Ezetimibe Lipid-Lowering Trial on Prevention of Atherosclerotic Cardiovascular Disease in 75 or Older (EWTOPIA 75): A Randomized, Controlled Trial.

BACKGROUND: Evidence regarding the primary prevention of coronary artery disease events by low-density lipoprotein cholesterol (LDL-C) lowering therapy in older individuals, aged ≥75 years, is insufficient. This trial tested whether LDL-C-lowering therapy with ezetimibe is useful for the primary prevention of cardiovascular events in older patients. METHODS: This multicenter, prospective, randomized, open-label, blinded end-point evaluation conducted at 363 medical institutions in Japan examined the preventive efficacy of ezetimibe for patients aged ≥75 years, with elevated LDL-C without history of coronary artery disease. Patients, who all received dietary counseling, were randomly assigned (1:1) to receive ezetimibe (10 mg once daily) versus usual care with randomization stratified by site, age, sex, and baseline LDL-C. The primary outcome was a composite of sudden cardiac death, myocardial infarction, coronary revascularization, or stroke. RESULTS: Overall, 3796 patients were enrolled between May 2009 and December 2014, and 1898 each were randomly assigned to ezetimibe versus control. Median follow-up was 4.1 years. After exclusion of 182 ezetimibe patients and 203 control patients because of lack of appropriate informed consent and other protocol violations, 1716 (90.4%) and 1695 (89.3%) patients were included in the primary analysis, respectively. Ezetimibe reduced the incidence of the primary outcome (hazard ratio [HR], 0.66; 95% CI, 0.50-0.86; P=0.002). Regarding the secondary outcomes, the incidences of composite cardiac events (HR, 0.60; 95% CI, 0.37-0.98; P=0.039) and coronary revascularization (HR, 0.38; 95% CI, 0.18-0.79; P=0.007) were lower in the ezetimibe group than in the control group; however, there was no difference in the incidence of stroke, all-cause mortality, or adverse events between trial groups. CONCLUSIONS: LDL-C-lowering therapy with ezetimibe prevented cardiovascular events, suggesting the importance of LDL-C lowering for primary prevention in individuals aged ≥75 years with elevated LDL-C. Given the open-label nature of the trial, its premature termination and issues with follow-up, the magnitude of benefit observed should be interpreted with caution. Clinical Registration: URL: https://www.umin.ac.jp. Unique identifier: UMIN000001988.

Effect of losartan on serum uric acid in hypertension treated with a diuretic: the COMFORT study.

It has been shown that losartan, an angiotensin II receptor blocker (ARB), reduces serum uric acid levels. However, the effects of losartan on serum uric acid levels in the patients treated with a thiazide diuretic have not been fully elucidated. We have investigated the effects of losartan compared with other ARBs on blood variables and blood pressure control in hypertensive patients treated with a thiazide diuretic using data from the COMFORT study. The present analysis included a total of 118 hypertensive subjects on combination treatment with ARBs except for losartan and a diuretic who were randomly assigned to a daily regimen of a combination pill (losartan 50 mg/hydrochlorothiazide 12.5 mg) or to continuation of two pills, an ARB except for losartan and a diuretic. Blood pressures were evaluated at 1, 3, and 6 months after randomization and changes in blood variables including serum uric acid were evaluated during 6 months treatment period. Mean follow-up blood pressure levels were not different between the combination pill (losartan treatment) group and the control (ARBs except for losartan) group. On the other hand, serum uric acid significantly decreased in the combination pill group compared with the control group (-0.44 versus + 0.10 mg/dl; p = 0.01), although hematocrit, serum creatinine, sodium and potassium were not different between the groups. These results suggest that the treatment regimen switched from a combination therapy of ARBs except for losartan and a diuretic to a combination pill (losartan/ hydrochlorothiazide) decreases serum uric acid without affecting blood pressure control.

Does a combination pill of antihypertensive drugs improve medication adherence in Japanese? A randomized controlled trial.

