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

J Clin Lipidol. May-Jun 2018;12(3):784-800.e4. doi: 10.1016/j.jacl.2018.02.001. Epub 2018 Feb 9.


Background: Statins impact the metabolism, concentrations, composition, and function of circulating lipoproteins.

Objective: We evaluated time course relationships between statin-mediated reduction in atherogenic apolipoprotein B (ApoB)-containing particles and dynamic intravascular remodeling of ApoAI-containing lipoprotein subpopulations in the mixed dyslipidemia of metabolic syndrome.

Methods: Insulin-resistant, hypertriglyceridemic, hypercholesterolemic, obese males (n = 12) were treated with pitavastatin (4 mg/d) and response evaluated at 6, 42, and 180 days.

Results: Reduction in low-density lipoprotein (LDL) cholesterol, ApoB, and triglycerides (TGs) was essentially complete at 42 days (-38%, -32%, and -35%, respectively); rapid reduction equally occurred in remnant cholesterol, ApoCII, CIII, and E levels (day 6; -35%, -50%, -23%, and -26%, respectively). Small dense LDLs (LDL4 and LDL5 subpopulations) predominated at baseline and were markedly reduced on treatment (-29% vs total LDL mass). Cholesteryl ester (CE) transfer protein activity and mass decreased progressively (-18% and -16%, respectively); concomitantly, TG depletion (up to -49%) and CE enrichment occurred in all high-density lipoprotein (HDL) particle subpopulations with normalization of CE/TG mass ratio at 180 days. ApoAI was redistributed from LpAI to LpAI:AII particles in HDL2a and HDL3a subpopulations; ApoCIII was preferentially depleted from LpAI:AII-rich particles on treatment.

Conclusion: Overall, statin action exhibits duality in mixed dyslipidemia, as CE transfer protein-mediated normalization of the HDL CE/TG core lags markedly behind subacute reduction in elevated levels of atherogenic ApoB-containing lipoproteins. Normalization of the HDL neutral lipid core is consistent with enhanced atheroprotective function. The HDL CE/TG ratio constitutes a metabolomic marker of perturbed HDL metabolism in insulin-resistant states, equally allowing monitoring of statin impact on HDL metabolism, structure, and function.

Trial registration: ClinicalTrials.gov NCT01595828.

Keywords: CETP; High-density lipoprotein; Low-density lipoprotein; Metabolic syndrome; Mixed dyslipidemia; Pitavastatin; Remnants; Very low–density lipoproteins.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cholesterol Ester Transfer Proteins / metabolism*
  • Dyslipidemias / blood
  • Dyslipidemias / complications*
  • Dyslipidemias / drug therapy*
  • Dyslipidemias / metabolism
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use
  • Lipoproteins / blood*
  • Lipoproteins / chemistry
  • Male
  • Metabolic Syndrome / complications*
  • Middle Aged
  • Phenotype
  • Time Factors
  • Treatment Outcome


  • Cholesterol Ester Transfer Proteins
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Lipoproteins

Associated data

  • ClinicalTrials.gov/NCT01595828