Response Letter
Low-Density Lipoprotein Cholesterol Targeting: A Continued Controversy
Angiology 2014, Vol. 65(3) 263-264 ª The Author(s) 2013 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0003319713508641 ang.sagepub.com
Thomas F. Whayne Jr, MD, PhD1
I thank Drs Joven, Martin-Paredero, and Camps1 for their commentary regarding my article on the assessment of low-density lipoprotein cholesterol (LDL-C) targets.2 Such controversy directed at our continuing efforts to deliver improving patient care is good. To respond, there appears to be excellent supporting evidence for LDL-C lowering as a target including the Lipid Research Clinic (LRC) study, which first established the lipid hypothesis,3,4 the quantitative coronary angiography work of Blankenhorn et al in the Cholesterol Lowering Atherosclerosis Study (CLAS),5-7 the Program on the Surgical Control of the Hyperlipidemias (POSCH) ileal bypass study of Buchwald et al,8,9 the LDL-Apheresis Atherosclerosis Regression Study (LAARS) of Kroon et al,10 and data on hypobetalipoproteinemia showing an association with reduced cardiovascular (CV) risk.11 The LRC study involved cholestyramine which has no significant CV effects other than LDL-C reduction as is the case with the colestipol used in CLAS with some additional effects from the nicotinic acid used. The POSCH study has only the ileal bypass involved in LDL-C reduction, and LAARS shows additional CV advantage for LDL-C apheresis over and above the simvastatin given. Hypobetalipoproteinemia involves only a very low LDL-C. Then, there are more recent statin studies such as the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE-IT-TIMI 22),12 the Greek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) study,13 the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) study subgroup,14 which add support to the concept that a lower LDL-C is better as well as multiple other studies that confirm LDL-C lowering as beneficial in medical management and therefore, unavoidably, a therapeutic target. Many clinicians have still not come on board regarding the possibility of CV risk reduction and there are many who have barely accepted the usefulness of LDL-C reduction. Indeed, LDL-C reduction has excellent evidence behind it and is useful even with some measurement imperfections such as those pointed out by Joven et al1 as well as their critique of it as a surrogate marker. Some major new medications are specifically directed at major LDL-C reductions and will offer further evaluation of the issue as phase 3 clinical trial evidence becomes available.15 Of course, LDL-C as a target or anything else available is not limiting or anywhere near the ultimate answer to modifying
CV risk. An example is the Scandinavian Simvastatin Survival Study (4S) in which the use of simvastatin resulted in a 38% to 42% reduction in the occurrence of major coronary events at low to high predicted risk, respectively.16 Despite the LDL-C lowering and other beneficial pleiotropic effects of simvastatin, the remaining unattained but desired further 58% to 62% CV risk reduction emphasizes the other factors that must be considered and the work remaining to be accomplished to more favorably modify CV risk. As pointed out by Joven et al, there are other lipoprotein disturbances with some demonstrating additional statin benefit.1 Such multiple other factors also include attention to quantity and quality such as with the LDL-C subclasses,17 the still poorly understood complexities (some of which are harmful) of high-density lipoprotein cholesterol (HDL-C),18,19 triglycerides,20 high-sensitivity C-reactive protein,21 the metabolic syndrome,22 and other yet-to-be defined factors that are the future of CV risk reduction. However, for now, LDL-C targeting has a place, the status of which the sophisticated clinician must constantly evaluate and assess, as Joven et al1 appropriately emphasized. References 1. Joven J, Martin-Paredero V, Camps J. Treat-to-target low-density lipoprotein cholesterol: time to debate a too simple and dogmatic paradigm. Angiology. 2013. 2. Whayne TF Jr. Assessment of low-density lipoprotein targets. Angiology. 2013;64(6):411-416. 3. The lipid research clinics coronary primary prevention trial results. I. Reduction in incidence of coronary heart disease. JAMA. 1984;251(3):351-364. 4. The lipid research clinics coronary primary prevention trial results. II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. JAMA. 1984;251(3):365-374.
