Increase in glycemic set point, alongside a decrease in waist circumference, in the non-diabetic population during the Japanese National Intervention Program for metabolic syndrome: A single-center, large-scale, matched-pair analysis.

BACKGROUND: In 2008, the Japanese government implemented a National Intervention Program for metabolic syndrome. Low-risk individuals were not direct targets of this intervention. Nevertheless, they were indirectly enlightened by this massive campaign. Documentation of the metabolic shifts in low-risk individuals following the program launch may inform public health policy regarding approaches to metabolic risks in the general population. METHODS: We conducted a cross-sectional analysis of data from non-diabetic participants who underwent general health check-ups at the Physical Check-up Center of Sumitomo Hospital. Participants during 2007-2008 were pair-matched with those during 2015-2016 with respect to sex, age, smoking status, hemoglobin level, and red blood cell (RBC) count. Each participant was included only once in the study. RESULTS: Totals of 3,140 men and 2,048 women were pair-matched. The non-diabetic participants showed lower waist circumference, blood pressure, heart rate, and serum lipid concentrations during the second study period. In contrast, the entire distributions of fasting plasma glucose (FPG) concentration in both sexes and glycated hemoglobin (HbA1c) in women were shifted upwards. In men, Δ FPG was +1.6 mg/dL (P < 0.001) and Δ HbA1c was ±0% (P = 0.6). In women, Δ FPG was +3.0 mg/dL (P < 0.001), and Δ HbA1c was +0.1% (P < 0.001). Δ Homeostasis model assessment of ß-cell function was -6.6 in men (P < 0.001) and -10.3 in women (P < 0.001). The homeostasis model assessment of insulin resistance did not change significantly. CONCLUSIONS: The "glycemic set point" has increased in non-diabetic people in Japan during recent years. Lifestyle or environmental changes may have caused this metabolic shift through obesity-independent pathways, possibly through effects on pancreatic ß-cell function. The underlying mechanism awaits further investigation.

Probucol Trial for Secondary Prevention of Atherosclerotic Events in Patients with Coronary Heart Disease (PROSPECTIVE).

AIMS: Although intensive statin therapy reduced cardiovascular risks, cardiovascular events have not been completely prevented. Probucol is a potent antioxidant and reduces tendon xanthomas in familial hypercholesterolemia patients despite reduction of high-density lipoprotein (HDL)-cholesterol (HDL-C). We investigated whether probucol can reduce cardiovascular events on top of conventional lipid-lowering therapy in patients with coronary heart disease (CHD). METHODS: PROSPECTIVE is a multicenter, randomized, prospective study that recruited 876 Japanese patients with CHD and dyslipidemia with a low-density lipoprotein (LDL)-cholesterol (LDL-C) level of ≥ 140 mg/dL without medication or those treated with lipid-lowering drugs. Lipid-lowering agents were administered during the study period in the control group (n=438), and probucol 500 mg/day was added to lipid-lowering therapy in the probucol group (n=438). Patients were randomly assigned to two treatment groups by adjusting the LDL-C level and presence of diabetes and hypertension and followed up for more than 3 years. The primary end point was a composite of cerebrovascular and cardiovascular events (cardiovascular disease death including sudden death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina, hospitalization for heart failure, or coronary revascularization). The secondary end point was carotid intima-media thickness in a subset of patients. RESULTS: The incidence of the primary end point showed a trend to be lower in the probucol group compared with that in the control group despite reduced HDL-C without serious adverse events. Anti-atherogenic effects of probucol may be attributed to its potent antioxidative function and enhancement of reverse cholesterol transport. CONCLUSION: Since there was no statistical significance between the probucol and control groups despite a marked reduction of HDL-C, further studies on the clinical outcomes of probucol on top of conventional therapy may be necessary in the future (UMIN000003307).

Cholesteryl ester transfer protein: An enigmatic pharmacology - Antagonists and agonists.

