study ( n ¼ 33 346) reported that the risk of acute pancreatitis increased significantly over the quartiles of serum TGs, highlighting that serum TGs as a risk factor may have been underestimated. 307”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [307] Lindkvist, 2012, A prospective cohort study on risk of acute pancreatitis related to serum triglycerides, cholesterol and fasting glucose, Pancreatology source

      Not checked in the free run.

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

    Premisecitation
    § 9.1.2 Familial hypercholesterolaemia · p. 37

    Extrapolations from available data estimate HeFH frequency at between 1 in 200 and 1 in 250, corresponding to 14 to 34 million cases worldwide.

    “Based on extrapolations from available data, the frequency of HeFH can be estimated to be between 1/200 and 1/250, putting the total number of cases at between 14 and 34 million worldwide. 121,298”
    Quote in the paperNot a substantial claim0 of 2 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.

    • cites [298] de Ferranti, 2016, Prevalence of familial hypercholesterolemia in the 1999 to 2012 United States National Health and Nutrition Examination Surveys (NHANES), Circulation source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 9.1.2.3 Familial hypercholesterolaemia in children · p. 38

    Observational studies suggest that early treatment in children can reduce LDL-C burden, improve endothelial function, attenuate atherosclerosis development, and improve coronary outcomes.

    “Although placebo-controlled trials are missing in children, there are observational studies suggesting that early treatment can reduce LDL-C burden, improve endothelial function, substantially attenuate development of atherosclerosis and improve coronary outcomes. 303”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [303] Wiegman, 2015, Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment, 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
    § 9.1.4 Genetic causes of hypertriglyceridaemia · p. 39

    Gene therapy for LPL deficiency has been developed and tested in clinical trials, and alipogene tiparvovec was approved by the EMA in 2013.

    “Recently, gene therapy for LPL deficiency has been developed and tested in clinical trials 305 and the alipogene tiparvovec was approved by the EMA in 2013.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [305] Gaudet, 2013, Efficacy and long-term safety of alipogene tiparvovec (AAV1-LPLS447X) gene therapy for lipoprotein lipase deficiency: an open-label trial, Gene Ther source

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    § 7.7.2 Efficacy in clinical trials · p. 35

    A meta-analysis of 63,030 subjects from 20 trials found no overall effect of omega-3 fatty acids on composite CV events (RR 0.96, 95% CI 0.90-1.02, P=0.24) or total mortality (RR 0.95, 95% CI 0.86-1.04, P=0.28).

    “One meta-analysis included 63 030 subjects from 20 trials and reported no overall effect of omega-3 fatty acids on composite CV events { relative risk [RR] 0.96 [95% confidence interval (CI) 0.90, 1.02]; P ¼ 0.24 } or total mortality [RR 0.95 (95% Cl 0.86, 1.04); P ¼ 0.28].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [285] Kotwal, 2012, Omega 3 fatty acids and cardiovascular outcomes: systematic review and meta-analysis, Circ Cardiovasc Qual Outcomes source

      Not checked in the free run.

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    Premisecitation
    § 9.3.3 Non-statin lipid-lowering drugs · p. 40

    IMPROVE-IT included patients at least 50 years old who had been hospitalized within the preceding 10 days for ACS, and 24% were women.

    “The IMPROVE-IT study 63 included patients at least 50 years of age who had been hospitalized within the preceding 10 days for an ACS (24% women).”
    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

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

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    § 9.4 Older persons · p. 40

    The proportion of patients with MI over 85 years of age has increased several fold.

    “The proportion of patients with MI . 85 years of age has increased several fold. 319”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [319] Rosengren, 2012, Better treatment and improved prognosis in elderly patients with AMI: but do registers tell the whole truth, Eur Heart J source

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    Premisecitation
    § 9.1.2 Familial hypercholesterolaemia · p. 37

    The Dutch Lipid Clinic Network criteria are commonly used for FH diagnosis, and other criteria include the Simon Broome register and WHO criteria.

    “The commonly used criteria from the Dutch Lipid Clinic Network (DLCN) are shown in Table 21 . Other criteria are the Simon Broome register or the WHO criteria. 299,300”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [299] Risk of fatal coronary heart disease in familial hypercholesterolaemia, 1991, Scientific Steering Committee on behalf of the Simon Broome Register Group, BMJ source

      Not checked in the free run.

    • cites [300] World Health Organization, 1999, Human Genetics Programme. Familial hypercholesterolemia: report of a second WHO consultation. WHO/HGN/FH/Cons/992

      Not checked in the free run.

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    Premisenone given
    § 7.7.2 Efficacy in clinical trials · p. 35

    n-3 fatty acids reduce triglycerides but have trivial effects on other lipoproteins.

    “n-3 fatty acids reduce TGs, but their effects on other lipoproteins are trivial.”
    Quote in the paperNot a substantial claim

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    Premisecitation
    § 8.1 Statins · p. 36

    A meta-analysis of intervention studies in dyslipidaemic patients found that statin-induced HDL-C elevations varied with dose and were typically 5-10%.

    “In a meta-analysis 291 of several intervention studies in dyslipidaemic patients, elevations in HDL-C varied with dose among the respective statins; such elevations were typically in the range of 5-10%.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [291] Barter, 2010, Effect of statins on HDL-C: a complex process unrelated to changes in LDL-C: analysis of the VOYAGER Database, J Lipid Res source

      Not checked in the free run.

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    Premisecitation
    § 9.3.3 Non-statin lipid-lowering drugs · p. 40

    The ACCORD lipid study showed less primary event reduction with combination therapy in women, whereas the recent FIELD analysis showed consistent CV event reduction in women and men.

    “The ACCORD lipid study showed less primary event reduction with combination therapy in women, but the recent FIELD study analysis showed consistent CV event reduction in women and men. 315”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [315] d'Emden, 2014, Favourable effects of fenofibrate on lipids and cardiovascular disease in women with type 2 diabetes: results from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, Diabetologia source

      Not checked in the free run.

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    § 9.3.4 Hormone therapy · p. 40

    Oestrogen replacement therapy has some favourable effects on the lipid profile but has not been shown to reduce CV risk.

    “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

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    Premisecitation
    § 9.1.2 Familial hypercholesterolaemia · p. 37

    HeFH frequency was previously estimated at 1 in 500, but recent whole-population studies suggest higher frequencies, up to 1 in 137 in some populations.

    “The frequency of HeFH in the population has earlier been estimated at 1/500; however, recent studies from whole populations suggest that the frequency is higher, in some populations as high as 1/137. 297”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [297] Benn, 2012, Familial hypercholesterolemia in the Danish general population: prevalence, coronary artery disease, and cholesterol-lowering medication, J Clin Endocrinol Metab source

      Not checked in the free run.

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    § 9.5 Diabetes and metabolic syndrome · p. 42

    Recent meta-analyses indicate people with MetS have a two-fold increase in CV 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 1.5-fold 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.

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    Premisecitation
    § 9.4.1 Primary prevention · p. 41

    Several studies show that a healthy lifestyle early in life prevents CVD in older age and reduces lifetime CVD risk.

    “Several studies have shown that a healthy lifestyle early in life prevents CVD in older age and reduces lifetime risk for CVD. 53,323-325”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [53] Lloyd-Jones, 2006, Prediction of lifetime risk for cardiovascular disease by risk factor burden at 50 years of age, Circulation source

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    • cites [323] Berry, 2012, Lifetime risks of cardiovascular disease, N Engl J Med source

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    • cites [324] Giang, 2013, Stroke and coronary heart disease: predictive power of standard risk factors into old age—long-term cumulative risk study among men in Gothenburg, Sweden, Eur Heart J source

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    • cites [325] Wilhelmsen, 2011, Factors associated with reaching 90 years of age: a study of men born in 1913 in Gothenburg, Sweden, J Intern Med source

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    Premisecitation
    § 9.4.2 Secondary prevention · p. 41

    In the SAGE trial, atorvastatin 80 mg compared with pravastatin 40 mg in patients aged 65-83 with stable CAD was associated with lower all-cause mortality (HR 0.33) and a nonsignificant trend toward fewer major CAD events.

