Simvastatin but not bezafibrate decreases plasma lipoprotein-associated phospholipase A₂ mass in type 2 diabetes mellitus: relevance of high sensitive C-reactive protein, lipoprotein profile and low-density lipoprotein (LDL) electronegativity.
OBJECTIVE
Plasma lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) levels predict incident cardiovascular disease, impacting Lp-PLA(2) as an emerging therapeutic target. We determined Lp-PLA(2) responses to statin and fibrate administration in type 2 diabetes mellitus, and assessed relationships of changes in Lp-PLA(2) with subclinical inflammation and lipoprotein characteristics.


METHODS
A placebo-controlled cross-over study (three 8-week treatment periods with simvastatin (40 mg daily), bezafibrate (400mg daily) and their combination) was carried out in 14 male type 2 diabetic patients. Plasma Lp-PLA(2) mass was measured by turbidimetric immunoassay.


RESULTS
Plasma Lp-PLA(2) decreased (-21 ± 4%) in response to simvastatin (p<0.05 from baseline and placebo), but was unaffected by bezafibrate (1 ± 5%). The drop in Lp-PLA(2) during combined treatment (-17 ± 3%, p<0.05) was similar compared to that during simvastatin alone. The Lp-PLA(2) changes during the 3 active lipid lowering treatment periods were related positively to baseline levels of high sensitive C-reactive protein, non-HDL cholesterol, triglycerides, the total cholesterol/HDL cholesterol ratio and less LDL electronegativity (p<0.02 to p<0.01), and inversely to baseline Lp-PLA(2) (p<0.01). LpPLA(2) responses correlated inversely with changes in non-HDL cholesterol, triglycerides and the total cholesterol/HDL cholesterol ratio during treatment (p<0.05 to p<0.02).


CONCLUSIONS
In type 2 diabetes mellitus, plasma Lp-PLA(2) is likely to be lowered by statin treatment only. Enhanced subclinical inflammation and more severe dyslipidemia may predict diminished LpPLA(2) responses during lipid lowering treatment, which in turn appear to be quantitatively dissociated from decreases in apolipoprotein B lipoproteins. Conventional lipid lowering treatment may be insufficient for optimal LpPLA(2) lowering in diabetes mellitus.
Department of Endocrinology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.
Alexander
A
Constantinides
Rindert
R
de Vries
Jeroen J J
JJ
van Leeuwen
Thomas
T
Gautier
L Joost
LJ
van Pelt
Alexandros D
AD
Tselepis
Laurent
L
Lagrost
Robin P F
RP
Dullaart
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000187:drug effects*; D001629:Bezafibrate / Q000494:pharmacology / Q000627:therapeutic use*; D002097:C-Reactive Protein / Q000187:drug effects; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D050171:Dyslipidemias / Q000150:complications / Q000188:drug therapy*; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D008077:Lipoproteins, LDL / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D019821:Simvastatin / Q000494:pharmacology / Q000627:therapeutic use*; D014280:Triglycerides
D000960:Hypolipidemic Agents; D008077:Lipoproteins, LDL; D014280:Triglycerides; C099252:oxidized low density lipoprotein; D002097:C-Reactive Protein; D019821:Simvastatin; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D001629:Bezafibrate