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Objective: To prospectively investigate population‐based metabolomics for incident gout and reproduce the findings for recurrent flares, accounting for serum urate. Methods: We conducted a prediagnostic metabolome‐wide analysis among 105,615 UK Biobank participants with nuclear magnetic resonance metabolomic profiling data (168 total metabolites) from baseline blood samples collected 2006–2010 in those without history of gout. We calculated hazard ratios (HRs) for incident gout, adjusted for gout risk factors, excluding and including serum urate levels, overall and according to fasting duration before sample collection. Potential causal effects were tested with 2‐sample Mendelian randomization. Poisson regression was used to calculate rate ratios (RRs) for the association with recurrent flares among incident gout cases. Results: Correcting for multiple testing, 88 metabolites were associated with risk of incident gout (N = 1,303 cases) before serum urate adjustment, including glutamine and glycine (inversely), and lipids, branched‐chain amino acids, and most prominently, glycoprotein acetyls (GlycA; P = 9.17 × 10−32). Only GlycA remained associated with incident gout following urate adjustment (HR 1.52 [95% confidence interval (95% CI) 1.22–1.88] between extreme quintiles); the HR increased progressively with fasting duration before sample collection, reaching 4.01 (95% CI 1.36–11.82) for ≥8 hours of fasting. Corresponding HRs per SD change in GlycA levels were 1.10 (95% CI 1.04–1.17) overall and 1.54 (95% CI 1.21–1.96) for ≥8 hours of fasting. GlycA levels were also associated with recurrent gout flares among incident gout cases (RR 1.90 [95% CI 1.27–2.85] between extreme quintiles) with larger associations with fasting. Mendelian randomization corroborated a potential causal role for GlycA on gout risk. Conclusion: This prospective, population‐based study implicates GlycA, a stable long‐term biomarker reflecting neutrophil overactivity, in incident and recurrent gout flares (central manifestation from neutrophilic synovitis) beyond serum urate. [ABSTRACT FROM AUTHOR]

Introduction: Cardiovascular disease (CVD) is the leading cause of mortality in people with Type 2 diabetes mellitus (T2DM). Statins reduce low‐density lipoproteins and positively affect CVD outcomes. Statin type and dose have differential effects on glycaemia and risk of incident T2DM; however, the impact of gender, and of individual drugs within the statin class, remains unclear. Aim: To compare effects of simvastatin and atorvastatin on lipid and glycaemic control in men and women with and without T2DM, and their association with incident T2DM. Methods: The effect of simvastatin and atorvastatin on lipid and glycaemic control was assessed in the T2DM DiaStrat cohort. Prescribed medications, gender, age, BMI, diabetes duration, blood lipid profile and HbA1c were extracted from Electronic Care Record, and compared in men and women prescribed simvastatin and atorvastatin. Analyses were replicated in the UKBiobank in those with and without T2DM. The association of simvastatin and atorvastatin with incident T2DM was also investigated in the UKBiobank. Cohorts where matched for age, BMI and diabetes duration in men and women, in the UKBioBank analysis, where possible. Results: Simvastatin was associated with better LDL (1.6 ± 0.6 vs 2.1 ± 0.9 mmol/L, p <.01) and total cholesterol (3.6 ± 0.7 vs 4.2 ± 1.0 mmol/L, p <.05), and glycaemic control (62 ± 17 vs 67 ± 19 mmol/mol, p <.059) than atorvastatin specifically in women in the DiaStrat cohort. In the UKBiobank, both men and women prescribed simvastatin had better LDL (Women: 2.6 ± 0.6 vs 2.6 ± 0.7 mmol/L, p <.05; Men: 2.4 ± 0.6 vs 2.4 ± 0.6, p <.01) and glycaemic control (Women:54 ± 14 vs 56 ± 15mmol/mol, p <.05; Men, 54 ± 14 vs 55 ± 15 mmol/mol, p <.01) than those prescribed atorvastatin. Simvastatin was also associated with reduced risk of incident T2DM in both men and women (p <.0001) in the UKBiobank. Conclusions: Simvastatin is associated with superior lipid and glycaemic control to atorvastatin in those with and without T2DM, and with fewer incident T2DM cases. Given the importance of lipid and glycaemic control in preventing secondary complications of T2DM, these findings may help inform prescribing practices. [ABSTRACT FROM AUTHOR]

Background: Severe hypercholesterolemia (HC, LDL‐C > 4.9 mmol/L) affects over 30 million people worldwide. In this study, we validated a new polygenic risk score (PRS) for LDL‐C. Methods: Summary statistics from the Global Lipid Genome Consortium and genotype data from two large populations were used. Results: A 36‐SNP PRS was generated using data for 2,197 white Americans. In a replication cohort of 4,787 Finns, the PRS was strongly associated with the LDL‐C trait and explained 8% of its variability (p = 10–41). After risk categorization, the risk of having HC was higher in the high‐ versus low‐risk group (RR = 4.17, p < 1 × 10−7). Compared to a 12‐SNP LDL‐C raising score (currently used in the United Kingdom), the PRS explained more LDL‐C variability (8% vs. 6%). Among Finns with severe HC, 53% (66/124) versus 44% (55/124) were classified as high risk by the PRS and LDL‐C raising score, respectively. Moreover, 54% of individuals with severe HC defined as low risk by the LDL‐C raising score were reclassified to intermediate or high risk by the new PRS. Conclusion: The new PRS has a better predictive role in identifying HC of polygenic origin compared to the currently available method and can better stratify patients into diagnostic and therapeutic algorithms. [ABSTRACT FROM AUTHOR]

Aims: To investigate the risk of cardiovascular disease (CVD) events and all-cause mortality in patients with statin-related adverse drug reaction (ADR) consultation in primary care and examine whether different treatments following the ADR affect subsequent outcomes., Methods: This was a retrospective cohort study of statin users between 2004 and 2019 using IQVIA Medical Research Data (formally known as the THIN database). Patients with statin-related ADR consultation were matched by propensity score (1:1) to statin users without ADR consultation based on demographics, comorbidities and concomitant medication. Cox proportional hazard regression was used to compare the risk of subsequent CVD event and all-cause mortality, stratified by history of CVD. In the secondary analysis among patients with statin-related ADR, treatment changes within a 1-year period following the ADR were examined and the outcomes were compared between different treatment groups., Results: Among 1 564 687 statin users, 19 035 (1.22%) had a statin-related ADR consultation in primary care. The mean (standard deviation) follow-up time was 6.32 (3.74) years and 5.31 (3.83) years for CVD primary and secondary prevention cohorts, respectively. Statin-related ADR consultation was associated with subsequent CVD events in both cohorts (adjusted hazard ratio [HR] of 1.39 [95% CI 1.23, 1.57] and 1.34 [95% CI 1.25,1.42], respectively). In the secondary analysis among patients with statin-related ADR consultation, we found that (i) continued statin prescription or combination of any statin with additional lipid-lowering treatment (LLT) and (ii) other LLT only were associated with lower risks of CVD event (adjusted HR 0.71 [95% CI 0.64, 0.78] and 0.75 [95% CI 0.62, 0.92], respectively) and all-cause mortality (adjusted HR 0.46 [95% CI 0.42, 0.50] and 0.52 [95% CI, 0.43, 0.64], respectively), compared to discontinuation of all LLT., Conclusion: Statin-related ADR was associated with an increased risk of subsequent CVD event, indicating that these patients should be monitored more closely. Continued lipid-lowering medication is of importance to protect against CVD events and mortality., (© 2022 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)