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Serum uric acid level and all-cause and cardiovascular mortality in peritoneal dialysis patients: A systematic review and dose-response meta-analysis of cohort studies.
Kang, T, Hu, Y, Huang, X, Amoah, AN, Lyu, Q
PloS one. 2022;(2):e0264340
Abstract
BACKGROUND The association between serum uric acid (SUA) and all-cause and cardiovascular disease (CVD) mortality in peritoneal dialysis (PD) patients is controversial. Therefore, we aimed to determine the relationship between SUA and all-cause and CVD mortality in PD patients. METHOD Web of Science, EMBASE, PubMed and the Cochrane Library databases were searched from their inception to 7 April 2021. Effect estimates were presented as hazard ratios (HRs) with 95% confidence intervals (95% CIs) and pooled using random effects model. RESULT Thirteen cohort studies with 22418 patients were included in this systematic review, of which 9 were included in the meta-analysis. Before switching the reference group, pooled result for the highest SUA category was significantly greater than the median for all-cause mortality (HR = 2.41, 95% CI: 1.37-4.26). After switching the reference group, the highest SUA category did not demonstrate an increased all-cause (HR = 1.40, 95% CI: 0.95-2.05) or CVD (HR = 1.30, 95% CI: 0.72-2.34) mortality compared with the lowest SUA category. Dose-response analysis suggested a nonlinear association between SUA and all-cause mortality risk (Pnonlinearity = 0.002). CONCLUSION This meta-analysis didn't find the relationship between SUA levels and all-cause and CVD mortality risk in PD patients. More rigorously designed studies are warranted in the future.
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Impacts of Sodium/Glucose Cotransporter-2 Inhibitors on Circulating Uric Acid Concentrations: A Systematic Review and Meta-Analysis.
Akbari, A, Rafiee, M, Sathyapalan, T, Sahebkar, A
Journal of diabetes research. 2022;:7520632
Abstract
BACKGROUND Several trials have assessed the antihyperglycemic effects of sodium/glucose cotransporter-2 inhibitors (SGLT2i) in patients with type 2 diabetes mellitus (T2DM). We conducted a quantitative analysis to assess the impact of SGLT2is on serum uric acid (SUA) in patients with T2DM. METHODS Placebo-controlled trials published before 13 August 2021 were identified by searching PubMed, Embase, Web of Science, and Scopus. The intervention group received SGLT2i as monotherapy or add-on treatment, and the control group received a placebo that was replaced with SGLT2i. Clinical trials providing changes in SUA were included. The mean change of SUA, glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), and body weight were calculated (PROSPERO CRD42021287019). RESULTS After screening of 1172 papers, 59 papers were included in the systematic review. A total of 55 trials (122 groups) of 7 types of SGLT2i on patients with T2DM were eligible for meta-analysis. All SGLT2is significantly decreased SUA levels compared with the placebo groups: empagliflozin mean difference (MD) = -40.98 μmol/L, 95% CI [-47.63, -34.32], dapagliflozin MD = -35.17 μmol/L, 95% CI [-39.68, -30.66], canagliflozin MD = -36.27 μmol/L, 95% CI [-41.62, -30.93], luseogliflozin MD = -24.269 μmol/L, 95% CI [-33.31, -15.22], tofogliflozin MD = -19.47 μmol/L, 95% CI [-27.40, -11.55], and ipragliflozin MD = -18.85 μmol/L, 95% CI [-27.20, -10.49]. SGLT2i also decreased FPG, body weight, and HbA1c levels. SUA reduction persisted during long-term treatment with SGLT2i (except for empagliflozin), while the SUA reduction was affected by the duration of diabetes. CONCLUSIONS SGLT2i can be a valid therapeutic strategy for patients with T2DM and comorbid hyperuricemia. Besides reducing FPG, body weight, and HbA1c, SGLT2i can significantly decrease SUA levels compared to placebo (Total MD = -34.07 μmol/L, 95% CI [-37.00, -31.14]).
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Network Meta-Analysis of Drug Therapies for Lowering Uric Acid and Mortality Risk in Patients with Heart Failure.