1
Division of Cardiovascular Medicine, Gill Heart Institute, University of Kentucky, Lexington, KY, USA
Corresponding Author: Thomas F. Whayne Jr, Division of Cardiovascular Medicine, Gill Heart Institute, University of Kentucky, 326 Wethington Building, 900 South Limestone Street, Lexington, KY 40536, USA. Email: [email protected]
Downloaded from ang.sagepub.com at University of New England on June 2, 2015
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Angiology 65(3)
5. Blankenhorn DH, Johnson RL, Nessim SA, Azen SP, Sanmarco ME, Selzer RH. The Cholesterol Lowering Atherosclerosis Study (CLAS): design, methods, and baseline results. Control Clin Trials. 1987;8(4):356-387. 6. Blankenhorn DH, Nessim SA, Johnson RL, Sanmarco ME, Azen SP, Cashin-Hemphill L. Beneficial effects of combined colestipol-niacin therapy on coronary atherosclerosis and coronary venous bypass grafts. JAMA. 1987;257(23):3233-3240. 7. Blankenhorn DH, Selzer RH, Mack WJ, et al. Evaluation of colestipol/niacin therapy with computer-derived coronary end point measures. A comparison of different measures of treatment effect. Circulation. 1992;86(6):1701-1709. 8. Buchwald H, Stoller DK, Campos CT, Matts JP, Varco RL. Partial ileal bypass for hypercholesterolemia. 20- to 26-year followup of the first 57 consecutive cases. Ann Surg. 1990;212(3): 318-329; discussion 329-331. 9. Buchwald H, Varco RL, Boen JR, et al. Effective lipid modification by partial ileal bypass reduced long-term coronary heart disease mortality and morbidity: five-year posttrial follow-up report from the POSCH. Program on the Surgical Control of the Hyperlipidemias. Arch Intern Med. 1998;158(11):1253-1261. 10. Kroon AA, Aengevaeren WR, van der Werf T, et al. LDLApheresis Atherosclerosis Regression Study (LAARS). Effect of aggressive versus conventional lipid lowering treatment on coronary atherosclerosis. Circulation. 1996;93(10):1826-1835. 11. Schonfeld G. The hypobetalipoproteinemias. Annu Rev Nutr. 1995;15:23-34. 12. Wiviott SD, Cannon CP, Morrow DA, Ray KK, Pfeffer MA, Braunwald E. Can low-density lipoprotein be too low? The safety and efficacy of achieving very low low-density lipoprotein with intensive statin therapy: a PROVE IT-TIMI 22 substudy. J Am Coll Cardiol. 2005;46(8):1411-1416. 13. Athyros VG, Papageorgiou AA, Mercouris BR, et al. Treatment with atorvastatin to the National Cholesterol Educational Program goal versus ‘usual’ care in secondary coronary heart disease prevention. The GREek Atorvastatin and Coronary-heart-disease
14.
15. 16.
17.
18.
19.
20.
21.
22.
Evaluation (GREACE) study. Curr Med Res Opin. 2002;18(4): 220-228. Hsia J, MacFadyen JG, Monyak J, Ridker PM. Cardiovascular event reduction and adverse events among subjects attaining low-density lipoprotein cholesterol
Low-Density Lipoprotein Cholesterol Targeting: A Continued Controversy
Angiology 2014, Vol. 65(3) 263-264 ª The Author(s) 2013 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0003319713508641 ang.sagepub.com
Thomas F. Whayne Jr, MD, PhD1
I thank Drs Joven, Martin-Paredero, and Camps1 for their commentary regarding my article on the assessment of low-density lipoprotein cholesterol (LDL-C) targets.2 Such controversy directed at our continuing efforts to deliver improving patient care is good. To respond, there appears to be excellent supporting evidence for LDL-C lowering as a target including the Lipid Research Clinic (LRC) study, which first established the lipid hypothesis,3,4 the quantitative coronary angiography work of Blankenhorn et al in the Cholesterol Lowering Atherosclerosis Study (CLAS),5-7 the Program on the Surgical Control of the Hyperlipidemias (POSCH) ileal bypass study of Buchwald et al,8,9 the LDL-Apheresis Atherosclerosis Regression Study (LAARS) of Kroon et al,10 and data on hypobetalipoproteinemia showing an association with reduced cardiovascular (CV) risk.11 The LRC study involved cholestyramine which has no significant CV effects other than LDL-C reduction as is the case with the colestipol used in CLAS with some additional effects from the nicotinic acid used. The POSCH study has only the ileal bypass involved in LDL-C reduction, and LAARS shows additional CV advantage for LDL-C apheresis over and above the simvastatin given. Hypobetalipoproteinemia involves only a very low LDL-C. Then, there are more recent statin studies such as the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE-IT-TIMI 22),12 the Greek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) study,13 the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) study subgroup,14 which add support to the concept that a lower LDL-C is better as well as multiple other studies that confirm LDL-C lowering as beneficial in medical management and therefore, unavoidably, a therapeutic target. Many clinicians have still not come on board regarding the possibility of CV risk reduction and there are many who have barely accepted the usefulness of LDL-C reduction. Indeed, LDL-C reduction has excellent evidence behind it and is useful even with some measurement imperfections such as those pointed out by Joven et al1 as well as their critique of it as a surrogate marker. Some major new medications are specifically directed at major LDL-C reductions and will offer further evaluation of the issue as phase 3 clinical trial evidence becomes available.15 Of course, LDL-C as a target or anything else available is not limiting or anywhere near the ultimate answer to modifying
