FormalPara Key Points

Patients with a diagnosis of gout have a higher risk of cardiovascular disease (CVD).

Treatment of patients with gout with urate-lowering therapy may delay the onset of CVD.

Studies have demonstrated anti-inflammatory agents used for the treatment for gout likely decrease the incidence of CVD, even in general populations.

1 Introduction

Cardiovascular disease (CVD) affects more than 90 million Americans and by 2030, nearly one of every two adults living in USA is expected to be affected by CVD [1]. While traditional cardiovascular (CV) risk factors such as hypertension, smoking, diabetes mellitus, age, obesity, and dyslipidemia [2] are strongly associated with CVD, inflammation has emerged as a risk factor for the development of early coronary artery disease, and possibly acute CV events, such as myocardial infarction (MI). Evidence supports an increased CVD risk in inflammatory conditions, such as gout [3,4,5].

Gout is the most common inflammatory arthritis in adults worldwide [6]. Recent data from the National Health and Nutrition Examination Survey (NHANES) demonstrate rising trends in the incidence and prevalence of gout [7]. Increased serum urate (SU) levels, or hyperuricemia, are a precursor to gout. Urate-lowering therapy (ULT) reduces SU. Urate-lowering therapy may decrease systemic inflammation, generation of oxidative species, and reverse endothelial dysfunction through hyperuricemia-dependent or hyperuricemia-independent pathways. This review examines the data for increased CVD in gout and the potential underlying mechanisms (including hyperuricemia, inflammation, endothelial dysfunction, oxidative stress) and the effect of ULT on CVD.

2 Role of Hyperuricemia in Cardiovascular Disease

2.1 Hypertension

Hyperuricemia, or increased SU, is a potential risk factor for hypertension, a leading cause of CVD [8] (Table 1). Increased SU preceded primary hypertension and correlated with elevated blood pressure in children and adults [9, 10]. Sanchez-Lozada et al. used a rat model of hyperuricemia to demonstrate the pathophysiologic mechanisms by which increased SU levels cause changes in renal morphology [11]. Oxonic acid, a uricase inhibitor, was administered to rats to induce hyperuricemia, who were also fed a low-sodium diet to further potentiate hyperuricemia. The control group was given only a low-sodium diet. A third group of rats was given allopurinol in addition to oxonic acid and a low-sodium diet. Blood pressure and SU levels were monitored at 2 and 5 weeks after the start of the infusion of oxonic acid. Compared with the controls, hyperuricemia and hypertension were present in the experimental group given oxonic acid and a low-sodium diet, secondary to hypertrophic vascular remodeling. Hyperuricemia, glomerular hypertension, and hypertension were prevented in the group receiving allopurinol, in whom the glomerular afferent arteriolar thickening was prevented [11].

Two separate systematic reviews and meta-analyses demonstrated the association of hyperuricemia and hypertension. Grayson et al. examined 18 prospective cohort studies encompassing 55,607 patients. There was a 41% increased risk of hypertension [relative risk (RR), 1.41, 95% confidence interval (CI) 1.23–1.58] in subjects with hyperuricemia when compared with those who did not have hyperuricemia. A dose-dependent relationship between SU levels and hypertension was also seen. For every 1-mg/dL increase in SU, there was a 13% increase in risk of hypertension. In this systematic review, hyperuricemia was defined as an average SU level of 6.2 mg/dL and greater [12].

Wang et al. reviewed 25 studies and included 97,824 subjects in a more recent meta-analysis and confirmed that hyperuricemia was associated with a higher risk of hypertension by 48% (RR 1.48, 95% CI 1.33–1.65). For every 1-mg/dL increase in SU, the risk for hypertension increased by 15% (RR 1.15, 95% CI 1.06–1.26) [13].

2.2 Cardiovascular Disease and Cardiovascular Mortality

In a meta-analysis of 402,997 adults with hyperuricemia (26 studies; several adjusted for potential confounding variables), Kim et al. found a 9% increase in coronary heart disease (CHD) incidence (RR 1.09, 95% CI 1.03–1.16) and a 13% increase in CHD mortality (RR 1.13, 95% CI 1.01–1.30) in people with hyperuricemia compared with people with normouricemia. Compared with normouricemia, women with hyperuricemia had a 67% increased risk of CHD mortality (RR 1.67, 95% CI 1.30–2.04), while men with hyperuricemia did not (RR 1.09, 95% CI 0.98–1.19). Each 1-mg/dL increase in SU conferred a 12% increase in CHD mortality overall (RR 1.12, 95% CI 1.05–1.19) [14]. Traditional risk factors for CHD were adjusted in most studies included in this analysis.