Kodama, S, Fujihara, K, Horikawa, C, Yamada, M, Sato, T, Yaguchi, Y, Yamamoto, M, Kitazawa, M, Matsubayashi, Y, Yamada, T, et al
Cardiovascular drugs and therapy. 2021;(6):1217-1225
Abstract
PURPOSE This network meta-analysis aimed to assess the current efficacy of decreasing the uric acid (UA) level with drugs to reduce mortality in patients with heart failure (HF). METHODS Electronic literature searches using EMBASE and MEDLINE of studies published from 1 Jan 1950 to 26 Dec 2019 were conducted for randomized controlled trials or non-randomized cohort studies that included at least one group of patients who took UA-lowering drugs and with a study outcome of all-cause mortality. A random-effects network meta-analysis was performed within a frequentist framework. Hierarchy of treatments was expressed as the surface under the cumulative ranking curve (SUCRA) value, which is in proportion to mean rank (best is 100%). RESULTS Nine studies, which included seven different types of groups, were eligible for analysis. The "untreated uricemia" group in which patients had hyperuricemia but without treatment had a significantly higher risk of mortality than the "no uricemia" group in which patients had no hyperuricemia (relative risk (RR)(95% confidence interval (CI), 1.43 (1.08-1.89)). The "start-allo" group wherein patients started to take allopurinol did not have a significantly lower risk of mortality than the "untreated uricemia" group (RR (95% CI), 0.68 (0.45-1.01)). However, in the "start-allo" group the SUCRA value was comparable to that in the "no uricemia" group (SUCRA 65.4% for "start-allo"; 64.1% for "no uricemia"). CONCLUSIONS Results suggested that allopurinol therapy was not associated with a significantly improved prognosis in terms of mortality but could potentially counteract the adverse effects associated with longstanding hyperuricemia in HF patients.
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Associations of serum uric acid with total and cause-specific mortality: Findings from individuals and pooling prospective studies.
Mazidi, M, Katsiki, N, Mikhailidis, DP, Banach, M, ,
Atherosclerosis. 2020;:49-58
Abstract
BACKGROUND AND AIMS There is considerable controversy regarding the link between serum uric acid (SUA) and mortality. We prospectively evaluated the association between SUA and risk of total and cause specific (coronary heart disease [CHD], cerebrovascular and cancer) mortality by using the National Health and Nutrition Examination Surveys (NHANES, 1999-2010). Furthermore, a systematic review and meta-analysis of cohort studies was performed to investigate pooled associations of SUA with all-cause and cause-specific mortality. METHODS Vital status through December 31, 2011 was ascertained. PubMed-Medline, SCOPUS, Web of Science and Google Scholar databases were searched (up to April 2018). Adjusted Cox proportional hazard regression models were used to determine the association between SUA and mortality. The DerSimonian-Laird method and generic inverse variance methods were used for quantitative data synthesis. RESULTS Overall, 21,025 individuals were included (mean age = 47.6 years, 48.7% men) and 3520 deaths occurred during the 144 months of follow-up. In adjusted models, individuals in the highest quartile of SUA had 10 and 8% greater risk of CHD and stroke mortality, whereas there was no link between SUA, all-cause and cancer mortality. The associations of CHD and stroke mortality with SUA were more pronounced in women and, among women, in those aged >50 years. Furthermore, all-cause mortality was positively and significantly related to SUA concentrations only in women. In the meta-analysis, SUA was shown to predict the risk of total (21%), CHD (24%) and stroke (29%) mortality. Furthermore, participants with a higher level of central adiposity had a greater risk of mortality from CHD and stroke for the same level of SUA. CONCLUSIONS Our results highlight the adverse impact of SUA on mortality, particularity in older (>50 years) women. The clinical implications of these findings remain to be established in future trials.
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Serum uric acid and risk of cardiovascular mortality: a systematic review and dose-response meta-analysis of cohort studies of over a million participants.