BACKGROUND: In order to achieve target blood pressure levels to prevent cardiovascular disease, combination therapy of antihypertensive drugs is often required, although it is thought that requiring a patient to take many different pills would reduce adherence to the medication regimen. Whether antihypertensive treatment with a single pill combining antihypertensive drugs would improve medication adherence and blood pressure control was investigated. METHODS AND RESULTS: A total of 207 hypertensive subjects were randomly assigned to a combination pill group (losartan 50mg/hydrochlorothiazide 12.5mg; n=103) or a control group (an angiotensin receptor blocker and a thiazide diuretic; n=104). Medication adherence was evaluated by pill counts at 1, 3, and 6 months after randomization. The mean adherence rates over 6 months were not different between the 2 groups: 98% in the combination pill group and 98% in the control group. Moreover, the 2 groups included similar numbers of subjects with relatively poor adherence rates (<90%) in each treatment period. The mean blood pressures over the 6-month treatment period were not different between the groups: 131/75 mmHg in the combination pill group and 130/75 mmHg in the control group (P=0.84/0.96). CONCLUSIONS: There were no appreciable effects of the combination pill of antihypertensive drugs on medication adherence or blood pressure control in Japanese patients over a 6-month period.

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.

Comparison of three α-glucosidase inhibitors for glycemic control and bodyweight reduction in Japanese patients with obese type 2 diabetes.

AIMS/INTRODUCTION: α-Glucosidase inhibitors (αGIs) are widely used for the primary treatment of type 2 diabetes. We compared the clinical effects of three αGIs (miglitol, acarbose and voglibose) in patients with obese type 2 diabetes. MATERIALS AND METHODS: Japanese patients (n = 81) with obese type 2 diabetes (body mass index [BMI] ≥25 kg/m(2)) were enrolled in this multicenter, open-label study. The participants were randomized into the miglitol (n = 18), acarbose (n = 22), voglibose (n = 19) or control (n = 22) groups. Glycemic control (fasting blood glucose and glycated hemoglobin [HbA1c]), bodyweight, BMI, serum insulin, serum lipids (low-density lipoprotein and high-density lipoprotein cholesterol, and triacylglycerols) and adipocytokines (leptin and adiponectin) were evaluated every 4 weeks for 12 weeks. RESULTS: In the miglitol group, HbA1c was improved significantly from the baseline at all points. The changes in HbA1c at 8 and 12 weeks from baseline were greater in the miglitol group than the control group. The voglibose group showed significant improvements in HbA1c at 12 weeks. Bodyweight and BMI were decreased significantly in the miglitol group. In addition, significant correlations were observed between the decrements in HbA1c and bodyweights over 12 weeks in the miglitol (r = 0.759, P < 0.001) and voglibose groups (r = 0.667, P = 0.002). Serum lipid and adipocytokine levels were not altered in any groups. CONCLUSIONS: αGIs, especially miglitol, can effectively control blood glucose and bodyweight in obese type 2 diabetes. This study was registered with UMIN (no. UMIN000006465).

Effects of pravastatin and atorvastatin on HDL cholesterol and glucose metabolism in patients with dyslipidemia and glucose intolerance: the PRAT study.

AIMS: While statins have the property of increasing high-density lipoprotein cholesterol (HDL-C) in addition to lowering low-density lipoprotein cholesterol (LDL-C), a potential adverse effect on glucose metabolism has raised a concern over statin therapy. In a comparative trial, we investigated the effects of low-dose pravastatin and atorvastatin on HDL-C and glucose metabolism in patients with elevated LDL-C levels and glucose intolerance. METHODS: Eligible patients were men aged ≥20 years or postmenopausal women who had LDL-C ≥140 mg/dL, HDL-C <80 mg/dL, and triglycerides <500 mg/dL and who had glucose intolerance. The patients were randomly allocated to either pravastatin (10 mg/day) or atorvastatin (10 mg/day) treatment for 12 months in an unblinded fashion. The percent changes from the baseline were compared between the treatments. RESULTS: Of 202 patients who were randomized to either of the two treatments, 195 patients started the study medication, and 187 patients underwent the follow-up measurements at 6 or 12 months (pravastatin, n= 93; atorvastatin, n= 94). HDL-C increased by 4.3% (p= 0.03) in the pravastatin group and by 5.8% (p=0.0005) in the atorvastatin group and showed no between-group difference (p= 0.38). LDL-C decreased substantially in both groups (pravastatin, 21.5%; atorvastatin, 35.5%), and the decrease was much greater in the atorvastain group (p<0.0001). HbA1c slightly increased in both groups, but showed no measurable difference in the increase between the two treatments (p=0.30). CONCLUSION: Pravastatin and atorvastatin of 10 mg per day each increased HDL-C by almost the same extent. These two statins did not show a differential effect on glucose metabolism.

