Skip to main content
SpringerLink
Log in

Novel Lipids Targets in the Era of Metabolic Syndrome

Toward a Better Prediction of Cardiovascular Risk

  • Review Article
  • Published:
High Blood Pressure & Cardiovascular Prevention Aims and scope Submit manuscript

Abstract

During the last decades, the prevalence of obesity, diabetes mellitus and metabolic syndrome (MetS) has dramatically risen in developed countries. A further increase in MetS and diabetes can be anticipated because of projections of a greater prevalence of obesity in the future. Albeit the cardiovascular (CV) risk in patients with MetS has been considered high, a large proportion of these patients present with normal low-density lipoprotein-cholesterol (LDL-C) levels. Conversely, these patients often display high levels of apolipoprotein B-100 (apoB), triglycerides (TG) and non-high-density lipoprotein-cholesterol (non-HDL-C). Among routine lipoprotein assessment, the use of non-HDL-C has shown several advantages over LDL-C, particularly in the presence of hypertriglyceridaemia. Non-HDL-C is a combined measurement of LDL-C, lipoprotein (a), small dense LDL-C (sd-LDL-C), chilomicron remnants, and intermediate-density lipoproteins. Several studies have shown that non-HDL-C is a strong predictor of subclinical atherosclerosis and CV events as well as a reasonable surrogate of apoB measurement. Moreover, current evidence is supporting that non-HDL-C accurately predicts major CV events even in patients with normal TG values. However, current recommendations suggest non-HDL-C only when TG exceeds 200 mg/dL, recommending the use of LDL-C as the primary target of therapy in all the other conditions. These definitions contrast with the finding of normal LDL-C in obesity, diabetes and MetS, all considered high-risk conditions. Therefore, a redefinition of LDL-C as a predictor of CV events is needed also in the view of an increased prevalence of insulin resistance, abdominal obesity and diabetes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Table I

Similar content being viewed by others

References

  1. Yusuf S, Reddy S, Ounpuu S, et al. Global burden of cardiovascular diseases, part I: general considerations, the epidemiologic transition, risk factors, and impact of urbanization. Circulation 2001; 104: 2746–53

    Article  PubMed  CAS  Google Scholar 

  2. Grundy SM, Cleeman JI, Merz CN, et al., National Heart, Lung, and Blood Institute; American College of Cardiology Foundation; American Heart Association. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004; 110: 227–39

    Article  PubMed  Google Scholar 

  3. Brunzell JD, Davidson M, Furberg CD, et al. Lipoprotein management in patients with cardiometabolic risk: consensus conference report from the American Diabetes Association and the American College of Cardiology Foundation. J Am Coll Cardiol 2008; 51: 1512–24

    Article  PubMed  Google Scholar 

  4. Carr MC, Brunzell JD. Abdominal obesity and dyslipidemia in the metabolic syndrome: importance of type 2 diabetes and familial combined hyperlipidemia in coronary artery disease risk. J Clin Endocrin Metab 2004; 6: 2601–7

    Article  Google Scholar 

  5. Simon A, Chironi G, Gariepy J, et al. Differences between markers of atherogenic lipoproteins in predicting high cardiovascular risk and subclinical atherosclerosis in asymptomatic men. Atherosclerosis 2005; 179: 339–44

    Article  PubMed  CAS  Google Scholar 

  6. Frontini MG, Srinivasan SR, Xu JH, et al. Utility of non-high-density lipoprotein cholesterol versus other lipoprotein measures in detecting subclinical atherosclerosis in young adults (The Bogalusa Heart Study). Am J Cardiol 2007; 100: 64–8

    Article  PubMed  CAS  Google Scholar 

  7. Orakzai SH, Nasir K, Blaha M, et al. Non-HDL cholesterol is strongly associated with coronary artery calcification in asymptomatic individuals. Atherosclerosis 2009; 202: 289–95

