Skip to main content
Log in

Clinical and Biological Relevance of Statin-Mediated Changes in HDL Metabolism

  • Statin Drugs (MB Clearfield, Section Editor)
  • Published:
Current Atherosclerosis Reports Aims and scope Submit manuscript

Abstract

Although prospective studies consistently show that individuals with low levels of high-density lipoprotein (HDL) cholesterol are at increased cardiovascular risk, it is still not clear whether or not this relationship still holds in patients treated with statins who have achieved optimal low-density lipoprotein cholesterol levels. Additionally, the hypothesis that statin-mediated increases in HDL cholesterol levels have a impact on cardiovascular risk has not been clearly demonstrated. Statin therapy has little impact on the cholesterol content carried by HDL in the bloodstream (i.e., HDL cholesterol levels), but statins can induce a significant redistribution of HDL particle size, particle concentration, and physicochemical and functional properties. Our objective is to summarize the evidence arising from epidemiological, clinical, and experimental studies that suggests a potential role for statin therapy in the modulation of parameters of HDL metabolism and reverse cholesterol transport.

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. McQueen MJ, Hawken S, Wang X, et al. Lipids, lipoproteins, and apolipoproteins as risk markers of myocardial infarction in 52 countries (the INTERHEART study): a case-control study. Lancet. 2008;372:224–33.

    Article  CAS  PubMed  Google Scholar 

  2. Walldius G, Jungner I, Holme I, Aastveit AH, Kolar W, Steiner E. High apolipoprotein B, low apolipoprotein A-I, and improvement in the prediction of fatal myocardial infarction (AMORIS study): a prospective study. Lancet. 2001;358:2026–33.

    Article  CAS  PubMed  Google Scholar 

  3. Endo A, Kuroda M, Tanzawa K. Competitive inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase by ML-236A and ML-236B fungal metabolites, having hypocholesterolemic activity. FEBS Lett. 1976;72:323–6.

    Article  CAS  PubMed  Google Scholar 

  4. Tamehiro N, Shigemoto-Mogami Y, Kakeya T, et al. Sterol regulatory element-binding protein-2- and liver X receptor-driven dual promoter regulation of hepatic ABC transporter A1 gene expression: mechanism underlying the unique response to cellular cholesterol status. J Biol Chem. 2007;282:21090–9.

    Article  CAS  PubMed  Google Scholar 

  5. Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005;366:1267–78.

    Article  CAS  PubMed  Google Scholar 

  6. Fruchart JC, Sacks F, Hermans MP, et al. The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in patients with dyslipidemia. Am J Cardiol. 2008;102:1K–34K.

    Article  PubMed  Google Scholar 

  7. LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352:1425–35.

    Article  CAS  PubMed  Google Scholar 

  8. Barter P, Gotto AM, LaRosa JC, et al. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med. 2005;357:1301–10.

    Article  Google Scholar 

  9. Nicholls SJ, Tuzcu EM, Sipahi I, et al. Statins, high-density lipoprotein cholesterol, and regression of coronary atherosclerosis. JAMA. 2007;297:499–508.

    Article  CAS  PubMed  Google Scholar 

  10. El Harchaoui K, Arsenault BJ, Franssen R, et al. High-density lipoprotein particle size and concentration and coronary risk. Ann Intern Med. 2009;150:84–93.

    Article  PubMed  Google Scholar 

  11. Mackey RH, Greenland P, Goff Jr DC, Lloyd-Jones D, Sibley CT, Mora S. High-density lipoprotein cholesterol and particle concentrations, carotid atherosclerosis, and coronary events: MESA (Multi-Ethnic Study of Atherosclerosis). J Am Coll Cardiol. 2012;60:508–16.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Parish S, Offer A, Clarke R, et al. Lipids and lipoproteins and risk of different vascular events in the MRC/BHF Heart Protection Study. Circulation. 2012;125:2469–78.

