Duality of statin action on lipoprotein subpopulations in the mixed dyslipidemia of metabolic syndrome: Quantity vs quality over time and implication.

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Duality of statin action on lipoprotein subpopulations in the mixed dyslipidemia of metabolic syndrome: Quantity vs quality over time and implication of CETP M. John Chapman, BSc (Hons), PhD, DSc, Alexina Orsoni, PhD, Paul Robillard, BSc, Patrice Therond, DPharm, Philippe Giral, MD Journal of Clinical Lipidology Volume 12, Issue 3, Pages 784-800.e4 (May 2018) DOI: 10.1016/j.jacl.2018.02.001 Copyright © 2017 National Lipid Association Terms and Conditions

Figure 1 Interindividual variation in MetS subjects in response to pitavastatin treatment (4 mg/d) over the time course from baseline (D0), to 6 days (D6), to 42 days (D42), and to 180 days (D180). (A) LDL-C (n = 12) and (B) fasting triglycerides (n = 11); data for 1 subject whose response presented as an outlier (>10-fold variation in SD value) were excluded. MetS, metabolic syndrome; LDL-C, low-density lipoprotein cholesterol. Journal of Clinical Lipidology 2018 12, 784-800.e4DOI: (10.1016/j.jacl.2018.02.001) Copyright © 2017 National Lipid Association Terms and Conditions

Figure 2 Time course of the impact of pitavastatin treatment (4 mg/d) in MetS subjects on total mass (TG, CE, FC, PL, and protein; expressed as mg/dL plasma) of individual lipoprotein subfractions isolated by density gradient ultracentrifugation. Subfractions are VLDL + IDL and LDL (LDL1 + LDL2 to LDL5) at baseline (D0), and 180 days (D180), and for HDL subfractions at baseline (D0), 6 days (D6), 42 days (D42), and 180 days (D180). The hydrated density limits of individual fractions were VLDL + IDL, d < 1.019 g/mL; LDL1 + LDL2, 1.019–1.029 g/mL; LDL3, 1.029–1.039 g/mL; LDL4, 1.039–1.050 g/mL; LDL5, 1.050–1.063 g/mL; HDL2b, 1.063–1.091 g/mL; HDL2a, 1.091–1.110 g/mL; HDL3a, 1.110–1.133 g/mL; HDL3b, 1.133–1.156 g/mL; and HDL3c, 1.156–1.179 g/mL. Inserts: % change between baseline and D180 in total mass of (1) VLDL + IDL and LDL subfractions and (2) HDL subfractions. ***P < .001, **.001 < P < .01, and *0.01 < P < .05 vs D0. VLDL, very low–density lipoproteins; IDL, intermediate–density lipoprotein; LDL, low-density lipoprotein; HDL, high-density lipoprotein; TG, triglyceride; CE, cholesteryl ester; FC, free cholesterol; PL, phospholipid. Journal of Clinical Lipidology 2018 12, 784-800.e4DOI: (10.1016/j.jacl.2018.02.001) Copyright © 2017 National Lipid Association Terms and Conditions

Figure 3 Time course of the impact of pitavastatin treatment (4 mg/d) in MetS subjects on the mass ratio of cholesteryl esters (CE) to TGs among VLDL + IDL, LDL, and HDL subfractions at baseline (D0), 6 days (D6), 42 days (D42), and 180 days (D180). The hydrated density limits of individual lipoprotein subfractions from the density gradient are as given in the legend in Figure 2. ***P < .001, **.001 < P < .01, and *0.01 < P < .05 vs D0. VLDL, very low–density lipoproteins; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; HDL, high-density lipoprotein; TG, triglyceride. Journal of Clinical Lipidology 2018 12, 784-800.e4DOI: (10.1016/j.jacl.2018.02.001) Copyright © 2017 National Lipid Association Terms and Conditions

Figure 4 Impact of pitavastatin treatment (4 mg/d) on plasma LCAT activity, CETP mass, and CETP activity in MetS subjects over the time course of 180 days (D180). (A) LCAT activity, expressed as %, in plasma at baseline (D0), 6 days (D6), 42 days (D42), and 180 days (D180); (B) CETP mass, expressed as μg/mL plasma and (C) CETP activity, expressed as pmoles/mL plasma/min at baseline (D0), 6 days (D6), 42 days (D42), and 180 days (D180). **.001 < P < .01 and *0.01 < P < .05 vs D0. CETP, cholesteryl ester transfer protein; LCAT, lecithin:cholesterol acyltransferase. Journal of Clinical Lipidology 2018 12, 784-800.e4DOI: (10.1016/j.jacl.2018.02.001) Copyright © 2017 National Lipid Association Terms and Conditions