    Article  PubMed  CAS  Google Scholar 

  8. Hecht HS, Superko HR, Smith LK, et al. Relation of coronary artery calcium identified by electron beam tomography to serum lipoprotein levels and implications for treatment. Am J Cardiol 2001; 87: 406–12

    Article  PubMed  CAS  Google Scholar 

  9. Sniderman AD, Furberg CD, Keech A, et al. Apolipoproteins versus lipids as indices of coronary risk and as targets for statin treatment. Lancet 2003; 361: 777–80

    Article  PubMed  CAS  Google Scholar 

  10. Sacks FM. The apolipoprotein story. Atheroscler Suppl 2006; 7: 23–7

    Article  PubMed  CAS  Google Scholar 

  11. Wilson PW, Meigs JB, Sullivan L, et al. Prediction of incident diabetes mellitus in middle-aged adults: the Framingham Offspring Study. Arch Intern Med 2007; 167: 1068–74

    Article  PubMed  Google Scholar 

  12. Hossain P, Kawar B, El Nahas M. Obesity and diabetes in the developing world: a growing challenge. N Engl J Med 2007; 356: 213–5

    Article  PubMed  CAS  Google Scholar 

  13. Grundy SM, Howard B, Smith Jr S, et al. Prevention Conference VI: diabetes and cardiovascular disease executive summary — conference proceeding for healthcare professionals from a special writing group of the American Heart Association. Circulation 2002; 105: 2231–9

    Article  PubMed  Google Scholar 

  14. Howard BV, Rodriguez BL, Bennett PH, et al. Prevention Conference VI: diabetes and cardiovascular disease: Writing Group I — epidemiology. Circulation 2002; 105: e132–7

    Article  PubMed  Google Scholar 

  15. Boyle JP, Honeycutt AA, Narayan KM, et al. Projection of diabetes burden through 2050: impact of changing demography and disease prevalence in the US. Diabetes Care 2001; 24: 1936–40

    Article  PubMed  CAS  Google Scholar 

  16. Levitzky YS, Pencina MJ, D’Agostino RB, et al. Impact of impaired fasting glucose on cardiovascular disease: the Framingham Heart Study. J Am Coll Cardiol 2008; 51: 264–70

    Article  PubMed  CAS  Google Scholar 

  17. Gu K, Cowie CC, Harris MI. Diabetes and decline in heart disease mortality in US adults. JAMA 1999; 281: 1291–7

    Article  PubMed  CAS  Google Scholar 

  18. Norhammar A, Malmberg K, Rydén L, et al., Register of Information and Knowledge about Swedish Heart Intensive Care Admission (RIKS-HIA). Under utilisation of evidence-based treatment partially explains for the unfavourable prognosis in diabetic patients with acute myocardial infarction. Eur Heart J 2003; 24: 838–44

    Article  PubMed  Google Scholar 

  19. Franklin K, Goldberg RJ, Spencer F, et al., GRACE Investigators. Implications of diabetes in patients with acute coronary syndromes. The Global Registry of Acute Coronary Events. Arch Intern Med 2004; 164: 1457–63

    Article  PubMed  Google Scholar 

  20. Hasdai D, Behar S, Wallentin L, et al. A prospective survey of the characteristics, treatments and outcomes of patients with acute coronary syndromes in Europe and the Mediterranean basin; the Euro Heart Survey of Acute Coronary Syndromes (Euro Heart Survey SCA). Eur Heart J 2002; 23: 1190–201

    Article  PubMed  CAS  Google Scholar 

  21. Malmberg K, Yusuf S, Gerstein Hc, et al. Impact of diabetes on long-term prognosis in patients with unstable angina and non-Q-wave myocardial infarction: results of the OASIS (Organization to Assess Strategies for Ischemic Syndromes) Registry. Circulation 2000; 102: 1014–9

    Article  PubMed  CAS  Google Scholar 

  22. Grundy SM, Cleeman JI, Daniels SR, et al., American Heart Association; National Heart, Lung, and Blood Institute. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 2005; 112: 2735–52