Rahimi-Sakak, F, Maroofi, M, Rahmani, J, Bellissimo, N, Hekmatdoost, A
BMC cardiovascular disorders. 2019;(1):218
Abstract
BACKGROUND Cardiovascular disease (CVD) is the leading cause of death worldwide. Some studies have suggested anassociation between serum uric acid levels and cardiovascular mortality; however, the results have not been summarized in a meta-analysis. METHODS A comprehensive search of all related studies until April 2018was performed in MEDLINE/PubMed and Scopus databases DerSimonianand Laird random-effects models were used to combine hazard ratios (HRs) with 95% confidence intervals (CIs). Dose-response analysis was also carried out. RESULTS Thirty-two studies containing forty-four arms with 1,134,073 participants reported association between uric acid and risk of CVD mortality were included in our analysis. Pooled results showed a significant positive association between uric acid levels and risk of CVD mortality (HR 1.45, 95% CI 1.33-1.58, I2 = 79%). Sub-group analysis showed this relationshipwasstronger in women compared to men. Moreover, there was a significant non-linear association between uric acid levels and the risk of CVD mortality (r = 0.0709, p = 0.001). CONCLUSION Our analysis indicates a positive dose-response association between SUA and CVD mortality risk.
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Empagliflozin reduces blood pressure and uric acid in patients with type 2 diabetes mellitus: a systematic review and meta-analysis.
Zhao, D, Liu, H, Dong, P
Journal of human hypertension. 2019;(4):327-339
Abstract
The antidiabetic effect of empagliflozin in patients with type 2 diabetes mellitus has been explored in several trials. We performed this meta-analysis determining the effects of empagliflozin on blood pressure, uric acid, estimated glomerular filtration rate, blood lipids, blood glucose, and body weight in patients with type 2 diabetes mellitus. We searched three electronic databases (Pubmed, Web of Science, and Cochrane Central) for all published articles evaluating the effects of empagliflozin on blood glucose or blood pressure in subjects with type 2 diabetes mellitus. Total 5781 patients were included in 12 randomized controlled trials with a follow-up of 28 ± 22 weeks. Empagliflozin 10 or 25 mg reduced systolic and diastolic blood pressure, uric acid, hemoglobin A1c, fasting plasma glucose, and body weight in patients with type 2 diabetes mellitus (all p < 0.001). There were no differences for changes of estimated glomerular filtration rate between empagliflozin 10 or 25 mg and placebo in these patients (all p > 0.05). In conclusion, empagliflozin reduces systolic and diastolic blood pressure, uric acid, hemoglobin A1c, fasting plasma glucose, and body weight. These data suggest the beneficial effects of empagliflozin on these cardiovascular risk factors in patients with type 2 diabetes mellitus.
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Genome-wide meta-analysis identifies multiple novel loci associated with serum uric acid levels in Japanese individuals.
Nakatochi, M, Kanai, M, Nakayama, A, Hishida, A, Kawamura, Y, Ichihara, S, Akiyama, M, Ikezaki, H, Furusyo, N, Shimizu, S, et al
Communications biology. 2019;:115
Abstract
Gout is a common arthritis caused by elevated serum uric acid (SUA) levels. Here we investigated loci influencing SUA in a genome-wide meta-analysis with 121,745 Japanese subjects. We identified 8948 variants at 36 genomic loci (P<5 × 10-8) including eight novel loci. Of these, missense variants of SESN2 and PNPLA3 were predicted to be damaging to the function of these proteins; another five loci-TMEM18, TM4SF4, MXD3-LMAN2, PSORS1C1-PSORS1C2, and HNF4A-are related to cell metabolism, proliferation, or oxidative stress; and the remaining locus, LINC01578, is unknown. We also identified 132 correlated genes whose expression levels are associated with SUA-increasing alleles. These genes are enriched for the UniProt transport term, suggesting the importance of transport-related genes in SUA regulation. Furthermore, trans-ethnic meta-analysis across our own meta-analysis and the Global Urate Genetics Consortium has revealed 15 more novel loci associated with SUA. Our findings provide insight into the pathogenesis, treatment, and prevention of hyperuricemia/gout.
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Combinational effect of angiotensin receptor blocker and folic acid therapy on uric acid and creatinine level in hyperhomocysteinemia-associated hypertension.
