The
n e w e ng l a n d j o u r na l
of
m e dic i n e
c or r e sp ondence
Niacin for Reduction of Cardiovascular Risk
Yearly Absolute Risk Reduction (percentage points)
To the Editor: The lack of benefit for treatment level prior to randomization allowed less scope with niacin and laropiprant that is described in for a treatment that increases this level. This the Heart Protection Study 2–Treatment of HDL 1.4 to Reduce the Incidence of Vascular Events (HSP24S 1 1.2 THRIVE) (July 17 issue) was expected, given the POSCH 1.0 low level of low-density lipoprotein (LDL) cholesHIT CDP Niacin 0.8 terol (63 mg per deciliter) and the normal level of GISSI-P LIPID high-density lipoprotein (HDL) cholesterol (44 mg HPS 0.6 CARE per deciliter) prior to randomization. With statin 0.4 CARDS TNT HPS2IDEAL therapy, a high pretreatment LDL cholesterol level 0.2 THRIVE (190 mg per deciliter) is associated with an abso0.0 lute reduction in the risk of myocardial infarc60 80 100 120 140 160 180 200 tion and death from cardiovascular causes of LDL Cholesterol Level in Control Group (mg/dl) approximately 1.2 percentage points yearly, an intermediate level (120 to 150 mg per deciliter) Figure 1. Absolute Reduction in the Risk of Myocardial with a reduction of approximately 0.6 percentage Infarction or Death from Cardiovascular Causes in Trials points yearly, and a low level (approximately 100 mg of Secondary Prevention with Statin Therapy versus Nonstatin Therapy. per deciliter) with a reduction of approximately The graph shows the yearly absolute reduction in the 0.3 percentage points yearly (Fig. 1).2,3 With nonrisk of myocardial infarction or death from cardiovasstatin therapy (niacin,4 gemfibrozil, fish oil, and cular causes in statin-based secondary prevention partial ileal bypass), the relationship between the (open symbols), as compared with nonstatin-based LDL cholesterol level and the absolute risk reducsecondary prevention (solid symbols), as a function of tion is similar to that observed with statins. The the low-density lipoprotein (LDL) cholesterol level before randomization (specifically the LDL cholesterol absolute risk reduction with niacin–laropiprant level in the control group). Symbols are labeled with in HSP2-THRIVE falls near the regression line for the respective trial acronyms. The LDL cholesterol level statins, suggesting that the results are those exin the Coronary Drug Project (CDP) trial was calculated pected on the basis of the low LDL cholesterol with the assumption that the high-density lipoprotein level prior to randomization. (HDL) cholesterol level was 40 mg per deciliter, since the HDL cholesterol and LDL cholesterol levels were I contend that an LDL cholesterol–lowering not measured. The HPS2-THRIVE trial was added to lipid-based treatment would probably not reduce the previously published figure as a filled circle. To conthe risk of myocardial infarction or death from vert the values for cholesterol to millimoles per liter, cardiovascular causes in the HPS2-THRIVE popmultiply by 0.02586. The abbreviation 4S denotes Scanulation. In addition, the normal HDL cholesterol dinavian Simvastatin Survival Study, CARDS Collaborathis week’s letters 1940 Niacin for Reduction of Cardiovascular Risk 1944 Spread of Artemisinin Resistance in Malaria 1945 Epidemiology of Blunt Head Trauma in Children 1940
n engl j med 371;20
tive Atorvastatin Diabetes Study, CARE Cholesterol and Recurrent Events, GISSI-P Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico–Prevenzione, HIT HDL Intervention Trial, HPS Medical Research Council–British Heart Foundation Heart Protection Study, IDEAL Incremental Decrease in Endpoints through Aggressive Lipid Lowering, LIPID Long-Term Intervention with Pravastatin in Ischemic Disease, POSCH Program on the Surgical Control of the Hyperlipidemias, and TNT Treating to New Targets.