    Article  PubMed  Google Scholar 

  23. Ford ES, Giles WH, Dietz WH. Prevalence of the MetS among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 2002; 287: 356–9

    Article  PubMed  Google Scholar 

  24. Grundy SM. Metabolic syndrome: a multiplex cardiovascular risk factor. J Clin Endocrinol Metab 2007; 92: 399–404

    Article  PubMed  CAS  Google Scholar 

  25. Park YW, Zhu S, Palaniappan L, et al. The MetS: prevalence and associated risk factor findings in the US population from the Third National Health and Nutrition Examination Survey, 1988–1994. Arch Intern Med 2003; 163: 427–36

    Article  PubMed  Google Scholar 

  26. Lakka HM, Lakka TA, Tuomilehto J, et al. Abdominal obesity is associated with increased risk of acute coronary events in men. Eur Heart J 2002; 23: 706–13

    Article  PubMed  Google Scholar 

  27. Ingelsson E, Sullivan LM, Murabito JM, et al. Prevalence and prognostic impact of subclinical cardiovascular disease in individuals with the metabolic syndrome and diabetes. Diabetes 2007; 56: 1718–26

    Article  PubMed  CAS  Google Scholar 

  28. Gami AS, Witt BJ, Howard DE, et al. Metabolic syndrome and risk of incident cardiovascular events and death: a systematic review and meta-analysis of longitudinal studies. J Am Coll Cardiol 2007; 49: 403–14

    Article  PubMed  CAS  Google Scholar 

  29. Barr EL, Zimmet PZ, Welborn TA, et al. Risk of cardiovascular and all-cause mortality in individuals with diabetes mellitus, impaired fasting glucose, and impaired glucose tolerance: the Australian Diabetes, Obesity, and Lifestyle Study (AusDiab). Circulation 2007; 116: 151–7

    Article  PubMed  CAS  Google Scholar 

  30. Kahn SE, Hull RL, Utzschneider KM. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 2006; 444: 840–6

    Article  PubMed  CAS  Google Scholar 

  31. Goldstein BJ. Insulin resistance: from benign to type 2 diabetes mellitus. Rev Cardiovasc Med 2003; 4Suppl. 6: S3–10

    PubMed  Google Scholar 

  32. Pou KM, Massaro JM, Hoffmann U, et al. Patterns of abdominal fat distribution: the Framingham Heart Study. Diabetes Care 2009; 32(3): 481–5

    Article  PubMed  Google Scholar 

  33. Fox CS, Massaro JM, Hoffmann U, et al. Abdominal visceral and subcutaneous adipose tissue compartments: association with metabolic risk factors in the Framingham Heart Study. Circulation 2007; 116: 39–48

    Article  PubMed  Google Scholar 

  34. Austin MA, Breslow JL, Hennekens CH, et al. Low-density lipoprotein subclass patterns and risk of myocardial infarction. JAMA 1988; 260: 1917–21

    Article  PubMed  CAS  Google Scholar 

  35. Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet 2005; 365: 1415–28

    Article  PubMed  CAS  Google Scholar 

  36. Bloomgarden ZT. Dyslipidemia and the metabolic syndrome. Diabetes Care 2004; 27: 3009–16

    Article  PubMed  Google Scholar 

  37. Ginsberg HN, Huang LS. The insulin resistance syndrome: impact on lipoprotein metabolism and atherothrombosis. J Cardiovasc Risk 2000; 7: 325–31

    PubMed  CAS  Google Scholar 

  38. Kolovou GD, Anagnostopoulou K, Pilatis ND, et al. Fasting serum triglyceride and high-density lipoprotein cholesterol levels in patients intended to be treated for dyslipidemia. Vasc Health Risk Manag 2005; 1: 155–61

    Article  PubMed  CAS  Google Scholar 

  39. Chait A, Brazg RL, Tribble DL, et al. Susceptibility of small, dense, low-density lipoproteins to oxidative modification in subjects with the atherogenic lipoprotein phenotype, pattern B. Am J Med 1993; 94: 350–6

