Risk of gout flare after medication: prescription symmetry sequence analysis.

OBJECTIVES: The research aimed to study the following questions: (1) five well-known gout-related medications were selected to test the validity of the prescription symmetry sequence analysis in Taiwan; (2) four exploratory medications were selected to test their relation to gout flares. METHODS: We utilized the 2003-2017 dataset of the Taiwan National Health Insurance Program containing all claims data with 2 million beneficiaries as a data source. In order to explore the temporal association, we designed a scenario of medication-induced gout flares. Nine medications were selected as the index agent, including aspirin (low-dose), thiazide diuretics, loop diuretics, ethambutol, pyrazinamide, metformin, pioglitazone, fenofibrate, and losartan. The gout flare was defined as subjects with use of the marker agent for treatment of gout flares. The observation-window period between initiation of the index agent and initiation of the marker agent was 1 year. Subjects who used an index agent and a marker agent on the same day were excluded. The prescription symmetry sequence analysis was carried out to compare the observed number of persons who took an index agent prior to starting a marker agent with the observed number of persons who took a marker agent before starting an index agent. The adjusted sequence ratio (adjusted SR) with 95% confidence interval was applied to estimate the relation between an index agent and the marker agent. RESULTS: Among five medications including aspirin (low-dose), thiazide diuretics, loop diuretics, ethambutol, and pyrazinamide, the adjusted sequence ratio ranged from 1.15 to 3.35 and all reached statistical significance. Fenofibrate use and losartan use were associated with a lower probability of gout flares, with reaching statistical significance (adjusted SR = 0.60 for fenofibrate and adjusted SR = 0.92 for losartan). Metformin use was associated with a greater probability of gout flares, with reaching statistical significance (adjusted SR = 1.14). Pioglitazone use did not reach statistical significance. CONCLUSION: Based on the confirmatory analysis including five well-known gout-related medications, this study supports that the prescription symmetry sequence analysis can be used to detect an adverse drug event associated with one potential offending agent. The exposure to fenofibrate or losartan might be a protective factor against gout flares. Metformin use could be associated with a greater probability of gout flares, but this finding should be validated by other studies. KEY POINTS: • What is already known about this subject? 1. The prescription symmetry sequence analysis is a useful method for detecting an adverse drug reaction associated with one potential offending drug. 2. Numerous medications are found to induce gout flares. • What does this study add? 1. The prescription symmetry sequence analysis supports the evidence that aspirin (low-dose), thiazide diuretics, loop diuretics, ethambutol and pyrazinamide are associated with a greater probability of gout flares. 2. The exposure to fenofibrate or losartan might be a protective factor against gout flares. 3. Metformin use could be associated with a greater probability of gout flares. • How might this impact on clinical practice or future developments? 1. Clinicians should always consider the possibility of medication-induced gout flares. If gout flares develop, discontinuation of risky medications is the first step. Then prescribing cascades can be eliminated.

Thiazide-associated hyponatremia increases the risk of major adverse cardiovascular events among elderly Taiwanese patients.

BACKGROUND: Thiazide-associated hyponatremia (TAH) has been supposed to increase the risk of major adverse cardiovascular events (MACE) in the elderly. Therefore, this study aimed to evaluate the association of TAH with the risk of MACE in elderly Taiwanese patients. METHODS: Data from the longitudinal generation tracking database (LGTD 2010) of the Health and Welfare Data Science Center (HWDC) were retrospectively assessed. The TAH study group was defined as using > 30 cumulative daily defined doses (CDDDs) thiazide diuretics within one year before diagnosis of hyponatremia. The control group (1:3 propensity score matching) had no diagnosis of hyponatremia but had used > 30 CDDDs thiazide diuretics within one year. Data on MACE were extracted using International Classification of Diseases codes. Outcomes were assessed using a multivariable Cox proportional hazard model and Kaplan-Meier analysis. RESULTS: A total of 1155 and 3465 individuals were enrolled in the TAH and the control groups, respectively. The rates of MACE (11.1% vs. 7.3%) and death (22.8% vs.12.2%) were significantly higher in the TAH group than the control group. In the TAH group, the adjusted HRs were 1.29 (CI 1.01 ‒ 1.65) for MACE, 1.39 (CI 1.19 ‒ 1.63) for all-cause death, and 1.61 (CI 0.90 ‒ 2.92) for stroke. CONCLUSION: TAH in patients above 65-years-old is associated with a 29% higher risk of MACE, 39% higher risk of all-cause death, and 61% higher risk of stroke. This work suggests that thiazides prescription in elderly patients should be more careful. However, further research is required to confirm our findings.

Isolinderalactone Induces Apoptosis, Autophagy, Cell Cycle Arrest and MAPK Activation through ROS-Mediated Signaling in Colorectal Cancer Cell Lines.