nejm.org
november 13, 2014
The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF GEORGIA on August 10, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
correspondence
trial should have been performed in persons conclude that HDL cholesterol is not an indepenwith a lower HDL cholesterol level, in those with dent cardiovascular risk factor. a higher LDL cholesterol level, in those with Fernando Meneses, M.D. small, dense LDL cholesterol, or in some combi- Jerusalen Clinic nation of these groups. Quito, Ecuador Christopher M. Rembold, M.D. University of Virginia Charlottesville, VA [email protected]
[email protected] No potential conflict of interest relevant to this letter was reported. 1. Lloyd-Jones DM. Niacin and HDL cholesterol — time to face
No potential conflict of interest relevant to this letter was reported. 1. Landray MJ, Haynes R, Hopewell JC, et al. Effects of extended-
release niacin with laropiprant in high-risk patients. N Engl J Med 2014;371:203-12. 2. Rembold CM. To statin or to non-statin in coronary disease — considering absolute risk is the answer. Atherosclerosis 2007; 195:1-6. 3. Rembold CM. To statin or to non-statin in coronary disease — considering absolute risk is the answer. Atherosclerosis 2008; 200:447. 4. Coronary Drug Project Research Group. Clofibrate and niacin in coronary heart disease. JAMA 1975;231:360-81. DOI: 10.1056/NEJMc1411240
facts. N Engl J Med 2014;371:271-3.
2. 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. 3. Camont L, Chapman MJ, Kontush A. Biological activities of HDL subpopulations and their relevance to cardiovascular disease. Trends Mol Med 2011;17:594-603. 4. Camont L, Lhomme M, Rached F, et al. Small, dense highdensity lipoprotein-3 particles are enriched in negatively charged phospholipids: relevance to cellular cholesterol efflux, antioxidative, antithrombotic, anti-inflammatory, and antiapoptotic functionalities. Arterioscler Thromb Vasc Biol 2013;33:2715-23. 5. 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;62:1909-10. DOI: 10.1056/NEJMc1411240
To the Editor: In his editorial on HPS2-THRIVE, Lloyd-Jones questions the hypothesis that the HDL cholesterol level is a causal cardiovascular risk factor, noting that an increase in the plasma levels of HDL cholesterol with various therapies has not resulted in cardiovascular benefit.1 However, the studies on which he bases this conclusion did not quantify subpopulations of patients who have an HDL cholesterol level with demonstrated antiatherogenic properties and did not measure cholesterol efflux capacity. It has been shown that cholesterol efflux capacity from macrophages, a measure of HDL cholesterol function, is independent of the plasma level of HDL cholesterol,2 because only small, dense, protein-rich HDL cholesterol particles appear to show potent atheroprotective properties across the spectrum of subpopulations of patients with various HDL cholesterol levels.3 The atheroprotective activity of HDL cholesterol was strongly interrelated with the subpopulation with HDL3 cholesterol but not with the subpopulation with HDL2 cholesterol.4 Also, in a small, prospective, randomized study that measured plasma levels of HDL cholesterol, cholesterol efflux capacity, and the HDL inflammatory index, the addition of niacin to statin therapy led to favorable changes in the patients’ lipid profiles without a demonstrable effect on HDL cholesterol functionality.5 It is, therefore, premature to
To the Editor: In HPS2-THRIVE, there was a trend toward better outcomes in subgroups with a high baseline LDL cholesterol level (≥58 mg per deciliter) or a high apolipoprotein B level. With niacin, the percentage reduction in the LDL cholesterol level becomes less with low pretreatment levels, whereas statins are associated with a fairly constant percentage reduction over a wide range of baseline levels.1 Data from Hong Kong show no average reduction with niacin in the LDL cholesterol level among patients with a baseline level below approximately 65 mg per deci liter, and some patients had an increase (Fig. 1). Similar relationships were seen for non-HDL cholesterol and apolipoprotein B. Niacin increases the HDL cholesterol level substantially but has modest effects on the apolipoprotein A-I level (mean [±SD] increase of 4.4±9.6% in the Hong Kong study), which may be a better marker of HDL particle functionality than the HDL cholesterol level.2 We might predict that when the benefits of reducing the LDL cholesterol level are lost at low baseline levels, the potential benefit from the small increase in the apolipoprotein A-I level could be offset by adverse effects, such as increased glucose levels. The role of laropiprant in the HPS2-THRIVE outcome is uncertain, but a troublesome exanthematous rash developed in 14% of the Hong Kong Chinese patients who re-