    Article  PubMed  CAS  Google Scholar 

  40. Chapman MJ, Guérin M, Bruckert E. Atherogenic, dense low-density lipoproteins: pathophysiology and new therapeutic approaches. Eur Heart J 1998; 19Suppl. A: A24–30

    PubMed  CAS  Google Scholar 

  41. Tribble DL, Holl LG, Wood PD, et al. Variations in oxidative susceptibility among six low density lipoprotein subfractions of differing density and particle size. Atherosclerosis 1992; 93: 189–99

    Article  PubMed  CAS  Google Scholar 

  42. De Graaf J, Hak-Lemmers HL, Hectors MP, et al. Enhanced susceptibility to in vitro oxidation of the dense low density lipoprotein subfraction in healthy subjects. Arterioscler Thromb 1991; 11: 298–306

    Article  PubMed  Google Scholar 

  43. Alexander CM. The coming of age of the metabolic syndrome. Diabetes Care 2003; 26: 3180–1

    Article  PubMed  Google Scholar 

  44. St-Pierre AC, Cantin B, Dagenais GR, et al. Apolipoprotein-B, low-density lipoprotein cholesterol, and the long-term risk of coronary heart disease in men. Am J Cardiol 2006; 97: 997–1001

    Article  PubMed  CAS  Google Scholar 

  45. Sniderman AD. Apolipoprotein B versus non-high-density lipoprotein cholesterol: and the winner is... Circulation 2005; 112: 3366–7

    Article  PubMed  Google Scholar 

  46. Denke MA. Weighing in before the fight: low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol versus apolipoprotein B as the best predictor for coronary heart disease and the best measure of therapy. Circulation 2005; 112: 3368–70

    Article  PubMed  Google Scholar 

  47. Sniderman AD. Non-HDL cholesterol versus apolipoprotein B in diabetic dyslipoproteinemia: alternatives and surrogates versus the real thing. Diabetes Care 2003; 26: 2207–8

    Article  PubMed  Google Scholar 

  48. Bittner V, Hardison R, Kelsey SF, et al. Non-high-density lipoprotein cholesterol levels predict five-year outcome in the Bypass Angioplasty Revascularization Investigation (BARI).; Bypass Angioplasty Revascularization Investigation. Circulation 2002 Nov 12; 106(20): 2537–42

    Article  PubMed  CAS  Google Scholar 

  49. Jiang R, Schulze MB, Li T, et al. Non-HDL cholesterol and apolipoprotein B predict cardiovascular disease events among men with type 2 diabetes. Diabetes Care 2004; 27: 1991–7

    Article  PubMed  CAS  Google Scholar 

  50. Liu J, Sempos C, Donahue RP, et al. Joint distribution of non-HDL and LDL cholesterol and coronary heart disease risk prediction among individuals with and without diabetes. Diabetes Care 2005; 28: 1916–21

    Article  PubMed  Google Scholar 

  51. Ridker PM, Rifai N, Cook NR, et al. Non-HDL cholesterol, apolipoproteins A-I and B100, standard lipid measures, lipid ratios, and CRP as risk factors for cardiovascular disease in women. JAMA 2005; 294: 326–33

    Article  PubMed  CAS  Google Scholar 

  52. Liu J, Sempos CT, Donahue RP, et al. Non-high-density lipoprotein and very-low-density lipoprotein cholesterol and their risk predictive values in coronary heart disease. Am J Cardiol 2006; 98: 1363–8

    Article  PubMed  CAS  Google Scholar 

  53. Cui Y, Blumenthal RS, Flaws JA, et al. Non-high-density lipoprotein cholesterol level as a predictor of cardiovascular disease mortality. Arch Intern Med 2001; 161: 1413–9

    Article  PubMed  CAS  Google Scholar 

  54. Chien KL, Hsu HC, Su TC, et al. Apolipoprotein B and non-high density lipoprotein cholesterol and the risk of coronary heart disease in Chinese. J Lipid Res 2007; 48: 2499–505