The cholesteryl ester transfer protein (CETP) system moves cholesteryl esters (CE) from high density lipoproteins (HDL) to lower density lipoproteins, i.e. very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) in exchange for triglycerides (TGs). This shuttle process will ultimately form complexes facilitating a bidirectional exchange of CE and TGs, the end process being CE delivery to catabolic sites. The CETP system is generally characteristic of higher animal species; lower species, not provided with this system, have higher and enlarged HDL enriched with apo E, suitable for tissue receptor interaction. Discovery of the CETP system has led to the development of agents interfering with CETP, thus elevating HDL-C and potentially preventing cardiovascular (CV) disease. Activation of CETP leads instead to reduced HDL-C levels, but also to an enhanced removal of CE from tissues. CETP antagonists are mainly small molecules (torcetrapib, anacetrapib, evacetrapib, dalcetrapib) and have provided convincing evidence of a HDL-C raising activity, but disappointing results in trials of CV prevention. In contrast, the CETP agonist probucol leads to HDL-C lowering followed by an increment of tissue cholesterol removal (reduction of xanthomas, xanthelasmas) and positive findings in secondary prevention trials. The drug has an impressive anti-inflammatory profile (markedly reduced interleukin-1ß expression). Newer agents, some of natural origin, have additional valuable pharmacodynamic properties. The pharmacological approach to the CETP system remains enigmatic, although the failure of CETP antagonists has dampened enthusiasm. Studies on the system, a crossroad for any investigation on cholesterol metabolism, have however provided crucial contributions and will still be confronting any scientist working on CV prevention.

Accelerated Atherogenicity in Tangier Disease.

We report a case of Tangier disease with Leriche syndrome and bleeding tendency. In this male patient, nasal hemorrhage had been observed frequently throughout childhood. At 46 years old, he experienced effort angina, and coronary angiography demonstrated 75% stenosis in the right coronary artery. Orange-colored tonsils, mild hepatosplenomegaly and very low levels of serum high-density lipoprotein cholesterol (HDL-C) were observed, and the patient was diagnosed with Tangier disease. At 52 years old, effort angina recurred. Coronary angiography revealed 75% stenosis of the left main trunk, left anterior descending, and right coronary arteries. Stenosis of the brachiocephalic and right common iliac arteries was also recorded. Stents were implanted, and coronary artery bypass surgery was performed. At 53 years old, 15 months after surgery, the patient reported intermittent claudication, coldness of feet, and impotence. Aortic angiography showed progression of the stenosis at the bifurcation of the common iliac artery. The patient was diagnosed with Leriche syndrome, and aorta-left external iliac artery graft bypass surgery was performed. After surgery, oozing from subcutaneous tissue and leaking from the anastomotic region were observed. Additional analysis revealed two single-nucleotide polymorphisms (V825I and N935T) in the ATP-binding cassette transporter A1 (ABCA1) gene, and accumulation of small dense low-density lipoprotein together with low levels of HDL-C. In Tangier disease, HDL-C is markedly decreased because of ABCA1 deficiency. However, this is the first reported case to exhibit extensive atherosclerosis and bleeding tendency. This patient had atypical extensive and multiple atherosclerotic lesions, accompanied by Leriche syndrome and uncontrollable bleeding.

Obesity.

Excessive fat deposition in obesity has a multifactorial aetiology, but is widely considered the result of disequilibrium between energy intake and expenditure. Despite specific public health policies and individual treatment efforts to combat the obesity epidemic, >2 billion people worldwide are overweight or obese. The central nervous system circuitry, fuel turnover and metabolism as well as adipose tissue homeostasis are important to comprehend excessive weight gain and associated comorbidities. Obesity has a profound impact on quality of life, even in seemingly healthy individuals. Diet, physical activity or exercise and lifestyle changes are the cornerstones of obesity treatment, but medical treatment and bariatric surgery are becoming important. Family history, food environment, cultural preferences, adverse reactions to food, perinatal nutrition, previous or current diseases and physical activity patterns are relevant aspects for the health care professional to consider when treating the individual with obesity. Clinicians and other health care professionals are often ill-equipped to address the important environmental and socioeconomic drivers of the current obesity epidemic. Finally, understanding the epigenetic and genetic factors as well as metabolic pathways that take advantage of 'omics' technologies could play a very relevant part in combating obesity within a precision approach.

A Novel Mutation in the type Iα Regulatory Subunit of Protein Kinase A (PRKAR1A) in a Cushing's Syndrome Patient with Primary Pigmented Nodular Adrenocortical Disease.

