A randomized, double-blind, placebo-controlled study of the effect of ezetimibe on glucose metabolism in subjects with type 2 diabetes mellitus and hypercholesterolemia.

BACKGROUND: Recent evidence points to an increased incidence of new-onset diabetes and a negative impact on glucose parameters with statin use. This study examined the safety of ezetimibe vs placebo for change from baseline to week 24 in HbA1c (primary endpoint), glycoalbumin, and fasting plasma glucose (secondary endpoints) in Japanese subjects with type 2 diabetes and hypercholesterolemia. METHODS: This was a randomized, double-blind, placebo-controlled, parallel-group, multi-site trial. Adults with type 2 diabetes and hypercholesterolemia whose LDL-C measured <140 mg/dl (subjects receiving lipid-lowering drugs) or <160 mg/dl (subjects not receiving lipid-lowering drugs) at the start of the screening phase, were randomized after a 5-week wash-out period to ezetimibe 10 mg or placebo (1:1) for 24 weeks. Changes in HbA1c, glycoalbumin and fasting plasma glucose from baseline to week 24 were evaluated. The non-inferiority margin was set at 0.5% for HbA1c. RESULTS: Overall, 152 subjects were randomized (75 to ezetimibe and 77 to placebo). From baseline to 24 weeks, HbA1c significantly increased in both the ezetimibe and placebo groups (between-treatment difference 0.08 [95% CI: -0.07 to 0.23]). Ezetimibe was statistically non-inferior to placebo. At 24 weeks, the mean change from baseline in glycoalbumin levels (between-treatment differences 0.00 [95% CI: -0.47, 0.47]) and fasting plasma glucose (between-treatment differences -4.8 [95% CI: -12.1, 2.1]) were similar in both treatment groups. CONCLUSIONS: These results suggest that ezetimibe 10 mg does not result in dysregulation of glucose metabolism in Japanese patients with type 2 diabetes and hypercholesterolemia over 24 weeks of treatment. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01611883 .

Add-on effect of hydrochlorothiazide 12.5 mg in Japanese subjects with essential hypertension uncontrolled with losartan 50 mg and amlodipine 5 mg.

This study assessed the antihypertensive efficacy of a triple combination, fixed-dose therapy of losartan 50 mg (L50)/hydrochlorothiazide 12.5 mg (H12.5)/amlodipine 5 mg (A5) versus co-administration of L50 plus A5 (L50+A5) in Japanese subjects with uncontrolled essential hypertension. Initially, all subjects received single-blind treatment with L50+A5 for 8 weeks. Subjects whose blood pressure (BP) remained stable within pre-specified limits during the last 4 weeks of L50+A5 administration were randomized (n =3 27) to double-blind treatment with L50/H12.5/A5 or L50+A5 for 8 weeks. Primary and secondary efficacy endpoints were mean change from baseline to Week 8 in trough diastolic BP (DBP) and trough systolic BP (SBP), respectively. Safety was assessed throughout the study. The treatment difference for L50/H12.5/A5 versus L50+A5 in mean change from baseline in DBP at Week 8 was -1.1 mm Hg (95% confidence interval (CI) -2.7, 0.6; P = 0.205). However, the treatment difference in mean change from baseline in SBP at Week 8 was -3.2 mm Hg (95% CI: -5.7, -0.8; P=0.011). A chance imbalance in the change in DBP before randomization between groups was identified in a post-hoc analysis as a major reason for the smaller-than-expected difference in DBP between groups. The overall safety profile was generally similar between groups. In conclusion, treatment with L50/H12.5/A5 for 8 weeks did not demonstrate a significant difference in DBP reduction, but demonstrated a nominally significant difference in SBP reduction, compared with L50+A5. L50/H12.5/A5 was well tolerated. (ClinicalTrials.gov identifier NCT01302691.).

Efficacy and safety of fixed-dose losartan/hydrochlorothiazide/amlodipine combination versus losartan/hydrochlorothiazide combination in Japanese patients with essential hypertension.

Japanese patients with uncontrolled essential hypertension received single-blind losartan 50 mg/hydrochlorothiazide 12.5 mg (L50/H12.5) for 8 weeks. Patients whose blood pressure (BP) remained uncontrolled were randomized double-blind to fixed-dose losartan 50 mg/hydrochlorothiazide 12.5 mg/amlodipine 5 mg (L50/H12.5/A5) or L50/H12.5 for 8 weeks followed by open-label L50/H12.5/A5 for 44 weeks. Adverse events were assessed. After 8 weeks, diastolic and systolic BP were reduced significantly more with L50/H12.5/A5 versus L50/H12.5 (both p < 0.001). Mean changes in diastolic and systolic BP were sustained for 44 weeks. L50/H12.5/A5 was well-tolerated and improved BP significantly versus L50/H12.5 in Japanese patients with uncontrolled essential hypertension.