    Article  CAS  PubMed  Google Scholar 

  13. Charlton-Menys V, Betteridge DJ, Colhoun H, et al. Apolipoproteins, cardiovascular risk and statin response in type 2 diabetes: the Collaborative Atorvastatin Diabetes Study (CARDS). Diabetologia. 2009;52:218–25.

    Article  CAS  PubMed  Google Scholar 

  14. Soedamah-Muthu SS, Colhoun HM, Thomason MJ, et al. The effect of atorvastatin on serum lipids, lipoproteins and NMR spectroscopy defined lipoprotein subclasses in type 2 diabetic patients with ischaemic heart disease. Atherosclerosis. 2003;167:243–55.

    Article  CAS  PubMed  Google Scholar 

  15. Ridker PM, Genest J, Boekholdt SM, et al. HDL cholesterol and residual risk of first cardiovascular events after treatment with potent statin therapy: an analysis from the JUPITER trial. Lancet. 2010;376:333–9.

    Article  CAS  PubMed  Google Scholar 

  16. Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359:2195–207.

    Article  CAS  PubMed  Google Scholar 

  17. Boekholdt SM, Arsenault BJ, Mora S, et al. Levels and changes of HDL cholesterol and apolipoprotein A-I in relation to risk of cardiovascular events among statin-treated patients; a meta-analysis. Circulation. 2013;128:1504–12. We have recently published a meta-analysis of individual patient data that included eight landmark statin trials with apoA-I and apoB measurements. We found that even in individuals who achieved very low levels of LDL cholesterol, patients with low levels of HDL cholesterol or low apoA-I levels were at high cardiovascular risk. Investigating the effect of 1-year changes in these parameters and cardiovascular risk, we found that changes in apoA-I levels, but not changes in HDL cholesterol levels, were associated with cardiovascular risk.

  18. Larach DB, de Goma EM, Rader DJ. Targeting high density lipoproteins in the prevention of cardiovascular disease? Curr Cardiol Rep. 2012;14:684–91.

    Article  PubMed Central  PubMed  Google Scholar 

  19. Briel M, Ferreira-Gonzalez I, You JJ, et al. Association between change in high density lipoprotein cholesterol and cardiovascular disease morbidity and mortality: systematic review and meta-regression analysis. BMJ. 2009;338:b92.

    Article  PubMed Central  PubMed  Google Scholar 

  20. Grover SA, Kaouache M, Joseph L, Barter P, Davignon J. Evaluating the incremental benefits of raising high-density lipoprotein cholesterol levels during lipid therapy after adjustment for the reductions in other blood lipid levels. Arch Intern Med. 2009;169:1775–80.

    Article  CAS  PubMed  Google Scholar 

  21. Ray K, Wainwright NW, Visser L, et al. Changes in HDL cholesterol and cardiovascular outcomes after lipid modification therapy. Heart. 2012;98:780–5.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Khera AV, Cuchel M, de la Llera-Moya M, et al. Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. N Engl J Med. 2011;364:127–35. This cross-sectional study showed that cholesterol efflux capacities were associated with the presence of atherosclerosis and coronary artery disease, independently of HDL cholesterol levels.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Li XM, Tang WH, Mosior MK, et al. Paradoxical association of enhanced cholesterol efflux with increased incident cardiovascular risks. Arterioscler Thromb Vasc Biol. 2013;33(7):1696–705. This cross-sectional study also showed that cholesterol efflux capacities were associated with coronary artery disease, independently of HDL cholesterol levels. However, in a second prospective study, it was found that cholesterol efflux capacities were positively associated with cardiovascular risk.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Rader DJ. Molecular regulation of HDL metabolism and function: implications for novel therapies. J Clin Invest. 2006;116:3090–100.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Asztalos BF, de la Llera-Moya M, Dallal GE, Horvath KV, Schaefer EJ, Rothblat GH. Differential effects of HDL subpopulations on cellular ABCA1- and SR-BI-mediated cholesterol efflux. J Lipid Res. 2005;46:2246–53.

