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Factors Influencing Change in Serum Uric Acid After Administration of the Sodium-Glucose Cotransporter 2 Inhibitor Luseogliflozin in Patients With Type 2 Diabetes Mellitus.
Chino, Y, Kuwabara, M, Hisatome, I
Journal of clinical pharmacology. 2022;(3):366-375
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Abstract
Although sodium-glucose cotransporter 2 (SGLT2) inhibitors lower serum uric acid, their long-term effect on uric acid metabolism is not well understood. We analyzed pooled data from studies wherein patients with type 2 diabetes mellitus received luseogliflozin, an SGLT2 inhibitor. Upon stratifying patients by baseline glycated hemoglobin (HbA1c ) or serum uric acid, lower HbA1c or higher serum uric acid level was associated with a greater reduction in serum uric acid after treatment. At week 12 of treatment, significant increases in urinary glucose/creatinine (Cr) ratio and urinary uric acid clearance/Cr clearance ratio (CUA /CCr ratio) and a significant reduction in serum uric acid were observed. Comparison of the subgroups of patients with a reduction or an increase in serum uric acid showed that the increase subgroup had a higher estimated glomerular filtration rate (eGFR) at baseline, and the eGFR was significantly reduced, associated with a significant reduction in the CUA /CCr ratio. Multiple regression analysis showed that the reduction in serum uric acid in the luseogliflozin group was strongly associated with baseline high serum uric acid, low HbA1c levels, and an increase in eGFR. Luseogliflozin was shown to reduce serum uric acid by enhancing urinary uric acid excretion in association with increased urinary glucose. Treatment with luseogliflozin resulted in increased serum uric acid in some patients, which may be due to reduced glomerular filtration of uric acid via the tubuloglomerular feedback. SGLT2 inhibitors reduced serum uric acid desirably in patients with type 2 diabetes mellitus with low HbA1c and high serum uric acid.
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A Randomized Pilot Study of DASH Patterned Groceries on Serum Urate in Individuals with Gout.
Juraschek, SP, Miller, ER, Wu, B, White, K, Charleston, J, Gelber, AC, Rai, SK, Carson, KA, Appel, LJ, Choi, HK
Nutrients. 2021;(2)
Abstract
The Dietary Approaches to Stop Hypertension (DASH) diet reduces serum urate (SU); however, the impact of the DASH diet has not been previously evaluated among patients with gout. We conducted a randomized, controlled, crossover pilot study to test the effects of ~$105/week ($15/day) of dietitian-directed groceries (DDG), patterned after the DASH diet, on SU, compared with self-directed grocery shopping (SDG). Participants had gout and were not taking urate lowering therapy. Each intervention period lasted 4 weeks; crossover occurred without a washout period. The primary endpoint was SU. Compliance was assessed by end-of-period fasting spot urine potassium and sodium measurements and self-reported consumption of daily servings of fruit and vegetables. We randomized 43 participants (19% women, 49% black, mean age 59 years) with 100% follow-up. Mean baseline SU was 8.1 mg/dL (SD, 0.8). During Period 1, DDG lowered SU by 0.55 mg/dL (95% CI: 0.07, 1.04) compared to SDG by 0.0 mg/dL (95% CI: -0.44, 0.44). However, after crossover (Period 2), the SU difference between groups was the opposite: SDG reduced SU by -0.48 mg/dL (95% CI: -0.98, 0.01) compared to DDG by -0.05 mg/dL (95% CI: -0.48, 0.38; P for interaction by period = 0.11). Nevertheless, DDG improved self-reported intake of fruit and vegetables (3.1 servings/day; 95% CI: 1.5, 4.8) and significantly reduced total spot urine sodium excretion by 22 percentage points (95% CI: -34.0, -8.6). Though relatively small in scale, this pilot study suggests that dietitian-directed, DASH-patterned groceries may lower SU among gout patients not on urate-lowering drugs. However, behavior intervention crossover trials without a washout period are likely vulnerable to strong carryover effects. Definitive evaluation of the DASH diet as a treatment for gout will require a controlled feeding trial, ideally with a parallel-design.
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Effect of a high fructose diet on metabolic parameters in carriers for hereditary fructose intolerance.