    Article  PubMed  CAS  Google Scholar 

  55. Lu W, Resnick HE, Jablonski KA, et al. Non-HDL cholesterol as a predictor of cardiovascular disease in type 2 diabetes: the strong heart study. Diabetes Care 2003; 26: 16–23

    Article  PubMed  Google Scholar 

  56. Pischon T, Girman CJ, Sacks FM, et al. Non-high-density lipoprotein cholesterol and apolipoprotein B in the prediction of coronary heart disease in men. Circulation 2005; 112: 3375–83

    Article  PubMed  CAS  Google Scholar 

  57. Ingelsson E, Schaefer EJ, Contois JH, et al. Clinical utility of different lipid measures for prediction of coronary heart disease in men and women. JAMA 2007; 298: 776–85

    Article  PubMed  CAS  Google Scholar 

  58. Robinson JG, Wang S, Smith BJ, et al. Meta-analysis of the relationship between non-high-density lipoprotein cholesterol reduction and coronary heart disease risk. J Am Coll Cardiol 2009; 53: 316–22

    Article  PubMed  CAS  Google Scholar 

  59. Shepherd J. Does statin monotherapy address the multiple lipid abnormalities in type 2 diabetes? Atheroscler Suppl 2005; 6: 15–9

    Article  PubMed  CAS  Google Scholar 

  60. Brunzell JD. Clinical practice: hypertriglyceridemia. N Engl J Med 2007 Sep 6; 357(10): 1009–17

    Article  PubMed  CAS  Google Scholar 

  61. Grundy SM. Low-density lipoprotein, non-high-density lipoprotein, and apolipoprotein B as targets of lipid-lowering therapy. Circulation 2002; 106: 2526–9

    Article  PubMed  Google Scholar 

  62. Ballantyne CM, Raichlen JS, Cain VA. Statin therapy alters the relationship between apolipoprotein B and low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol targets in high-risk patients: the MERCURY II (Measuring Effective Reductions in Cholesterol Using Rosuvastatin) trial. J Am Coll Cardiol 2008; 52: 626–32

    Article  PubMed  CAS  Google Scholar 

  63. Pedersen TR, Olsson AG, Faergeman O, et al. Lipoprotein changes and reduction in the incidence of major coronary heart disease events in the Scandinavian Simvastatin Survival Study (4S). Circulation 1998; 97: 1453–60

    Article  PubMed  CAS  Google Scholar 

  64. Athyros VG, Papageorgiou AA, Symeonidis AN, et al. Non-high density lipoprotein cholesterol and coronary events during long-term statin treatment. Atherosclerosis 2003; 168: 397–8

    Article  PubMed  CAS  Google Scholar 

  65. Holme I, Cater NB, Faergeman O, et al. Lipoprotein predictors of cardiovascular events in statin-treated patients with coronary heart disease. insights from the incremental decrease in end-points through aggressive lipid-lowering trial (IDEAL). Lipid-Lowering Study Group. Ann Med 2008; 40: 456–64

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

No sources of funding were used to assist in the preparation of this review. The authors have no conflicts of interest that are directly relevant to the content of this review.

Author information

Authors and Affiliations

  1. Division of Cardiology, II Faculty of Medicine, University of Rome “Sapienza”, Sant’Andrea Hospital, Via di Grottarossa 1039, 00189, Rome, Italy

    Francesco Paneni, Francesca Palano & Marco Testa

Authors
  1. Francesco Paneni
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Francesca Palano
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marco Testa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Francesco Paneni.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Paneni, F., Palano, F. & Testa, M. Novel Lipids Targets in the Era of Metabolic Syndrome. High Blood Press Cardiovasc Prev 16, 93–100 (2009). https://doi.org/10.2165/11316980-000000000-00000

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/11316980-000000000-00000

Keywords

Search

Navigation