    Article  CAS  PubMed  Google Scholar 

  26. Arsenault BJ, Brodeur MR, Rhainds D, et al. Serum from patients with aortic valvular stenosis shows decreased cholesterol efflux capacities despite similar high-density lipoprotein cholesterol levels. Arterioscler Thromb Vasc Biol. 2012;32:A104.

    Article  Google Scholar 

  27. Guerin M, Lassel TS, Le Goff W, Farnier M, Chapman MJ. Action of atorvastatin in combined hyperlipidemia : preferential reduction of cholesteryl ester transfer from HDL to VLDL1 particles. Arterioscler Thromb Vasc Biol. 2000;20:189–97.

    Article  CAS  PubMed  Google Scholar 

  28. Asztalos BF, Le Maulf F, Dallal GE, et al. Comparison of the effects of high doses of rosuvastatin versus atorvastatin on the subpopulations of high-density lipoproteins. Am J Cardiol. 2007;99:681–5.

    Article  CAS  PubMed  Google Scholar 

  29. Asztalos BF, Horvath KV, McNamara JR, Roheim PS, Rubinstein JJ, Schaefer EJ. Effects of atorvastatin on the HDL subpopulation profile of coronary heart disease patients. J Lipid Res. 2002;43:1701–7.

    Article  CAS  PubMed  Google Scholar 

  30. Dallinga-Thie GM, van Tol A, Dullaart RP. Plasma pre beta-HDL formation is decreased by atorvastatin treatment in type 2 diabetes mellitus: role of phospholipid transfer protein. Biochim Biophys Acta. 2009;1791:714–8.

    Article  CAS  PubMed  Google Scholar 

  31. Ansell BJ, Navab M, Hama S, et al. Inflammatory/antiinflammatory properties of high-density lipoprotein distinguish patients from control subjects better than high-density lipoprotein cholesterol levels and are favorably affected by simvastatin treatment. Circulation. 2003;108:2751–6.

    Article  CAS  PubMed  Google Scholar 

  32. Patel PJ, Khera AV, Jafri K, Wilensky RL, Rader DJ. The anti-oxidative capacity of high-density lipoprotein is reduced in acute coronary syndrome but not in stable coronary artery disease. J Am Coll Cardiol. 2011;58:2068–75.

    Article  CAS  PubMed  Google Scholar 

  33. Khera AV, Patel PJ, Reilly MP, Rader DJ. The addition of niacin to statin therapy improves high-density lipoprotein cholesterol levels but not metrics of functionality. J Am Coll Cardiol. 2013;61(10 Suppl):E1390.

    Article  Google Scholar 

  34. Boden WE, Probstfield JL, Anderson T, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011;365:2255–67.

    Article  PubMed  Google Scholar 

  35. HPS2-THRIVE Collaborative Group. HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of ER niacin/laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment. Eur Heart J. 2013;34:1279–91.

    Article  Google Scholar 

  36. Khera AV, Plutzky J. Management of low levels of high-density lipoprotein-cholesterol. Circulation. 2013;128:72–8.

    Article  PubMed  Google Scholar 

  37. Martin G, Duez H, Blanquart C, et al. Statin-induced inhibition of the Rho-signaling pathway activates PPARα and induces HDL apoA-I. J Clin Invest. 2001;107:1423–32.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Boekholdt SM, Arsenault BJ, Mora S, et al. 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. 2012;307:1302–9.

    Article  CAS  PubMed  Google Scholar 

  39. Schaefer EJ, Asztalos BF. The effects of statins on high-density lipoproteins. Curr Atheroscler Rep. 2006;8:41–9.

    Article  CAS  PubMed  Google Scholar 

  40. McTaggart F, Jones P. Effects of statins on high-density lipoproteins: a potential contribution to cardiovascular benefit. Cardiovasc Drugs Ther. 2008;22:321–38.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Karalis IK, Bergheanu SC, Wolterbeek R, et al. Effect of increasing doses of rosuvastatin and atorvastatin on apolipoproteins, enzymes and lipid transfer proteins involved in lipoprotein metabolism and inflammatory parameters. Curr Med Res Opin. 2010;26:2301–13. These authors measured the activity and plasma levels of several enzymes that modulate HDL metabolism and reported that these were highly impacted by statin therapy.