Debray, FG, Seyssel, K, Fadeur, M, Tappy, L, Paquot, N, Tran, C
Clinical nutrition (Edinburgh, Scotland). 2021;(6):4246-4254
Abstract
BACKGROUND & AIMS Hyperuricemia is an independent risk factor for the metabolic syndrome and cardiovascular disease. We hypothesized that asymptomatic carriers for hereditary fructose intolerance (OMIM 22960) would have increased uric acid and altered component of the metabolic syndrome when exposed to fructose overfeeding. METHODS Six heterozygotes for HFI (hHFI) and 6 controls (Ctrl) were studied in a randomized, controlled, crossover trial. Participants ingested two identical test meals containing 0.7 g kg-1 glucose and 0.7 g kg-1 fructose according to a cross-over design, once after a 7-day on a low fructose diet (LoFruD, <10 g/d) and on another occasion after 7 days on a high fructose diet (HiFruD, 1.4 g kg-1 day-1 fructose + 0.1 g kg-1 day-1 glucose). Uric acid, glucose, and insulin concentrations were monitored in fasting conditions and over 2 h postprandial, and insulin resistance indexes were calculated. RESULTS HiFruD increased fasting uric acid (p < 0.05) and reduced fasting insulin sensitivity estimated by the homeostasis model assessment (HOMA) for insulin resistance (p < 0.05), in both groups. Postprandial glucose concentrations were not different between hHFI and Ctrl. However HiFruD increased postprandial plasma uric acid, insulin and hepatic insulin resistance index (HIRI) in hHFI only (all p < 0.05). CONCLUSIONS Seven days of HiFruD increased fasting uric acid and slightly reduced fasting HOMA index in both groups. In contrast, HiFruD increased postprandial uric acid, insulin concentration and HIRI in hHFI only, suggesting that heterozygosity for pathogenic Aldolase B variants may confer an increased susceptibility to the effects of dietary fructose on uric acid and hepatic insulin sensitivity. This trial was registered at the U.S. Clinical Trials Registry as NCT03545581.
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Effect of Urate-Elevating Inosine on Early Parkinson Disease Progression: The SURE-PD3 Randomized Clinical Trial.
, , Schwarzschild, MA, Ascherio, A, Casaceli, C, Curhan, GC, Fitzgerald, R, Kamp, C, Lungu, C, Macklin, EA, Marek, K, et al
JAMA. 2021;(10):926-939
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Abstract
IMPORTANCE Urate elevation, despite associations with crystallopathic, cardiovascular, and metabolic disorders, has been pursued as a potential disease-modifying strategy for Parkinson disease (PD) based on convergent biological, epidemiological, and clinical data. OBJECTIVE To determine whether sustained urate-elevating treatment with the urate precursor inosine slows early PD progression. DESIGN, PARTICIPANTS, AND SETTING Randomized, double-blind, placebo-controlled, phase 3 trial of oral inosine treatment in early PD. A total of 587 individuals consented, and 298 with PD not yet requiring dopaminergic medication, striatal dopamine transporter deficiency, and serum urate below the population median concentration (<5.8 mg/dL) were randomized between August 2016 and December 2017 at 58 US sites, and were followed up through June 2019. INTERVENTIONS Inosine, dosed by blinded titration to increase serum urate concentrations to 7.1-8.0 mg/dL (n = 149) or matching placebo (n = 149) for up to 2 years. MAIN OUTCOMES AND MEASURES The primary outcome was rate of change in the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS; parts I-III) total score (range, 0-236; higher scores indicate greater disability; minimum clinically important difference of 6.3 points) prior to dopaminergic drug therapy initiation. Secondary outcomes included serum urate to measure target engagement, adverse events to measure safety, and 29 efficacy measures of disability, quality of life, cognition, mood, autonomic function, and striatal dopamine transporter binding as a biomarker of neuronal integrity. RESULTS Based on a prespecified interim futility analysis, the study closed early, with 273 (92%) of the randomized participants (49% women; mean age, 63 years) completing the study. Clinical progression rates were not significantly different between participants randomized to inosine (MDS-UPDRS score, 11.1 [95% CI, 9.7-12.6] points per year) and placebo (MDS-UPDRS score, 9.9 [95% CI, 8.4-11.3] points per year; difference, 1.26 [95% CI, -0.59 to 3.11] points per year; P = .18). Sustained elevation of serum urate by 2.03 mg/dL (from a baseline level of 4.6 mg/dL; 44% increase) occurred in the inosine group vs a 0.01-mg/dL change in serum urate in the placebo group (difference, 2.02 mg/dL [95% CI, 1.85-2.19 mg/dL]; P<.001). There were no significant differences for secondary efficacy outcomes including dopamine transporter binding loss. Participants randomized to inosine, compared with placebo, experienced fewer serious adverse events (7.4 vs 13.1 per 100 patient-years) but more kidney stones (7.0 vs 1.4 stones per 100 patient-years). CONCLUSIONS AND RELEVANCE Among patients recently diagnosed as having PD, treatment with inosine, compared with placebo, did not result in a significant difference in the rate of clinical disease progression. The findings do not support the use of inosine as a treatment for early PD. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02642393.