    “The atorvastatin group had a lower all-cause mortality (HR 0.33) and a nonsignificant 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
    § 9.5 Diabetes and metabolic syndrome · p. 42

    Diabetes confers excess mortality risk after ACS despite modern therapies, indicating poor prognosis for coronary patients with T2DM.

    “diabetes confers excess mortality risk following ACS despite modern therapies, highlighting the poor prognosis of coronary patients with T2DM”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [345] Donahoe, Diabetes and mortality following acute coronary syndromes, JAMA 2007;

      Not checked in the free run.

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    Premisecitation
    § 9.4.2 Secondary prevention · p. 41

    In HPS, simvastatin reduced coronary death by 18% and coronary events by 25% over 5 years, with similar reductions across age groups younger than 65, 65-70, and older than 70.

    “After 5 years the relative risk reduction was 18% for coronary death and 25% for coronary events. The reduction was similar in age groups”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [333] Heart Protection Study Collaborative Group, 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.

    Premisereasoning
    § 9.5.1 Specific features of dyslipidaemia in insulin resistance and type 2 diabetes ( Table 25 ) · p. 42

    TRL remnants, small dense LDL, and small dense HDL together comprise the atherogenic lipid profile, which is also characterized by increased apoB concentration due to more apoB-containing particles.

    “Together, TRL remnants, small dense LDL and small dense HDL comprise the atherogenic lipid profile, which is also characterized by an increase in apoB concentration due to an increased number of apoB-containing particles.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given
    § Table 25 Summary of dyslipidaemia in metabolic syndrome and in type 2 diabetes · p. 42

    TRLs, including chylomicrons, VLDL, and their remnants, carry a single apoB molecule, as do LDL particles.

    “including chylomicrons, VLDL and their remnants, carry a single apoB molecule, also like LDL particles.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § 9.5 Diabetes and metabolic syndrome · p. 42

    Recent data indicate diabetes itself increases CVD risk about two-fold on average, with wide variation by 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

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    Premisenone given
    § Table 25 Summary of dyslipidaemia in metabolic syndrome and in type 2 diabetes · p. 42

    Abnormal lipid profile features precede the onset of T2DM by several years and are common in subjects with central obesity, MetS, and T2DM.

    “The abnormal features of the lipid profile precede the onset of T2DM by several years and are common in subjects with central obesity, MetS and T2DM.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § 9.4.2 Secondary prevention · p. 41

    A Swedish MI registry study found statin treatment associated with lower CV mortality in very old post-MI 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

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    Premisecitation
    § 9.4.2 Secondary prevention · p. 41

    In the PROSPER trial, pravastatin 40 mg daily in patients aged 70-82 with CVD or high CVD risk reduced the relative risk of a combined CAD endpoint by 15% but did not reduce stroke.

    “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
    § 9.5 Diabetes and metabolic syndrome · p. 42

    Hypertension, dyslipidaemia, and abdominal obesity commonly co-exist with T2DM and further aggravate risk, which is highest in people with T2DM and features of MetS.

    “Hypertension, dyslipidaemia and abdominal obesity commonly co-exist with T2DM and further aggravate the risk, which is highest in people with T2DM and features of MetS. 343,344”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [343] Liu, 2007, Ten-year risk of cardiovascular incidence related to diabetes, prediabetes, and the metabolic syndrome, Am Heart J source

      Not checked in the free run.

    • cites [344] Despres, 2012, Body fat distribution and risk of cardiovascular disease: an update, Circulation source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 9.5.2.2 Triglycerides and high-density lipoprotein cholesterol · p. 42

    The FIELD trial did not significantly reduce the primary endpoint of CAD events but did significantly reduce CVD events by 11%.

    “The FIELD trial failed to reduce significantly the primary endpoint of CAD events (CAD death or non-fatal MI). CVD events were reduced significantly by 11%.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [261] Keech, 2005, 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.

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    Premisecitation
    § 9.4 Older persons · p. 41

    A meta-analysis found that high total cholesterol is a significant risk factor for CAD mortality at all ages, but the association is attenuated in older adults; 1 mmol/L lower TC was associated with HR 0.44 in ages 40-49 versus HR 0.85 in ages 80-89.

    “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; 1 mmol/L (38.7 mg/dL) lower TC was associated with about onehalf [hazard ratio (HR) 0.44] lower CAD mortality in the age group 40-49 years compared with an HR of 0.85 in those 80-89 years old.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [321] Prospective Studies Collaboration, 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

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    • 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.

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    Premisecitation
    § 9.5 Diabetes and metabolic syndrome · p. 42

    Diabetes is an independent risk factor for CVD and is associated with higher CVD risk, with a greater excess 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 claim0 of 2 sources checked
    • cites [340] Gregg, 2014, Changes in diabetes-related complications in the United States, 1990–2010, N Engl J Med source

      Not checked in the free run.

    • cites [341] Emerging Risk Factors Collaboration, 2010, Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies, Lancet source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 9.4.2 Secondary prevention · p. 41

    In a CTT meta-analysis, statin rate ratios for major vascular events were 0.78 in age younger than 65, 0.78 in 65-75, and 0.84 in older than 75.

    “rate ratios for the effects of statins on major vascular events were 0.78, 0.78 and 0.84 in age groups , 65, 6575 and . 75 years, respectively. 64”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [64] Cholesterol Treatment Trialists' (CTT) Collaboration, 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.

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

    Premisenone given
    § 9.5.1 Specific features of dyslipidaemia in insulin resistance and type 2 diabetes ( Table 25 ) · p. 42

    Diabetic dyslipidaemia is a cluster of metabolically interrelated plasma lipid and lipoprotein abnormalities.

    “Diabetic dyslipidaemia is a cluster of plasma lipid and lipoprotein abnormalities that are metabolically interrelated.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning
    § Table 25 Summary of dyslipidaemia in metabolic syndrome and in type 2 diabetes · p. 42

    The malignant nature of diabetic dyslipidaemia is not always revealed by routine lipid measures because LDL-C may remain within the normal range; non-HDL-C may reveal it better.

    “Therefore the malignant nature of diabetic dyslipidaemia is not always revealed by the lipid measures used in clinical practice, as LDL-C may remain within the normal range. It may be better revealed by non-HDL-C.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § 9.5 Diabetes and metabolic syndrome · p. 42

    Although the difference in CVD risk between people with and without diabetes has narrowed substantially over recent decades, strong associations remain between diabetes and vascular outcomes.

    “Although the difference in CVD risk between individuals with and without diabetes has narrowed substantially over the last decades, there are strong associations between diabetes and vascular outcomes. 340,341”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [340] Gregg, 2014, Changes in diabetes-related complications in the United States, 1990–2010, N Engl J Med source

      Not checked in the free run.

    • cites [341] Emerging Risk Factors Collaboration, 2010, Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies, Lancet source

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    Premisecitation
    § 9.5.2 Evidence for lipid-lowering therapy · p. 42

    The CTT meta-analysis indicates that people with T2DM have a relative risk reduction comparable to non-diabetic patients, but because they are at higher absolute risk, their absolute benefit is greater and NNT is lower.

