Abstract Patients with gout often have co-morbidities such as cardiovascular disease, renal failure and metabolic syndrome components. Some studies, but not all, have suggested that hyperuricaemia and gout are associated with increased risk of myocardial infarction, renal failure and death primarily because of increased risk of cardiovascular events. Therefore, knowledge of the effects of urate-lowering therapy (ULT) on co-morbidities, in particular cardiovascular events and chronic kidney disease, is crucial. Randomized controlled trials (RCTs) have suggested that allopurinol, a xanthine oxidase inhibitor, could improve exercise capacity in patients with chronic stable angina and could decrease blood pressure in adolescents. In contrast, a well-designed RCT found no effect of allopurinol in patients with heart failure. The impact of ULT in patients with chronic kidney disease is unclear. Some RCTs found that allopurinol could slow the decline in kidney function, whereas a recent controlled trial found no benefit of febuxostat. Large randomized placebo-controlled trials are warranted to confirm or not the benefit of ULT on co-morbidities. urate-lowering therapy, gout, co-morbidities, allopurinol, febuxostat Rheumatology key messages The causality between hyperuricaemia, gout and co-morbidities is controversial. Some randomized controlled trials have suggested that urate-lowering therapies might have cardiac and renal benefit. Large randomized placebo-controlled trials are warranted to confirm or not the benefit of urate-lowering therapy for cardiorenal co-morbidities. Introduction Gout is strongly associated with several co-morbidities, particularly traditional vascular risk factors and chronic kidney disease (CKD) [1–3]. Data from epidemiological studies have suggested that gout and hyperuricaemia are independent risk factors for cardiovascular (CV) diseases and renal dysfunction . In addition, animal studies have uncovered a mechanistic approach to the vascular toxicity of uric acid . However, the causality between hyperuricaemia and these outcomes remains uncertain because confounders, reverse causality or common aetiological factors might explain these epidemiological results. These uncertainties have not been solved by recent studies involving Mendelian randomization. Overall, data from these recent studies are negative: most, but not all [6–8], found no association between hyperuricaemia, CV diseases [9, 10] and CKD  or metabolic syndrome components [12, 13]. Causality can also be addressed by investigating the effect of urate-lowering therapy (ULT) on co-morbidities, therefore knowledge of the effects of ULT on CV and renal outcomes is of major interest. ULT and CV outcomes The mechanisms that may link hyperuricaemia and gout with CV events are unclear but may include oxidative stress generated by xanthine oxidase (XO), the enzyme that catalyzes the formation of urate [4, 14]. Other explanations are a direct contribution to endothelial dysfunction  and low-grade inflammation associated with increased urate levels and tophi . Recently a cross-sectional study showed that coronary heart disease could be more severe in hyperuricaemic patients with asymptomatic monosodium urate crystal deposition than normouricaemic or hyperuricaemic patients without crystal deposits, which suggests a vascular deleterious effect of monosodium urate crystals . Small randomized trials found that XO inhibitors (XOIs) improved endothelial dysfunction and decreased oxidative stress in patients with stable coronary artery disease . Two small randomized placebo-controlled trials found that high-dose allopurinol (600 mg/day) led to regression of left ventricular mass in 66 patients with ischaemic heart disease  and enhanced exercise capacity in 65 with chronic stable angina . Except for one study , pharmaco-epidemiological studies also suggested a benefit of XOIs in patients with coronary artery disease, with reduced risk of myocardial infarction in those receiving allopurinol [21–23]. Data for patients with heart failure (HF) are more controversial. Large epidemiological studies found that allopurinol decreased morbidity and mortality rates in patients with congestive heart failure and a history of gout . Similarly, in an observational study, allopurinol was associated with an ∼30% reduced risk of readmission for HF or death in patients with a history of gout . However, the sole well-designed randomized controlled trial (RCT) of patients with HF (n = 253) had negative results. Patients (n = 253) with symptomatic HF and hyperuricaemia [serum uric acid (sUA) level ⩾9.5 mg/dl] were randomized to receive allopurinol (600 mg/day) or a placebo in a double-blind, multicentre trial. The primary composite endpoint at 24 weeks was based on survival, worsening HF and patient global assessment. At 24 weeks, clinical status did not differ between the allopurinol- and placebo-treated patients . ULT seems to have a beneficial effect on blood pressure (BP), but only in obese adolescents . In one trial of adolescents (n = 30) with hyperuricaemia and newly diagnosed hypertension, treatment with