Comparison of pitavastatin with atorvastatin in increasing HDL-cholesterol and adiponectin in patients with dyslipidemia and coronary artery disease : The COMPACT-CAD study

AbstractBackgroundMany large-scale clinical trials have confirmed that statins are effective in reducing low-density lipoprotein cholesterol (LDL-C) level, resulting in reducing cardiovascular events. Recent studies have focused on the effects of statins on high-density lipoprotein cholesterol (HDL-C). Here we compared the effects of two statins on lipid profile and other metabolic parameters.MethodsThe study population included 129 patients with stable coronary artery disease, hypercholesterolemia, and hypo-HDL-cholesterolemia (HDL-C<50mg/dl). They were randomly allocated to treatment by pitavastatin 2–4mg/day or atorvastatin 10–20mg/day and followed-up for 30 months. The primary endpoint was percent changes in HDL-C and adiponectin during the study. The secondary endpoints were percent and absolute changes in markers of glucose metabolism, serum lipids, and apolipoproteins.ResultsThe effects of 30-month treatment with pitavastatin on HDL-C were significantly greater than those of atorvastatin (%change: pitavastatin: 20.1±25.7%, atorvastatin: 6.3±19.8%, p=0.01; absolute change: pitavastatin: 7.3±9.1mg/dl, atorvastatin: 2.3±8.0mg/dl, p=0.02). A similar trend was seen with regard to apolipoprotein-AI (ApoAI) (%change: pitavastatin: 20.8±19.3%, atorvastatin: 11.4±17.6%, p=0.03; absolute change: pitavastatin: 23.1±20.2mg/dl, atorvastatin: 12.1±19.4mg/dl, p=0.02). Treatment with pitavastatin, but not atorvastatin, significantly increased adiponectin levels. Neither statin had a significant effect on hemoglobin A1c. No severe adverse events were registered during the study.ConclusionLong-term treatment with pitavastatin resulted in significantly greater increases in serum HDL-C and ApoAI levels without adverse effects on glucose metabolism, compared with atorvastatin

Activation of AMP-activated Protein Kinase Suppresses Oxidized Low-density Lipoprotein-induced Macrophage Proliferation*

Macrophage-derived foam cells play important roles in the progression of atherosclerosis. We reported previously that ERK1/2-dependent granulocyte/macrophage colony-stimulating factor (GM-CSF) expression, leading to p38 MAPK/ Akt signaling, is important for oxidized low density lipoprotein (Ox-LDL)-induced macrophage proliferation. Here, we investigated whether activation of AMP-activated protein kinase (AMPK) could suppress macrophage proliferation. Ox-LDL-induced proliferation of mouse peritoneal macrophages was assessed by [3H]thymidine incorporation and cell counting assays. The proliferation was significantly inhibited by the AMPK activator 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) and restored by dominant-negative AMPKα1, suggesting that AMPK activation suppressed macrophage proliferation. AICAR partially suppressed Ox-LDL-induced ERK1/2 phosphorylation and GM-CSF expression, suggesting that another mechanism is also involved in the AICAR-mediated suppression of macrophage proliferation. AICAR suppressed GM-CSF-induced macrophage proliferation without suppressing p38 MAPK/Akt signaling. GM-CSF suppressed p53 phosphorylation and expression and induced Rb phosphorylation. Overexpression of p53 or p27kip suppressed GM-CSF-induced macrophage proliferation. AICAR induced cell cycle arrest, increased p53 phosphorylation and expression, and suppressed GM-CSF-induced Rb phosphorylation via AMPK activation. Moreover, AICAR induced p21cip and p27kip expression via AMPK activation, and small interfering RNA (siRNA) of p21cip and p27kip restored AICAR-mediated suppression of macrophage proliferation. In conclusion, AMPK activation suppressed Ox-LDL-induced macrophage proliferation by suppressing GM-CSF expression and inducing cell cycle arrest. These effects of AMPK activation may represent therapeutic targets for atherosclerosis