    “The CTT meta-analysis further indicates that subjects with T2DM will have a relative risk reduction that is comparable to that seen in non-diabetic patients, but being at higher absolute risk, the absolute benefit will be greater, resulting in a lower number needed to treat (NNT).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [64] Cholesterol Treatment Trialists' (CTT) Collaboration, 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
    § 9.5.2.2 Triglycerides and high-density lipoprotein cholesterol · p. 42

    In a post hoc analysis of FIELD, fenofibrate reduced CVD events by 27% in patients with elevated triglycerides (>2.3 mmol/L) and reduced HDL-C, with NNT 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
    § 9.4 Older persons · p. 40

    Coronary care has improved for older adults, with improving prognosis after a first MI.

    “Coronary care has also been improved for older adults, with improving prognosis after the first MI. 320”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [320] Gale, 2012, Resolving inequalities in care? Reduced mortality in the elderly after acute coronary syndromes. The Myocardial Ischaemia National Audit Project 2003–2010, Eur Heart J source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 9.4.1 Primary prevention · p. 41

    In that meta-analysis, statin treatment reduced MI with RR 0.61 and stroke with RR 0.76.

    “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

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    Premisecitation
    § 9.5.2.2 Triglycerides and high-density lipoprotein cholesterol · p. 42

    The Helsinki Heart Study reported a significant reduction in CVD outcomes with gemfibrozil, whereas FIELD and ACCORD did not show a reduction in total CVD outcomes.

    “Although the Helsinki Heart Study reported a significant reduction in CVDoutcomeswith gemfibrozil, neither the FIELD nor the ACCORD study showed a reduction in total CVD outcomes. 261,262,265”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [261] Keech, 2005, 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.

    • cites [262] ACCORD Study Group, 2010, Effects of combination lipid therapy in type 2 diabetes mellitus, N Engl J Med source

      Not checked in the free run.

    • cites [265] Frick, 1987, Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease, N Engl J Med source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § 9.4 Older persons · p. 41

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

    “However, 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

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    Premisecitation
    § 9.9.2 Evidence for lipid management in patients with chronic kidney disease · p. 46

    In a meta-analysis of 11 RCTs including 21,293 patients with CKD (6,857 on dialysis), statins reduced all-cause mortality by 34%, CV mortality by 31%, CV events by 45%, and stroke by 34% in non-dialysis patients.

    “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

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  • Classified as probably not a substantial claim.

    Interpretationnone given
    § 9.8 Autoimmune diseases · p. 45

    There is no firm indication to use lipid-lowering therapy only on the basis of the presence of an autoimmune disease.

    “However, there is no firm indication to use lipid-lowering therapy only on the basis of the presence of the disease ( Table 29 ).”
    Quote in the paperSubstantial claim

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    Premisecitation
    § 9.5.2.2 Triglycerides and high-density lipoprotein cholesterol · p. 43

    A meta-analysis of fibrates in 11,590 people with T2DM showed fibrates significantly reduced non-fatal MI risk by 21% but had no effect on overall mortality or coronary mortality.

    “a meta-analysis 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 paperSubstantial 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.

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    Premisereasoning
    § 9.5.4 Type 1 diabetes · p. 43

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

    “The lipid profile in 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
    § 9.5.4 Type 1 diabetes · p. 43

    Emerging evidence highlights frequent coexistence of MetS with type 1 diabetes, resulting in double diabetes that increases CVD risk.

    “Emerging evidence highlights the frequent coexistence of MetS with type 1 diabetes, resulting in this so-called double diabetes increasing CVD risk. 356”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [356] Chillaron, 2014, Type 1 diabetes, metabolic syndrome and cardiovascular risk, Metabolism source

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    Premisecitation
    § 9.5.3 Treatment strategies for subjects with type 2 diabetes and metabolic syndrome · p. 43

    If LDL-C goals are not achieved on maximally tolerated statins, drug combinations may offer additional LDL-C lowering, but outcome evidence is limited.

    “If LDL-C goals are not achieved on maximally tolerated doses of statins, drug combinations may offer additional lowering of LDL-C, but the evidence from outcome studies is limited. 354”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [354] Ilanne-Parikka, 2008, Effect of lifestyle intervention on the occurrence of metabolic syndrome and its components in the Finnish Diabetes Prevention Study, Diabetes Care source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisenone given
    § 9.8 Autoimmune diseases · p. 45

    No specific LDL-C goal beyond that indicated by individual total risk has been set for patients with autoimmune diseases.

    “Furthermore, no specific LDL-C goal beyond that indicated by individual total risk has been set for such patients.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning
    § 9.9.2 Evidence for lipid management in patients with chronic kidney disease · p. 46

    Stage 5 CKD or dialysis is a very high-risk condition in which different factors influence outcome, and RCTs of lipid-altering therapies have not provided convincing evidence of reduced CVD events in such patients.

    “Stage 5 CKD (or on dialysis) is indeed a very high-risk condition in which different factors influence outcome; results from RCTs of lipid-altering therapies have not provided convincing evidence of reduced CVD events in such patients.”
    Quote in the paperSubstantial claim

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

    Premisenone given
    § 9.5.4 Type 1 diabetes · p. 43

    In type 1 diabetes, there are potentially atherogenic changes in the composition of both HDL and LDL particles.

    “However, there are potentially atherogenic changes in the composition of both HDL and LDL particles.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning
    § 9.9.1 Lipoprotein profile in chronic kidney disease · p. 46

    Most patients with stage 3-5 CKD have mixed dyslipidaemia and a highly atherogenic lipid profile with adverse changes in all lipoproteins.

    “Altogether, most patients with stage 3-5 CKD have mixed dyslipidaemia and the lipid profile is highly atherogenic, with adverse changes in all lipoproteins.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § 9.6.1 Specific lipid management issues in acute coronary syndrome · p. 43

    Studies of PCSK9 inhibitors that included post-ACS or very high-risk patients were promising, and definitive outcome studies are awaited.

    “Results in studies with PCSK9 inhibitors that included post-ACS/very high-risk patients were promising 115,116 and definitive outcome studies are awaited.”
    Quote in the paperNot a substantial 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

      Not checked in the free run.

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

      Not checked in the free run.

  • May combine two claims.

    Premisenone given
    § 9.9.1 Lipoprotein profile in chronic kidney disease · p. 45

    In initial stages of CKD, triglycerides are specifically elevated and HDL-C lowered; the triglyceride elevation is caused by both increased production and impaired removal of TRLs due to changes in regulatory enzymes and proteins.

    “In the initial stages of CKD, TGs are specifically elevated and HDL-C lowered; the elevation of TGs is caused by both increased production and impaired removal of TRLs due to changes in regulatory enzymes and proteins.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § 9.6.1 Specific lipid management issues in acute coronary syndrome · p. 44

    Supplementation with highly purified n-3 PUFAs reduced mortality in MI 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.

    Interpretationnone given
    § 9.7.2 Chronic heart failure · p. 44

    There is no evidence of harm from statins after the occurrence of HF, so discontinuation is not needed if patients are already on this medication.

    “In any case, there is no evidence for harm in patients on statin treatment after the occurrence of HF, and therefore there is no need for discontinuation if patients are already on this medication.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § 9.5.2.2 Triglycerides and high-density lipoprotein cholesterol · p. 43

    In a post hoc analysis of the 4S trial, patients with low HDL-C (<1 mmol/L) and elevated triglycerides (>1.80 mmol/L) had a relative risk of major coronary events of 0.48 with simvastatin and a relative risk of overall mortality of 0.44.

    “A post hoc analysis of patients with low HDL-C [ , 1 mmol/L ( ≏ 40 mg/dL)] and elevated TGs [ . 1.80 mmol/L ( ≏ 160 mg/dL)] in the 4S trial demonstrated a relative risk for major coronary events of 0.48 with simvastatin. The respective relative risk for overall mortality was 0.44. 352”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [352] Ballantyne, 2001, Influence of low high-density lipoprotein cholesterol and elevated triglyceride on coronary heart disease events and response to simvastatin therapy in 4S, Circulation 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 · p. 46

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

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

    Premisenone given
    § 9.8 Autoimmune diseases · p. 45

    The immune system is believed to be involved in the pathogenesis of atherosclerosis, with inflammatory and autoimmune components participating.

