Masato Ageta

A 52-Week, Randomized, Open-Label, Parallel-Group Comparison of the Tolerability and Effects of Pitavastatin and Atorvastatin on High-Density Lipoprotein Cholesterol Levels and Glucose Metabolism in Japanese Patients with Elevated Levels of Low-Density Lipoprotein Cholesterol and Glucose Intolerance

BACKGROUND Statin therapy has been found to produce substantial reductions in low-density lipoprotein cholesterol (LDL-C) levels, resulting in a reduced risk for cardiovascular events. Recently, research interest has focused on modification of high-density lipoprotein cholesterol (HDL-C) levels for the potential prevention of cardiovascular events. The effects of pitavastatin and atorvastatin on HDL-C have not been directly compared. OBJECTIVES This study compared the effects of pitavastatin and atorvastatin on HDL-C and other lipids and glucose metabolism in Japanese patients with elevated LDL-C levels and glucose intolerance. The tolerability of the 2 treatments was also compared. METHODS This was a multicenter, open-label, parallel-group trial. Patients with LDL-C levels>or=140 mg/dL and glucose intolerance (defined according to Japanese criteria for borderline diabetes and World Health Organization criteria for impaired fasting glucose and impaired glucose tolerance) were randomly assigned to receive either pitavastatin 2 mg/d or atorvastatin 10 mg/d for 52 weeks. Levels of serum lipids and lipoproteins and measures of glucose metabolism (fasting insulin, fasting glucose, glycosylated hemoglobin, and homeostasis model assessment for insulin resistance) were obtained at baseline and at 8, 26, and 52 weeks of treatment. The effect of study drug on glucose metabolism was evaluated as a tolerability outcome. Tolerability was further assessed based on adverse events, either spontaneously reported or elicited by questioning; physical examination findings; and clinical laboratory test results. Study physicians rated the relationship of adverse events to study medication as unrelated, suspected, or probable. RESULTS Two hundred seven patients were enrolled in the study, and efficacy was evaluated in 173 patients (88 pitavastatin, 85 atorvastatin). Thirty-four patients were excluded for reasons including failure to start medication or lack of >or=6 months of follow-up. Women accounted for 62% (108/173) of the evaluable population, which had a mean age of 63.3 years and a mean weight of 63.0 kg; 89% (154/173) had diabetes mellitus. The percent change in HDL-C levels was significantly greater in the pitavastatin group compared with the atorvastatin group (8.2 vs 2.9, respectively; P=0.031), as was the percent change in apolipoprotein (Apo) A-I (5.1 vs 0.6; P=0.019). The percent change in LDL-C levels was significantly lower with atorvastatin compared with pitavastatin (-40.1 vs -33.0, respectively; P=0.002), as were the percent changes in non-HDL-C (-37.4 vs -31.1; P=0.004), Apo B (-35.1 vs -28.2; P<0.001), and Apo E (-28.1 vs -17.8; P<0.001). The significant results for these parameters were unchanged when all 189 subjects who received>or=1 dose of study medication were included in the analysis, using last-value-carried-forward methodology. There were no significant differences between treatments with respect to the measures of glucose metabolism. Both statins appeared to be well tolerated. Adverse events occurred in 9% (9/96) of the pitavastatin group and 14% (13/93) of the atorvastatin group (P=NS). Two patients in the pitavastatin group and none in the atorvastatin group had an alanine aminotransferase value>3 times the upper limit of normal (P=NS). CONCLUSIONS In these patients with elevated LDL-C levels and glucose intolerance, 52 weeks of treatment with pitavastatin 2 mg/d was associated with significantly greater increases in HDL-C and Apo A-I levels than atorvastatin 10 mg/d. Both treatments were well tolerated.

Novel mutations in ABCA1 gene in Japanese patients with Tangier disease and familial high density lipoprotein deficiency with coronary heart disease.

Mutations in the ATP-binding cassette transporter 1 (ABCA1) gene have been recently identified as the molecular defect in Tangier disease (TD) and familial high density lipoprotein deficiency (FHA). We here report novel mutations in the ABCA1 gene in two sisters from a Japanese family with TD who have been described previously (S. Ohtaki, H. Nakagawa, N. Kida, H. Nakamura, K. Tsuda, S. Yokoyama, T. Yamamura, S. Tajima, A. Yamamoto, Atherosclerosis 49 (1983)) and a family with FHA. Both probands of TD and FHA developed coronary heart disease. Sequence analysis of the ABCA1 gene from the patients with TD revealed a homozygous G to A transition at nucleotide 3805 of the cDNA resulting in the substitution of Asp 1229 with Asn in exon 27, and a C to T at nucleotide 6181 resulting in the substitution of Arg 2021 with Trp in exon 47. Sequence analysis of the ABCA1 gene from the FHA patient revealed a homozygous 4 bp CGCC deletion from nucleotide 3787 to 3790 resulting in premature termination by frameshift at codon 1224. These mutations were confirmed by restriction digestion analysis, and were not found in 141 control subjects. Our findings indicate that mutations in the ABCA1 gene are associated with TD as well as FHA.

