Best Practice & Research Clinical Endocrinology & Metabolism xxx (2013) 1–16
Contents lists available at ScienceDirect
Best Practice & Research Clinical Endocrinology & Metabolism journal homepage: www.elsevier.com/locate/beem
3
Targeting LDL: Is lower better and is it safe? Evan A. Stein, MD, PhD, Voluntary Professor a, *, Frederick J. Raal, MB, BCh, PhD, Professor and Head b a
Department of Pathology & Laboratory Medicine, University of Cincinnati, Cincinnati, OH 45215, USA Division of Endocrinology and Metabolism, Department of Medicine, Carbohydrate & Lipid Metabolism Research Unit, Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa b
Keywords: LDL cholesterol Friedewald formula statins PCSK9 inhibitors
Low density lipoprotein cholesterol (LDL-C) is one of the most validated targets in clinical medicine. Large randomized, outcome trials have demonstrated a clear relationship between reducing LDL-C and cardiovascular disease (CVD) risk, which has been maintained to LDL-C levels of 5.2
631 1445 2976 7082 17,310 1116
0.62 1.25 1.75 2.33 3.63 5.72
0.43 1.05 1.6 2.23 3.65 5.84
27.6 14.7 7.9 3.6 0.6 2.6
a b c
(0.24) (0.27) (0.24) (0.29) (0.66) (0.78)
(0.17) (0.18) (0.15) (0.22) (0.67) (0.74)
(31.8) (14.0) (12.5) (9.6) (7.2) (8.4)
Calculated by Friedewald formula. PUC ¼ preparative ultracentrifugation. percent difference ¼ 100 (calculated LDL-C – PUC LDL-C)/PUC LDL-C.
Please cite this article in press as: Stein EA, Raal FJ, Targeting LDL: Is lower better and is it safe?, Best Practice & Research Clinical Endocrinology & Metabolism (2013), http://dx.doi.org/10.1016/ j.beem.2013.10.010
E.A. Stein, F.J. Raal / Best Practice & Research Clinical Endocrinology & Metabolism xxx (2013) 1–16
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Fig. 5. Percent difference between LDL-C by Friedewald and PUC in samples from patients participating in phase 2 trials with evolocumab a monoclonal antibody to PCSK9 [47].
Decrease in End Points through Aggressive Lipid Lowering/IDEAL”) [48]. The studies were designed to test ‘lower was better’ with a control group assigned to a lower dose or less effective statin and ‘test’ group to high-dose of effective statin [9,16]. Both control groups had on treatment mean LDL-C approximately 2.6 mmol/L and ‘aggressive’ treated groups mean LDL-C between 1.94 and 2.06 mmol/L. In patients with LDL-C levels 2.6 mmol/L during the trial there was no longer a significant relationship between LDL-C and risk of CVD but non-HDL cholesterol and apo B continued to be positively associated with CVD outcome. They concluded that future treatment guidelines favored the use of non-HDL cholesterol or apo B instead of LDL-C as the primary treatment target. However this study, and other similar studies, have not performed analysis on trials with LDL-C
Contents lists available at ScienceDirect
Best Practice & Research Clinical Endocrinology & Metabolism journal homepage: www.elsevier.com/locate/beem
3
Targeting LDL: Is lower better and is it safe? Evan A. Stein, MD, PhD, Voluntary Professor a, *, Frederick J. Raal, MB, BCh, PhD, Professor and Head b a
Department of Pathology & Laboratory Medicine, University of Cincinnati, Cincinnati, OH 45215, USA Division of Endocrinology and Metabolism, Department of Medicine, Carbohydrate & Lipid Metabolism Research Unit, Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa b
Keywords: LDL cholesterol Friedewald formula statins PCSK9 inhibitors
Low density lipoprotein cholesterol (LDL-C) is one of the most validated targets in clinical medicine. Large randomized, outcome trials have demonstrated a clear relationship between reducing LDL-C and cardiovascular disease (CVD) risk, which has been maintained to LDL-C levels of 5.2
631 1445 2976 7082 17,310 1116
0.62 1.25 1.75 2.33 3.63 5.72
0.43 1.05 1.6 2.23 3.65 5.84
27.6 14.7 7.9 3.6 0.6 2.6
a b c
(0.24) (0.27) (0.24) (0.29) (0.66) (0.78)
(0.17) (0.18) (0.15) (0.22) (0.67) (0.74)
(31.8) (14.0) (12.5) (9.6) (7.2) (8.4)
Calculated by Friedewald formula. PUC ¼ preparative ultracentrifugation. percent difference ¼ 100 (calculated LDL-C – PUC LDL-C)/PUC LDL-C.
Please cite this article in press as: Stein EA, Raal FJ, Targeting LDL: Is lower better and is it safe?, Best Practice & Research Clinical Endocrinology & Metabolism (2013), http://dx.doi.org/10.1016/ j.beem.2013.10.010
E.A. Stein, F.J. Raal / Best Practice & Research Clinical Endocrinology & Metabolism xxx (2013) 1–16
9
Fig. 5. Percent difference between LDL-C by Friedewald and PUC in samples from patients participating in phase 2 trials with evolocumab a monoclonal antibody to PCSK9 [47].
Decrease in End Points through Aggressive Lipid Lowering/IDEAL”) [48]. The studies were designed to test ‘lower was better’ with a control group assigned to a lower dose or less effective statin and ‘test’ group to high-dose of effective statin [9,16]. Both control groups had on treatment mean LDL-C approximately 2.6 mmol/L and ‘aggressive’ treated groups mean LDL-C between 1.94 and 2.06 mmol/L. In patients with LDL-C levels 2.6 mmol/L during the trial there was no longer a significant relationship between LDL-C and risk of CVD but non-HDL cholesterol and apo B continued to be positively associated with CVD outcome. They concluded that future treatment guidelines favored the use of non-HDL cholesterol or apo B instead of LDL-C as the primary treatment target. However this study, and other similar studies, have not performed analysis on trials with LDL-C