    “The immune system is believed to be involved in the pathogenesis of atherosclerosis. Inflammatory components of the immune response as well as autoimmune elements (e.g. autoantibodies, autoantigens and autoreactive lymphocytes) are involved in these processes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § 9.8 Autoimmune diseases · p. 45

    Statins are effective in reducing disease activity, CV events, and mortality (particularly in primary prevention) in autoimmune diseases, while discontinuation increases MI 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.

  • May combine two claims.

    Premisecitation
    § 9.7.2 Chronic heart failure · p. 44

    In two large RCTs, statins showed no benefit on hard endpoints such as CV mortality, non-fatal MI, and stroke in patients with mainly systolic heart failure, despite decreases in hospitalizations and marked reductions 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 Investigators, 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.

    Premisecitation
    § 9.7.3 Valvular disease · p. 45

    Early observational noncontrolled trials suggested aggressive lipid lowering slowed progression of aortic stenosis, but this was not confirmed in RCTs.

    “Suggestions for an association between aortic stenosis, LDL-C and Lp(a), as well as between cholesterol and increased risk for calcification of bioprosthetic valves, were matched with early observational noncontrolled trials that showed beneficial effects of aggressive lipid lowering in slowing the progression of aortic stenosis. However, this was not confirmed in RCTs. 243,377,378”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [243] Rossebø, 2008, Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis, N Engl J Med source

      Not checked in the free run.

    • cites [377] Cowell, 2005, A randomized trial of intensive lipid-lowering therapy in calcific aortic stenosis, N Engl J Med source

      Not checked in the free run.

    • cites [378] Chan, 2010, Effect of lipid lowering with rosuvastatin on progression of aortic stenosis: results of the aortic stenosis progression observation: measuring effects of rosuvastatin (ASTRONOMER) trial, Circulation source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 9.9 Chronic kidney disease · p. 45

    CV mortality in patients with stage 3 and stage 4 CKD 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] Chronic Kidney Disease Prognosis Consortium, 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.

    Interpretationreasoning
    § 9.9.1 Lipoprotein profile in chronic kidney disease · p. 45

    Consequently, non-HDL-C and apoB levels are clearly increased in CKD.

    “Consequently, non-HDL-C and apoB levels are clearly increased.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning
    § 9.5.4 Type 1 diabetes · p. 43

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

    “This is explained by subcutaneous administration of insulin that increases LPL activity in adipose tissue and skeletal muscle and consequently the turnover rate of VLDL particles.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § 9.6.1 Specific lipid management issues in acute coronary syndrome · p. 43

    Ezetimibe further reduced LDL-C and offered additional benefit (6.4% relative risk reduction in composite clinical endpoint) when added to simvastatin in post-ACS 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
    § 9.9.2 Evidence for lipid management in patients with chronic kidney disease · p. 46

    In AURORA, involving 2776 patients on haemodialysis, rosuvastatin lowered LDL-C as expected but had no significant effect on the composite CVD 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
    § 9.10 Transplantation ( Table 31 ) · p. 47

    A recent systematic review found a strong trend toward fewer cardiovascular events and lower mortality with statins in renal transplant patients.

    “A recent systematic review demonstrated a strong trend towards reduced CVD events and mortality with statins in renal transplant patients. 403”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • 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.

    Study design and conductcitation
    § 9.9.2 Evidence for lipid management in patients with chronic kidney disease · p. 46

    The SHARP trial did not have sufficient power to assess effects in the primary outcome separately in dialysis and non-dialysis patients, but there was no good statistical evidence that proportional effects differed between these groups.

    “The trial did not have sufficient power to assess the effects in the primary outcome separately in dialysis and non-dialysis patients, but there was no good statistical evidence that the proportional effects in dialysis patients differed from those seen in patients not on dialysis”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [397] Baigent, 2011, The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial, Lancet 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 · p. 46

    A cost-effectiveness analysis of statins for primary CVD prevention in CKD showed statins reduced absolute CVD risk but increased rhabdomyolysis risk and competing risks associated with progressive CKD partly offset these gains.

    “A cost-effectiveness analysis of statins for primary CVD prevention in CKD 398 showed that statins reduced absolute CVD risk in patients with CKD but that the increased risk for rhabdomyolysis, and competing risks associated with progressive CKD, partly offset these gains.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [398] Erickson, 2013, Cost-effectiveness of statins for primary cardiovascular prevention in chronic kidney disease, J Am Coll Cardiol source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation
    § 9.9.4 Recommendations of lipid management for patients with chronic kidney disease · p. 46

    The KDIGO organization produced an updated clinical practice guideline for lipid management in chronic kidney disease, drawing on evidence for lipid management in that population.

    “Based on the evidence for lipid management in patients with CKD, the Kidney Disease: Improving Global Outcomes (KDIGO) organization developed an updated clinical practice guideline for lipid management in CKD. 399”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [399] Tonelli, 2014, Lipid management in chronic kidney disease: synopsis of the Kidney Disease: Improving Global Outcomes 2013 clinical practice guideline, Ann Intern Med 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 · p. 46

    A systematic review of statins in 3465 kidney transplant patients free of CHD from 22 studies concluded statins may reduce CV events, although treatment effects were imprecise; heterogeneity prevented comparison of different statin regimens and additional studies are recommended.

    “A systematic review of the benefits and harms of statins in patients with a functioning kidney transplant included 3465 patients, free of CHD, from 22 studies. The authors concluded that statins may reduce CV events, although treatment effects were imprecise; due to heterogeneity, different statin regimens could not be compared and additional studies are recommended. 228”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [228] Palmer, 2014, HMG CoA reductase inhibitors (statins) for kidney transplant recipients, Cochrane Database Syst Rev

      Not checked in the free run.

226 of 226

  • The paper relies on this without support.

    Atherosclerotic cardiovascular disease usually results from multiple 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 together can produce 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.

    Risk is continuous and no threshold exists at which a drug is automatically indicated.

    “risk is a continuum and there is no threshold at which, for example, a drug is automatically indicated.”

  • The paper relies on this without support.

    Therapeutic trials have used a fixed follow-up period rather than lifetime risk.

    “therapeutic trials have been based on a fixed follow-up period and not on lifetime risk”

  • The paper relies on this without support.

    People older than 65 years benefit from smoking cessation and control of hypertension and hyperlipidaemia.

    “While such subjects benefit from smoking cessation and control of hypertension and hyperlipidaemia”

  • The paper relies on this without support.

    Most cost-effectiveness studies rely on simulation.

    “Most cost-effectiveness studies rely on simulation.”

  • The paper relies on this without support.

    The reduction in risk from treatment is generally not more than about one-third of the baseline risk.

    “in general it will not be more than about one-third of the baseline risk.”

  • The paper relies on this without support.

    Risk will be overestimated in countries with decreasing CVD mortality and underestimated in countries with increasing mortality.

    “Risk will be overestimated in countries with a decreasing CVD mortality, and underestimated in countries in which mortality is increasing.”

  • The paper relies on this without support.

    Risk estimates appear lower in women than in men.

    “Risk estimates appear lower in women than in men.”

  • The paper relies on this without support.

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

    “However, risk is only deferred in women; the risk of a 60-year-old woman is similar to that of a 50-year-old man.”

  • The paper relies on this without support.

    Ultimately more women die from CVD than men.

    “Ultimately more women die from CVD than men.”

  • The paper relies on this without support.