Figure 5 Impact of pitavastatin treatment (4 mg/d) on the density distribution of apolipoproteins B, AI, AII, and CIII and Lp(a) and HDL particles LpAI and LpAI:AII in MetS subjects over the time course [baseline (D0) and 180 days (D180)]. (A) ApoB and Lp(a); (B) ApoAI and ApoAII; (C) LpAI; (D) LpAI:AII; and (E) ApoCIII. The hydrated density limits of individual lipoprotein subfractions from the density gradient are as given in the legend in Figure 2. Concentrations are expressed as mg/dL plasma. ***P < .001, **.001 < P < .01, and *0.01 < P < .05 vs D0. ApoAI, apolipoprotein AI; VLDL, very low–density lipoproteins; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; HDL, high-density lipoprotein; TG, triglyceride; LpAI, lipoprotein particles containing only ApoAI; LpAI:AII, lipoprotein particles containing both ApoAI and ApoAII. Journal of Clinical Lipidology 2018 12, 784-800.e4DOI: (10.1016/j.jacl.2018.02.001) Copyright © 2017 National Lipid Association Terms and Conditions

Figure 5 Impact of pitavastatin treatment (4 mg/d) on the density distribution of apolipoproteins B, AI, AII, and CIII and Lp(a) and HDL particles LpAI and LpAI:AII in MetS subjects over the time course [baseline (D0) and 180 days (D180)]. (A) ApoB and Lp(a); (B) ApoAI and ApoAII; (C) LpAI; (D) LpAI:AII; and (E) ApoCIII. The hydrated density limits of individual lipoprotein subfractions from the density gradient are as given in the legend in Figure 2. Concentrations are expressed as mg/dL plasma. ***P < .001, **.001 < P < .01, and *0.01 < P < .05 vs D0. ApoAI, apolipoprotein AI; VLDL, very low–density lipoproteins; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; HDL, high-density lipoprotein; TG, triglyceride; LpAI, lipoprotein particles containing only ApoAI; LpAI:AII, lipoprotein particles containing both ApoAI and ApoAII. Journal of Clinical Lipidology 2018 12, 784-800.e4DOI: (10.1016/j.jacl.2018.02.001) Copyright © 2017 National Lipid Association Terms and Conditions

Figure 5 Impact of pitavastatin treatment (4 mg/d) on the density distribution of apolipoproteins B, AI, AII, and CIII and Lp(a) and HDL particles LpAI and LpAI:AII in MetS subjects over the time course [baseline (D0) and 180 days (D180)]. (A) ApoB and Lp(a); (B) ApoAI and ApoAII; (C) LpAI; (D) LpAI:AII; and (E) ApoCIII. The hydrated density limits of individual lipoprotein subfractions from the density gradient are as given in the legend in Figure 2. Concentrations are expressed as mg/dL plasma. ***P < .001, **.001 < P < .01, and *0.01 < P < .05 vs D0. ApoAI, apolipoprotein AI; VLDL, very low–density lipoproteins; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; HDL, high-density lipoprotein; TG, triglyceride; LpAI, lipoprotein particles containing only ApoAI; LpAI:AII, lipoprotein particles containing both ApoAI and ApoAII. Journal of Clinical Lipidology 2018 12, 784-800.e4DOI: (10.1016/j.jacl.2018.02.001) Copyright © 2017 National Lipid Association Terms and Conditions

Figure S1 Summary of the clinical protocol of the CAPITAIN study in metabolic syndrome subjects, indicating key inclusion and exclusion criteria and the time course of plasma lipid, lipoprotein, and biomarker analyses. VLDL, very low–density lipoproteins; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; HDL, high-density lipoprotein; TG, triglyceride; CETP, cholesteryl ester transfer protein; LCAT, lecithin:cholesterol acyltransferase. Journal of Clinical Lipidology 2018 12, 784-800.e4DOI: (10.1016/j.jacl.2018.02.001) Copyright © 2017 National Lipid Association Terms and Conditions