n engl j med 371;20 nejm.org november 13, 2014
The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF GEORGIA on August 10, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
1941
The
n e w e ng l a n d j o u r na l
of
m e dic i n e
Percentage Change in LDL Cholesterol Level
HDL cholesterol level does not affect cardiovascular risk. This opinion is largely based on the reR2 =0.26 sults of HPS2-THRIVE and the Atherothrombosis P
n e w e ng l a n d j o u r na l
of
m e dic i n e
c or r e sp ondence
Niacin for Reduction of Cardiovascular Risk
Yearly Absolute Risk Reduction (percentage points)
To the Editor: The lack of benefit for treatment level prior to randomization allowed less scope with niacin and laropiprant that is described in for a treatment that increases this level. This the Heart Protection Study 2–Treatment of HDL 1.4 to Reduce the Incidence of Vascular Events (HSP24S 1 1.2 THRIVE) (July 17 issue) was expected, given the POSCH 1.0 low level of low-density lipoprotein (LDL) cholesHIT CDP Niacin 0.8 terol (63 mg per deciliter) and the normal level of GISSI-P LIPID high-density lipoprotein (HDL) cholesterol (44 mg HPS 0.6 CARE per deciliter) prior to randomization. With statin 0.4 CARDS TNT HPS2IDEAL therapy, a high pretreatment LDL cholesterol level 0.2 THRIVE (190 mg per deciliter) is associated with an abso0.0 lute reduction in the risk of myocardial infarc60 80 100 120 140 160 180 200 tion and death from cardiovascular causes of LDL Cholesterol Level in Control Group (mg/dl) approximately 1.2 percentage points yearly, an intermediate level (120 to 150 mg per deciliter) Figure 1. Absolute Reduction in the Risk of Myocardial with a reduction of approximately 0.6 percentage Infarction or Death from Cardiovascular Causes in Trials points yearly, and a low level (approximately 100 mg of Secondary Prevention with Statin Therapy versus Nonstatin Therapy. per deciliter) with a reduction of approximately The graph shows the yearly absolute reduction in the 0.3 percentage points yearly (Fig. 1).2,3 With nonrisk of myocardial infarction or death from cardiovasstatin therapy (niacin,4 gemfibrozil, fish oil, and cular causes in statin-based secondary prevention partial ileal bypass), the relationship between the (open symbols), as compared with nonstatin-based LDL cholesterol level and the absolute risk reducsecondary prevention (solid symbols), as a function of tion is similar to that observed with statins. The the low-density lipoprotein (LDL) cholesterol level before randomization (specifically the LDL cholesterol absolute risk reduction with niacin–laropiprant level in the control group). Symbols are labeled with in HSP2-THRIVE falls near the regression line for the respective trial acronyms. The LDL cholesterol level statins, suggesting that the results are those exin the Coronary Drug Project (CDP) trial was calculated pected on the basis of the low LDL cholesterol with the assumption that the high-density lipoprotein level prior to randomization. (HDL) cholesterol level was 40 mg per deciliter, since the HDL cholesterol and LDL cholesterol levels were I contend that an LDL cholesterol–lowering not measured. The HPS2-THRIVE trial was added to lipid-based treatment would probably not reduce the previously published figure as a filled circle. To conthe risk of myocardial infarction or death from vert the values for cholesterol to millimoles per liter, cardiovascular causes in the HPS2-THRIVE popmultiply by 0.02586. The abbreviation 4S denotes Scanulation. In addition, the normal HDL cholesterol dinavian Simvastatin Survival Study, CARDS Collaborathis week’s letters 1940 Niacin for Reduction of Cardiovascular Risk 1944 Spread of Artemisinin Resistance in Malaria 1945 Epidemiology of Blunt Head Trauma in Children 1940
n engl j med 371;20
tive Atorvastatin Diabetes Study, CARE Cholesterol and Recurrent Events, GISSI-P Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico–Prevenzione, HIT HDL Intervention Trial, HPS Medical Research Council–British Heart Foundation Heart Protection Study, IDEAL Incremental Decrease in Endpoints through Aggressive Lipid Lowering, LIPID Long-Term Intervention with Pravastatin in Ischemic Disease, POSCH Program on the Surgical Control of the Hyperlipidemias, and TNT Treating to New Targets.