    Relative risks may be unexpectedly high in young persons, even if absolute risk levels are low.

    “Relative risks may be unexpectedly high in young persons, even if absolute risk levels are low.”

  • The paper relies on this without support.

    In apparently healthy persons, CVD risk is most frequently the result of multiple, interacting risk factors.

    “In apparently healthy persons, CVD risk is most frequently the result of multiple, interacting risk factors.”

  • The paper relies on this without support.

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

    “All risk estimation systems are relatively crude and require attention to qualifying statements.”

  • The paper relies on this without support.

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

    “Additional factors affecting risk can be accommodated in electronic risk estimation systems such as HeartScore (www.heartscore.org).”

  • The paper relies on this without support.

    A total CV risk estimate is part of a continuum.

    “A total CV risk estimate is part of a continuum.”

  • The paper relies on this without support.

    The cut-off points used to define high risk are in part arbitrary and based on the 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.”

  • The paper relies on this without support.

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

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

  • The paper relies on this without support.

    In several clinical conditions, dyslipidaemia may contribute to an increased risk of developing CVD.

    “In several clinical conditions, dyslipidaemia may contribute to an increased risk of developing CVD.”

  • The paper relies on this without support.

    Autoimmune chronic inflammatory conditions such as rheumatoid arthritis, SLE and psoriasis are associated with increased CV risk and dyslipidaemia.

    “Autoimmune chronic inflammatory conditions such as rheumatoid arthritis, systemic lupus erythematosus (SLE) and psoriasis are associated with increased CV risk and dyslipidaemia.”

  • The paper relies on this without support.

    In women, diabetes or hypertension during pregnancy are risk indicators, and in men, erectile dysfunction.

    “Furthermore, in women, diabetes or hypertension during pregnancy are risk indicators, and in men, erectile dysfunction.”

  • The paper relies on this without support.

    Patients with CKD are at increased risk for CVD events.

    “Patients with CKD are also at increased risk for CVD events and should be screened for dyslipidaemias.”

  • The paper relies on this without support.

    Clinical manifestations of genetic dyslipidaemias may signal a severe lipoprotein disorder, especially FH, which is the most frequent monogenic disorder associated with premature CVD.

    “Clinical manifestations of genetic dyslipidaemias, including xanthomas, xanthelasmas and premature arcus cornealis ( , 45 years), should be sought because they may signal the presence of a severe lipoprotein disorder, especially familial hypercholesterolaemia (FH), which is the most frequent monogenic disorder associated with premature CVD.”

  • The paper relies on this without support.

    Antiretroviral therapies may be associated with accelerated atherosclerosis.

    “Antiretroviral therapies may be associated with accelerated atherosclerosis.”

  • The paper relies on this without support.

    When available, apoB can be considered as an equivalent to non-HDL-C.

    “When available, apoB can be considered as an equivalent to non-HDL-C.”

  • The paper relies on this without support.

    The use of non-HDL-C may overcome some problems of direct methods, but it is still dependent on a correct analysis of HDL-C.

    “The use of non-HDL-C may overcome some of these problems, but it is still dependent on a correct analysis of HDL-C.”

  • The paper relies on this without support.

    An alternative to non-HDL-C may be the analysis of apoB.

    “An alternative to non-HDL-C may be the analysis of apoB.”

  • The paper relies on this without support.

    The analysis of apoB is accurate, with small variations.

    “The analysis of apoB is accurate, with small variations, and is recommended as an alternative when available.”

  • The paper relies on this without support.

    Near patient testing using dry chemistry methods may give a crude estimate.

    “These methods may give a crude estimate, but should be verified by analysis in an established certified laboratory.”

  • The paper relies on this without support.

    TGs are affected by food, resulting in an average 0.3 mmol/L higher plasma level.

    “TGs are affected by food, resulting in, on average, an ≏ 0.3 mmol/L (27 mg/dL) higher plasma level, depending on the composition and the time frame of the last meal.”

  • The paper relies on this without support.

    Most risk estimation systems and virtually all drug trials are based on TC and LDL-C, and clinical benefit from other measures has largely been based on post hoc analyses.

    “Throughout this section it should be noted that most risk estimation systems and virtually all drug trials are based on TC and LDL-C, and that clinical benefit from using other measures, including apoB, non-HDL-C and various ratios, while sometimes logical, has largely been based on post hoc analyses.”

  • The paper relies on this without support.

    Traditional measures of risk such as TC, LDL-C and HDL-C remain robust and supported by a major evidence base.

    “While the role of the alternative analyses is being established, traditional measures of risk such as TC, LDL-C and HDL-C remain robust and supported by a major evidence base.”

  • The paper relies on this without support.

    Multiple clinical trials have established that reduction of TC or LDL-C is associated with statistically and clinically significant reductions in CV events and mortality.

    “Furthermore, multiple clinical trials have established beyond all reasonable doubt that, at least in high-risk subjects, reduction of TC or LDL-C is associated with statistically and clinically significant reductions in CV events and mortality.”

  • The paper relies on this without support.

    In individual cases, TC may be misleading, especially in women, and in subjects with diabetes or high TGs.

    “In individual cases, however, TC may be misleading. This is especially so in women, who often have higher 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.

    Assessment of total risk is not required in patients with familial hyperlipidaemia or TC >7.5 mmol/L; these patients are always at high risk.

    “Note that assessment of total risk is not required in patients with familial hyperlipidaemia (including FH) or those with TC . 7.5 mmol/L (290 mg/dL). These patients are always at high risk and should receive special attention.”

  • The paper relies on this without support.

    In most clinical studies LDL-C has been calculated using the Friedewald formula.

    “In most clinical studies LDL-C has been calculated using the Friedewald formula.”

  • The paper relies on this without support.

    Despite its limitations, the calculated LDL-C value is still widely used.

    “Despite its limitations, the calculated LDL-C value is still widely used.”

  • The paper relies on this without support.

    With very low LDL-C or high TGs, the Friedewald formula may underestimate LDL-C, even giving negative values.

    “With very low LDL-C or in patients with high TGs, the Friedewald formula may underestimate LDL-C, even giving negative values.”

  • The paper relies on this without support.

    Direct methods for LDL-C are available and widely used.

    “Direct methods for the determination of LDL-C are available and are now widely used.”

  • The paper relies on this without support.

    Several limitations of the Friedewald formula may be overcome with direct methods.

    “Several of the limitations of the Friedewald formula may be overcome with the direct methods.”

  • The paper relies on this without support.

    Non-HDL-C is used as an estimation of total atherogenic lipoproteins and relates well to apoB.

    “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.”

  • The paper relies on this without support.

    Non-HDL-C is easily calculated from TC minus HDL-C.

    “Non-HDL-C is easily calculated from TC minus HDL-C.”

  • The paper relies on this without support.

    Several analyses comparing variables in risk algorithms have been published, but data are inconclusive.

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

  • The paper relies on this without support.

    Non-HDL-C has strong predictive power, and practical aspects favor its use in certain situations.

    “Non-HDL-C has been shown to have a strong predictive power, and although the scientific background from randomized trials is weaker, there are practical aspects of using non-HDL-C instead of LDL-C in certain situations.”

  • The paper relies on this without support.

    Non-HDL-C is simple to calculate and does not require additional analyses.

    “Non-HDL-C is simple to calculate and does not require additional analyses.”

  • The paper relies on this without support.

    Both Friedewald's formula and direct LDL-C estimations have limitations in subjects with HTG and very low LDL-C.

    “Both Friedewald's formula and direct LDL-C estimations have limitations in subjects with HTG and in subjects with very low LDL-C.”

  • The paper relies on this without support.

    Goals for non-HDL-C are easily calculated as LDL-C goals plus 0.8 mmol/L.