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Effect of Curcumin on Serum Urate in Asymptomatic Hyperuricemia: A Randomized Placebo-Controlled Trial.
Bupparenoo, P, Pakchotanon, R, Narongroeknawin, P, Asavatanabodee, P, Chaiamnuay, S
Journal of dietary supplements. 2021;(3):248-260
Abstract
BACKGROUND/OBJECTIVE Hyperuricemia leads to gout and renal complications and may increase cardiovascular risk. Curcumin inhibits xanthine oxidase and increases uricosuric activity and, as a result, decreases serum urate (SU). This randomized controlled trial aimed to determine the effects of curcumin versus placebo on SU in subjects with asymptomatic hyperuricemia (SU level ≥ 6 mg/dL in women or ≥ 7 mg/dL in men). METHODS Thirty-nine subjects with persistent hyperuricemia were randomized to receive curcumin (500-mg capsules twice daily, 20 subjects) or placebo (19 subjects). Primary outcome was the difference between SU before and 8 weeks after randomization. Secondary outcomes were differences between urine uric acid (UUA) clearance, fasting plasma glucose (FPG), and lipid profiles before and 8 weeks after randomization and adverse events. RESULTS Out of 39 subjects, there were no differences at baseline SU, UUA clearance, FPG, lipid profiles, and demographics between curcumin and placebo groups. After 8 weeks, SU was significantly decreased in both groups (6.9% in curcumin group, p = 0.002, and 5.0% in placebo group, p = 0.009). However, there was no difference in SU reduction between the two groups (p = 0.532). There were no differences in UUA, FPG, lipid profiles, or adverse events in either group at 8 weeks after randomization. The most common adverse event was diarrhea with no treatment required. CONCLUSION Curcumin was not superior to placebo in reducing serum urate and in increasing UUA clearance.
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Effects of Dietary Patterns on Serum Urate: Results From a Randomized Trial of the Effects of Diet on Hypertension.
Juraschek, SP, Yokose, C, McCormick, N, Miller, ER, Appel, LJ, Choi, HK
Arthritis & rheumatology (Hoboken, N.J.). 2021;(6):1014-1020
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Abstract
OBJECTIVE To determine whether the Dietary Approaches to Stop Hypertension (DASH) diet or an alternative, simplified diet, emphasizing high-fiber fruits and vegetables (the FV diet), lowers serum urate levels. METHODS We conducted a secondary study of the DASH feeding study, a 3-arm, parallel-design, randomized trial of 459 adults with systolic blood pressure (BP) of <160 mm Hg and diastolic BP of 80-95 mm Hg, who were not receiving BP medications. Participants were randomized to receive 8 weeks of monitored feeding and ate 1 of 3 diets: 1) a typical American diet (control), 2) the FV diet, a diet rich in fruits and vegetables but otherwise similar to the control diet, or 3) the DASH diet, which was rich in fruits, vegetables, and low-fat dairy products, and reduced in fat, saturated fat, and cholesterol. Body weight was kept constant throughout the study. Serum urate levels were measured at baseline and after 8 weeks of feeding. RESULTS For the 327 participants with available specimens (mean ± SD age 45.4 ± 11.0 years, 47% women, 50% African American), the mean ± SD baseline serum urate level was 5.7 ± 1.5 mg/dl. Compared to the control diet, the FV diet reduced the mean serum urate level by 0.17 mg/dl (95% confidence interval [95% CI] -0.34, 0.00; P = 0.051) and the DASH diet reduced the mean serum urate level by 0.25 mg/dl (95% CI -0.43, -0.08; P = 0.004). These effects increased with increasing baseline serum urate levels (<5, 5-5.9, 6-6.9, 7-7.9, and ≥8 mg/dl) for those receiving the DASH diet (a reduction of 0.08, 0.12, 0.42, 0.44, and 0.73 mg/dl, respectively; P for trend = 0.04), but not for those receiving the FV diet. CONCLUSION Our findings indicate that the DASH diet reduces serum urate levels, particularly among those with hyperuricemia. These findings support the growing need for a dedicated trial to test the DASH diet among patients with hyperuricemia and gout.