nejm.org
november 13, 2014
The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF GEORGIA on August 10, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
correspondence
trial should have been performed in persons conclude that HDL cholesterol is not an indepenwith a lower HDL cholesterol level, in those with dent cardiovascular risk factor. a higher LDL cholesterol level, in those with Fernando Meneses, M.D. small, dense LDL cholesterol, or in some combi- Jerusalen Clinic nation of these groups. Quito, Ecuador Christopher M. Rembold, M.D. University of Virginia Charlottesville, VA [email protected]
[email protected] No potential conflict of interest relevant to this letter was reported. 1. Lloyd-Jones DM. Niacin and HDL cholesterol — time to face
No potential conflict of interest relevant to this letter was reported. 1. Landray MJ, Haynes R, Hopewell JC, et al. Effects of extended-
release niacin with laropiprant in high-risk patients. N Engl J Med 2014;371:203-12. 2. Rembold CM. To statin or to non-statin in coronary disease — considering absolute risk is the answer. Atherosclerosis 2007; 195:1-6. 3. Rembold CM. To statin or to non-statin in coronary disease — considering absolute risk is the answer. Atherosclerosis 2008; 200:447. 4. Coronary Drug Project Research Group. Clofibrate and niacin in coronary heart disease. JAMA 1975;231:360-81. DOI: 10.1056/NEJMc1411240
facts. N Engl J Med 2014;371:271-3.
2. 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. 3. Camont L, Chapman MJ, Kontush A. Biological activities of HDL subpopulations and their relevance to cardiovascular disease. Trends Mol Med 2011;17:594-603. 4. Camont L, Lhomme M, Rached F, et al. Small, dense highdensity lipoprotein-3 particles are enriched in negatively charged phospholipids: relevance to cellular cholesterol efflux, antioxidative, antithrombotic, anti-inflammatory, and antiapoptotic functionalities. Arterioscler Thromb Vasc Biol 2013;33:2715-23. 5. 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;62:1909-10. DOI: 10.1056/NEJMc1411240
To the Editor: In his editorial on HPS2-THRIVE, Lloyd-Jones questions the hypothesis that the HDL cholesterol level is a causal cardiovascular risk factor, noting that an increase in the plasma levels of HDL cholesterol with various therapies has not resulted in cardiovascular benefit.1 However, the studies on which he bases this conclusion did not quantify subpopulations of patients who have an HDL cholesterol level with demonstrated antiatherogenic properties and did not measure cholesterol efflux capacity. It has been shown that cholesterol efflux capacity from macrophages, a measure of HDL cholesterol function, is independent of the plasma level of HDL cholesterol,2 because only small, dense, protein-rich HDL cholesterol particles appear to show potent atheroprotective properties across the spectrum of subpopulations of patients with various HDL cholesterol levels.3 The atheroprotective activity of HDL cholesterol was strongly interrelated with the subpopulation with HDL3 cholesterol but not with the subpopulation with HDL2 cholesterol.4 Also, in a small, prospective, randomized study that measured plasma levels of HDL cholesterol, cholesterol efflux capacity, and the HDL inflammatory index, the addition of niacin to statin therapy led to favorable changes in the patients’ lipid profiles without a demonstrable effect on HDL cholesterol functionality.5 It is, therefore, premature to
To the Editor: In HPS2-THRIVE, there was a trend toward better outcomes in subgroups with a high baseline LDL cholesterol level (≥58 mg per deciliter) or a high apolipoprotein B level. With niacin, the percentage reduction in the LDL cholesterol level becomes less with low pretreatment levels, whereas statins are associated with a fairly constant percentage reduction over a wide range of baseline levels.1 Data from Hong Kong show no average reduction with niacin in the LDL cholesterol level among patients with a baseline level below approximately 65 mg per deci liter, and some patients had an increase (Fig. 1). Similar relationships were seen for non-HDL cholesterol and apolipoprotein B. Niacin increases the HDL cholesterol level substantially but has modest effects on the apolipoprotein A-I level (mean [±SD] increase of 4.4±9.6% in the Hong Kong study), which may be a better marker of HDL particle functionality than the HDL cholesterol level.2 We might predict that when the benefits of reducing the LDL cholesterol level are lost at low baseline levels, the potential benefit from the small increase in the apolipoprotein A-I level could be offset by adverse effects, such as increased glucose levels. The role of laropiprant in the HPS2-THRIVE outcome is uncertain, but a troublesome exanthematous rash developed in 14% of the Hong Kong Chinese patients who re-
n engl j med 371;20 nejm.org november 13, 2014
The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF GEORGIA on August 10, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
1941
The
n e w e ng l a n d j o u r na l
of
m e dic i n e
Percentage Change in LDL Cholesterol Level
HDL cholesterol level does not affect cardiovascular risk. This opinion is largely based on the reR2 =0.26 sults of HPS2-THRIVE and the Atherothrombosis P