    “Goals for non-HDL-C are easily calculated as LDL-C goals plus 0.8 mmol/L (30 mg/dL).”

  • The authors state this as an assumption.

    Methodological errors may accumulate in the Friedewald formula because it requires three separate analyses of TC, TGs, and HDL-C.

    “Methodological errors may accumulate since the formula necessitates three separate analyses of TC, TGs and HDL-C.”

  • The authors state this as an assumption.

    A constant cholesterol:TG ratio in VLDL is assumed in the Friedewald formula.

    “A constant cholesterol:TG ratio in very low-density lipoprotein (VLDL) is assumed.”

  • The paper relies on this without support.

    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.”

  • The paper relies on this without support.

    Apolipoprotein B is the major apolipoprotein of VLDL, IDL, and LDL.

    “ApoB is the major apolipoprotein of the atherogenic lipoprotein families (VLDL, IDL and LDL).”

  • The paper relies on this without support.

    Apolipoprotein B is a good estimate of the number of atherogenic particles in plasma.

    “ApoB is a good estimate of the number of these particles in plasma.”

  • The paper relies on this without support.

    Apolipoprotein A1 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.”

  • The paper relies on this without support.

    Each HDL particle may carry from one to five apolipoprotein A1 molecules.

    “However, each HDL particle may carry from one to five apoA1 molecules.”

  • The paper relies on this without support.

    Plasma apolipoprotein A1 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.”

  • The paper relies on this without support.

    Apolipoprotein CIII is a key regulator of triglyceride metabolism, and high apoCIII plasma levels are associated with high plasma 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.”

  • The paper relies on this without support.

    Lipoprotein(a) contains a unique protein, apolipoprotein(a), that is 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.”

  • The paper relies on this without support.

    Plasma lipoprotein(a) level is to a major extent genetically determined.

    “The plasma level of Lp(a) is to a major extent genetically determined.”

  • The paper relies on this without support.

    Measurement of lipoprotein(a) is particularly stable over time.

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

  • The paper relies on this without support.

    An effect on cardiovascular disease events targeting lipoprotein(a) has not been shown.

    “Aneffect on CVD events targeting Lp(a) has not been shown.”

  • The paper relies on this without support.

    Antisense drugs targeting the lipoprotein(a) gene reduce circulating levels of this protein by up to 80%.

    “Antisense drugs targeting the Lp(a) gene reduce the circulating levels of this protein by up to 80%.”

  • The paper relies on this without support.

    The causal relation of lipoprotein subclasses to atherosclerosis is unclear.

    “However, the causal relation of subclasses to atherosclerosis is unclear.”

  • The paper relies on this without support.

    Several genes have been associated with cardiovascular disease.

    “Several genes have been associated with CVD.”

  • The paper relies on this without support.

    Apolipoprotein E is present in three isoforms: apoE2, apoE3, and apoE4.

    “ApoEis present in three isoforms (apoE2, apoE3 and apoE4).”

  • The paper relies on this without support.

    Apolipoprotein E 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.”

  • The paper relies on this without support.

    There has not been a randomized controlled trial to support the AHA/ACC recommendation for high-dose statins in all high-risk people regardless of baseline LDL-C level.

    “Despite this, there has not been an RCT to support the AHA/ACC recommendation for the use of high-dose statins in all high-risk people regardless of baseline LDL-C level.”

  • The paper relies on this without support.

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

    “No level of LDL-C below which benefit ceases or harm occurs has been defined.”

  • The paper relies on this without support.

    To date, no specific goals for HDL-C or triglyceride levels have been determined in clinical trials.

    “To date, no specific goals for HDL-C or TG levels have been determined in clinical trials, although increases in HDL-C predict atherosclerosis regression and low HDL-C is associated with excess events and mortality in CADpatients, even when LDL-C is , 1.8 mmol/L (70 mg/dL).”

  • The paper relies on this without support.

    Increases in HDL-C predict atherosclerosis regression and low HDL-C is associated with excess events and mortality in CAD patients, even when LDL-C is below 1.8 mmol/L.

    “To date, no specific goals for HDL-C or TG levels have been determined in clinical trials, although increases in HDL-C predict atherosclerosis regression and low HDL-C is associated with excess events and mortality in CADpatients, even when LDL-C is , 1.8 mmol/L (70 mg/dL).”

  • The paper relies on this without support.

    Clinical trial evidence is lacking on the effectiveness of intervening in HDL-C or triglyceride levels to reduce cardiovascular risk further.

    “However, clinical trial evidence is lacking on the effectiveness of intervening in these variables to reduce CV risk further.”

  • The paper relies on this without support.

    Most evidence linking nutrition to cardiovascular disease is based on observational studies and investigations of effects of dietary changes on cardiovascular risk factors.

    “However, despite the strong support of lifestyle intervention for CVD prevention coming from the PREDIMED and other intervention studies with CVD endpoints, most evidence linking nutrition to CVD is based on observational studies and investigations of the effects of dietary changes on CV risk factors.”

  • The paper relies on this without support.

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

    “Stearic acid, in contrast to other SFAs (lauric, myristic and palmitic), does not increase TC levels.”

  • The paper relies on this without support.

    A positive relationship exists between dietary cholesterol and coronary artery disease mortality, partly independent of total cholesterol levels.

    “A positive relationship exists between dietary cholesterol and CADmortality, which is partly independent of TC levels.”

  • The paper relies on this without support.

    Dietary carbohydrate is neutral on LDL-C, so carbohydrate-rich foods are an option to replace saturated fat in the diet.

    “Dietary carbohydrate is 'neutral' on LDL-C; therefore, carbohydrate-rich foods represent one of the possible options to replace saturated fat in the diet.”

  • The paper relies on this without support.

    Beneficial effects of weight reduction and physical exercise on cardiovascular risk profile go beyond LDL-C reduction and involve other lipoprotein classes and other risk factors.

    “However, the beneficial effects of weight reduction and physical exercise on the CV risk profile go beyond LDL-C reduction and involve not only other lipoprotein classes but also other risk factors.”

  • The paper relies on this without support.

    Replacing saturated fat with n-6 polyunsaturated fatty acids produces a more relevant hypotriglyceridaemic effect than other replacements.

    “A more relevant hypotriglyceridaemic effect is observed when saturated fat is replaced by n-6 PUFA.”

  • The paper relies on this without support.

    A dietary approach based exclusively on natural foods will seldom reach an n-3 polyunsaturated fatty acid intake adequate to achieve a clinically significant effect.

    “however, a dietary approach based exclusively on natural foods will seldom reach an intake adequate to achieve a clinically significant effect.”

  • The paper relies on this without support.

    In people with severe hypertriglyceridaemia, chylomicrons are equally present in the fasting state.

    “In people with severe HTG, in whom chylomicrons are equally present in the fasting state, it is appropriate to reduce the total amount of dietary fat as much as possible ( , 30 g/day).”

  • The paper relies on this without support.

    Medium-chain triglycerides avoid the formation of chylomicrons because they are directly transported and metabolized in the liver following transport in the portal vein.

    “In these patients, the use of medium chain TGs (from C6 to C12) that avoid the formation of chylomicrons may be considered since they are directly transported and metabolized in the liver following transport in the portal vein.”

  • The paper relies on this without support.

    Monounsaturated fatty acid consumption as a replacement for saturated fatty acids has almost no effect on HDL cholesterol.

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

  • The paper relies on this without support.

    n-6 polyunsaturated fatty acids induce a slight decrease in HDL cholesterol.

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

  • The paper relies on this without support.

    Moderate alcohol consumption is associated with increased HDL cholesterol 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.”

  • The paper relies on this without support.

    Weight reduction has a beneficial influence on HDL cholesterol levels, with a 0.01 mmol/L increase per kilogram decrease when weight reduction has stabilized.