Efficacy and safety of losartan 100 mg/hydrochlorothiazide 12.5 mg in Japanese subjects with essential hypertension: two randomized, controlled trials.

Two randomized studies were designed to assess the safety, tolerability and efficacy of losartan 100 mg (L100) plus hydrochlorothiazide 12.5 mg (H12.5) in a single fixed-dose combination. In one study, subjects received losartan 50 mg (L50) plus H12.5 during an 8-week filter period. They were then randomized to either L100/H12.5 or L50/H12.5 for another 8 weeks, followed by L100/H12.5 for 44 weeks. The primary end point was safety of L100/H12.5 for 52 weeks. In the second study, subjects received L100 during an 8-week filter period. Subjects were then randomized to receive either L100/H12.5 or L100 for a further 8 weeks. The primary end point was change from baseline in sitting diastolic blood pressure (SiDBP) at week 8. Safety was assessed throughout both studies. L100/H12.5 reduced SiDBP and sitting systolic blood pressure (SiSBP) at 8 weeks, and when compared with L100, the differences were statistically significant for both measures (P<0.001). L100/H12.5 reductions SiDBP for 8 weeks were comparable to L50/H12.5. The efficacy of L100/H12.5 was maintained to week 52. Drug-related adverse events with an incidence ⩾ 2% in the L100/H12.5 group during the 52-week extension period were an increase in aspartate aminotransferase and in blood uric acid. Additionally, mean uric acid levels were reduced by 0.57 mg dl(-1) from baseline with long-term treatment with L100/H12.5 in subjects whose baseline uric acid level was >7.0 mg dl(-1). In conclusion, L100/H12.5 was shown to be more effective than L100 at reducing SiDBP and SiSBP and showed good tolerability in Japanese patients with essential hypertension.

Diurnal expressions of four subtypes of melatonin receptor genes in the optic tectum and retina of goldfish.

Four subtypes of melatonin receptor genes (Mel(1a) 1.4, Mel(1a) 1.7, Mel(1b), and Mel(1c)) are considered to be expressed to mediate various physiological functions of melatonin in goldfish (Carassius auratus). To examine their tissue distribution and diurnal changes in expression levels, we cloned partial gene fragments for these melatonin receptor subtypes, and established specific RT-PCR and quantitative real-time PCR systems. Mel(1a) 1.4 and Mel(1b) were predominantly expressed in various neuronal and peripheral tissues, while Mel(1a) 1.7 and Mel(1c) were expressed in the restricted tissues. All subtype genes were expressed in the optic tectum, diencephalon, mesencephalon, vagal lobe, retina and spleen. The real-time PCR analyses showed that significant differences among time were observed for Mel(1a) 1.4 in the optic tectum and for Mel(1a) 1.7 and Mel(1b) in the retina. In the retina, the levels of Mel(1a) 1.7 and Mel(1b) mRNAs showed diurnal changes with one peak at ZT24. The present results show differential distribution of four subtypes of melatonin receptor mRNAs in the neuronal and peripheral tissues. However, the expressions of all subtype genes in the retinorecipient brain regions and retina reinforce the role of the melatonin receptor in processing visual information. Furthermore, the present study demonstrates diurnal expressions of the major subtype genes, i.e. Mel(1a) 1.4 in the optic tectum and Mel(1a) 1.7 in the retina.

Two osteoclastic markers expressed in multinucleate osteoclasts of goldfish scales.

Complementary DNAs encoding two major osteoclastic markers, tartrate-resistant acid phosphatase (TRAP) and cathepsin K (Cath K) were cloned from the scales of a teleost, the goldfish. This is the first report of the full coding sequence of TRAP and Cath K molecules in fish. In the goldfish scale both TRAP and Cath K mRNAs were expressed in the multinucleate osteoclasts, which showed large numbers of mitochondria and lysosomes, and a well developed ruffled border. These characteristic features of osteoclasts in the scales are similar to those in mammals. Most teleosts use the scale as an internal calcium reservoir during the reproductive season. The expression of TRAP and Cath K mRNAs in the scale significantly increased in April, which is a reproductive season, compared with that in October, a non-reproductive season. Thus, both of these molecular markers should be useful for the study of osteoclasts in the teleost scale.