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Sodium-Glucose Cotransporter-2 (SGLT-2) Attenuates Serum Uric Acid (SUA) Level in Patients with Type 2 Diabetes.
Hussain, M, Elahi, A, Hussain, A, Iqbal, J, Akhtar, L, Majid, A
Journal of diabetes research. 2021;:9973862
Abstract
BACKGROUND Hyperuricemia has a strong association with diabetes mellitus. Hyperuricemia can lead to cardiovascular and renal complications in patients with diabetes. The goal of this study was to compare the effect of sodium-glucose cotransporter-2 (SGLT-2) inhibitors dapagliflozin and empagliflozin on serum uric acid (SUA) levels in patients with type 2 diabetes against traditional oral antihyperglycemic drugs (OADs). METHODS In this double-blind randomized controlled trial, 70 patients with type 2 diabetes and elevated SUA levels were assigned to two treatment groups. Patients in group A received SGLT-2 inhibitors tablet dapagliflozin 5 mg to 10 mg and empagliflozin 10 mg to 25 mg. Group B patients received OADs such as glimepiride, metformin, sitagliptin, gliclazide, and glibenclamide as monotherapy or combination therapy. The changes in SUA level were primary end points while changes in body weight and body mass index (BMI) from baseline to end point were secondary end points. RESULTS After four weeks of treatment, we noted a significant reduction of mean SUA levels in the SGLT-2 inhibitor group from 7.5 ± 2.5 to 6.3 ± 0.8 mg/dl versus comparator group from 7.1 ± 1.8 to 6.8 ± 2.2 mg/dl (p = 0.001). Mean body weight was significantly reduced in the SGLT-2 group from 82 ± 10.4 to 78 ± 12.5 kg versus comparator group from 78 ± 13.2 to 79.2 ± 9.7 kg (p = 0.001). Similarly, the mean BMI of patients in the SGLT-2 group was significantly reduced from 25.7 ± 3.2 to 24.2 ± 3.2 kg/m2 versus comparator group from 27.5 ± 4.2 to 28 ± 3.6 kg/m2 (p = 0.002). CONCLUSION SGLT-2 inhibitors have a strong potential to decrease SUA levels in patients with type 2 diabetes.
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Effects of a Behavioral Weight Loss Intervention and Metformin Treatment on Serum Urate: Results from a Randomized Clinical Trial.
Hu, JR, Yeh, HC, Mueller, NT, Appel, LJ, Miller, ER, Maruthur, NM, Jerome, GJ, Chang, AR, Gelber, AC, Juraschek, SP
Nutrients. 2021;(8)
Abstract
Background: Lower body mass index (BMI) has been associated with lower serum urate (SU), but only in observational studies. We sought to determine the effects of behavioral weight loss and metformin treatment on SU in a randomized trial. Methods and Findings: The Survivorship Promotion In Reducing IGF-1 Trial (SPIRIT) was a parallel three-arm randomized controlled trial of overweight/obese adult cancer survivors without gout at a single center in Maryland, United States. Participants were randomized to: (1) coach-directed weight loss (behavioral telephonic coaching), (2) metformin (up to 2000 mg daily), or (3) self-directed weight loss (informational brochures; reference group). SU and BMI were assessed at baseline and at 3, 6, and 12 months post-randomization. The 121 participants had a mean ± standard deviation (SD) age of 60 ± 9 years, 79% were female, and 45% were Black. At baseline, BMI was 35 ± 5 kg/m2, and SU was 5.6 ± 1.3 mg/dL. Compared to the self-directed group, at 12 months, the coach-directed group reduced BMI by 0.9 kg/m2 (95% confidence interval (CI): -1.5, -0.4) and metformin reduced BMI by 0.6 kg/m2 (95% CI: -1.1, -0.1). However, compared to the self-directed group, the coach-directed group unexpectedly increased SU by 0.3 mg/dL (95% CI: 0.05, 0.6), and metformin non-significantly increased SU by 0.2 mg/dL (95% CI: -0.04, 0.5); these effects were attenuated when analyses included change in estimated glomerular filtration rate (eGFR). Conclusions: In this randomized trial of cancer survivors without gout, reductions in BMI either increased or did not change SU, potentially due to effects on eGFR. These results do not support a focus on BMI reduction for SU reduction; however, long-term studies are needed. ClinicalTrials.gov Registration: NCT02431676.
