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Cited by 275Lipoproteins and Cardiovascular HealthCholesterol and Lipid MetabolismParaoxonase enzyme and polymorphisms

HDL cholesterol: reappraisal of its clinical relevance

Open access
März, Winfried, Kleber, Marcus E., Scharnagl, Hubert, Speer, Timotheus, Zewinger, Stephen, Ritsch, Andreas, Parhofer, Klaus G., von Eckardstein, Arnold +2 more·2017·Clinical Research in Cardiology
DOI 10.1007/s00392-017-1106-1PMC PMC5565659
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Abstract

BACKGROUND: While several lines of evidence prove that elevated concentrations of low-density lipoproteins (LDL) causally contribute to the development of atherosclerosis and its clinical consequences, high-density lipoproteins are still widely believed to exert atheroprotective effects. Hence, HDL cholesterol (HDL-C) is in general still considered as "good cholesterol". Recent research, however, suggests that this might not always be the case and that a fundamental reassessment of the clinical significance of HDL-C is warranted. METHOD: This review article is based on a selective literature review. RESULTS: In individuals without a history of cardiovascular events, low concentrations of HDL-C are inversely associated with the risk of future cardiovascular events. This relationship may, however, not apply to patients with metabolic disorders or manifest cardiovascular disease. The classical function of HDL is to mobilise cholesterol from extrahepatic tissues for delivery to the liver for excretion. These roles in cholesterol metabolism as well as many other biological functions of HDL particles are dependent on the number as well as protein and lipid composition of HDL particles. They are poorly reflected by the HDL-C concentration. HDL can even exert negative vascular effects, if its composition is pathologically altered. High serum HDL-C is therefore no longer regarded protective. In line with this, recent pharmacological approaches to raise HDL-C concentration have not been able to show reductions of cardiovascular outcomes. CONCLUSION: In contrast to LDL cholesterol (LDL-C), HDL-C correlates with cardiovascular risk only in healthy individuals. The calculation of the ratio of LDL-C to HDL-C is not useful for all patients. Low HDL-C should prompt examination of additional metabolic and inflammatory pathologies. An increase in HDL-C through lifestyle change (smoking cessation, physical exercise) has positive effects and is recommended. However, HDL-C is currently not a valid target for drug therapy.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that HDL-C is not generally protective and is a poor surrogate for HDL function, with its inverse association to cardiovascular risk applying mainly to individuals without manifest disease. It concludes that low HDL-C should prompt evaluation for metabolic or inflammatory pathology, lifestyle-induced HDL-C increases are beneficial, but HDL-C is not currently a valid drug target.

Key findings

  • The epidemiological relationship is complex: no further prognostic improvement is seen above HDL-C ~60 mg/dl (1.5 mmol/l); a register study of more than 1 million US veterans found a U-shaped relationship with total mortality and a nadir at 50 mg/dL (1.25 mmol/L); in Framingham analyses, CV risk increased by 30% when low HDL-C occurred with either LDL-C ≥100 mg/dl or TG ≥100 mg/dl, and by 60% when both TG and LDL-C were ≥100 mg/dl.
  • Genetic and mechanistic data challenge a general protective role: monogenic HDL deficiencies due to APOA1, ABCA1, or LCAT mutations are not consistently associated with increased atherosclerosis; SR-BI mutations (P279S, P376L) raise HDL-C but increase cardiovascular risk; and HDL-C measurements do not reflect reverse cholesterol transport or cholesterol efflux capacity.
  • HDL can become dysfunctional in disease: acute-phase HDL shows increased serum amyloid A, sPLA2-IIa, and ceruloplasmin and a lower proportion of Apo A1; in coronary disease, kidney disease, and diabetes, HDL may lack protective vascular effects or exert harmful effects; HDL-C corrected by SAA correlates with risk better than HDL-C alone in several independent cohorts.
  • Therapies that raise HDL-C have not shown outcome benefit: a meta-analysis of 18 prospective randomized fibrate studies found a 10% reduction in severe cardiovascular events and 14% reduction in albuminuria progression; a meta-analysis of 11 niacin outcome studies reported reductions of 34% in cardiovascular events and 25% in adverse coronary endpoints, but HPS2-THRIVE (25,673 patients) showed no reduction in vascular events and increased severe side effects; three of four prospective CETP inhibitor studies were terminated for increased mortality or futility. Lifestyle increases in HDL-C are reported as physical activity 5–10%, smoking cessation 5–10%, weight loss 5–20%, alcohol consumption 5–15%, and Mediterranean diet 0–5%.