CV risk. An example is the Scandinavian Simvastatin Survival Study (4S) in which the use of simvastatin resulted in a 38% to 42% reduction in the occurrence of major coronary events at low to high predicted risk, respectively.16 Despite the LDL-C lowering and other beneficial pleiotropic effects of simvastatin, the remaining unattained but desired further 58% to 62% CV risk reduction emphasizes the other factors that must be considered and the work remaining to be accomplished to more favorably modify CV risk. As pointed out by Joven et al, there are other lipoprotein disturbances with some demonstrating additional statin benefit.1 Such multiple other factors also include attention to quantity and quality such as with the LDL-C subclasses,17 the still poorly understood complexities (some of which are harmful) of high-density lipoprotein cholesterol (HDL-C),18,19 triglycerides,20 high-sensitivity C-reactive protein,21 the metabolic syndrome,22 and other yet-to-be defined factors that are the future of CV risk reduction. However, for now, LDL-C targeting has a place, the status of which the sophisticated clinician must constantly evaluate and assess, as Joven et al1 appropriately emphasized. References 1. Joven J, Martin-Paredero V, Camps J. Treat-to-target low-density lipoprotein cholesterol: time to debate a too simple and dogmatic paradigm. Angiology. 2013. 2. Whayne TF Jr. Assessment of low-density lipoprotein targets. Angiology. 2013;64(6):411-416. 3. The lipid research clinics coronary primary prevention trial results. I. Reduction in incidence of coronary heart disease. JAMA. 1984;251(3):351-364. 4. The lipid research clinics coronary primary prevention trial results. II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. JAMA. 1984;251(3):365-374.
1
Division of Cardiovascular Medicine, Gill Heart Institute, University of Kentucky, Lexington, KY, USA
Corresponding Author: Thomas F. Whayne Jr, Division of Cardiovascular Medicine, Gill Heart Institute, University of Kentucky, 326 Wethington Building, 900 South Limestone Street, Lexington, KY 40536, USA. Email: [email protected]
Downloaded from ang.sagepub.com at University of New England on June 2, 2015
264
Angiology 65(3)
5. Blankenhorn DH, Johnson RL, Nessim SA, Azen SP, Sanmarco ME, Selzer RH. The Cholesterol Lowering Atherosclerosis Study (CLAS): design, methods, and baseline results. Control Clin Trials. 1987;8(4):356-387. 6. Blankenhorn DH, Nessim SA, Johnson RL, Sanmarco ME, Azen SP, Cashin-Hemphill L. Beneficial effects of combined colestipol-niacin therapy on coronary atherosclerosis and coronary venous bypass grafts. JAMA. 1987;257(23):3233-3240. 7. Blankenhorn DH, Selzer RH, Mack WJ, et al. Evaluation of colestipol/niacin therapy with computer-derived coronary end point measures. A comparison of different measures of treatment effect. Circulation. 1992;86(6):1701-1709. 8. Buchwald H, Stoller DK, Campos CT, Matts JP, Varco RL. Partial ileal bypass for hypercholesterolemia. 20- to 26-year followup of the first 57 consecutive cases. Ann Surg. 1990;212(3): 318-329; discussion 329-331. 9. Buchwald H, Varco RL, Boen JR, et al. Effective lipid modification by partial ileal bypass reduced long-term coronary heart disease mortality and morbidity: five-year posttrial follow-up report from the POSCH. Program on the Surgical Control of the Hyperlipidemias. Arch Intern Med. 1998;158(11):1253-1261. 10. Kroon AA, Aengevaeren WR, van der Werf T, et al. LDLApheresis Atherosclerosis Regression Study (LAARS). Effect of aggressive versus conventional lipid lowering treatment on coronary atherosclerosis. Circulation. 1996;93(10):1826-1835. 11. Schonfeld G. The hypobetalipoproteinemias. Annu Rev Nutr. 1995;15:23-34. 12. Wiviott SD, Cannon CP, Morrow DA, Ray KK, Pfeffer MA, Braunwald E. Can low-density lipoprotein be too low? The safety and efficacy of achieving very low low-density lipoprotein with intensive statin therapy: a PROVE IT-TIMI 22 substudy. J Am Coll Cardiol. 2005;46(8):1411-1416. 13. Athyros VG, Papageorgiou AA, Mercouris BR, et al. Treatment with atorvastatin to the National Cholesterol Educational Program goal versus ‘usual’ care in secondary coronary heart disease prevention. The GREek Atorvastatin and Coronary-heart-disease
14.
15. 16.
17.
18.
19.
20.
21.
22.
Evaluation (GREACE) study. Curr Med Res Opin. 2002;18(4): 220-228. Hsia J, MacFadyen JG, Monyak J, Ridker PM. Cardiovascular event reduction and adverse events among subjects attaining low-density lipoprotein cholesterol