As a part of the Systolic Hypertension in the Elderly Program, Franse et al. studied the role of elevated SU and incident CV events in subjects with hypertension randomized to either diuretic treatment or placebo and followed for 5 years [15]. The primary CV outcome of interest was stroke; secondary outcomes were incident MI, CHD, and all-cause mortality. In total, 4327 patients who were 60 years or older were initially treated with placebo or given chlorthalidone to reduce systolic blood pressure to a goal of < 160 mmHg or at least a 20-mmHg reduction in systolic blood pressure. In the active treatment group, there was no increase in the risk of stroke or any CV event when compared to placebo after adjusting for appropriate risk factors [15]. The decrease in blood pressure secondary to treatment with a diuretic may have offset the risk of increased CV events due to increased SU.

Other studies have also demonstrated the association between hyperuricemia and the development of CVD. Santos et al. found white men with elevated SU and no symptoms of CHD had a far greater risk of accumulating coronary artery calcium than those with normal SU [16]. A cross-sectional population-based study from NHANES data demonstrated an association between increased SU and CV events, defined as CVD mortality and ischemic heart disease mortality in both black and white, male and female individuals. For each 59-µmol/L (equivalent to 1-mg/dL) increase in SU, a 21% increase in the risk (hazard ratio (HR) 1.21, 95% CI 1.11–1.34) of CV mortality was noted in this population [17].

Not all data, however, have shown a clear association between SU and an increased risk of CVD. In an analysis of the Framingham heart study that included 6763 patients, there was no greater adjusted (for risk factors and confounders) incidence of CHD, CVD-specific mortality, or all-cause mortality based on the SU levels. This prospective study showed that the association between SU and cardiac outcomes was eliminated after adjusting for diuretic use, indicating that diuretic use was the covariate responsible for the noted association of SU with CV outcomes (i.e., confounder) [18]. In NHANES, by comparison, the effect of diuretics on SU and its association with mortality was only seen in a small subset of male individuals. This difference is likely explained by the difference in the race/ethnicity of included subjects in both studies. While the Framingham study consists of mainly white Americans, NHANES is representative of the population of USA. Unadjusted CVD mortality and all-cause mortality rates were higher in the NHANES population, but this could be explained by the slightly older population in the NHANES study group. Owing to the inclusion of a representative US population in NHANES, the results of this cross-sectional study have greater external validity, i.e., are more generalizable than the Framingham study, which has higher internal validity but limited generalizability as a cohort study.

3 Clinical Evidence of Association of Gout with Cardiovascular Disease

Gout is associated with an increased risk of MI, cerebrovascular accidents, and death from CVD. In a secondary analysis of a large prospective randomized controlled trial (RCT), Krishnan et al. found the presence of gout to confer a greater risk of acute MI in their study of 12,866 men (OR 1.26, 95% CI 1.14–1.40), independent of hyperuricemia. The Multiple Risk Factor Intervention Trial randomized men into an interventional program aimed at smoking cessation and reducing serum cholesterol and blood pressure vs. usual care as determined by their personal physician. 10.5% of men with a diagnosis of gout vs. 8.4% of men without gout experienced an MI during the same follow-up period. Men with hyperuricemia and gout had a 30% increased risk (HR 1.30, 95% CI 1.04–1.61) of death from any CVD after adjusting for traditional CV risk factors [4]. Another population-based study found women with gout to have an increased risk for acute MI. Women with gout were 39% more susceptible to MI (RR 1.39, 95% CI 1.20–1.61) than those with no gout. Adjusted risk ratios showed women with gout were at a higher risk of acute MI than men with gout [19]. These findings were similar to a more recent study by Clarson et al. that found women with gout to be at a greater risk for all vascular disease in comparison to men (HR, 1.25 vs. 1.06) [20].