    “Weight reduction has a beneficial influence on HDL-C levels: a 0.01 mmol/L (0.4 mg/dL) increase is observed for every kilogram decrease in body weight when weight reduction has stabilized.”

  • The paper relies on this without support.

    LDL cholesterol is the primary lipoprotein target for reducing cardiovascular risk.

    “LDL-C represents the primary lipoprotein target for reducing CV risk and therefore it deserves special emphasis in the evaluation of lifestyle measures useful for CVD prevention.”

  • The paper relies on this without support.

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

    “Because the trans fatty acids produced in the partial hydrogenation of vegetable oils account for 80% of total intake, the food industry has an important role in decreasing the trans fatty acid content of the food supply.”

  • The paper relies on this without support.

    Fat intakes greater than 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.”

  • The paper relies on this without support.

    Statins reduce the synthesis of cholesterol 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.

    The reduction in intracellular cholesterol concentration induces increased expression of LDL receptors on the surface of hepatocytes, which results in increased uptake of LDL cholesterol from the blood and a decreased plasma concentration of 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.

    Plasma lipid levels are largely determined by genetic factors.

    “Plasma lipid levels are to a very large extent determined by genetic factors.”

  • The paper relies on this without support.

    FH is a common monogenic dyslipidaemia that causes premature CVD through lifelong elevation of plasma LDL-C.

    “FH is a common monogenic dyslipidaemia causing premature CVD due to lifelong elevation of plasma levels of LDL-C.”

  • The paper relies on this without support.

    Untreated HeFH typically leads to CAD before age 55 in men and before age 60 in women.

    “If left untreated, men and women with heterozygous FH (HeFH) typically develop CAD before the ages of 55 and 60 years, respectively.”

  • The paper relies on this without support.

    For people with definite or probable HeFH, coronary heart disease risk is estimated to be at least ten times higher.

    “The risk of CHD among individuals with definite or probable HeFH is estimated to be increased at least 10-fold.”

  • The paper relies on this without support.

    FH is monogenic, caused by loss-of-function mutations in LDLR or apoB or a gain-of-function mutation in PCSK9.

    “FH is a monogenic disease caused by loss of function mutations in the LDLR or apoB genes or a gain of function mutation in the PCSK9 gene”

  • The paper relies on this without support.

    Most HoFH patients develop CAD and aortic stenosis before age 20 and die before age 30.

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

  • The paper relies on this without support.

    The risk of pancreatitis is clinically significant when TGs exceed 10 mmol/L, making preventive action mandatory.

    “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.

    HTG causes about 10% of all pancreatitis cases.

    “Notably, HTG is the cause of ≏ 10% of all cases with pancreatitis”

  • The paper relies on this without support.

    The benefit of statins in primary prevention is less well-established in women than in men.

    “The benefit of statins in primary prevention is less well-established in women than in men.”

  • The paper relies on this without support.

    Older adults are less likely than younger or middle-aged subjects to be prescribed lipid-lowering medications or to adhere to statin therapy.

    “Older adults are less likely to be prescribed lipid-lowering medications, or adhere to statin therapy, than younger or middle-age subjects.”

  • The paper relies on this without support.

    People with diabetes and CAD are at substantially higher CVD risk for future events.

    “Importantly, those with diabetes and CAD are at substantially higher CVD risk for future events.”

  • The paper relies on this without support.

    Conclusive evidence supports that hyperglycaemia accelerates atherosclerosis.

    “Conclusive evidence supports the proposition that hyperglycaemia accelerates atherosclerosis.”

  • The paper relies on this without support.

    Patients who have recently presented with ACS are at high risk of further CV events.

    “Patients who have presented recently with ACS are at high risk of experiencing further CV events.”

  • The paper relies on this without support.

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

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

  • The paper relies on this without support.

    HF patients have lower total cholesterol and LDL-C than patients without HF.

    “HF patients have lower TC and LDL-C than patients without HF.”

  • The paper relies on this without support.

    Low total cholesterol portends a poor prognosis in HF.

    “In contrast to patients without HF, low TC portends a poor prognosis in HF.”

  • The paper relies on this without support.

    Aortic stenosis increases the risk of CV events and mortality.

    “Aortic stenosis increases the risk of CV events and mortality.”

  • The paper relies on this without support.

    Aortic valve sclerosis is associated with increased risk of CAD even in the absence of increased risk profiles.

    “Aortic valve sclerosis (calcification of the aortic leaflets without impairment in leaflet excursion or a significant transvalvular pressure gradient) is associated with an increased risk of CAD even in the absence of increased risk profiles.”

  • The paper relies on this without support.

    The immune system is believed to be involved in the pathogenesis of atherosclerosis.

    “The immune system is believed to be involved in the pathogenesis of atherosclerosis.”

  • The paper relies on this without support.

    Autoimmune diseases are characterized by inflammatory vasculitis and endothelial dysfunction.

    “These diseases are characterized by inflammatory vasculitis and endothelial dysfunction.”

  • The paper relies on this without support.

    Safety issues and dose adjustment are important in advanced CKD because adverse events are commonly dose related and due to increased blood concentration.

    “Safety issues and dose adjustment are important in advanced stages of CKD (stages 3-5), as adverse events are commonly dose related and due to increased blood concentration of the compound.”

  • The paper relies on this without support.

    Lipid abnormalities are common in patients who have received a solid organ transplant.

    “Lipid abnormalities are common in patients who have undergone solid organ transplantation”

  • The paper relies on this without support.

    Lipid abnormalities in transplant patients promote atherosclerotic disease and transplant arterial vasculopathy, leading to major vascular events.

    “and predispose patients to the development of both atherosclerotic disease and transplant arterial vasculopathy, resulting in major vascular events.”

  • The paper relies on this without support.

    Diabetes, obesity, metabolic syndrome, and chronic kidney disease are common general causes of dyslipidaemia in transplant patients.

    “Common general causes of dyslipidaemia in these patients are diabetes, obesity, MetS and CKD.”

  • The paper relies on this without support.

    Immunosuppressive drug regimens have important adverse effects on lipid metabolism.

    “Immunosuppressive drug regimens also have important adverse effects on lipid metabolism.”

  • The paper relies on this without support.

    Glucocorticoid therapy causes weight gain and worsens insulin resistance, which increases total cholesterol, VLDL, triglycerides, and the size and density of LDL particles.

    “Glucocorticoid therapy causes weight gain and exacerbates insulin resistance, leading to increases in TC, VLDL and TGs and in the size and density of LDL particles.”

  • The paper relies on this without support.

    Calcineurin inhibitors raise hepatic lipase activity, lower LPL, and bind LDLR, reducing clearance of atherogenic lipoproteins.

    “Calcineurin inhibitors increase the activity of hepatic lipase, decrease LPL and bind LDLR, resulting in reduced clearance of atherogenic lipoproteins.”

  • The paper relies on this without support.

    Ciclosporin has a greater adverse effect on lipid profiles than tacrolimus.

    “A greater adverse impact on lipid profiles is seen with ciclosporin than with tacrolimus.”

  • The paper relies on this without support.

    Sirolimus causes dyslipidaemia in almost half of the patients who receive it.

    “Sirolimus, a structural analogue of tacrolimus, causes dyslipidaemia in almost half of the patients receiving it.”

  • The paper relies on this without support.

    Statins affect lipids similarly in transplant recipients and in the general population.

    “Statins have a similar effect on lipids in transplant recipients as in the general population.”

  • The paper relies on this without support.

    Ciclosporin is metabolized through CYP3A4 and may increase systemic statin exposure and the risk of myopathy.

    “especially with ciclosporin which is metabolized through CYP3A4 and may increase systemic statin exposure and the risk of myopathy.”