Colorectal cancer (CRC) is one of the most common malignancies worldwide. Isolinderalactone (ILL), a sesquiterpene isolated from the root extract of Lindera aggregata, has been reported to exhibit anti-proliferative and anti-metastatic activities in various cancer cell lines. However, the mechanisms associated with its antitumor effects on CRC cells remain unclear. ILL treatment significantly suppressed proliferation and induced cell cycle G2/M arrest in CRC cells by inhibiting the expression of cyclin B, p-cdc2, and p-cdc25c and up-regulating the expression of p21. In addition, ILL induced mitochondria-associated apoptosis through the up-regulation of cleaved -caspase-9 and -3 expression. ILL induced autophagy by increasing the levels of LC3B in CRC cells, which was partially rescued by treatment with an autophagy inhibitor (chloroquine). Furthermore, ILL increases the accumulation of reactive oxygen species (ROS) and activates the MAPK pathway. Application of the ROS scavenger, N-acetyl cysteine (NAC), effectively inhibited ILL toxicity and reversed ILL-induced apoptosis, cell cycle arrest, autophagy, and ERK activation. Taken together, these results suggest that ILL induces G2/M phase arrest, apoptosis, and autophagy and activates the MAPK pathway via ROS-mediated signaling in human CRC cells.

Sodium-glucose cotransporter-2 inhibitors use and the risk of gout: a systematic review and meta-analysis.

Objective: To assess the relationship between use of sodium-glucose cotransporter-2 inhibitors (SGLT2i) and the risk of gout among patients with type 2 diabetes mellitus (T2DM). Methods: A systemic review and meta-analysis were designed by reviewing articles published between 2000 January 1 and 2022 December 31 using PubMed system and Web of Science system based on the PRISMA 2020 guidelines. The end point of interest was gout (including gout flares, gout events, starting uric-acid lowering therapy and starting anti-gout drugs use) among patients with T2DM using SGLT2i versus not using SGLT2i. A random-effects model was utilized to measure the pooled hazard ratio (HR) with 95% confidence interval (CI) for the risk of gout associated with SGLT2i use. Results: Two prospective post-hoc analyses of randomized controlled trials and 5 retrospective electronic medical record-linkage cohort studies met the inclusion criteria. The meta-analysis demonstrated that there was a decreased risk of developing gout for SGLT2i use as comparing with non-use of SGLT2i among patients with T2DM (pooled HR=0.66 and 95%CI=0.57-0.76). Conclusions: This meta-analysis demonstrates that SGLT2i use is associated with a 34% decreased risk of developing gout among patients with T2DM. SGLT2i may be the treatment options for patients with T2DM who are at high risk of gout. More randomized controlled trials and real-world data are needed to confirm whether there is a class effect of SGLT2i for the risk reduction of gout among patients with T2DM.

Comparison of benzbromarone and allopurinol on the risk of chronic kidney disease in people with asymptomatic hyperuricemia.

OBJECTIVE: The objective of the study was to compare the relative effects of benzbromarone and allopurinol on the risk of developing chronic kidney disease in persons with asymptomatic hyperuricemia. METHODS: A retrospective cohort study was conducted to analyze a 2003-2015 national database including all claims data of 2 million beneficiaries in Taiwan. Asymptomatic hyperuricemia was defined as follows: persons using urate-lowering drugs who never developed gout flares. The benzbromarone group included persons ages 20-84 that had asymptomatic hyperuricemia and received benzbromarone alone. The allopurinol group included persons ages 20-84 that had asymptomatic hyperuricemia and received allopurinol alone. The maximum follow-up time was set as 5 years in this study. The main outcome was defined as follows: persons were newly diagnosed with chronic kidney disease. A Cox proportional hazards regression analysis was performed to test the association between variables and the risk of chronic kidney disease. RESULTS: After propensity score matching, 9107 persons in the benzbromarone group and 4554 persons in the allopurinol group were eligible for the study. Approximately 71% of the study subjects were males. The mean age was 56 years old. The incidence rate of chronic kidney disease was lower in the benzbromarone group than in the allopurinol group (1.18 versus 1.99/per 100 person-years, incidence ratio = 0.60, and 95% confidence interval = 0.52-0.68).The Cox proportional hazards regression analysis disclosed that after adjusting for co-variables, there was a decreased risk of developing chronic kidney disease in the benzbromarone group as compared with the allopurinol group (hazard ratio = 0.59, 95% confidence interval = 0.52-0.67 and P<0.001). CONCLUSIONS: The use of benzbromarone is associated with a lower hazard of developing chronic kidney disease as compared to allopurinol use among persons ages 20-84 with asymptomatic hyperuricemia. More studies are needed to confirm our findings.