A 40-year-old man presented with Cushing's syndrome due to bilateral adrenal hyperplasia with multiple nodules. Computed tomography scan results were atypical demonstrating an enlargement of the bilateral adrenal glands harboring multiple small nodules, but the lesion was clinically diagnosed to be primary pigmented nodular adrenocortical disease (PPNAD) based on both endocrinological test results and his family history. We performed bilateral adrenalectomy and confirmed the diagnosis histologically. An analysis of the patient and his mother's genomic DNA identified a novel mutation in the type Iα regulatory subunit of protein kinase A (PRKAR1A) gene; p.E17X (c.49G>T). This confirmed the diagnosis of PPNAD which is associated with Carney Complex.

Rationale and Design of the PROSPECTIVE Trial: Probucol Trial for Secondary Prevention of Atherosclerotic Events in Patients with Prior Coronary Heart Disease.

BACKGROUND: Reduction of serum LDL-cholesterol by statins was shown to improve clinical outcomes in patients with coronary heart disease (CHD). Although intensive statin therapy significantly reduced cardiovascular risks, atherosclerotic cardiovascular events have not been completely prevented. Therefore, effective pharmacologic therapy is necessary to improve "residual risks" in combination with statins. Probucol has a potent antioxidative effect, inhibits the oxidation of LDL, and reduces xanthomas. Probucol Trial for Secondary Prevention of Atherosclerotic Events in Patients with Prior Coronary Heart Disease (PROSPECTIVE) is a multicenter, randomized, prospective study designed to test the hypothesis that the addition of probucol to other lipid-lowering drugs will prevent cerebro- and cardiovascular events in patients with prior coronary events and high LDL cholesterol levels. STUDY DESIGN: The study will recruit approximately 860 patients with a prior CHD and dyslipidemia with LDL-C level ≥140 mg/dl without any medication and those treated with any lipid-lowering drugs with LDL-C level ≥100 mg/dl. Lipid-lowering agents are continuously administered during the study period in control group, and probucol (500 mg/day, 250 mg twice daily) is added to lipid-lowering therapy in the test group. The efficacy and safety of probucol with regard to the prevention of cerebro- and cardiovascular events and the intima-media thickness of carotid arteries as a surrogate marker will be evaluated. SUMMARY: PROSPECTIVE will determine whether the addition of probucol to other lipid-lowering drugs improves cerebro- and cardiovascular outcomes in patients with prior coronary heart disease. Furthermore, the safety of a long-term treatment with probucol will be clarified.

Did we abandon probucol too soon?

PURPOSE OF REVIEW: Probucol is a potent antioxidative drug that has been used for prevention and treatment of atherosclerotic cardiovascular diseases and xanthoma. Probucol has been used as a lipid-lowering drug for a long time especially in Japan, although Western countries quitted its use because of the reduction in serum HDL-cholesterol (HDL-C). This review highlights both basic and clinical studies that provide new insights into the pleiotropic effects of probucol. RECENT FINDINGS: Recently, the mechanisms for the pharmacologic actions of probucol have been elucidated at the molecular level with a special focus on HDL metabolism and its functions. Probucol enhances plasma cholesteryl ester transfer protein activity and hepatic scavenger receptor class B type I, causing a decrease in HDL-C. It also accelerates the antioxidative function of HDL via increase in paraoxonase 1 activity. Recent retrospective analyses of probucol-treated patients with heterozygous familial hypercholesterolemia and those after coronary revascularization demonstrated a strong beneficial effect of probucol on secondary prevention of cardiovascular events and mortality. SUMMARY: Probucol has pleiotropic and beneficial therapeutic effects on cardiovascular system. Although statins are effective for lowering LDL-cholesterol (LDL-C) and reducing coronary heart disease risk, probucol should be considered as an option in case statins are not effective.

Maltitol Prevents the Progression of Fatty Liver Degeneration in Mice Fed High-Fat Diets.

