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Statins and metabolic syndrome
International Congress Series 1253 (2003) 243 – 246
Statins and metabolic syndrome Maurizio Averna *, Alessia Lo Verde Dipartimento di Medicina Clinica e delle Patologie Emergenti, University of Palermo, Policlinico ‘‘Paolo Giaccone’’ Via del Vespro 141, 90127 Palermo, Italy Received 29 April 2003; accepted 29 April 2003
Abstract Metabolic syndrome (MS) is a multifactorial condition that represents a risk factor for the development of diabetes mellitus (DMII) and cardiovascular disease (CVD). Statins may play a role on some modifiable clinical features of MS; in fact, whereas therapeutic lifestyle changes are mandatory for MS with a 10-year coronary heart disease (CHD) risk < 20%, statins are recommended to reach the LDL-C goal in MS with a 10-year CHD risk >20% and to correct the other associated lipid and non-lipid abnormalities. In fact, they have a VLDL lowering action in hypertriglyceridemia, they reduce the amount of small and dense LDL, they increase the HDL-C, they reduce the atherogenic lipoproteins, and they decrease the inflammatory marker levels. D 2003 Elsevier Science B.V. All rights reserved. Keywords: Metabolic syndrome; Statins; Cardiovascular risk; Rosuvastatin
This report will focus on (1) definition of the role of metabolic syndrome (MS) as risk factor for the development of diabetes mellitus (DMII) and cardiovascular disease (CVD), (2) individuation of the MS features modifiable by the statins, and (3) evaluation of the indications to the use of these drugs to prevent the damages and the complications following MS. MS is a disorder with a heavy epidemiological impact, as shown by the data of the study NAHNES III, a large retrospective survey which performed an analysis of the prevalence of MS among 8814 US adults during 20 years, from 1988 to 1994 [1]. This study also demonstrates how MS has a different prevalence by age, arising in the fourth to fifth decade and especially over the 60th year of age and reaching a prevalence of about 45% in the adult decades of life. * Corresponding author. Tel.: +39-91-6552993; fax: +39-91-6552936. E-mail address: [email protected] (M. Averna). 0531-5131/03 D 2003 Elsevier Science B.V. All rights reserved. doi:10.1016/S0531-5131(03)00821-5
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M. Averna, A. Lo Verde / International Congress Series 1253 (2003) 243–246
Many studies demonstrated the relation existing between the presence and the degree of severity of the MS and the incidence of pathologically relevant conditions consequent to an impairment of the circulatory system. According to the Framingham Scoring Scheme 1, which sorts the patients with MS in three different classes of severity, the incidence of cardiovascular complications shows a direct proportional correlation with the severity of the illness, with the most affected patients presenting the higher 10-year risk to develop coronary heart disease (CHD) [2]. An additional demonstration of the causal role of MS in determining cardiovascular complications is suggested by the Framingham Offspring Study, an observational study in which 3374 individuals were investigated during 8 years for the onset of CVD, CHD, and DMII [3]. The group of patients, which at the beginning of the study had at least three features of MS (see the NCEP ATP III definition below), showed a heavily increased risk to develop the clinical events. The definition of MS, on the basis of NCEP ATP III, is the presence of at least three of the following criteria:
abdominal obesity (>102 cm for men, >88 cm for women); plasma triglyceride z 150 mg/dl (1.7 mmol/l); HDL cholesterol < 40 mg/dl (1.0 mmol/l) for men, < 50 mg/dl (1.3 mmol/l) for women; BP >130/ z 85 mm Hg; fasting glucose z 110 mg/dl (6.1 mmol/l).