The risk of ischemic cerebrovascular disease associated with benzbromarone use in gout people: A retrospective cohort study in Taiwan.

Epidemiological studies have shown that people having hyperuricemia are at increased risk of ischemic cerebrovascular disease. This research aimed to study the relation of ischemic cerebrovascular disease with benzbromarone use among persons with gout-related disorders. This was a retrospective cohort design utilizing a 2003 to 2015 national health insurance database in Taiwan. Subjects aged 20 to 99 years who already had suffered from gout-related disorders were included as eligible subjects. Eligible persons who had the benzbromarone prescription alone were selected into the benzbromarone group. Sex-matched and age-matched eligible persons who never used any urate-lowering agents were selected into the control group. An index date was set as a date of benzbromarone being prescribed. The end-point was defined as ischemic cerebrovascular disease being newly diagnosed. A hazard ratio was applied to measure the association strength between benzbromarone use and ischemic cerebrovascular disease. Totally, there were 13,398 persons in the benzbromarone group and 13,398 persons in the control group. The incidence rate of ischemic cerebrovascular disease seemed to be modestly higher in the benzbromarone group than the control group, but it did not achieve statistical significance (0.78 vs 0.75 every 100 person-years, incidence rate ratio = 1.05, 95% confidence interval = 0.94-1.16). A crude hazard ratio of ischemic cerebrovascular disease showed 1.05 in the benzbromarone group (95% confidence interval = 0.94-1.17, P = .373) comparing with the control group. No significant association can be detected between benzbromarone use and the probability of ischemic cerebrovascular disease among persons with gout-related disorders. We think that reduction of the serum uric acid by use of benzbromarone could not be related to the probability of ischemic cerebrovascular disease. Further research is suggested to clarify this issue.

Allopurinol Use and the Risk of Type 2 Diabetes Mellitus: A Meta-Analysis of Cohort Studies.

Objective: To assess whether there is a relation between allopurinol use and the probability of type 2 diabetes mellitus (T2DM) in persons with gout and/or hyperuricemia. Methods: According to the PRISMA 2020 guidelines, a meta-analysis was performed by searching literature published from 2000 to 2021 in two electronic databases (Ebscohost and PubMed). The end point was set as a new diagnosis ofT2DM between people with the use of allopurinol and people with non-use of allopurinol. The random-effects model was performed to evaluate the pooled hazard ratio (HR) with 95% confidence interval (CI) for T2DM associated with allopurinol use. Results: Three cohort studies could meet the inclusion criteria in the meta-analysis. There was a high heterogeneity of the outcome between studies (I2 = 99%). The research duration ranged from 13 to 16 years. The subject number in each work ranged from 1114 to 138,652. A meta-analysis disclosed that there was not an association between allopurinol use and the risk of developing T2DM (pooled HR = 1.01 and 95%CI = .55-1.84). Conclusions: The meta-analysis shows that no correlation is detected between allopurinol use and the risk of T2DM in individuals with gout and/or hyperuricemia. Because there are not enough eligible studies, the strength of evidence in our meta-analysis is weak. More cohort studies are needed to determine an association between use of allopurinol and the probability of T2DM for individuals with gout and/or hyperuricemia.

Allopurinol use and the risk of dementia: A meta-analysis of case-control studies.

BACKGROUND: This study aimed to compare the risk of dementia between exposed to allopurinol and not exposed to allopurinol in persons who had gout and/or hyperuricemia. METHODS: The meta-analysis was conducted to select case-control research written in English through the help of PubMed and Web of Science. The pooled odds ratio (OR) with 95% confidence interval based on the fixed-effect model was applied to compare the allopurinol exposure among cases (subjects with dementia) and controls (subjects without dementia). RESULTS: A total of 4 case-control studies relating the allopurinol exposure to the risk of dementia were identified. The study duration was from 9 to 14 years. The number of study persons was from 3148 to 137,640. The male percentage of study subjects was from 36.9 to 62.5. The mean age of study persons was from 72.3 to 78.7 years. Overall, the odds of the allopurinol exposure among cases were lower than the odds of the allopurinol exposure among control subjects (OR = 0.91, 95% confidence interval = 0.87-0.95, P < .001). The heterogeneity between these eligible studies was low (I² = 0%). The sensitivity analysis revealed that after excluding the studies with concern, the pooled OR did not achieve statistical significance. CONCLUSIONS: This is the first meta-analysis to report that there is a negative relationship between the allopurinol exposure and the risk of dementia. Although the results favor the hypothesis, currently it is unable to draw strong conclusions about the protective effect of allopurinol against dementia due to inclusion of only a few eligible studies. Randomized controlled trials are needed to explore the relationship between allopurinol exposure and the probability of dementia.