Singh, Y, Samuel, VP, Dahiya, S, Gupta, G, Gillhotra, R, Mishra, A, Singh, M, SreeHarsha, N, Gubbiyappa, SK, Tambuwala, MM, et al
Biotechnology and applied biochemistry. 2019;(5):715-719
Abstract
Homocysteine [HSCH2 CH2 CH(NH2 )COOH] (Hcy) is a sulfur-containing amino acid of 135.18 Da of molecular weight, generated during conversion of methionine to cysteine. If there is a higher accumulation of Hcy in the blood, that is usually above 15 µmol/L, it leads to a condition referred to as hyperhomocysteinemia. A meta-analysis of observational study suggested an elevated concentration of Hcy in blood, which is termed as the risk factors leading to ischemic heart disease and stroke. Further experimental studies stated that Hcy can lead to an increase in the proliferation of vascular smooth muscle cells and functional impairment of endothelial cells. The analyses confirmed some of the predictors for Hcy presence, such as serum uric acid (UA), systolic blood pressure, and hematocrit. However, angiotensin-converting enzyme inhibitors angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) alone are inadequate for controlling UA and creatinine level, although the addition of folic acid may be beneficial in hypertensive patients who are known to have a high prevalence of elevated Hcy. We hypothesized that combination therapy with an ARB (olmesartan) and folic acid is a promising treatment for lowering the UA and creatinine level in hyperhomocysteinemia-associated hypertension.
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Uric acid lowering in relation to HbA1c reductions with the SGLT2 inhibitor tofogliflozin.
Ouchi, M, Oba, K, Kaku, K, Suganami, H, Yoshida, A, Fukunaka, Y, Jutabha, P, Morita, A, Otani, N, Hayashi, K, et al
Diabetes, obesity & metabolism. 2018;(4):1061-1065
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Abstract
An integrated analysis was performed with data from 4 phase 2 and phase 3 studies of tofogliflozin in which patients with type 2 diabetes mellitus received the sodium-glucose cotransporter 2 inhibitor tofogliflozin for up to 24 weeks. Sex differences, baseline haemoglobin A1c (HbA1c) and serum uric acid (UA) levels, and log10 -transformed urinary N-acetyl-β-D-glucosaminidase ratio were significantly correlated with the reduction in serum UA levels at both 4 and 24 weeks in multivariate analysis (respectively, P < .0001). The decrease in HbA1c levels was greatest in the group with the highest baseline HbA1c level (quartile 4; HbA1c > 8.6%) and lowest in the group with the lowest baseline HbA1c level (quartile 1; HbA1c ≤ 7.4%). The decrease in serum UA levels was greatest in the quartile 1 group and lowest in the quartile 4 group. In most groups, the maximum decrease in serum UA levels was seen in the first 4 weeks, while the maximum decrease in HbA1c was seen at week 24. Thus, serum UA levels were significantly decreased in patients with moderate HbA1c levels.
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Evaluation of the diet wide contribution to serum urate levels: meta-analysis of population based cohorts.
Major, TJ, Topless, RK, Dalbeth, N, Merriman, TR
BMJ (Clinical research ed.). 2018;:k3951
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Abstract
OBJECTIVE To systematically test dietary components for association with serum urate levels and to evaluate the relative contributions of estimates of diet pattern and inherited genetic variants to population variance in serum urate levels. DESIGN Meta-analysis of cross sectional data from the United States. DATA SOURCES Five cohort studies. REVIEW METHODS 16 760 individuals of European ancestry (8414 men and 8346 women) from the US were included in analyses. Eligible individuals were aged over 18, without kidney disease or gout, and not taking urate lowering or diuretic drugs. All participants had serum urate measurements, dietary survey data, information on potential confounders (sex, age, body mass index, average daily calorie intake, years of education, exercise levels, smoking status, and menopausal status), and genome wide genotypes. The main outcome measures were average serum urate levels and variance in serum urate levels. β values (95% confidence intervals) and Bonferroni corrected P values from multivariable linear regression analyses, along with regression partial R2 values, were used to quantitate associations. RESULTS Seven foods were associated with raised serum urate levels (beer, liquor, wine, potato, poultry, soft drinks, and meat (beef, pork, or lamb)) and eight foods were associated with reduced serum urate levels (eggs, peanuts, cold cereal, skim milk, cheese, brown bread, margarine, and non-citrus fruits) in the male, female, or full cohorts. Three diet scores, constructed on the basis of healthy diet guidelines, were inversely associated with serum urate levels and a fourth, data driven diet pattern positively associated with raised serum urate levels, but each explained ≤0.3% of variance in serum urate. In comparison, 23.9% of variance in serum urate levels was explained by common, genome wide single nucleotide variation. CONCLUSION In contrast with genetic contributions, diet explains very little variation in serum urate levels in the general population.