Thus, the MS represent a multifactorial condition in which coexisted an impairment of insulin sensitivity, an altered lipoprotein profile, and a pro-inflammatory state that lead to the complication abovementioned. Some of these features are modifiable by changes in lifestyle, nutritional intervention, or drugs, and in particular, statins today seem to play an important role in the management of the metabolic abnormalities that we observe in the MS. In fact, the study of the nutritional aspects of the MS has shown a central position of the cholesterol-absorptive pathway as a new component of the syndrome [4]. It seems that we can individuate a class of subjects, the low cholesterol absorbers, which have a reduced cholestanol/cholesterol ratio and are also high cholesterol producers, having a high lathosterol/cholesterol ratio. This condition results in a low cholesterol absorption, and this status is associated to a rise in BMI and insulin resistance (IR) and to the development of a lipoprotein profile characterized by high levels of triglycerides and low levels of HDL-C; this profile (Atherogenic Lipoprotein Phenotype, ALP) is known to be highly responsible of the atherogenesis into the arterial wall and is statistically correlated to a major onset of cardiovascular and cerebrovascular diseases [5]. In addition to these quantitative modifications in circulating serum levels, the alterations of the lipoproteins in the ALP is characterized by qualitative changes in size and density, with the production of small dense LDL and the accumulation of remnants of VLDLs and chylomicrons, both highly atherogenic. The data about the non-lipid features associated with MS, such as the pro-inflammatory state, measured by circulating C-reactive protein (C-RP) levels, and insulin resistance also demonstrated a strong independent correlation with an increased risk of CVD. C-RP levels
M. Averna, A. Lo Verde / International Congress Series 1253 (2003) 243–246
245
show a significant independent association with all the clinical features of MS [6], and insulin levels are known to be directly associated with increased risk of CAD. The complexity of the MS and the deep interrelations existing between its clinical features represent a critical node for delineating a preventive strategy in order to reduce the high metabolic and cardiovascular risk of these patient. In this field, statins are considered as the first-choice drugs in the hands of physicians within a multifactorial approach that includes, as mentioned above, nutritional and behavioural interventions. Statins have an evident lowering effect on the triglyceride levels, which are usually elevated in MS [7]. Atorvastatin and the new statin, rosuvastatin, show the stronger triglyceride lowering effect [8,9]. Their efficacy may reach, at the highest dosages, almost 50% of reduction, but is already present and relevant at lower dosages. The reduction in triglyceride plasma levels in VLDLs also modify the interactions with the LDL receptor which mediates the reuptake mechanism, resulting in favourable changes in the whole lipid balance with a reduction of many atherogenic particles, such as chylomicrons and VLDL remnants, and a shift through a less dangerous pattern of circulating lipids [10]. The triglyceride lowering effect is demonstrated to be rapid and safe, and it should be considered in the case of failure to achieve a satisfactory correction by diet or lifestyle changes in high-risk patients, in which a more aggressive approach is indicated. Guidelines indicate that a secondary target of the therapy of MS is the reduction of the so-called non-HDL cholesterol; this lipoprotein fraction is represented by the LDL and the VLDL particles and is calculated as TC-HDL-C; the therapeutic goal to be reached in the case of elevated serum triglyceridemia (>200 mg/dl) has been fixed as LDL-C goal + 30 mg/dl. Most of the statins demonstrate a good efficacy on this parameter, with a reduction that average 20– 30% and almost 40% for atorvastatin. In addition to this, statins have several pleiotropic effects that result in a benefit on other features of MS. In fact, they may obtain a significant reduction in C-RP levels, as shown by several studies, and an increase of HDL-C levels. The C-RP lowering effect is statistically significant, and it can be reached within 14 days from the beginning of treatment and seems to be independent from the lipid lowering effect [11,12]. Rising HDL cholesterol, whose strong inverse correlation with vascular risk is well known, is therefore another important goal; some statins, especially simvastatin and rosuvastatin, have the most powerful effect [9,13]. Finally we can conclude that the choice of the more adequate approach is a central point of the management of the MS (see Table 1) The metabolic syndrome, according to ATPIII, is a secondary target of therapy. Therapeutic lifestyle changes are mandatory for MS Table 1 The metabolic syndrome: targets of statins therapy Hypertriglyceridemia Low HDL Generation of small, dense LDL Accumulation of chylomicron remnants Accumulation of VLDL remnants Pro-Inflammatory state Progression of the IGT
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M. Averna, A. Lo Verde / International Congress Series 1253 (2003) 243–246
with a 10-year CHD risk < 20%. Statins are useful to reach the LDL-C goal in MS with a 10-year CHD risk >20% and to correct the other associated lipid and non-lipid abnormalities [14,15]. In fact, they have a VLDL lowering action in hypertriglyceridemia, they reduce the amount of small and dense LDL, they increase the HDL-C, they reduce the atherogenic lipoproteins, and they decrease the inflammatory markers levels.