Nonalcoholic fatty liver disease (NAFLD) progresses to nonalcoholic steatohepatitis, ultimately leading to cirrhosis and liver cancer. It is important to prevent this progression during the initial stages of hepatic fatty degeneration. Maltitol is a polyol produced by the hydrogenation of maltose. We investigated the efficacy of maltitol for treating hepatic fatty degeneration in C57BL/6 male mice using a high-fat diet model. Intake of 5.0% maltitol for 8 weeks significantly suppressed weight gain, hepatic fatty degeneration, hyperglycemia, and hypercholesterolemia. With maltitol intake, sterol regulatory element-binding protein 1c (SREBP1c) mRNA expression was significantly decreased, and farnesoid X receptor (FXR), peroxisome proliferator-activated receptor α (PPARα), and hydroxymethylglutaryl-Co reductase expressions were significantly higher in the liver. The increase in SREBP1c and suppression of FXR and PPARα expressions are correlated with NAFLD. Our results suggest that maltitol may prevent steatosis of NAFLD with a high-fat diet.

Resolution of gelatinous bone marrow transformation following hormone replacement therapy in a patient with primary insufficiency of the adrenal and thyroid glands.

A 59-year-old man with recurrent oral cancer presented with severe pancytopenia, hyponatremia and hypoglycemia. Endocrine testing showed a partial primary adrenal insufficiency and primary hypothyroidism. The bone marrow biopsy showed a gelatinous transformation with hypocellularity and fat atrophy. His pancytopenia, hyponatremia and hypoglycemia resolved following treatment with corticosteroids and thyroid hormone replacement therapy. The follow-up bone marrow biopsy demonstrated a resolution of the gelatinous transformation. This case is a rare example of a patient with a primary insufficiency of the adrenal and thyroid glands that is associated with gelatinous bone marrow transformation (GMT). The GMT was resolved through the administration of corticosteroids and thyroid hormone replacement therapy.

NUDT3 rs206936 is associated with body mass index in obese Japanese women.

The predominant risk factor of metabolic syndrome is intra-abdominal fat accumulation, which is determined by waist circumference, waist-hip ratio measurements and visceral fat area (VFA); the latter can be accurately measured by performing computed tomography (CT). In addition to environmental factors, genetic factors play an important role in obesity and fat distribution. New genetic loci associated with body mass index (BMI) and adiposity have been identified by genome-wide association studies (GWASs). This study utilized CT to investigate whether single nucleotide polymorphisms (SNPs) that confer susceptibility to higher BMI are associated with VFA, subcutaneous fat area (SFA), and the ratio of VFA to SFA (V/S ratio). We measured the VFA and SFA of 1424 obese Japanese subjects (BMI ≥ 25 kg/m(2), 635 men and 789 women) who were genotyped for 13 single nucleotide polymorphisms (SNPs) reported by recent GWASs, namely, TNNI3K rs1514175, PTBP2 rs1555543, ADCY3 rs713586, IRS1 rs2943650, POC5 rs2112347, NUDT3 rs206936, LINGO2 rs10968576, STK33 rs4929949, MTIF3 rs4771122, SPRY2 rs534870, MAP2K5 rs2241423, QPCTL rs2287019, and ZC3H4 rs3810291. The G-allele of NUDT3 rs206936 was significantly associated with increased BMI (P = 5.3 × 10(-5)) and SFA (P = 0.00039) in the obese Japanese women. After adjustment with BMI, the association between rs206936 and SFA was not observed. This significant association was not observed in the men. The other SNPs analyzed were not significantly associated with BMI, VFA, SFA, or V/S ratio. Our results suggest that NUDT3 rs206936 is associated with BMI in Japanese women.

Gene expression levels of S100 protein family in blood cells are associated with insulin resistance and inflammation (Peripheral blood S100 mRNAs and metabolic syndrome).

