Multimorbidity, Polypharmacy, Severe Hypoglycemia, and Glycemic Control in Patients Using Glucose-Lowering Drugs for Type 2 Diabetes: A Retrospective Cohort Study Using Health Insurance Claims in Japan.

INTRODUCTION: This study aimed to understand the actual status of multimorbidity and polypharmacy among patients with type 2 diabetes using glucose-lowering drugs, and to assess the effects of patient characteristics on severe hypoglycemia and glycemic control. METHODS: We designed a retrospective cohort study using health insurance claims and medical checkup data in Japan from April 2016 to February 2021 and identified patients with type 2 diabetes who were prescribed glucose-lowering drugs. We analyzed data on patient characteristics, including multimorbidity and polypharmacy, calculated the incidence rate for severe hypoglycemic events, applied a negative binomial regression model to explore factors that affected severe hypoglycemia, and analyzed the status of glycemic control in the subcohort for which HbA1c data were available. RESULTS: Within the analysis population (n = 93,801), multimorbidity was present in 85.5% and mean ± standard deviation for oral drug prescriptions was 5.6 ± 3.5 per patient, while for those aged 75 years or older these numbers increased to 96.3% and 7.1 ± 3.5, respectively. The crude incidence rate for severe hypoglycemia was 5.85 (95% confidence interval 5.37, 6.37) per 1000 person-years. Risk factors for severe hypoglycemia included younger and older age, prior severe hypoglycemia, use of insulin, sulfonylurea, two-drug therapy including sulfonylurea or glinides, three-or-more-drug therapy, excessive polypharmacy, and comorbidities including end-stage renal disease (ESRD) requiring dialysis. Subcohort analysis (n = 26,746) showed that glycemic control is not always maintained according to guidelines. CONCLUSION: Patients with type 2 diabetes, particularly older patients, experienced high multimorbidity and polypharmacy. Several risk factors for severe hypoglycemia were identified, most notably younger age, ESRD, history of severe hypoglycemia, and insulin therapy. TRIAL REGISTRATION: The University Hospital Medical Information Network Clinical Trials Registry (UMIN000046736).

The Association Between Hypouricemia and Cardiometabolic Diseases: Analyzing Nationwide Data From Medical Checkup and Health Insurance Records.

OBJECTIVES: The aims of this study were to evaluate the association between hypouricemia and cardiometabolic diseases, such as hypertension, dyslipidemia, and reduced kidney function, and to explore the sex-specific optimal range for serum uric acid (sUA) associated with the lowest risk for these diseases. METHODS: In this cross-sectional study, we identified individuals with sUA data between April 2018 and March 2019 and recorded the frequency of cardiometabolic comorbidities according to sUA. Univariable and multivariable logistic regression analyses were performed for the overall population and after classifying by sex to assess the association between sUA and cardiometabolic comorbidities. RESULTS: Among 796,508 individuals, a J-shaped association was observed between the sUA level and cardiometabolic diseases in the overall population. The adjusted odds ratios (95% confidence interval) for hypertension, dyslipidemia, and reduced renal function in individuals with sUA ≤1.0 mg/dL compared with those with sUA ranging between 2.1 and 3.0 mg/dL were 1.38 (1.13-1.69), 1.52 (1.30-1.78), and 2.17 (1.47-3.20), respectively. A J-shaped association between sUA and hypertension was observed only in women. The optimal range of sUA associated with the lowest risk for hypertension was assumed to be <6 mg/dL in men and 1-4 mg/dL in women. A J-shaped association between the sUA and dyslipidemia and reduced renal function was observed in both men and women. The optimal range of sUA for dyslipidemia and reduced renal function was approximately 2-5 mg/dL in men and 1-4 mg/dL in women. CONCLUSIONS: Excess and extremely low uric acid levels may be related to an increased cardiometabolic risk.

Temporal trends in the prevalence and characteristics of hypouricaemia: a descriptive study of medical check-up and administrative claims data.