References [1] E.S. Ford, W.H. Giles, W.H. Dietz, Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey, JAMA 287 (3) (2002 January 16) 356 – 359. [2] G.L. Vega, Results of expert meetings: obesity and cardiovascular disease. Obesity, the metabolic syndrome, and cardiovascular disease, Am. Heart J. 142 (6) (2001 December) 1108 – 1116. [3] W.F.P. Wilson, R.B.S.R. D’Agostino, H. Parise, J.B. Meigs, The metabolic syndrome as a precursor of cardiovascular disease and type 2 diabetes mellitus, Diabetes 51 (Supplement 2) (2002 June), A242. [4] P. Simonen, H. Gylling, A.N. Howard, T.A. Miettinen, Introducing a new component of the metabolic syndrome: low cholesterol absorption, Am. J. Clin. Nutr. 72 (2000) 82 – 88. [5] M.A. Austin, M.C. King, K.M. Vranizan, R.M. Krauss, Atherogenic lipoprotein phenotype. A proposed genetic marker for coronary heart disease risk, Circulation 82 (2) (1990 August) 495 – 506. [6] M. Frohlich, A. Imhof, G. Berg, W.L. Hutchinson, M.B. Pepys, H. Boeing, R. Muche, H. Brenner, W. Koenig, Association between C-reactive protein and features of the metabolic syndrome: a populationbased study, Diabetes Care 23 (12) (2000 December) 1835 – 1837. [7] E.A. Stein, M. Lane, P. Laskarzewski, Comparison of statins in hypertriglyceridemia, Am. J. Cardiol. 81 (4A) (1998 February 26) 66B – 69B. [8] R.G. Bakker-Arkema, M.H. Davidson, R.J. Goldstein, J. Davignon, J.L. Isaacsohn, S.R. Weiss, L.M. Keilson, W.V. Brown, V.T. Miller, L.J. Shurzinske, D.M. Black, Efficacy and safety of a new HMG-CoA reductase inhibitor, atorvastatin, in patients with hypertriglyceridemia, JAMA 275 (2) (1996 January 10) 128 – 133. [9] Data presented at XIV International Symposium on Drugs Affecting Lipid Metabolism, September 9 – 12, New York, NY, USA, 2001. [10] S.H. Gianturco, C.J. Packard, J. Shepherd, L.C. Smith, A.L. Catapano, H.D. Sybers, A.M. Gotto Jr., Abnormal suppression of 3-hydroxy-3-methylglutaryl-CoA reductase activity in cultured human fibroblasts by hypertriglyceridemic very low density lipoprotein subclasses, Lipids 15 (6) (1980 June) 456 – 463. [11] I. Jialal, D. Stein, D. Balis, S.M. Grundy, B. Adams-Huet, S. Devaraj, Effect of hydroxymethyl glutaryl coenzyme a reductase inhibitor therapy on high sensitive C-reactive protein levels, Circulation 103 (15) (2001 April 17) 1933 – 1935. [12] J.K. Plenge, T.L. Hernandez, K.M. Weil, P. Poirier, G.K. Grunwald, S.M. Marcovina, R.H. Eckel, Simvastatin lowers C-reactive protein within 14 days: an effect independent of low-density lipoprotein cholesterol reduction, Circulation 106 (12) (2002 September 17) 1447 – 1452. [13] J.J.P. Kastelein, J.L. Isaacsohn, L. Ose, D.B. Hunninghake, J. Frohlich, M.H. Davidson, R. Habib, C.A. Dujovne, J.R. Crouse III, M. Liu, M.R. Melino, L.B.A. O’Grady, M. Mercuri, Y.B. Mitchel, Comparison of effects of simvastatin versus atorvastatin on high-density lipoprotein cholesterol and apolipoprotein A-I levels, Am. J. Cardiol. 86, 265 – 269. [14] C.M. Ballantyne, T.C. Andrews, J.A. Hsia, J.H. Kramer, C. Shear, Correlation of non-high-density lipoprotein cholesterol with apolipoprotein B: effect of 5 hydroxymethylglutaryl coenzyme A reductase inhibitors on non-high-density lipoprotein cholesterol levels, Am. J. Cardiol. 88 (3) (2001 August 1), 221 – 223. [15] D.T. Stein, S. Devaraj, D. Balis, B. Adams-Huet, I. Jialal, Effect of statin therapy on remnant lipoprotein cholesterol levels in patients with combined hyperlipidemia, Arterioscler. Thromb. Vasc. Biol. 21 (12) (2001 December) 2026 – 2031.