Methods

  • Design: narrative review article based on a selective literature review, not a systematic review or meta-analysis.
  • Data: synthesizes epidemiological studies (e.g., Framingham, EPIC-Norfolk, IDEAL, US veterans), genetic studies, mechanistic and laboratory studies, and randomized drug trials of fibrates, niacin, CETP inhibitors, and HDL mimetics.
  • Analysis: qualitative synthesis with tables and figures; no primary data collection or formal quantitative pooling is reported.

Limitations

  • Stated limitations: Not stated in the paper.
  • Evident: the selective literature review may be subject to selection bias and lacks a systematic search or formal quality assessment; conclusions depend on cited studies and expert interpretation.
  • Evident: many cited findings are observational, retrospective, or from trials with mixed or negative results, and no formal meta-analysis is performed.

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

Integrity signals

Registry

Crossref · 10.1007/s00392-017-1106-1

Cites

115 of 115 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 83 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    In patients who underwent coronary angiography, the relationship of HDL-C to long-term prognosis was weakened in stable coronary heart disease.

    “In patients who underwent coronary angiography, we have observed that HDL-C correlates inversely with cardiovascular mortality in the absence of CHD, that the relationship of HDL-C to long-term prognosis was weakened in stable coronary heart disease, whereas in clinically unstable patients the relationship was completely abolished [74].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [74] Silbernagel G, Schottker B, Appelbaum S et al (2013) High-density lipoprotein cholesterol, coronary artery disease, and cardiovascular mortality. Eur Heart J 34(46):3563–3571 source

      Not checked in the free run.

  • Findingcitation

    In patients who underwent coronary angiography, the relationship of HDL-C to long-term prognosis was completely abolished in clinically unstable patients.

    “In patients who underwent coronary angiography, we have observed that HDL-C correlates inversely with cardiovascular mortality in the absence of CHD, that the relationship of HDL-C to long-term prognosis was weakened in stable coronary heart disease, whereas in clinically unstable patients the relationship was completely abolished [74].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [74] Silbernagel G, Schottker B, Appelbaum S et al (2013) High-density lipoprotein cholesterol, coronary artery disease, and cardiovascular mortality. Eur Heart J 34(46):3563–3571 source

      Not checked in the free run.

  • Findingcitation

    A slightly increased cardiovascular mortality was observed at low concentrations of CETP in the blood despite high HDL-C.

    “We observed a slightly increased cardiovascular mortality at low concentrations of CETP in the blood despite high HDL-C [37].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [37] Ritsch A, Scharnagl H, Eller P et al (2010) Cholesteryl ester transfer protein and mortality in patients undergoing coronary angiography: the Ludwigshafen Risk and Cardiovascular Health study. Circulation 121(3):366–374 source

      Not checked in the free run.

  • Findingcitation

    In patients who underwent coronary angiography, HDL-C correlates inversely with cardiovascular mortality in the absence of CHD.

    “In patients who underwent coronary angiography, we have observed that HDL-C correlates inversely with cardiovascular mortality in the absence of CHD, that the relationship of HDL-C to long-term prognosis was weakened in stable coronary heart disease, whereas in clinically unstable patients the relationship was completely abolished [74].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [74] Silbernagel G, Schottker B, Appelbaum S et al (2013) High-density lipoprotein cholesterol, coronary artery disease, and cardiovascular mortality. Eur Heart J 34(46):3563–3571 source

      Not checked in the free run.

  • Findingcitation

    Three out of four prospective studies with CETP inhibitors had to be terminated due to increased mortality in the treatment group or due to futility.

    “However, three out of four prospective studies with CETP inhibitors had to be terminated due to increased mortality in the treatment group or due to futility (Table 3).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [106] Barter PJ, Caulfield M, Eriksson M et al (2007) Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 357(21):2109–2122 source

      Not checked in the free run.