These studies that show a clear association between gout and CVD raise the question: is gout a cardiac risk equivalent for CVD similar to diabetes mellitus (DM) or hypertension? A study of insurance claims data of US Medicare beneficiaries showed that patients with a diagnosis of gout and no DM had a decreased risk of MI (HR 0.81, 95% CI 0.76–0.87), but a similar risk of stroke (HR 1.02, 95% CI 0.95–1.10), in comparison to patients with DM and no gout, suggesting that gout is not a cardiac risk equivalent for MI, but is a cardiac risk equivalent for stroke. In this cohort, subjects with gout and DM had a 35% (HR 1.35, 95% CI 1.25–1.47) increased risk of MI and a 42% (HR 1.42, 95% CI 1.29–1.56) increased risk of stroke when compared with those with only DM after adjusting for confounding variables. This finding suggested that a diagnosis of gout confers an increased risk of MI and stroke, in addition to DM [21]. While a diagnosis of hyperuricemia or gout confers a greater risk of CVD, there is insufficient evidence to identify gout as an equivalent risk factor for CVD similar to smoking and diabetes. Because it is known that gout patients have higher incidence of CVD, aggressive screening and treatment of gout patients should occur routinely in primary care settings. This has the potential to effectively improve cardiovascular outcomes for patients with gout (Table 1).

Table 1 Summary of studies examining the association of serum urate (SU) with hypertension
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4 Pathogenic Explanation for Cardiovascular Disease in Gout

Increased SU is also associated with increased levels of C-reactive protein (CRP), tumor necrosis factor, and other systemic markers of inflammation, such as interleukin-1 (IL-1), which in turn lead to a greater risk of adverse CV outcomes [5, 22]. Inflammation results in increased oxidative stress. In turn, oxidative stress is linked to atherogenesis through the production of reactive oxidative species in endothelial cells and activation of the enzyme, xanthine oxidase, which further propagates the production of harmful free radicals [23]. The free radicals lead to increased oxidization of low-density lipoproteins [24, 25] in inflammatory conditions, such as gout, and have been associated with CVD [23, 26].

Previous studies linked systemic inflammatory conditions such as lupus and rheumatoid arthritis to incident CVD [27], which bear similarity to gout with regards to chronic inflammation. Mouse models with antibody-induced arthritis were shown to develop cardiac remodeling, impaired contractility, and diastolic dysfunction secondary to chronic inflammation and oxidative stress [28]. Use of IL-1 inhibitors has proven to be efficacious in the resolution of rheumatoid arthritis symptoms and has led to a functional improvement in patients with known CVD through the reduction in oxidative stress [29].

Targeting systemic markers of inflammation as well as proatherogenic factors has been shown to decrease the risk of CV events [5, 30], including the Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS, see Sect. 6 for details) [5]. Several underlying mechanisms of CVD have been hypothesized in gout including hyperuricemia-associated endothelial dysfunction through impaired nitric oxide-mediated vasodilation [31,32,33], increased oxidized low-density lipoproteins [24, 25], dyslipidemia [34], and/or acute and chronic inflammation [5, 22] (Fig. 1). Each of these factors may contribute to atherosclerosis and endothelial damage increasing the incidence of CV events. The endothelial damage and dysfunction may be a pathogenic explanation for an increased incidence of acute vascular events associated with hyperuricemia. Association of gout with metabolic syndrome and its components, which are established risk factors for CVD, may also contribute to an increased risk of CV [35]. In a representative sample of the population of USA, Choi et al. utilized data from NHANES-III and found a three-fold higher prevalence of metabolic syndrome in people with gout (n = 223) compared with those without gout (n = 8584), > 60% vs. 25% [35]. While the strength of this cross-sectional study is the large sample size, it had an important limitation of misclassification of disease because the authors used survey data from the NHANES database, not validated by a physician [35].

Fig. 1
figure 1

Pathogenic explanation for an increased risk of cardiovascular disease in gout. LDL low-density lipoprotein (reproduced from Singh [27], with permission from BMJ Publishing Group Ltd)

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5 Urate-Lowering Therapy and its Association with Lowering of Cardiovascular Risk

The 2012 American College of Rheumatology gout treatment guideline recommends a target SU of ≤ 6 mg/dL as a goal for the management of gout, and a target SU of < 5 mg/dL in people with tophaceous gout [36]. Therapies to lower SU, ULTs, can be divided into two categories uricostatic and uricosuric drugs [37]. The uricostatic agents, allopurinol and febuxostat, are inhibitors of xanthine oxidase, a key enzyme involved in the degradation of purines. Xanthine oxidase inhibitors are the first-line therapy for the management of gout and symptomatic hyperuricemia [36, 38]. Allopurinol is cost effective and is efficacious as first-line therapy for the management of gout [39]. The uricosuric drugs, probenecid and lesinurad, prevent the reabsorption of uric acid in the renal tubule that can provide additional urate lowering [40].