Statins and metabolic syndrome Maurizio Averna *, Alessia Lo Verde Dipartimento di Medicina Clinica e delle Patologie Emergenti, University of Palermo, Policlinico ‘‘Paolo Giaccone’’ Via del Vespro 141, 90127 Palermo, Italy Received 29 April 2003; accepted 29 April 2003
Abstract Metabolic syndrome (MS) is a multifactorial condition that represents a risk factor for the development of diabetes mellitus (DMII) and cardiovascular disease (CVD). Statins may play a role on some modifiable clinical features of MS; in fact, whereas therapeutic lifestyle changes are mandatory for MS with a 10-year coronary heart disease (CHD) risk < 20%, statins are recommended to reach the LDL-C goal in MS with a 10-year CHD risk >20% and to correct the other associated lipid and non-lipid abnormalities. In fact, they have a VLDL lowering action in hypertriglyceridemia, they reduce the amount of small and dense LDL, they increase the HDL-C, they reduce the atherogenic lipoproteins, and they decrease the inflammatory marker levels. D 2003 Elsevier Science B.V. All rights reserved. Keywords: Metabolic syndrome; Statins; Cardiovascular risk; Rosuvastatin
This report will focus on (1) definition of the role of metabolic syndrome (MS) as risk factor for the development of diabetes mellitus (DMII) and cardiovascular disease (CVD), (2) individuation of the MS features modifiable by the statins, and (3) evaluation of the indications to the use of these drugs to prevent the damages and the complications following MS. MS is a disorder with a heavy epidemiological impact, as shown by the data of the study NAHNES III, a large retrospective survey which performed an analysis of the prevalence of MS among 8814 US adults during 20 years, from 1988 to 1994 [1]. This study also demonstrates how MS has a different prevalence by age, arising in the fourth to fifth decade and especially over the 60th year of age and reaching a prevalence of about 45% in the adult decades of life. * Corresponding author. Tel.: +39-91-6552993; fax: +39-91-6552936. E-mail address: [email protected] (M. Averna). 0531-5131/03 D 2003 Elsevier Science B.V. All rights reserved. doi:10.1016/S0531-5131(03)00821-5
244
M. Averna, A. Lo Verde / International Congress Series 1253 (2003) 243–246
Many studies demonstrated the relation existing between the presence and the degree of severity of the MS and the incidence of pathologically relevant conditions consequent to an impairment of the circulatory system. According to the Framingham Scoring Scheme 1, which sorts the patients with MS in three different classes of severity, the incidence of cardiovascular complications shows a direct proportional correlation with the severity of the illness, with the most affected patients presenting the higher 10-year risk to develop coronary heart disease (CHD) [2]. An additional demonstration of the causal role of MS in determining cardiovascular complications is suggested by the Framingham Offspring Study, an observational study in which 3374 individuals were investigated during 8 years for the onset of CVD, CHD, and DMII [3]. The group of patients, which at the beginning of the study had at least three features of MS (see the NCEP ATP III definition below), showed a heavily increased risk to develop the clinical events. The definition of MS, on the basis of NCEP ATP III, is the presence of at least three of the following criteria:
abdominal obesity (>102 cm for men, >88 cm for women); plasma triglyceride z 150 mg/dl (1.7 mmol/l); HDL cholesterol < 40 mg/dl (1.0 mmol/l) for men, < 50 mg/dl (1.3 mmol/l) for women; BP >130/ z 85 mm Hg; fasting glucose z 110 mg/dl (6.1 mmol/l).