Effects of fenofibrate on high-density lipoprotein particle size in patients with hyperlipidemia: A randomized, double-blind, placebo-controlled, multicenter, crossover study

BACKGROUND Fenofibrate lowers serum total cholesterol and triglyceride levels while it elevates serum high-density lipoprotein cholesterol (HDL-C) level. OBJECTIVE The aim of this study was to investigate the effects of fenofibrate on the particle size of high-density lipoprotein (HDL). METHODS Patients with hyperlipidemia (as defined by serum triglyceride level > or = 150 mg/dL in the fasting state) were enrolled in this randomized, double-blind, placebo-controlled, multicenter, crossover study. Fenofibrate 300 mg (corresponding to 200 mg of micronized fenofibrate) or placebo was administered orally once daily after dinner for 8 weeks, followed by crossover of the 2 drugs for an additional 8 weeks. RESULTS Fifty hyperlipidemic patients (31 men, 19 women; mean [SD] age, 54.6 [12.7] years) were enrolled. Serum total cholesterol and triglyceride levels were significantly reduced with fenofibrate treatment compared with placebo (9.4% [P = 0.007] and 34.4% [P < 0.001], respectively), whereas HDL-C levels were significantly elevated (by 25.8% [P < 0.001]). Lipoprotein lipase (LPL) activity, LPL protein level, and hepatic triglyceride lipase activity increased by 10.5%, 13.4%, and 11.4%, respectively, with fenofibrate compared with placebo. HDL was classified into 3 groups by particle size: HDL3 <88 A; HDL2a > or = 88 A but <98 A; and HDL2b > or = 98 A. The amount of HDL3 increased significantly with fenofibrate compared with placebo (P < 0.001). Fenofibrate was well tolerated during the study. Abnormal clinical laboratory values were noted in 20 of 48 patients (41.7%), but these events were mild and not clinically significant. CONCLUSION Taken together, these findings indicate that fenofibrate therapy increased the HDL subfraction with the smallest diameter (HDL3), which is largely responsible for withdrawing cholesterol from peripheral cells.

A Comparative Study of Olmesartan and Valsartan on Insulin Sensitivity in Hypertensive Patients with Diabetes Mellitus or Impaired Glucose Tolerance (OVIS Study)

Activation of renin angiotensin system is implicated in insulin resistance. In mega trials, it has been suggested that angiotensin receptor blockers may be beneficial on insulin sensitivity in hypertensive patients. We conducted a multicenter, open-label, parallel-group trial to compare the effects of olmesartan and valsartan on insulin sensitivity and adiponectin levels in 206 hypertensive patients with diabetes mellitus or impaired glucose tolerance. Patients were randomly assigned to either olmesartan 20 mg/day or valsartan 80 mg/day treatment for 24 weeks. Blood pressure, fasting glucose, fasting insulin, glycosylated hemoglobin (HbA1c), homeostasis model assessment for insulin resistance (HOMA-IR), and serum adiponectin levels were measured. The efficacy was evaluated in 197 patients (olmesartan, n=98; valsartan, n=99). At baseline, all parameters except for systolic blood pressure (SBP) and serum triglyceride did not differ between the 2 groups. HbA1c decreased slightly after a 24-week treatment with valsartan, but not olmesartan, while the decrease did not significantly differ in the two groups. There was no difference in the change from the baseline between olmesartan and valsartan groups concerning fasting glucose, fasting insulin, HOMA-IR, and adiponectin levels after 24-week treatment. The decrease in SBP tended to be greater in the olmesartan group than in the valsartan group even with adjustment for the baseline difference. In conclusion, there was no significant difference in insulin sensitivity or adiponectin levels between the olmesartan and valsartan groups. In the standard dose, olmesartan significantly decreased SBP as compared with valsartan.

Abnormal apoproteinemia and its clinical significance

The purpose of this study is to demonstrate clinical significances, lipid composition of plasma lipoproteins, and plasma apoprotein concentrations in the patients with abnormal apoproteinemia (two apo E-3 deficiency, one patients with apo E-5, and two hypoalphalipoproteinemias). Apo E isoform was analyzed by the analytical isoelectric focusing of apo-VLDL using 7.5% of polyacrylamide gel in each subject. Plasma apo A-I, A-II, B, C-II, and E concentrations were measured by the single radial immunodifusion methods. Lipid concentrations of each plasma lipoproteins were measured after the isolation by the ultracentrifuge. Two patients with apo E-3 deficiency were type IV and II hyperlipoproteinemia, and the latter was diabetic treated with sulfonylurea. The diabetic female had a cholesterol-rich VLDL, and her plasma apo E was 12.4mg/dl, whereas another one male showed normal ratio of VLDL-TC/TG and apo E concentration. One chronic thyroidism had apo E-5, and his plasma apo E was 5.2mg/dl. However, his plasma apo B concentration was significantly higher than that of the healthy volunteers. He had no evidence of cardiovascular disease. His daughter has hyperthyroidism, but her apo E isoform was normal and plasma apo E level was also normal. One familial hypercholesterolemia and one hypertriglyceridemia showed hypo α-lipoproteinemia. Their plasma apo A-I, II were significantly lower, and apo B were markedly higher than those of the control, respectively. It is possible that the lower concentration of HDL-cholesterol can be based on the decreased HDL3-cholesterol rather than HDL2-cholesterol. The paper discuss their back grounds of abnormal apoproteinemia.

The Characteristics of Human Plasma Lipoprotein Metabolism: Influence of Low Caloric Diet on Hyperlipidemia

We have classified hyperlipidemia into three groups according to different levels of VLDL-TG, and postulated the effect of low calorie-diets on plasma TCh are as follows: 1) Low calorie-diets are effective on VLDL-TG in every type of hyperlipidemia, except hyperlipidemia with VLDL-TG under 180 mg/100ml; 2) There was a reciprocal relation between the decreased amount of plasma TCh and the change VLDL-TG induced by the diet; 3) Catabolism of VLDL was accelerated by an increased esterification of VLDL-FC; 4) In the the group with VLDL-TG less than or equal to 180 mg/100ml, the LDC showed a high level of TCh: protein ration, and in the group with VLDL-TG greater than or equal to 260 mg/100ml, there was to be low level of TG: protein ratio in VLDL: 5) In hyperlipidemia with plasma TCh unchanged by the diet LDL-TCh increased significantly without any increase in LDL protein and LDL-TG.