A list of studies assessing the effect of ULT on CVD outcomes is summarized in Table 2.

Table 2 Summary of studies detailing the effect of lowering serum urate with allopurinol on cardiovascular disease (CVD)
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The use of allopurinol to lower SU reversed the effects of decreased levels of nitric oxide on the endothelium thus decreasing endothelial damage in smaller RCTs with human subjects [41]. Xanthine oxidase inhibition with allopurinol also decreased flow-mediated vasodilation, a sign of improvement in the vascular endothelial function [42]. Allopurinol use was also associated with a reduction in blood pressure [43] and a decreased risk of incident MI in adults aged 65 years or older [44].

Febuxostat is a newer XO inhibitor that is metabolized in the liver in contrast to allopurinol. It is more expensive than allopurinol and is usually used clinically as a second-line agent, in patients who have allopurinol-associated adverse events, or do not achieve target SU on therapeutic doses [39]. The CONFIRMS study demonstrated greater urate-lowering ability of therapeutic doses of febuxostat when compared with low-dose allopurinol [52]. RCTs have been conducted to study the rate of CV events in patients taking febuxostat vs. allopurinol [45, 53]. In a phase III RCT, several major CV adverse events occurred with febuxostat [39]. As a condition of approval for febuxostat by the US Food and Drug Administration, a large-scale, industry-sponsored post-marketing surveillance study was performed to determine if a causal relationship existed between febuxostat use and adverse CV events. More than 6000 subjects with gout and known CVD, defined as history of MI, stroke, peripheral vascular disease, diabetes with micro- or macrovascular disease, or hospitalization for transient ischemic attack, were enrolled [45]. Patients were assigned to randomly receive either once-daily dosing of febuxostat or allopurinol. Subjects were followed for a median of 32 months. Major CV events (primary outcome) were similar between both groups. Febuxostat use was associated with a 49% (HR 1.49, 95% CI 1.01–2.22) higher risk of CV-specific mortality in comparison to allopurinol. A major limitation of this study was that nearly 50% of subjects discontinued treatment and did not follow up. The percentage of patients lost to follow-up was similar in both groups.

Notwithstanding the study’s limitations, one interpretation of this study is that allopurinol may be more cardioprotective than febuxostat or that febuxostat use in gout is associated with an increased CV risk. Without the knowledge of actual CV risk attributable to hyperuricemia and gout, it is difficult to know the baseline CV risk in subjects with gout. Therefore, it cannot be determined whether allopurinol is beneficial for CVD, or febuxostat is harmful, or if both allopurinol and febuxostat are potentially cardioprotective, but allopurinol is significantly more cardioprotective than febuxostat. Current evidence (as summarized in this article) supports the first two explanations rather than the last explanation. This issue remains unsolved at present. Carefully designed observational studies, mechanistic studies, and RCTs in the near future can address these questions.

Since the availability of febuxostat, one new oral ULT is now available for the treatment of gout. Lesinurad is a selective uric acid reabsorption inhibitor commonly used in combination with allopurinol/febuxostat for treating hyperuricemia in gout. In an RCT, Saag et al. demonstrated that the use of 200- and 400-mg doses of lesinurad with allopurinol led to a > 50% reduction in SU (p < 0.0001), while allopurinol alone caused a 28% reduction in SU after 6 months [40]. The rate of adverse CV events in this phase III efficacy trial was similar with allopurinol and lesinurad in comparison to allopurinol alone. Arhalofenate, a uricosuric drug that behaves similarly to lesinurad in preventing reabsorption of uric acid in the proximal tubule (but not yet approved for clinical use), was effective in decreasing gout flares and lowering SU when compared with allopurinol [54]. Further RCTs are required to determine if adverse CV events are lowered with arhalofenate. However, traditional, placebo-controlled, phase III efficacy RCTs, performed for obtaining efficacy estimates, are not powered to examine CV harms or benefits with these new and emerging therapies. Pharmaco-epidemiological or phase IV studies can further our understanding of CV effects of these new ULTs.