Thus, the MS represent a multifactorial condition in which coexisted an impairment of insulin sensitivity, an altered lipoprotein profile, and a pro-inflammatory state that lead to the complication abovementioned. Some of these features are modifiable by changes in lifestyle, nutritional intervention, or drugs, and in particular, statins today seem to play an important role in the management of the metabolic abnormalities that we observe in the MS. In fact, the study of the nutritional aspects of the MS has shown a central position of the cholesterol-absorptive pathway as a new component of the syndrome [4]. It seems that we can individuate a class of subjects, the low cholesterol absorbers, which have a reduced cholestanol/cholesterol ratio and are also high cholesterol producers, having a high lathosterol/cholesterol ratio. This condition results in a low cholesterol absorption, and this status is associated to a rise in BMI and insulin resistance (IR) and to the development of a lipoprotein profile characterized by high levels of triglycerides and low levels of HDL-C; this profile (Atherogenic Lipoprotein Phenotype, ALP) is known to be highly responsible of the atherogenesis into the arterial wall and is statistically correlated to a major onset of cardiovascular and cerebrovascular diseases [5]. In addition to these quantitative modifications in circulating serum levels, the alterations of the lipoproteins in the ALP is characterized by qualitative changes in size and density, with the production of small dense LDL and the accumulation of remnants of VLDLs and chylomicrons, both highly atherogenic. The data about the non-lipid features associated with MS, such as the pro-inflammatory state, measured by circulating C-reactive protein (C-RP) levels, and insulin resistance also demonstrated a strong independent correlation with an increased risk of CVD. C-RP levels
M. Averna, A. Lo Verde / International Congress Series 1253 (2003) 243–246
245
show a significant independent association with all the clinical features of MS [6], and insulin levels are known to be directly associated with increased risk of CAD. The complexity of the MS and the deep interrelations existing between its clinical features represent a critical node for delineating a preventive strategy in order to reduce the high metabolic and cardiovascular risk of these patient. In this field, statins are considered as the first-choice drugs in the hands of physicians within a multifactorial approach that includes, as mentioned above, nutritional and behavioural interventions. Statins have an evident lowering effect on the triglyceride levels, which are usually elevated in MS [7]. Atorvastatin and the new statin, rosuvastatin, show the stronger triglyceride lowering effect [8,9]. Their efficacy may reach, at the highest dosages, almost 50% of reduction, but is already present and relevant at lower dosages. The reduction in triglyceride plasma levels in VLDLs also modify the interactions with the LDL receptor which mediates the reuptake mechanism, resulting in favourable changes in the whole lipid balance with a reduction of many atherogenic particles, such as chylomicrons and VLDL remnants, and a shift through a less dangerous pattern of circulating lipids [10]. The triglyceride lowering effect is demonstrated to be rapid and safe, and it should be considered in the case of failure to achieve a satisfactory correction by diet or lifestyle changes in high-risk patients, in which a more aggressive approach is indicated. Guidelines indicate that a secondary target of the therapy of MS is the reduction of the so-called non-HDL cholesterol; this lipoprotein fraction is represented by the LDL and the VLDL particles and is calculated as TC-HDL-C; the therapeutic goal to be reached in the case of elevated serum triglyceridemia (>200 mg/dl) has been fixed as LDL-C goal + 30 mg/dl. Most of the statins demonstrate a good efficacy on this parameter, with a reduction that average 20– 30% and almost 40% for atorvastatin. In addition to this, statins have several pleiotropic effects that result in a benefit on other features of MS. In fact, they may obtain a significant reduction in C-RP levels, as shown by several studies, and an increase of HDL-C levels. The C-RP lowering effect is statistically significant, and it can be reached within 14 days from the beginning of treatment and seems to be independent from the lipid lowering effect [11,12]. Rising HDL cholesterol, whose strong inverse correlation with vascular risk is well known, is therefore another important goal; some statins, especially simvastatin and rosuvastatin, have the most powerful effect [9,13]. Finally we can conclude that the choice of the more adequate approach is a central point of the management of the MS (see Table 1) The metabolic syndrome, according to ATPIII, is a secondary target of therapy. Therapeutic lifestyle changes are mandatory for MS Table 1 The metabolic syndrome: targets of statins therapy Hypertriglyceridemia Low HDL Generation of small, dense LDL Accumulation of chylomicron remnants Accumulation of VLDL remnants Pro-Inflammatory state Progression of the IGT
246
M. Averna, A. Lo Verde / International Congress Series 1253 (2003) 243–246
with a 10-year CHD risk < 20%. Statins are useful to reach the LDL-C goal in MS with a 10-year CHD risk >20% and to correct the other associated lipid and non-lipid abnormalities [14,15]. In fact, they have a VLDL lowering action in hypertriglyceridemia, they reduce the amount of small and dense LDL, they increase the HDL-C, they reduce the atherogenic lipoproteins, and they decrease the inflammatory markers levels.