    • cites [107] Schwartz GG, Olsson AG, Abt M et al (2012) Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med 367(22):2089–2099 source

      Not checked in the free run.

  • May combine two claims. 19
  • Classified as probably not a substantial claim. 9
  • The quote only partly states this claim. 1

  • May combine two claims.

    Findingcitation

    In the HPS2-THRIVE study, no reduction in vascular events was observed with a combination of niacin with laropiprant, but rates of severe side effects such as bleeding, myopathy, infections and diabetes mellitus increased.

    “No reduction in vascular events was observed, but the rates of severe side effects such as bleeding, myopathy, infections and diabetes mellitus increased.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [95] Landray MJ, Haynes R, Hopewell JC et al (2014) Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med 371(3):203–212 source

      Not checked in the free run.

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

    Premisenone given

    The classical function of HDL is to mobilise cholesterol from extrahepatic tissues for delivery to the liver for excretion.

    “The classical function of HDL is to mobilise cholesterol from extrahepatic tissues for delivery to the liver for excretion.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The relationship between HDL-C and cardiovascular risk is not linear; no further improvement in prognosis is seen with HDL-C levels above approximately 60 mg/dl (1.5 mmol/l).

    “The relationship between HDL-C and cardiovascular risk is not linear; for instance, no further improvement in prognosis is seen with HDL-C levels above ~60 mg/dl (1.5 mmol/l) (Fig. 1) [3].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] Di Angelantonio E, Sarwar N, Perry P et al (2009) Major lipids, apolipoproteins, and risk of vascular disease. JAMA 302(18):1993–2000 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The concentration of HDL-C in plasma cannot be used as a measure of cholesterol efflux from vessel walls or of the efficiency of reverse cholesterol transport.

    “Therefore, the concentration of HDL-C in the plasma cannot be used as a measure of cholesterol efflux from vessel walls, or of the efficiency of RCT.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    There is a U-shaped relationship between HDL-C and total mortality, with 50 mg/dL (1.25 mmol/L) as the nadir associated with the lowest mortality.

    “A recent register study of more than 1 million US veterans found a U-shaped relationship between HDL-C and total mortality with 50 mg/dL (1.25 mmol/L) as the nadir associated with the lowest mortality [5].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Bowe B, Xie Y, Xian H, Balasubramanian S, Zayed MA, Al-Aly Z (2016) High density lipoprotein cholesterol and the risk of all-cause mortality among US Veterans. Clin J Am Soc Nephrol. doi: 10.2215/CJN.00730116 source

      Not checked in the free run.

  • The quote only partly states this claim.

    Premisecitation

    Compared with low HDL-C in isolation, cardiovascular risk increases by 30% when low HDL-C occurs together with high LDL-C and/or high triglycerides.

    “Cardiovascular (CV) risk increases by 30% for LDL-C ≥ 100 mg/dl and TG < 100 mg/dl or LDL-C < 100 mg/dl and TG ≥ 100 mg/dl.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [6] Bartlett J, Predazzi IM, Williams SM et al (2016) Is isolated low high-density lipoprotein cholesterol a cardiovascular disease risk factor? New insights from the Framingham offspring study. Circ Cardiovasc Qual Outcomes 9(3):206–212 source

      Not checked in the free run.

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

    Premisenone given

    ABCA1 mutations increase the risk for Alzheimer's disease.

    “Interestingly, ABCA1 mutations increase the risk for Alzheimer’s disease.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Lack of SR-BI increases HDL-C but is atherogenic.

    “On the other hand, lack of SR-BI increases HDL-C, but is atherogenic [42].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [42] Huby T, Doucet C, Dachet C et al (2006) Knockdown expression and hepatic deficiency reveal an atheroprotective role for SR-BI in liver and peripheral tissues. J Clin Invest 116(10):2767–2776 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mutations of SR-BI (P279S, P376L) are associated with both significant increases in HDL-C and increased cardiovascular risk.

    “Only recently, mutations of scavenger receptor (SR-BI) (P279S, P376L) have been described which are associated with both significant increases in HDL-C and increased cardiovascular risk [38–40].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [38] Vergeer M, Korporaal SJ, Franssen R et al (2011) Genetic variant of the scavenger receptor BI in humans. N Engl J Med 364(2):136–145 source

      Not checked in the free run.