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Lack of effect of tart cherry concentrate dose on serum urate in people with gout.
Stamp, LK, Chapman, P, Frampton, C, Duffull, SB, Drake, J, Zhang, Y, Neogi, T
Rheumatology (Oxford, England). 2020;(9):2374-2380
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OBJECTIVES Cherry concentrate has been suggested to reduce serum urate (SU) and gout flares. The aims of this study were to determine the magnitude of the effect of tart cherry concentrate on SU in people with gout, the most effective dose of tart cherry concentrate for lowering SU, and adverse effects. METHODS Fifty people with gout and SU > 0.36 mmol/l were recruited. Half were on allopurinol and half were on no urate-lowering therapy. Participants were randomized to receive tart cherry juice concentrate: placebo, 7.5 ml, 15 ml, 22.5 ml or 30 ml twice daily for 28 days. Blood samples were taken at baseline, then at 1, 3 and 5 h post cherry and then on days 1, 3, 7, 14, 21 and 28. The area under the curve for SU was calculated over the 28-day study period. RESULTS Cherry concentrate dose had no significant effect on reduction in SU area under the curve, urine urate excretion, change in urinary anthocyanin between day 0 and day 28, or frequency of gout flares over the 28-day study period (P = 0.76). There were 24 reported adverse events, with only one (hyperglycaemia) considered possibly to be related to cherry concentrate. Allopurinol use did not modify the effect of cherry on SU or urine urate excretion. CONCLUSION Tart cherry concentrate had no effect on SU or urine urate excretion. If there is an effect of cherry concentrate on gout flares over a longer time period, it is not likely to be mediated by reduction in SU. TRIAL REGISTRATION Australian New Zealand Clinical Trials Registry (ANZCTR), https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=368887, ANZCTR 12615000741583).
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Genetic factors associated with elevation of uric acid after treatment with thiazide-like diuretic in patients with essential hypertension.
Ohta, Y, Kamide, K, Hanada, H, Morimoto, S, Nakahashi, T, Takiuchi, S, Ishimitsu, T, Tsuchihashi, T, Soma, M, Tomohiro Katsuya, T, et al
Hypertension research : official journal of the Japanese Society of Hypertension. 2020;(3):220-226
Abstract
We investigated changes in blood pressure (BP) and metabolic adverse effects, especially elevation of uric acid (UA), after treatment with a thiazide-like diuretic (TD) in patients with essential hypertension. Furthermore, the role of genetic factors in the elevation of UA by TD was assessed by a 500 K SNP DNA microarray. The subjects included 126 hypertensive patients (57 women and 69 men, mean age 59 ± 12 years) who registered for the GEANE (Gene Evaluation for ANtihypertensive Effects) study. After one month of the nontreatment period, TD, indapamide, angiotensin II receptor antagonist valsartan, and Ca channel blocker amlodipine were administered to all patients for 3 months each in a randomized crossover manner. BP, renal function, serum UA level, and electrolytes were measured at baseline and at the end of each treatment period. Single nucleotide polymorphisms (SNPs) associated with UA elevation after treatment with indapamide were investigated by a genome-wide association study (GWAS). Indapamide significantly decreased both office and home BP levels. Treatment with indapamide also significantly reduced the estimated glomerular filtration rate and serum potassium and increased serum UA. Patients whose UA level increased more than 1 mg/dl showed significantly higher baseline office SBP and plasma glucose and showed greater decline in renal function compared with those who showed less UA increase (<1 mg/dl). Some SNPs strongly associated with an increase in UA after treatment with indapamide were identified. This study is the first report on SNPs associated with UA elevation after TD treatment. This information may be useful for the prevention of adverse effects after treatment with TD.