OBJECTIVE: Visceral fat obesity is located upstream of metabolic syndrome and atherosclerotic diseases. Accumulating evidences indicate that several immunocytes including macrophages infiltrate into adipose tissue and induce chronic low-grade inflammation. We recently analyzed the association between visceral fat adiposity and the gene expression profile in peripheral blood cells in human subjects and demonstrated the close relationship of visceral fat adiposity and disturbance of circadian rhythm in peripheral blood cells. In a series of studies, we herein investigated the association of visceral fat adiposity and mRNA levels relating to inflammatory genes in peripheral blood cells. APPROACH AND RESULTS: Microarray analysis was performed in peripheral blood cells from 28 obese subjects. Reverse transcription-polymerase chain reaction (RT-PCR) was conducted by using blood cells from 57 obese subjects. Obesity was defined as body mass index (BMI) greater than 25 kg/m2 according to the Japanese criteria. Gene expression profile analysis was carried out with Agilent whole human genome 4×44K oligo-DNA microarray. Gene ontology (GO) analysis showed that 14 genes were significantly associated with visceral fat adiposity among 239 genes relating to inflammation. Among 14 genes, RT-PCR demonstrated that S100A8, S100A9, and S100A12 positively correlated with visceral fat adiposity in 57 subjects. Stepwise multiple regression analysis showed that S100A8 and S100A12 mRNA levels were closely associated with HOMA-IR and S100A9 mRNA was significantly related to adiponectin and CRP. CONCLUSIONS: Peripheral blood mRNA levels of S100 family were closely associated with insulin resistance and inflammation.

Anti-inflammatory and anti-atherogenic properties of adiponectin.

Obesity-related disorders, such as insulin resistance, hypertension and atherosclerosis, are associated with chronic inflammation. Adiponectin is an adipocyte-derived secreted factor that is down-regulated in obese states. Adiponectin exerts the protective actions on obesity-linked diseases, such as insulin resistance and atherosclerosis by attenuating chronic inflammation in its target organs. Adiponectin also exerts the salutary effects on vascular disorders by directly acting on vascular component cells including endothelial cells, smooth muscle cells and macrophages. This review will focus on the role of adiponectin in control of inflammatory responses and atherogenic processes.

Visceral adiposity as a target for the management of the metabolic syndrome.

Atherosclerosis, the underlying cause of atherosclerotic cardiovascular disease (ACVD), develops due not only to a single cardiovascular risk factor but to a variety of complex factors. The concept of the multiple cardiometabolic risk factor clustering syndrome has been proposed as a highly atherogenic state, independent of hypercholesterolemia and smoking. Body fat distribution, especially visceral fat accumulation, is a major correlate of a cluster of diabetogenic, atherogenic, prothrombotic, and proinflammatory metabolic abnormalities referred to as the metabolic syndrome, with dysfunctional adipocytes and dysregulated production of adipocytokines (hypoadiponectinemia). Medical research has focused on visceral adiposity as an important component of the syndrome in Japanese subjects with a mild degree of adiposity compared with Western subjects. For the prevention of ACVD at least in Japan, it might be practical to stratify subjects with multiple risk factors for atherosclerotic cardiovascular disease based on visceral fat accumulation. Visceral fat reduction through health promotion programs using risk factor-oriented approaches may be effective in reducing ACVD events, as well as producing improvement in risks and hypoadiponectinemia. This review article discusses visceral adiposity as a key player in the syndrome. Visceral fat reduction with life-style modification is a potentially useful strategy in the prevention of ACVD in patients with the metabolic syndrome.

Relationship between serum cystatin C and serum adiponectin level in type 2 diabetic patients.

BACKGROUND: To investigate the relationship between serum levels of cystatin C and adiponectin in patients with type 2 diabetes. METHODS: We examined serum cystatin C and adiponectin levels in 234 patients with type 2 diabetes who visited our hospital. RESULTS: The serum level of cystatin C was positively correlated with age (P < 0.001), duration of diabetes (P = 0.013), serum creatinine (P < 0.001), uric acid (P < 0.001), and adiponectin (p = 0.001), while it was inversely correlated with estimated glomerular filtration rate (P < 0.001). Serum adiponectin was significantly higher in patients with high serum cystatin C levels than in those with normal cystatin C levels (8.3 ± 4.7 and 6.2 ± 3.2 µg/mL, respectively; P < 0.001). Adiponectin was also significantly higher in male patients with high cystatin C levels, but not in females. In multiple regression analysis, serum adiponectin was also independently and significantly correlated to age, diastolic blood pressure, high-density lipoprotein cholesterol, triglyceride and serum cystatin C. CONCLUSIONS: Serum adiponectin level was correlated with serum cystatin C level on simple and multiple regression analyses in patients with type 2 diabetes. Although circulating adiponectin is increased in advanced kidney disease, it might be biologically inactive due to binding to cystatin C and thus not display an anti-arteriosclerotic effect.