Singh et al. examined the effectiveness of allopurinol for the risk of MI [44], stroke [46], peripheral arterial disease (PAD) [48], and atrial fibrillation (AF) [47] in the Medicare population. Multivariable models demonstrated that allopurinol was associated with a 15% decreased risk (HR 0.85, 95% CI 0.77–0.95) of incident MI, defined as first-time MI after beginning allopurinol. Compared with those who did not take allopurinol, subjects who used allopurinol for more than half a year and up to 2 years had a 24% decreased risk of MI (HR 0.76, 95% CI 0.68–0.85), while those who used allopurinol for more than 2 years had a 28% decreased risk of incident MI (HR 0.72, 95% CI 0.60–0.87) [44], supporting the notion that allopurinol may be cardioprotective. Similar findings were seen for incident stroke, defined as first-time stroke after initiation of allopurinol, in Medicare recipients. Allopurinol use was associated with a 9% decreased risk of stroke (HR 0.91, 95% CI 0.83–0.99). Longer duration of allopurinol use was associated with a greater risk reduction in stroke. Compared with non-users, those who took allopurinol for more than 2 years had a 21% decreased risk (HR 0.79, 95% CI 0.65–0.96) of stroke vs. those who used allopurinol for more than half a year but less than 2 years who had a 12% decreased risk of stroke (HR 0.88, 95% CI 0.78–0.99) after adjusting for potential cofounders [46]. In the Medicare population, a 17% decreased risk (HR 0.83, 95% CI 0.74–0.93) of incident AF, defined as first-time AF after the initiation of allopurinol, was observed in patients taking allopurinol vs. non-users of the drug. In adjusted analyses, prolonged use of allopurinol (> 2 years) was associated with a 35% decreased risk of incident AF (HR 0.65, 95% CI 0.52–0.82), while use of allopurinol for more than 6 months but less than 2 years was associated with a 15% decreased risk of incident AF (HR 0.85, 95% CI 0.73–0.99) in comparison to those who did not take allopurinol [47].

The risk of incident PAD, defined as first-time PAD after initiation of allopurinol, was decreased by 12% (HR 0.88, 95% CI 0.81–0.95) in comparison to those not taking allopurinol. Longer duration of allopurinol use was associated with a decreased risk of incident PAD (181 days to 2 years, HR 0.88, 95% CI 0.79–0.97; > 2 years, HR 0.75, 95% CI 0.63–0.89) [48].

These observational studies assessing a 5% random sample of Medicare claims demonstrated the cardioprotective effects of allopurinol in a large representative sample of elderly US patients. Confirmation of these findings in a similar sample of older populations in an independent sample is needed. Further RCTs are needed to evaluate if long-term use (> 2 years) decreases the risk of incident MI, stroke, AF, and PAD.

Not all data show strong evidence for ULT in improving endothelial function. In a double-blinded randomized placebo study of 149 patients, Borgi et al. demonstrated no significant difference in endothelium-dependent vasodilation in groups treated with probenecid, allopurinol, or placebo despite decreased SU levels after 8 weeks of ULT in treatment arms [55]. The subjects in this study were either overweight or obese, which implies that while the study results can be generalized to this group, it cannot be generalized to the entire population. Additionally, it is likely that certain metabolic factors play a role in endothelial-mediated vasodilation.

Moreover, research suggests that more aggressive dosing of ULT is required to treat gout and hyperuricemia [56]. Data from NHANES 2007–2010 showed that almost half of adult Americans receiving ULT had SU ≥ 6 mg/dL, which falls short of the American College of Rheumatology gout treatment guideline that recommends a SU target of < 6 mg/dL for ULT. Whether appropriate ULT treatment of gout can also improve CV outcomes in people with gout remains to be seen. This hypothesis testing requires a large cohort study or RCT with a treat-to-SU-target vs. a non-targeted approach.

6 Does Treating Gout with Urate-Lowering Therapy or Anti-Inflammatory Agents Improve Cardiovascular Disease Outcomes?

Zhang et al. studied the efficacy of febuxostat vs. allopurinol in patients aged 65 years and older with gout. The primary outcome of interest was the occurrence of incident stroke or MI. The authors matched 24,900 users of febuxostat with 74,700 patients taking allopurinol. Incidence rates of MI or stroke were similar in both groups. The risk of MI or stroke in the febuxostat group differed by 2% (HR 1.02, 95% CI 0.95–1.10) vs. the allopurinol group, which was not statistically significant [57].