    • cites [39] Ljunggren SA, Levels JH, Hovingh K et al (2015) Lipoprotein profiles in human heterozygote carriers of a functional mutation P297S in scavenger receptor class B1. Biochim Biophys Acta 1851(12):1587–1595 source

      Not checked in the free run.

    • cites [40] Zanoni P, Khetarpal SA, Larach DB et al (2016) Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease. Science 351(6278):1166–1171 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Unlike HDL from healthy subjects, HDL from patients with CHD, kidney disease or diabetes mellitus have no protective vascular effects or may even cause paradoxical harmful effects.

    “Unlike HDL from healthy subjects, HDL from patients with CHD, kidney disease or diabetes mellitus have no protective vascular effects or may even cause paradoxical harmful effects [55, 56, 61, 70, 71, 75, 76].”
    Quote in the paperSubstantial claim0 of 7 sources checked
    • cites [55] Davidson WS, Silva RA, Chantepie S, Lagor WR, Chapman MJ, Kontush A (2009) Proteomic analysis of defined HDL subpopulations reveals particle-specific protein clusters: relevance to antioxidative function. Arterioscler Thromb Vasc Biol 29(6):870–876 source

      Not checked in the free run.

    • cites [56] Vaisar T, Pennathur S, Green PS et al (2007) Shotgun proteomics implicates protease inhibition and complement activation in the antiinflammatory properties of HDL. J Clin Invest 117(3):746–756 source

      Not checked in the free run.

    • cites [61] Sorrentino SA, Besler C, Rohrer L et al (2010) Endothelial-vasoprotective effects of high-density lipoprotein are impaired in patients with type 2 diabetes mellitus but are improved after extended-release niacin therapy. Circulation 121(1):110–122 source

      Not checked in the free run.

    • cites [70] Besler C, Heinrich K, Rohrer L et al (2011) Mechanisms underlying adverse effects of HDL on eNOS-activating pathways in patients with coronary artery disease. J Clin Invest 121(7):2693–2708 source

      Not checked in the free run.

    • cites [71] Speer T, Rohrer L, Blyszczuk P et al (2013) Abnormal high-density lipoprotein induces endothelial dysfunction via activation of Toll-like receptor-2. Immunity 38(4):754–768 source

      Not checked in the free run.

    • cites [75] Riwanto M, Rohrer L, Roschitzki B et al (2013) Altered activation of endothelial anti- and proapoptotic pathways by high-density lipoprotein from patients with coronary artery disease: role of high-density lipoprotein-proteome remodeling. Circulation 127(8):891–904 source

      Not checked in the free run.

    • cites [76] Huang Y, Wu Z, Riwanto M et al (2013) Myeloperoxidase, paraoxonase-1, and HDL form a functional ternary complex. J Clin Invest 123(9):3815–3828 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A meta-analysis of 18 prospective, randomised outcome studies concluded that fibrates reduce the rate of severe cardiovascular events by 10% and the progression of albuminuria by 14%.

    “A meta-analysis of 18 prospective, randomised outcome studies concluded that fibrates reduce the rate of severe cardiovascular events by 10% and the progression of albuminuria by 14% [86].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [86] Jun M, Foote C, Lv J et al (2010) Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis. Lancet 375(9729):1875–1884 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    In disease states, HDL may turn dysfunctional and can even have negative vascular effects.

    “In disease states, HDL may turn dysfunctional and can even have negative vascular effects.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In another study, cellular efflux was inversely correlated with prevalent atherosclerosis, but not with the long-term risk of cardiovascular events.

    “In another study, cellular efflux was inversely correlated with prevalent atherosclerosis, but not with the long-term risk of cardiovascular events [78].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [78] Li XM, Tang WH, Mosior MK et al (2013) Paradoxical association of enhanced cholesterol efflux with increased incident cardiovascular risks. Arterioscler Thromb Vasc Biol 33(7):1696–1705 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Drug-based inhibition of CETP in humans leads to a significant increase in HDL-C and a drop in LDL-C.