Association of low serum adiponectin levels with erosive esophagitis in men: an analysis of 2405 subjects undergoing physical check-ups.

BACKGROUND: Obesity is a risk factor for gastro-esophageal reflux disease (GERD). It is generally considered that intra-abdominal pressure in obese subjects is involved in the pathogenesis of GERD through acid exposure to the esophagus. Recently, visceral fat has been recognized as an endocrine organ that secretes various adipocytokines including adiponectin. The aim of this study was to elucidate the relation between adiponectin and erosive esophagitis. METHODS: This was a cross-sectional retrospective observational study: 2405 consecutive subjects who underwent screening esophago-gastro-duodenoscopy with serum adiponectin measurement as part of their physical check-up programs were analyzed. Clinical factors were compared between subjects with and without erosive esophagitis. The association between adiponectin and erosive esophagitis was assessed using a bootstrapping re-sampling method after adjustment for factors that tended to be different in univariate analysis. RESULTS: Serum adiponectin levels were significantly lower in those with erosive esophagitis (8.17 µg/ml) than in those without (10.1). The erosive esophagitis group had a greater body mass index (BMI) and waist circumference (WC) and a higher prevalence of hiatal hernia. Using the bootstrap method, with a lower adiponectin cut-off value of 3-7 µg/ml, the lower limit of the 95% confidence interval of the adjusted odds ratio consistently exceeded 1 after adjustment for BMI and hiatal hernia in men. When adjusting for WC instead of BMI, the effect of adiponectin was reduced but remained significant at a lower cut-off value (3-3.5 µg/ml). CONCLUSIONS: Low serum adiponectin levels may be associated with an increased risk for erosive esophagitis in men.

Adiponectin: an independent risk factor for coronary heart disease in men in the Framingham offspring Study.

OBJECTIVE: Our aim was to determine whether plasma adiponectin levels were an independent predictor of coronary heart disease (CHD) risk. METHODS AND RESULTS: Plasma adiponectin levels were measured in 3188 male and female participants from cycle 6 of the Framingham offspring Study (mean age: 57 years in both men and women; BMI: 28.5 kg/m(2) in men and 27.3 kg/m(2) in women), using a novel fully automated assay. Plasma adiponectin levels (median [25th percentile, 75th percentile]) were significantly higher in female than in male CHD-free subjects (14.8 [10.7,20.5] µg/ml versus 9.0 [7.0,12.2] µg/ml, p<0.001). Participants were followed for a mean of 7.5 years. After adjustment for age, BMI, smoking status, systolic blood pressure, treatment for hypertension, diabetes, use of cholesterol-lowering medication, total cholesterol level, high-density lipoprotein cholesterol level, and C-reactive protein levels, a higher plasma adiponectin level was a significant predictor of lower risk of future CHD events (n=117) in men (HR 0.49, p<0.0022). A similar trend was observed in women, but was no longer significant after multivariate adjustments. CONCLUSIONS: Our data indicate that plasma adiponectin levels are an independent predictor of CHD in Caucasian men initially free of CHD.

An allopurinol-controlled, randomized, double-dummy, double-blind, parallel between-group, comparative study of febuxostat (TMX-67), a non-purine-selective inhibitor of xanthine oxidase, in patients with hyperuricemia including those with gout in Japan: phase 3 clinical study.

BACKGROUND: Allopurinol has been widely used for treatment of hyperuricemia, however, it may be associated with various adverse effects. Febuxostat is potentially a safe and efficacious alternative. OBJECTIVES: Febuxostat or allopurinol was administered to patients with hyperuricemia including gout for 8 weeks to compare the efficacy and safety of these drugs. METHODS: Doses of febuxostat and allopurinol were 10 and 100 mg/d, respectively, during a 12-day introduction period and were increased to 40 and 200 mg/d for the subsequent treatment period of 44 days. RESULTS: : The percent changes in serum uric acid levels after 8 weeks were -40.75% for the febuxostat group and -34.41% for the allopurinol group (P < 0.001, analysis of variance, closing testing procedure). The percentage of patients achieving serum uric acid levels 6.0 mg/dL or less after 8 weeks was 82.0% for the febuxostat group and 70.0% for the allopurinol group (P = 0.019, logistic regression analysis). Regarding safety, 213 adverse events were observed in the febuxostat group and 220 events in the allopurinol group. For 10 patients (8.2%) in the febuxostat group and 14 patients (11.6%) in the allopurinol group, association with the study drugs could not be ruled out. There were no severe adverse drug reactions in the febuxostat group other than a high frequency of gout attacks induced by the sudden reduction in blood uric acid levels during the early treatment period. CONCLUSIONS: Febuxostat at 40 mg/d demonstrated more potent hypouricemic effects than allopurinol at 200 mg/d, was efficacious regardless of medical history of gout, and is considered safe for treatment of hyperuricemia.