We aimed to describe temporal trends in the prevalence and characteristics of hypouricaemia. We analysed medical check-up and administrative claims data to calculate hypouricaemia prevalence from 2009 to 2019. Then, using data from 2018 to 2019, we compared the characteristics of individuals with and without hypouricaemia. We also compared the characteristics of those with lower (serum uric acid [sUA] ≤ 1.0 mg/dL) and higher (1.0 mg/dL < sUA ≤ 2.0 mg/dL) hypouricaemia. In total, 1,600,290 subjects underwent medical check-ups. The age-adjusted prevalence of hypouricaemia remained stable at 0.2% overall (men, 0.1%; women, 0.4%). We identified 1704 subjects with hypouricaemia (598 men and 1106 women) among 796,508 subjects and studied their characteristics. The proportion of most pre-existing diseases, including urinary stones, was lower in those with hypouricaemia than in those without hypouricaemia. Cardio-metabolic diseases and Parkinson's disease were more frequent in men with hypouricaemia than those without hypouricaemia. Women with hypouricaemia tended to have healthier characteristics. Hypertension and dyslipidaemia were more common in the lower hypouricaemia group than in the higher hypouricaemia group. The age-adjusted prevalence of hypouricaemia remained stable over 10 years. The characteristics of hypouricaemia subjects appear to differ between the sexes and between lower and higher hypouricaemia groups. Key Points • The prevalence of hypouricaemia remained almost unchanged over 10 years. • Cardio-metabolic diseases and Parkinson's disease were more frequent in men with hypouricaemia than in those without hypouricaemia. • Subjects with extremely low serum urate (sUA ≤ 1.0 mg/dL) appeared to have higher cardio-metabolic disease risks. • Routine checks of sUA could be useful in screening or predicting these conditions.

Serum uric acid control for prevention of gout flare in patients with asymptomatic hyperuricaemia: a retrospective cohort study of health insurance claims and medical check-up data in Japan.

OBJECTIVES: In patients with gout, treating to target serum uric acid levels (sUA) of ≤6.0 mg/dL is universally recommended to prevent gout flare. However, there is no consensus on asymptomatic hyperuricaemia. Using Japanese health insurance claims data, we explored potential benefits of sUA control for preventing gout flare in subjects with asymptomatic hyperuricaemia. METHODS: This retrospective cohort study analysed the JMDC Claims Database from April 2012 through June 2019. Subjects with sUA ≥8.0 mg/dL were identified, and disease status (prescriptions for urate-lowering therapy (ULT), occurrence of gout flare, sUA) was investigated for 1 year. Time to first onset and incidence rate of gout flare were determined by disease status subgroups for 2 years or more. The relationship between gout flare and sUA control was assessed using multivariable analysis. RESULTS: The analysis population was 19 261 subjects who met eligibility criteria. We found fewer occurrences of gout flare, for both gout and asymptomatic hyperuricaemia, in patients who achieved sUA ≤6.0 mg/dL with ULT than in patients whose sUA remained >6.0 mg/dL or who were not receiving ULT. In particular, analysis by a Cox proportional-hazard model for time to first gout flare indicated that the HR was lowest, at 0.45 (95% CI 0.27 to 0.76), in subjects with asymptomatic hyperuricaemia on ULT (5.0

Factors associated with achieving target serum uric acid level and occurrence of gouty arthritis: A retrospective observational study of Japanese health insurance claims data.