    Article  CAS  PubMed  Google Scholar 

  42. Kuivenhoven JA, Jukema JW, Zwinderman AH, et al. The role of a common variant of the cholesteryl ester transfer protein gene in the progression of coronary atherosclerosis. The Regression Growth Evaluation Statin Study Group. N Engl J Med. 1998;338:86–93.

    Article  CAS  PubMed  Google Scholar 

  43. Boekholdt SM, Sacks FM, Jukema JW, et al. Cholesteryl ester transfer protein TaqIB variant, high-density lipoprotein cholesterol levels, cardiovascular risk, and efficacy of pravastatin treatment: individual patient meta-analysis of 13,677 subjects. Circulation. 2005;111:278–87.

    Article  CAS  PubMed  Google Scholar 

  44. Mauger JF, Couture P, Paradis ME, Lamarche B. Comparison of the impact of atorvastatin and simvastatin on apoA-I kinetics in men. Atherosclerosis. 2005;178:157–63.

    Article  CAS  PubMed  Google Scholar 

  45. Verges B, Florentin E, Baillot-Rudoni S, et al. Rosuvastatin 20 mg restores normal HDL-apoA-I kinetics in type 2 diabetes. J Lipid Res. 2009;50:1209–15.

    Article  CAS  PubMed  Google Scholar 

  46. Bellanger N, Orsoni A, Julia Z, et al. Atheroprotective reverse cholesterol transport pathway is defective in familial hypercholesterolemia. Arterioscler Thromb Vasc Biol. 2011;31:1675–81. Investigating the impact of FH on HDL function, this group found that HDL function was altered in these patients. For instance, the FH patients had HDL particles with impaired cholesterol efflux capacities. Additionally, in hypercholesterolemic mice compared with wild-type mice, reverse cholesterol transport was impaired.

    Article  CAS  PubMed  Google Scholar 

  47. Orsoni A, Villard EF, Bruckert E, et al. Impact of LDL apheresis on atheroprotective reverse cholesterol transport pathway in familial hypercholesterolemia. J Lipid Res. 2012;53:767–75. These investigators found that removal of apoB-containing lipoprotein particles via apheresis significantly improved HDL cholesterol efflux capacities in patients with FH.

    Article  CAS  PubMed  Google Scholar 

  48. Wan H, Gumbiner B, Joh T, Udata C, Forgues P, Garzone PD. Effects of RN316 (PF-04950615), a humanized IgG2Δa monoclonal antibody binding proprotein convertase subtilisin kexin type 9, on lipoprotein particles in hypercholesterolemic subjects. J Am Coll Cardiol. 2013;61(10 Suppl):E1387.

    Article  Google Scholar 

  49. Postmus I, Verschuren JJ, de Craen AJ, et al. Pharmacogenetics of statins: achievements, whole-genome analyses and future perspectives. Pharmacogenomics. 2012;13:831–40.

    Article  CAS  PubMed  Google Scholar 

Download references

Conflict of Interest

Benoit J. Arsenault is a consultant to Pfizer.

S. Matthijs Boekholdt is a consultant to Pfizer.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Benoit J. Arsenault.

Additional information

This article is part of the Topical Collection on Statin Drugs

Rights and permissions

Reprints and permissions

About this article

Cite this article

Arsenault, B.J., Boekholdt, S.M. Clinical and Biological Relevance of Statin-Mediated Changes in HDL Metabolism. Curr Atheroscler Rep 16, 379 (2014). https://doi.org/10.1007/s11883-013-0379-8

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11883-013-0379-8

Keywords

Navigation