References [1] E.S. Ford, W.H. Giles, W.H. Dietz, Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey, JAMA 287 (3) (2002 January 16) 356 – 359. [2] G.L. Vega, Results of expert meetings: obesity and cardiovascular disease. Obesity, the metabolic syndrome, and cardiovascular disease, Am. Heart J. 142 (6) (2001 December) 1108 – 1116. [3] W.F.P. Wilson, R.B.S.R. D’Agostino, H. Parise, J.B. Meigs, The metabolic syndrome as a precursor of cardiovascular disease and type 2 diabetes mellitus, Diabetes 51 (Supplement 2) (2002 June), A242. [4] P. Simonen, H. Gylling, A.N. Howard, T.A. Miettinen, Introducing a new component of the metabolic syndrome: low cholesterol absorption, Am. J. Clin. Nutr. 72 (2000) 82 – 88. [5] M.A. Austin, M.C. King, K.M. Vranizan, R.M. Krauss, Atherogenic lipoprotein phenotype. A proposed genetic marker for coronary heart disease risk, Circulation 82 (2) (1990 August) 495 – 506. [6] M. Frohlich, A. Imhof, G. Berg, W.L. Hutchinson, M.B. Pepys, H. Boeing, R. Muche, H. Brenner, W. Koenig, Association between C-reactive protein and features of the metabolic syndrome: a populationbased study, Diabetes Care 23 (12) (2000 December) 1835 – 1837. [7] E.A. Stein, M. Lane, P. Laskarzewski, Comparison of statins in hypertriglyceridemia, Am. J. Cardiol. 81 (4A) (1998 February 26) 66B – 69B. [8] R.G. Bakker-Arkema, M.H. Davidson, R.J. Goldstein, J. Davignon, J.L. Isaacsohn, S.R. Weiss, L.M. Keilson, W.V. Brown, V.T. Miller, L.J. Shurzinske, D.M. Black, Efficacy and safety of a new HMG-CoA reductase inhibitor, atorvastatin, in patients with hypertriglyceridemia, JAMA 275 (2) (1996 January 10) 128 – 133. [9] Data presented at XIV International Symposium on Drugs Affecting Lipid Metabolism, September 9 – 12, New York, NY, USA, 2001. [10] S.H. Gianturco, C.J. Packard, J. Shepherd, L.C. Smith, A.L. Catapano, H.D. Sybers, A.M. Gotto Jr., Abnormal suppression of 3-hydroxy-3-methylglutaryl-CoA reductase activity in cultured human fibroblasts by hypertriglyceridemic very low density lipoprotein subclasses, Lipids 15 (6) (1980 June) 456 – 463. [11] I. Jialal, D. Stein, D. Balis, S.M. Grundy, B. Adams-Huet, S. Devaraj, Effect of hydroxymethyl glutaryl coenzyme a reductase inhibitor therapy on high sensitive C-reactive protein levels, Circulation 103 (15) (2001 April 17) 1933 – 1935. [12] J.K. Plenge, T.L. Hernandez, K.M. Weil, P. Poirier, G.K. Grunwald, S.M. Marcovina, R.H. Eckel, Simvastatin lowers C-reactive protein within 14 days: an effect independent of low-density lipoprotein cholesterol reduction, Circulation 106 (12) (2002 September 17) 1447 – 1452. [13] J.J.P. Kastelein, J.L. Isaacsohn, L. Ose, D.B. Hunninghake, J. Frohlich, M.H. Davidson, R. Habib, C.A. Dujovne, J.R. Crouse III, M. Liu, M.R. Melino, L.B.A. O’Grady, M. Mercuri, Y.B. Mitchel, Comparison of effects of simvastatin versus atorvastatin on high-density lipoprotein cholesterol and apolipoprotein A-I levels, Am. J. Cardiol. 86, 265 – 269. [14] C.M. Ballantyne, T.C. Andrews, J.A. Hsia, J.H. Kramer, C. Shear, Correlation of non-high-density lipoprotein cholesterol with apolipoprotein B: effect of 5 hydroxymethylglutaryl coenzyme A reductase inhibitors on non-high-density lipoprotein cholesterol levels, Am. J. Cardiol. 88 (3) (2001 August 1), 221 – 223. [15] D.T. Stein, S. Devaraj, D. Balis, B. Adams-Huet, I. Jialal, Effect of statin therapy on remnant lipoprotein cholesterol levels in patients with combined hyperlipidemia, Arterioscler. Thromb. Vasc. Biol. 21 (12) (2001 December) 2026 – 2031.