Crittenden et al. examined the association of the use of colchicine for MI in patients with gout in a cross-sectional study that compared 576 subjects taking colchicine to 712 patients with no colchicine use. Compared with those who did not take colchicine, subjects taking colchicine had decreased CRP levels (2.5 vs. 3.4 mg/dL; p = 0.24), and a lower prevalence of MI (crude rates, 1.2% vs. 2.6%; p = 0.03) but no difference in all-cause mortality (crude rates, 3.9% vs. 5.1%; p = 0.18). Key study limitations were cross-sectional design, limited power, and residual confounding [58].

A summary of studies examining the effect of anti-inflammatory drugs on CVD mortality is presented in Table 3. In CANTOS, Ridker et al. studied the efficacy of the IL-1 monoclonal antibody, canakinumab, for the treatment of atherosclerotic disease. CANTOS compared the effect of IL-1 inhibition with canakinumab or placebo in 10,061 patients with a previous history of MI and elevated CRP levels [5]. Subjects were randomized to receive placebo or 50-mg, 150-mg, or 300-mg doses of the study drug every 3 months for a mean follow-up of more than 48 months [5]. The primary outcome of interest was non-fatal MI, non-fatal stroke, or CV death with a median follow-up of 3.7 years. The most marked effect was seen in the subjects receiving 150-mg doses of the IL-1 inhibitor. Compared with placebo, use of 150 mg of canakinumab was associated with a 15% reduction in non-fatal MI, stroke, or CV-specific death (odds ratio 0.85, 95% CI 0.74–0.98, p = 0.021), indicating the role of inflammation in the recurrence of CV events and amelioration of this risk with an effective reduction in inflammation. Subjects in the treatment arm reported higher rates of infection than those in the placebo group. While the study demonstrates a reduced risk of recurrent MI and a decrease in CV mortality, the increased risk of fatal infections is a cause for concern [5]. Further understanding of the effect of IL-1 inhibition on atherosclerosis is needed.

Table 3 Summary of studies detailing the effect of anti-inflammatory therapy on cardiovascular (CV) mortality
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7 Management of Asymptomatic Hyperuricemia

Asymptomatic hyperuricemia is defined as a SU ≥ 7.0 mg/dL with an absence of gouty attacks. Japanese researchers reported an increased incidence of CKD and cardiometabolic conditions in Japanese cohorts with asymptomatic hyperuricemia [59, 60]. The current guideline from the Japanese Society of Gout and Nucleic Acid Metabolism noted weak evidence to support the treatment of asymptomatic hyperuricemia [61]. Clinically, asymptomatic hyperuricemia is frequently treated with ULT in Japan. Vinik et al. examined studies performed in USA and Europe and found no evidence to recommend treatment to lower SU levels in asymptomatic hyperuricemia [62]. However, in a study that used Markov modeling to establish an association between SU and the risk of CVD, evidence for the treatment of asymptomatic hyperuricemia was found [63]. Akkineni et al. found that the use of allopurinol was most effective in decreasing vascular events in asymptomatic men with SU > 7.0 mg/dL and in asymptomatic women with SU > 5.0 mg/dL [63]. This indicates that double-blinded RCTs are required to determine if ULT should be recommended for people with asymptomatic hyperuricemia.

8 Conclusion

Gout is a debilitating disease affecting many elderly patients. Control of SU can be achieved with aggressive appropriate use of ULT. Associated comorbidities (which are also proatherogenic factors) and oxidative stress that worsen gout symptoms can also contribute to the pathogenesis of CVD. Chronic and recurrent acute inflammation and associated processes in gout also contribute to CVD risk. Recent literature indicates that anti-inflammatory agents may decrease CVD in the general population and potentially in people with chronic inflammatory conditions. Cardioprotective benefits of treating gout with allopurinol include a potential reduction in the risk of MI, stroke, atrial fibrillation, and other CVDs in observational studies in select populations. Observational studies have shown that a longer duration of ULT use (2 years of longer) may be needed to decrease CVD-specific morbidity. However, RCTs are required to validate findings of observational studies and to determine which subgroup populations of gout are most likely to benefit from appropriate long-term urate lowering with ULTs. Care providers should commence treatment quickly once a diagnosis of gout is conferred because the important role of inflammation in cardiac disease has become clear in the last two decades. Well-designed RCTs are needed to test these hypotheses generated from observational studies.