Effects of pioglitazone and/or simvastatin on low density lipoprotein subfractions in non-diabetic patients with high cardiovascular risk: A sub-analysis from the PIOSTAT study.
BACKGROUND
We analyzed the efficacy and possible synergistic actions of pioglitazone and simvastatin monotherapy versus their combination on LDL subfractions from a subpopulation from the PIOSTAT three-arm randomized controlled trial. PPARgamma agonists, such as pioglitazone, improve insulin sensitivity and glycemic control and appear to lower the concentration of atherogenic small dense LDL particles. Insulin resistance frequently occurs in non-diabetic patients with cardiovascular disease. Statins, such as simvastatin, reduce cardiovascular events by lowering LDL-C. So far, only scarce information exists for comparative efficacy and possible synergistic effects of combination therapy on LDL subfractions, cholesterol particle load, and particle number of atherogenic small dense LDL.


METHODS
125 non-diabetic patients with high cardiovascular risk were randomized to therapy with pioglitazone 45 mg/day, simvastatin 40 mg/day, or the combination of both, for 12 weeks. In the present sub-study, LDL subfractions from 88 patients were separated by very-fast ultracentrifugation.


RESULTS
Simvastatin monotherapy significantly reduced cholesterol and triglyceride concentrations in IDL, LDL1, and LDL2. The lipid concentrations and lipid loads in LDL3 remained unchanged. By contrast, treatment with pioglitazone reduced the cholesterol concentration in LDL3 (density 1.040-1.066 kg/l) from 0.38 to 0.31 mmol/l (p=0.0004) and of the cholesterol load per particle from 1058 to 934 mol/mol (p=0.0149). Even greater reductions of cholesterol in LDL3 were observed with the combination of pioglitazone and simvastatin: from 0.38 to 0.29 mmol/l (p=0.0006) and from 1021 to 903 mol/mol (p=0.0011), respectively. In addition, combination therapy reduced the particle number of LDL3 from 356 to 316 nmol/l (p=0.0074).


CONCLUSIONS
Simvastatin preferentially lowered LDL1 and LDL2 subfractions, whereas pioglitazone reduced LDL3 cholesterol and cholesterol load. In addition, the combination reduced the LDL3 particle number. Thus, our data suggest a synergistic action of pioglitazone and simvastatin on atherogenicity of small dense LDL particles.
Leonhardt
Wolfgang
W
Center for Clinical Studies, GWT TU Dresden GmbH, Germany.
Pfützner
Andreas
A
Müller
Jürgen
J
Pietzsch
Jens
J
Forst
Thomas
T
Karagiannis
Efstrathios
E
Lübben
Georg
G
Hanefeld
Markolf
M
D000328:Adult; D000368:Aged; D002318:Cardiovascular Diseases / Q000097:blood* / Q000188:drug therapy / Q000209:etiology; D002784:Cholesterol / Q000097:blood; D015331:Cohort Studies; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage*; D007004:Hypoglycemic Agents / Q000008:administration & dosage*; D008077:Lipoproteins, LDL / Q000097:blood*; D008297:Male; D008875:Middle Aged; D000077205:Pioglitazone; D012307:Risk Factors; D019821:Simvastatin / Q000008:administration & dosage*; D045162:Thiazolidinediones / Q000008:administration & dosage*; D016896:Treatment Outcome; D014280:Triglycerides / Q000097:blood
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007004:Hypoglycemic Agents; D008077:Lipoproteins, LDL; D045162:Thiazolidinediones; D014280:Triglycerides; D002784:Cholesterol; D019821:Simvastatin; D000077205:Pioglitazone