In this large UK primary care population, we found that the incidence of gout remained stable between 2000 and 2007. Our contemporary data corroborated previously shown risk factors, including alcohol intake, obesity, chronic renal impairment, cardiovascular conditions, and diuretic use. Furthermore, we have examined other purported medical conditions and medications, about which we are not aware of any previous large-scale evidence. We found that prior histories of ischemic heart disease, heart failure, hyperlipidemia, and psoriasis are independently associated with an increased risk of gout, whereas diabetes was associated with a lower risk of gout. Interestingly, among subtypes of hyperlipidemia, hypertriglyceridemia was associated with an increased risk, whereas this pattern was much less clear among patients with hypercholesterolemia. We also found that among post-transplant drugs cyclosporine was the only agent associated with increased risk of gout. Finally, the frequency of anti-gout medication use has remained relatively unchanged in recent years except for an increase of colchicine.
Our estimate of incidence rate increased from 0.4 per 1,000 person-years in women of 40 to 49 years, to 3.6 in women of 70 to 79 years. Our results are in line with a prior study  that reported an incidence rate of gout of 0.6 per 1,000 person-years in women <45 years and 2.5 in women over the age of 75. When we restricted our cohort to individuals aged 40 years and older, our estimate of incidence (3.5 per 1,000 person-years) was in close agreement with a recent UK study, which estimated an incidence rate of gout 3.2 per 1,000 person-years . Although the mean age of first diagnosis was 60.1 years in males and 67.7 years in females, almost 40% of all incident gout cases were younger than 60 years, indicating that many middle-aged subjects were affected. Male preponderance was more marked in individuals less than 60 years. The different age dependence between males and females in the incidence of gout could in part be due to hormonal status. The uricosuric effects of estrogens could lead to a protective effect on the risk of gout in premenopausal women [17–20]. We also observed that women on exogenous hormonal treatment had 14% less risk of developing gout, and the reduced risk disappeared after stopping HRT, a finding previously reported in a large prospective cohort study of female nurses .
Our findings confirm the relationship between traditional risk factors with well-known effects on increasing uric acid levels and subsequently the risk of gout [21, 22]. Our cohort data showed a clear dose-response relation between alcohol consumption and the risk of gout, similar to previous studies . Similarly, our results showed a continuous increased risk of gout with increasing BMI as well as a protective effect in individuals with a BMI under 20 kg/m2. Bidirectional associations between weight loss and the prevention of gout and weight gain and the development of gout were reported in the Health Professionals Follow up Study . Chronic renal impairment more than doubled the risk of developing incident gout, which is likely due to decreased urate excretion resulting in uric acid accumulation [4, 24]. Beyond the effect of this and other medical conditions, the use of diuretics, in particular among users of one year and longer than one year, was associated with a three-fold increased risk of gout.
We also evaluated other suspected risk factors lacking in large-scale epidemiologic data, such as lipid abnormalities, ischemic heart disease, congestive heart failure, psoriasis, and various medications. While all subtypes of hyperlipidemia showed independent associations with the risk of incident gout , the association with hypertriglyceridemia was most prominent. Elevated triglyceride level is a cardinal feature of insulin resistance, which is closely associated with elevated serum uric acid levels. Individuals with diabetes showed a reduced risk of gout. Some studies have reported lower uric acid levels among diabetes patients [26, 27]. We also found that prior history of congestive heart failure and ischemic heart disease was independently associated with an increased risk of gout. Associated relative tissue hypoxia, increased lactate levels, or accelerated adenosine triphosphate (ATP) consumption could increase the risk of hyperuricemia and gout in patients with these conditions [28, 29]. Recently, a case-control study with only 60 individuals with gout and 6 with heart failure (HF) reported an increased risk of gout among patients with HF [30, 31]. Interestingly, this study also reported that diuretic use did not increase the risk of gout after adjusting for HF and other cardiovascular conditions, as these factors are closely associated with each other [30, 31]. Our study, with substantially larger study samples (n with gout = 24,768 and n with HF = 3,564), was able to detect independent associations with each of these two factors. Psoriasis is a disorder associated with increased cell turnover leading to increased uric acid production  and our cohort confirmed a small but significantly increased risk of incident gout. Finally, the absence of an association between history of nephrolithiasis and risk of gout was consistent with the result reported by Kramer et al. [32, 33].
Current use of low-dose aspirin was more common among gout patients than controls. However, after adjusting for other covariates, including history of ischemic heart disease, low-dose aspirin was not associated with an increased risk of gout. This suggests that the independent pathogenetic role of low-dose aspirin use, if any, may be minor on the risk of incident gout. Our study confirmed an increased risk of gout among users of cyclosporine (an immunosuppressant drug indicated in organ transplant, psoriasis, rheumatoid arthritis, and nephrotic syndrome), whereas there was no association with use of azathioprine or other medications indicated after organ transplant [4, 34, 35]. The apparent association between NSAID use and risk of gout was restricted to patients recently started before the recorded diagnosis of gout. This observation suggests substantial confounding by indication, where use within the first month could be a proxy (treatment) for early manifestations of gout, although a true association cannot be ruled out entirely.
In terms of anti-gout medication use during recent years, we found that allopurinol use had the highest frequency, followed by colchicine, whereas a small proportion of gout patients were taking uricosuric drugs. Treatment patterns did not change in recent years, with only colchicine showing an increase. While allopurinol use seems to be in line with a previous study based on the GPRD between 1990 and 1999, colchicine use appears to have increased since the 1990s, when the authors reported an annual frequency of colchicine use of only 1 to 3% . In addition, it should be noted that the greater proportion of colchicine use could also be explained in part by the fact that our study is based exclusively on individuals newly-diagnosed with a first gout attack, when colchicine prophylaxis is used more often .
The strengths and limitations of our study deserve comment. Our study was performed with a large population-based database which contains computerized information entered by primary care physicians that permits the extrapolation of results to the general population. Also, under our design of incidence density sampling, the OR is an unbiased estimator of the incidence rate ratio. Some level of misclassification is unavoidable when working with computerized databases; however, the impact of non-differential misclassification would have most likely biased our estimates of effect toward the null and would not explain the strong associations and dose-response relationships observed in our study. Furthermore, in a secondary analysis when we restricted gout cases to those with GPs' diagnoses of gout combined with anti-gout medication use, our results remained similar (data not shown).