allopurinol (400 mg/day) normalized BP in 66% of patients . In another placebo-controlled study of 60 adolescents with obesity and pre-hypertension, allopurinol ⩽400 mg/day) or probenecid (⩽1 g/day) markedly reduced ambulatory systolic and diastolic BP, which suggests that the BP lowering resulted from sUA reduction . However, these results cannot be extended to adults: a recent RCT reported that ULT did not change adult BP . In this trial, 149 overweight and obese adults with an sUA level ⩾5.0 mg/dl were randomized to receive probenecid (500 mg once daily), allopurinol (300 mg once daily) or a placebo for 8 weeks. At the end of the study period, BP did not differ among the treatments . Impact of ULT in CKD patients The prevalence of CKD stage ⩾3 in gout was estimated at 24% in a recent meta-analysis of six studies . Reduced kidney function decreases urate excretion in urine and increases the risk of gout. In a large German CKD patient cohort, gout prevalence ranged from 16.0 to 35.6% for CKD patients with an estimated glomerular filtration rate (eGFR) >60 and <30 ml/min/1.73 m2, respectively . More recently, the 3-year incidence of gout in older patients with CKD was reported. The incidence in men was 0.8 and 4.6% for those with eGFR ⩾90 and ⩽30 ml/min/1.73 m2, respectively . Conversely, the risk of end-stage renal failure was found to be increased in patients with gout  and the risk of CKD increased in patients with asymptomatic hyperuricaemia [34, 35]. These findings can be explained by the formation of uric acid crystals in renal tubules, interstitial nephritis complicating kidney stones, crystalline deposits in the renal medulla , use of NSAIDs, a frequent association with hypertension or the possible renal toxicity of soluble uric acid . A meta-analysis of 19 RCTs based on 992 participants found a small but statistically significant improvement in eGFR [mean difference 3.2 ml/min/1.73 m2 (95% CI 0.16, 6.2); P = 0.039] and serum creatinine level [mean difference 0.63 mg/dl (95% CI 0.43, 0.82); P < 0.001] in patients with stages 3–5 CKD who were taking allopurinol for 4–24 months . A placebo-controlled monocentric RCT of 93 hyperuricaemic CKD patients suggested that febuxostat (40 mg daily) could have similar beneficial effects at 6 months . The mean eGFR in the febuxostat group showed a non-significant increase from 31.5 ml/min/1.73 m2 (s.d. 13.6) to 34.7 (s.d. 18.1) at 6 months. In contrast, the mean eGFR in the placebo group decreased from 32.6 ml/min/m2 (s.d. 11.6) to 28.2 (11.5) (P = 0.003). The difference between groups was 6.5 ml/min/1.73 m2 (95% CI 0.08, 12.81) at 6 months (P = 0.05). However, this renoprotective effect of febuxostat was not observed in a recent randomized placebo-controlled trial of 96 gout patients with moderate to severe renal impairment . ULT and mortality Several studies found gout associated with increased mortality, mainly due to CV events [4, 41, 42]. For instance, in the National Health and Nutrition Examination Survey trial (n = 15 773 participants), mortality was increased 50% for gouty patients, with a 1 mg/dl increase in sUA level associated with a 28% increase in mortality . A recent meta-analysis of RCTs assessed the effect of ULT on mortality. Pooled results from eight studies (n = 2221 participants) did not demonstrate a statistically significant difference in all-cause mortality when comparing any ULT (allopurinol or febuxostat) with placebo. However, the limited number of events precludes drawing any firm conclusions . Conclusions The causality between hyperuricaemia, gout and co-morbidities is still controversial. Some RCTs, but not all, have suggested that urate-lowering drug levels might have cardiac and renal benefits. However, the level of evidence provided by these RCTs, with often small sample sizes, is not great. Given the lack of clear evidence for the cardiorenal benefit of ULT, as well as the uncertainty about progression from asymptomatic hyperuricaemia to symptomatic disease in all patients, neither the EULAR , British Society for Rheumatology  or ACR  currently recommend ULT for the management of asymptomatic hyperuricaemia. Large randomized placebo-controlled trials are warranted to confirm or not the benefit of ULT for cardiorenal co-morbidities. Supplement: This supplement was funded by Grunenthal. Funding: No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this article. Disclosure statement: P.R. received fees for consultancy work or talks from AstraZeneca, Grunenthal, Ipsen, Menarini and Savient. T.B. received research grants from AstraZeneca, Ipsen and Menarini and fees for consultancy work or talks from Astella, AstraZeneca, Biomex, Grunenthal, Ipsen, Menarini, Novartis, Savient and Sobi. The other author has declared no conflicts of interest. References 1 Dalbeth N, Merriman TR, Stamp LK. Gout. Lancet 2016; 388: 2039– 52. http://dx.doi.org/10.1016/S0140-6736(16)00346-9 Google Scholar CrossRef Search ADS PubMed 2 Kuo CF, Grainge MJ, Mallen C, Zhang W, Doherty M. 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Published: Jan 1, 2018
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