    “Drug-based inhibition of CETP in humans leads to a significant increase in HDL-C and a drop in LDL-C [104, 105].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [104] Brousseau ME, Schaefer EJ, Wolfe ML et al (2004) Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol. N Engl J Med 350(15):1505–1515 source

      Not checked in the free run.

    • cites [105] Kastelein JJ (2007) Refocusing on use of cholesteryl ester transfer protein inhibitors. Am J Cardiol 100(11 A):n47–n52 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    CETP inhibition may eliminate the postulated atheroprotective effect of HDL or even be harmful if HDL gained adverse properties.

    “This may not only eliminate the postulated atheroprotective effect but even be harmful if HDL gained adverse properties [9, 74, 108].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [9] Annema W, von Eckardstein A (2016) Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy. Transl Res 173:30–57 source

      Not checked in the free run.

    • cites [74] Silbernagel G, Schottker B, Appelbaum S et al (2013) High-density lipoprotein cholesterol, coronary artery disease, and cardiovascular mortality. Eur Heart J 34(46):3563–3571 source

      Not checked in the free run.

    • cites [108] von Eckardstein A, Rohrer L (2016) HDLs in crises. Curr Opin Lipidol 27(3):264–273 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A subsequent meta-analysis of 11 outcome studies indicated that niacin reduced cardiovascular events and adverse coronary endpoints by 34% and 25%, respectively.

    “A subsequent meta-analysis of 11 outcome studies, which were mainly conducted in secondary prevention and included the AIM-HIGH-study [92], indicated that niacin reduced cardiovascular events and adverse coronary endpoints by 34 and 25%, respectively [94].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [94] Lavigne PM, Karas RH (2013) The current state of niacin in cardiovascular disease prevention: a systematic review and meta-regression. J Am Coll Cardiol 61(4):440–446 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CETP mediates the exchange of cholesterol and triglycerides between various lipoproteins and plays an important role in reverse cholesterol transport.

    “Cholesteryl ester transfer protein (CETP) mediates the exchange of cholesterol and triglycerides between various lipoproteins and thus plays an important role in RCT (Fig. 2) [98, 99].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [98] Fielding CJ, Fielding PE (1995) Molecular physiology of reverse cholesterol transport. J Lipid Res 36(2):211–228 source

      Not checked in the free run.

    • cites [99] Tall AR (1993) Plasma cholesteryl ester transfer protein. J Lipid Res 34(8):1255–1274 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    The prognosis with regard to cardiovascular disease cannot be determined via HDL-C; the ratio of HDL-C to LDL-C may be misleading if HDL-C is high and if comorbidities like CHD, diabetes mellitus or chronic kidney disease exist.

    “The prognosis with regard to cardiovascular disease cannot be determined via HDL-C; the ratio of HDL-C to LDL-C may be misleading if HDL-C is high and if comorbidities like CHD, diabetes mellitus or chronic kidney disease exist.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    Although HDL likely influences atherogenesis in a variety of ways, the focus is on the HDL-dependent aspects of RCT.

    “Although HDL likely influences atherogenesis in a variety of ways, the focus is on the HDL-dependent aspects of RCT (Table 4).”
    Quote in the paperSubstantial claim

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

    Interpretationnone given

    The positive effects of increasing HDL-C through lifestyle changes are especially true for smoking cessation and physical activity.

    “This is especially true for smoking cessation and physical activity.”
    Quote in the paperNot a substantial claim

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

    Interpretationnone given

    The primary goal of lipid therapy is currently the reduction of LDL cholesterol.

    “The primary goal of lipid therapy is currently the reduction of LDL cholesterol.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Cholesterol transported with HDL neither has any protective function nor reflects the functionality of HDL.

    “Cholesterol transported with HDL neither has any protective function nor reflects the functionality of HDL.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Mendelian randomisation studies show no protective effects of a genetically high HDL-C concentration.

  • May combine two claims.

    Interpretationcitation

    The determination of pathophysiologically relevant lipids or proteins associated with HDL may come to replace HDL-C in the future, but at present such assays are not yet available for routine clinical use.

    “The determination of pathophysiologically relevant lipids or proteins associated with HDL may come to replace HDL-C in the future, but at present such assays are not yet available for routine clinical use [9, 115].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [9] Annema W, von Eckardstein A (2016) Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy. Transl Res 173:30–57 source

      Not checked in the free run.