Double-dose pravastatin versus add-on ezetimibe with low-dose pravastatin - effects on LDL cholesterol, cholesterol absorption, and cholesterol synthesis in Japanese patients with hypercholesterolemia (PEAS study).

AIM: This study compared the effect of doubling the dose of pravastatin with that of adding ezetimibe to low-dose pravastatin on the LDL cholesterol (LDL-C) level and on cholesterol absorption and synthesis markers. The tolerability of the 2 regimens was also compared. METHODS: This was a multicenter, open-label, parallel-group trial. Subjects were aged from 20 to 74 years and had an LDL-C ≥ 120 mg/dL despite pravastatin therapy at 5-10 mg/day. They were randomly allocated to receive either add-on ezetimibe (10 mg/day) or double-dose pravastatin, and follow-up was performed for 12 weeks. The primary endpoints were the changes of LDL-C and apolipoprotein (apo) B levels after 12 weeks of treatment. Cholesterol absorption and synthesis markers were also determined. RESULTS: LDL-C and apo B decreased by 16% and 14% in the ezetimibe add-on group versus 5.9% and 4.4%, respectively, in the pravastatin double-dose group. The between-group differences of these decreases were highly significant. Cholesterol absorption markers (sitosterol, campesterol, and cholestanol) were reduced by 48%, 36%, and 10%, respectively, in the ezetimibe add-on group, and were increased by 17%, 14%, and 6%, respectively, in the pravastatin double-dose group. Lathosterol (a cholesterol synthesis marker) increased by 76% in the ezetimibe add-on group and by 24% in the pravastatin double-dose group. The difference was statistically significant. No serious adverse effect was observed in either group. CONCLUSIONS: Adding ezetimibe to low-dose pravastatin achieves greater decreases in LDL-C, apo B, and cholesterol absorption markers than doubling the dose of pravastatin.

Is the reno-protective effect of valsartan dose dependent? A comparative study of 80 and 160 mg day(-1).

Whether the reno-protective effect of angiotensin receptor blockers is dose dependent is unknown for the Japanese population. We sought to elucidate the dose-dependent reno-protective effects of valsartan in Japanese hypertensive patients with albuminuria. This was a multi-center, open-label, parallel-group trial. A total of 181 patients were randomized to receive either 80 (n=89) or 160 mg day(-1) (n=92) of valsartan for 24 weeks. Then, the effects on blood pressure, urinary albumin excretion (UAE), type IV collagen and beta(2)-microglobulin (beta2MG) were determined. Systolic and diastolic blood pressures decreased substantially by almost the same extent in the low-dose and high-dose groups, showing no inter-group difference during the treatment. The UAE value decreased significantly by 35% in both groups. Urinary excretion of beta2MG was significantly decreased in the high-dose group (17%), but not in the low-dose group (13%), although the decrease was not significantly different between the two groups (P=0.74). Urinary excretion of type IV collagen decreased non-significantly by 10% in the low-dose group and by 8% in the high-dose group, showing no significant inter-group difference (P=0.78). Low (80 mg day(-1)) and high (160 mg day(-1)) doses of valsartan showed a similar effect of lowering blood pressure. The high dose of valsartan resulted in a slightly greater decrease in urinary beta2MG, but it was inconclusive whether the high dose was more reno-protective as compared with the low dose.