PURPOSE: This study assessed factors associated with achieving target serum uric acid (sUA) level and occurrence of gouty arthritis in Japanese clinical practice. METHODS: Japanese health insurance claims and medical check-up data from October 2015 to March 2017 were analyzed to assess factors associated with target sUA achievement in gout and asymptomatic hyperuricemia and gouty arthritis in gout. Target sUA was further assessed by subgroup analysis of urate-lowering therapy (ULT) prescriptions and outcomes, stratified by renal function. RESULTS: Patients achieving target sUA tended toward older, female, higher ULT dose, higher adherence, more comorbidities, and/or antidiabetic drugs prescribed. Renal dysfunction and/or diuretic prescriptions were associated with reduced achievement of target sUA. Severe renal dysfunction was particularly influential (odds ratio [OR] = 0.22 [95% confidence interval (CI): 0.10-0.48] for <15, 0.15 [0.10-0.23] for ≥15 to <30, compared with eGFR ≥90 mL/min/1.73 m2 ). Across all renal function categories, mean prescribed ULT dose was low (febuxostat 17.0-21.0 mg/day, allopurinol 123.1-139.6 mg/day), and target sUA achievement was reduced among renal dysfunction patients. Gouty arthritis was more likely in patients with a prior history of such occurrences, and less likely for higher ULT adherence, sUA monitored regularly at medical facilities, and/or more comorbidities. CONCLUSION: In a real-world setting, severe renal dysfunction is the most important risk factor for failure to achieve the target sUA, suggesting suboptimal disease management in patients with gout or hyperuricemia complicated by this condition. Findings associated with gouty arthritis suggest that these occurrences could be successfully managed by regular monitoring of sUA and closer adherence to ULT.

Real-world treatment of gout and asymptomatic hyperuricemia: A cross-sectional study of Japanese health insurance claims data.

OBJECTIVES: To assess gout and asymptomatic hyperuricemia in Japan and review treatment conditions. METHODS: This retrospective cross-sectional study analyzed the prevalence of hyperuricemia and gout, and characteristics and treatment of patients with those conditions, using Japanese health insurance claims and medical check-up data collected from April 2016 through March 2017. RESULTS: Among 2,531,383 persons registered in the database, 1.1% (men 1.9%, women <0.1%) were diagnosed with gout and 2.6% (4.1%, 0.4%) with asymptomatic hyperuricemia. Medical check-ups showed 13.4% (19.6%, 1.0%) of patients with hyperuricemia (serum uric acid [sUA] > 7.0 mg/dL). Urate-lowering therapy (ULT) was prescribed for 80.7% of patients identified with gout and 72.4% identified with asymptomatic hyperuricemia. ULT adherence was satisfactory, but most patients were treated with low-dose ULT. Less than half of patients receiving ULT achieved the sUA target (≤6.0 mg/dL). In gout patients, the incidence of gout flare was 47.8% (0.74 flares/person-year). CONCLUSIONS: Although hyperuricemia prevalence is similar in Japan and worldwide, gout is comparatively rare in Japan. Gout and asymptomatic hyperuricemia are often treated with low-dose ULT, and many patients fail to reach target sUA, suggesting that gout management is suboptimal in Japan. Patients would benefit from stricter focus on a treat-to-target approach for gout management.

Linalyl acetate as a major ingredient of lavender essential oil relaxes the rabbit vascular smooth muscle through dephosphorylation of myosin light chain.

In a preliminary experiment, we found that lavender essential oil relaxes vascular smooth muscle. Thus, the present experiments were designed to investigate the relaxation mechanism of linalyl acetate as the major ingredient of lavender essential oil in rabbit carotid artery specimens. Linalyl acetate produced sustained and progressive relaxation during the contraction caused by phenylephrine. The relaxation effect of linalyl acetate at a concentration near the EC50 was partially but significantly attenuated by nitroarginine as an inhibitor of nitric oxide synthase, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one as an inhibitor of guanylyl cyclase, or by the denudation of endothelial cells. In specimens without endothelium, the phenylephrine-induced contraction and phosphorylation of myosin light chain (MLC) were significantly attenuated after the pretreatment with linalyl acetate. The relaxation caused by linalyl acetate in the endothelium-denuded specimens was clearly inhibited by calyculin A as an inhibitor of MLC phosphatase, although not by ML-9 as an inhibitor of MLC kinase. Furthermore, suppression of the phenylephrine-induced contraction and MLC phosphorylation with linalyl acetate was canceled by the pretreatment with calyculin A. These results suggest that linalyl acetate relaxes the vascular smooth muscle through partially activation of nitric oxide/cyclic guanosine monophosphate pathway, and partially MLC dephosphorylation via activating MLC phosphatase.