  • The paper relies on this without support.

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

    “Tacrolimus is also metabolized by CYP3A4, but appears to have less potential for harmful interaction with statins than ciclosporin.”
120 of 120

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?

  • Clinical guidelines do not recommend treatment to lower plasma triglyceride levels because randomized trials have not provided consistent evidence that lowering plasma triglyceride levels reduces cardiovascular event risk.

    “By contrast, the guidelines do not recommend treatment to lower plasma triglyceride levels because randomized trials have not provided consistent evidence that lowering plasma triglyceride levels reduces the risk of cardiovascular events.1,2”

    From Association of Triglyceride-Lowering <i>LPL</i> Variants and LDL-C–Lowering <i>LDLR</i> Variants With Risk of Coronary Heart Disease (2019) · cites this paper as [1]

    Section 7.3 (p. 33) explicitly recommends considering drug treatment to lower triglycerides in high-risk patients with levels above 2.3 mmol/L, contrary to the claim that the guidelines do not recommend such treatment. The same section says evidence for benefit is modest, and section 9.5.2.2 (p. 42) describes mixed trial results; those qualifications do not negate the conditional recommendation. (LLM, conf=0.90)

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • Despite advancements in dyslipidemia management, many individuals with hypertriglyceridemia remain inadequately managed, particularly those at high cardiovascular risk.

    “Despite advancements in dyslipidemia management, many individuals with hypertriglyceridemia remain inadequately managed, particularly those at high cardiovascular risk who demand more aggressive therapeutic strategies [3].”

    From Efficacy and safety of Olezarsen in treating hypertriglyceridemia: a systematic review and meta-analysis of randomized controlled trials (2025) · cites this paper as [3]

    Section 7.3 (p. 33) recommends considering drug treatment for high-risk patients with elevated triglycerides, supporting the need for additional treatment in some cases. It does not establish that many people with hypertriglyceridaemia are inadequately managed, and its recommendations are conditional rather than a general call for more aggressive treatment. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • The effects of SBO on TC, LDL cholesterol, and TC:HDL cholesterol relative to POo were not accompanied by significant differences in other lipid counterparts, apoB, and the apoB:apoA1 ratio.

    “these effects were not accompanied by significant differences in other lipid counterparts, apoB, and the apoB:apoA1 ratio (42).”

    From Eucaloric diets enriched in palm olein, cocoa butter, and soybean oil did not differentially affect liver fat concentration in healthy participants: a 16-week randomized controlled trial. (2021) · cites this paper as [42]

    Section 3.3.6 (p. 19) discusses apoB and the apoB:apoA1 ratio as risk measures, but reports no SBO-versus-POo comparison. A search for those oils and significant differences in lipid outcomes found no passage addressing the claim in our copy. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

  • Additional contributors to secondary HTG are renal disease, pregnancy, paraproteinaemia, and systemic lupus erythematosus.

    “Additional contributors to secondary HTG are renal disease (uraemia or glomerulonephritis), pregnancy (particularly in the third trimester), paraproteinaemia, and systemic lupus erythematosus.40”

    From Clinical review on triglycerides (2020) · cites this paper as [40]

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

    “The previous ESC/EAS lipid Guidelines were published in August 2016 [1].”

    From 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk (2019) · cites this paper as [1]

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.

  • Conflicting LDL-C reduction target for type 1 diabetes

    Major

    The prose recommends lowering LDL-C by at least 30% for patients with type 1 diabetes and microalbuminuria or renal disease, while Table 26 recommends at least 50% for the same group. The discrepancy changes the treatment target.

1 of 1

Cites

1 retracted

Flagged first, then by citations

2 of the 590 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. 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., Cooney, M.-T., ESC Scientific Document Group, Badimon, L., Funck-Brentano, C., Agewall, S., Barón-Esquivias, G., Borén, J., Bruckert, E., Cordero, A., Corsini, A., Giannuzzi, P., Gueyffier, F., Krstačić, G., Lettino, M., Lionis, C., Lip, G. Y. H., Marques-Vidal, P., Milicic, D., Pedro-Botet, J., Piepoli, M. F., Rigopoulos, A. G., Ruschitzka, F., Tuñón, J., von Eckardstein, A., Vrablik, M., Weiss, T. W., Williams, B., Windecker, S., Zimlichman, R., Zamorano, J. L., Aboyans, V., Achenbach, S., Agewall, S., Badimon, L., Barón-Esquivias, G., Baumgartner, H., Bax, J. J., Bueno, H., Carerj, S., Dean, V., Erol, Ç., Fitzsimons, D., Gaemperli, O., Kirchhof, P., Kolh, P., Lancellotti, P., Lip, G. Y. H., Nihoyannopoulos, P., Piepoli, M. F., Ponikowski, P., Roffi, M., Torbicki, A., Vaz Carneiro, A., Windecker, S., Zelveian, P. H., Siostrzonek, P., Ibrahimov, F., Sujayeva, V., Claeys, M. J., Pojskić, B., Postadzhiyan, A., Miličić, D., Georgiou, G. C., Rosolova, H., Klausen, C., Viigimaa, M., Kervinen, K., Kedev, S., Ferrières, J., Petriashvili, S., Kintscher, U., Rallidis, L., Gábor Kiss, R., Guðnason, T., Maher, V., Henkin, Y., Mureddu, G. F., Mussagaliyeva, A., Ibrahimi, P., Mirrakhimov, E., Latkovskis, G., Ben Lamin, H., Slapikas, R., Visser, L., Dingli, P., Ivanov, V., Wittekoek, J., Hovland, A., Rynkiewicz, A., Rato, Q., Ezhov, M., Zavatta, M., Nedeljkovic, M. A., Pella, D., Fras, Z., Marzal, D., Nilsson, L., Mach, F., Addad, F., Kayıkcıoglu, M., Mitchenko, O., & Wald, D.
Affiliations
University of Milan (IT)
Corresponding author
  • Catapano, Alberico L
  • Graham, Ian
ORCID
Venue
European Heart Journal
Publisher
Oxford University Press (OUP)
Published
2016-08-28
Volume
37
Issue
39
Pages
2999-3058
ISSN
  • 0195-668X (ISSN-L)
  • 1522-9645
DOI
10.1093/eurheartj/ehw272
OpenAlex
W2111099202
Cited by
3,162
References
590
Citations by year
2026: 72 · 2025: 120 · 2024: 156 · 2023: 184 · 2022: 257 · 2021: 304 · 2020: 418 · 2019: 603 · 2018: 503 · 2017: 341 · 2016: 53 · 2015: 39 · 2014: 36 · 2013: 33 · 2012: 33
FWCI
553.52
Type
journal article
Language
en
Open access
Locations
  • European Heart Journal (publishedVersion)
  • PubMed (publishedVersion)
  • Research Portal (Queen's University Belfast) (publishedVersion, other-oa)
  • Zurich Open Repository and Archive (University of Zurich) (acceptedVersion)
  • IRIS (submittedVersion)
  • HighWire Press Open Archive (submittedVersion)
  • ORBi (University of Liège) (submittedVersion, other-oa)
  • SERVAL (Université de Lausanne) (submittedVersion)
  • Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
  • Utrecht University Repository (Utrecht University) (submittedVersion)
Topics
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Clinical practice guidelines implementation
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
Keywords
dyslipidemia, dyslipidemia management, lipid-lowering therapy, cardiovascular risk, atherosclerosis, cardiovascular disease prevention, risk-benefit assessment, clinical guidelines
MeSH terms
Cardiology, Cardiovascular Diseases, Europe, Humans, Risk, Sex Factors, Societies, Medical, Dyslipidemias

About these checks

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

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

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

Statistics and arithmetic are recomputed, not judged.

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

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