Placebo-controlled, double-blind study of the non-purine-selective xanthine oxidase inhibitor Febuxostat (TMX-67) in patients with hyperuricemia including those with gout in Japan: phase 3 clinical study.

BACKGROUND: : Allopurinol has been widely used for treatment of hyperuricemia, however, it may be associated with various adverse effects. Febuxostat has been identified as a potentially safe and efficacious alternative. OBJECTIVES: : A multicenter study with randomized, placebo-controlled, double-blind, parallel-group comparison was carried out to evaluate the efficacy and safety of febuxostat in 103 patients with hyperuricemia (including patients with gout) in Japan. METHODS: : Subjects were treated with febuxostat (20 or 40 mg/d) or a placebo for 8 weeks. The variables evaluated were the percentage of patients achieving serum uric acid levels 6.0 mg/dL or less and the percent change in serum uric acid levels after 8 weeks. RESULTS: : The percentage of patients achieving serum uric acid levels 6.0 mg/dL or less after 8 weeks was 91.2% in the febuxostat 40-mg/d group, 45.7% in the 20-mg/d group, and 0.0% in the placebo group. The percent changes in serum uric acid levels after 8 weeks were -44.9% in the febuxostat 40-mg/d group, -28.9% in the 20-mg/d group, and -0.6% to -0.5% in the placebo group. No severe or medically significant adverse reaction attributable to febuxostat was noted, and there was no event that could pose a clinical problem. The efficacy did not differ depending on the presence/absence of gout history. CONCLUSIONS: : These results suggest that febuxostat (20 or 40 mg/d) is useful as a new means of treating hyperuricemia and is capable of reducing serum uric acid levels to 6.0 mg/dL or less (goal of treatment) with high safety regardless of the presence/absence of gout history.

An allopurinol-controlled, multicenter, randomized, open-label, parallel between-group, comparative study of febuxostat (TMX-67), a non-purine-selective inhibitor of xanthine oxidase, in patients with hyperuricemia including those with gout in Japan: phase 2 exploratory clinical study.

BACKGROUND: Allopurinol has been widely used for the treatment of hyperuricemia, however, it may be associated with various adverse effects. Febuxostat has been identified as a potentially safe and efficacious alternative. OBJECTIVES: Febuxostat was administered to patients with hyperuricemia including gout in Japan to compare its efficacy and safety with those of allopurinol. METHODS: The starting dose of febuxostat and allopurinol was 10 and 100 mg/d, respectively, and was increased to the fixed maintenance dose of 40 or 60 mg/d for febuxostat and 300 mg/d for allopurinol for 16 weeks. RESULTS: : The percent change in the serum uric acid level at 16 weeks compared with the baseline serum uric acid level was -42.96% ± 13.33% and -52.47% ± 9.79% for the febuxostat 40- and 60-mg/d groups, respectively, and -36.55% ± 18.59% for the allopurinol group, indicating that the hypouricemic effects of febuxostat increased in a dose-dependent manner and equaled to or surpassed those of allopurinol (P = 0.0239, 2-sample t test). The percentage of patients with serum uric acid levels of 6.0 mg/dL or less at 16 weeks was 88.9% and 100% for the febuxostat 40- and 60-mg/d groups, respectively, and 68.8% for the allopurinol group, showing higher achievements for the febuxostat groups compared with the allopurinol group. All adverse drug reactions were mild to moderate in severity, and there were no severe symptoms or reactions leading to drug discontinuation. CONCLUSIONS: These results suggest that febuxostat is safe at doses of 40 and 60 mg/d and has equal or greater efficacy than 300 mg/d allopurinol.