    • cites [115] Siddiqi HK, Kiss D, Rader D (2015) HDL-cholesterol and cardiovascular disease: rethinking our approach. Curr Opin Cardiol 30(5):536–542 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

    Low HDL-C is often a clinical indicator of disturbed metabolism of triglyceride-rich lipoproteins (e.g. in diabetes mellitus) or a chronic inflammation.

    “Low HDL-C is often a clinical indicator of disturbed metabolism of triglyceride-rich lipoproteins (e.g. in diabetes mellitus) or a chronic inflammation.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationnone given

    An increase in HDL-C through lifestyle changes has positive effects.

    “An increase in HDL-C through lifestyle changes has positive effects and is recommended.”
    Quote in the paperSubstantial claim

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

    Interpretationnone given

    Increasing HDL-C through lifestyle factors such as physical activity and smoking cessation is associated with vascular protective effects.

    “Increasing HDL-C through lifestyle factors such as physical activity and smoking cessation is associated with vascular protective effects.”
    Quote in the paperNot a substantial claim

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

    Interpretationnone given

    At present, HDL-C is not a target for drug-based treatment.

    “At present, HDL-C is not a target for drug-based treatment.”
    Quote in the paperNot a substantial claim
27 of 27

  • The paper relies on this without support.

    There is still no simple biomarker available for HDL functionality.

    “One problem is at present, however, that there is still no simple biomarker available for HDL functionality.”

  • The paper relies on this without support.

    Large epidemiological studies have found an inverse relationship between the concentration of HDL-C in plasma and CHD.

    “Large epidemiological studies have found an inverse relationship between the concentration of HDL-C in plasma and CHD.”

  • The paper relies on this without support.

    Mendelian randomisation studies show no protective effects of a genetically high HDL-C concentration.

    “Mendelian randomisation studies show no protective effects of a genetically high HDL-C concentration.”
3 of 3

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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.

  • Table 4 credits Kingwell et al. to the wrong reference

    Minor

    The Table 4 note cites [110] as a work by B.A. Kingwell et al., but reference 110 is by K.G. Parhofer. Kingwell et al. is listed as reference 111.

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Authors
März, W., Kleber, M. E., Scharnagl, H., Speer, T., Zewinger, S., Ritsch, A., Parhofer, K. G., von Eckardstein, A., Landmesser, U., & Laufs, U.
Affiliations
  • University of Graz (AT)
  • Heidelberg University (DE)
  • Universitätsklinikum des Saarlandes (DE)
  • Innsbruck Medical University (AT)
  • LMU Klinikum (DE)
  • Stiftung Charité (DE)
Corresponding author
Laufs, Ulrich
ORCID
Venue
Clinical Research in Cardiology
Publisher
Springer Science and Business Media LLC
Published
2017-03-24
Volume
106
Issue
9
Pages
663-675
ISSN
  • 1861-0684 (ISSN-L)
  • 1861-0692
DOI
10.1007/s00392-017-1106-1
PMC
PMC5565659
OpenAlex
W2599772444
Semantic Scholar
b8430363b5f3396a7f3dcaded64be43027f7cf3a
Cited by
275
References
115
Citations by year
2026: 9 · 2025: 20 · 2024: 30 · 2023: 39 · 2022: 34 · 2021: 46 · 2020: 37 · 2019: 34 · 2018: 15 · 2017: 11
FWCI
5.62
Type
journal article
Language
en
Open access
Licence
Locations
  • Clinical Research in Cardiology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, cc-by)
  • Zurich Open Repository and Archive (University of Zurich) (submittedVersion, cc-by)
  • Zurich Open Repository and Archive (University of Zurich)
Topics
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Paraoxonase enzyme and polymorphisms
Keywords
HDL cholesterol, cardiovascular risk, atherosclerosis, HDL particle composition, cholesterol efflux, lifestyle intervention, smoking cessation, physical activity, metabolic disorders, inflammation
MeSH terms
Animals, Cardiovascular Diseases, Humans, Cholesterol, HDL, Cholesterol, LDL, Risk Factors, Atherosclerosis

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