serum urate levels and incident gout over 11 years


A large individual participant data analysis documented a strong nonlinear relationship between serum urate levels and developing clinical gout (see gout serum urate conc and gout annrheumdis2018 in dropbox, or Dalbeth N. Ann Rheum Dis 2018; 77: 1048).

Details:
-- 4 longitudinal observational studies fit the criteria for inclusion: the Atherosclerosis Risk in Communities Study (ARIC) with 10,775 participants; the Coronary Artery Risk Development in Young Adults Study (CARDIA) with 3470 participants; and both the Original and Offspring cohorts of the Framingham Heart Study (FHS)
-- all studies had publicly-available patient-level data, incident gout data, serum urate levels measured prior to assessment of incident gout, minimum study duration of 3 years, and gout defined by using recognized criteria/doctor diagnosis/patient self-reported disease/or self-reported of doctor diagnosis
-- there was a total of 18,889 people who were gout-free at baseline with mean of 11.2 years of follow-up: 212,363 total patient-years
-- 43.8% men, mean age 49 (17-85)

Results:
-- overall cumulative incidence of gout for all participants:
    -- 0.6% at 3 years, 1.1% at 5 years, 2.4% at 10 years, 3.2% at 15 years
-- urate-specific  gout incidence overall (primary outcome):
    -- by 5 years: 0.33% for baseline serum urate <6 mg/dL​​​ up to 26% if ≥​10 mg/dL
    -- by 10 years: 0.79% for baseline serum urate <6 , up to 40% if ≥​10 mg/dL
    -- by 15 years: 1.1% for baseline serum urate <6 , up to 49% if ≥​10 mg/dL​ 
-- per the 5-year data, the incidence of gout was:
    -- for those with serum urate ≥​7, incidence ago was 9.8/1000 person-years
    -- for those with serum urate ≥​8, incidence ago was 20/1000 person-years
    -- for those with serum urate ≥​9, incidence ago was 34/1000 person-years
    -- for those with serum urate ≥​10, incidence ago was 53/1000 person-years
-- for women, the cumulative incidence of gout per baseline serum urate measurement was lower by 3 years of follow-up, but by 10 to 15 years of follow-up the cumulative incidence was the same as men
-- relative risk of developing gout, as compared to a baseline serum urate level <6 mg/dL​​ (all with p<0.001), the hazard ratio (HR), adjusted for age, sex, ethnicity, and cohort were:
    -- for baseline serum urate HR 6.0-6.9 was 2.7 (2.0-3.6)
    -- for baseline serum urate HR 7.0-7.9 was 6.6 (5.0-8.8)
    -- for baseline serum urate HR 8.0-8.9 was 15 (11-20)
    -- for baseline serum urate HR 9.0-9.9 was 30 (21-42) 
    -- adjusted HR for baseline serum urate ≥​10 was 64 (43-96)

Commentary:
-- the study revealed a strong non-linear concentration-dependent relationship between serum urate levels and incident gout
-- the overall prevalence of hyperuricemia is increasing in the US, as documented by the National Health and Nutrition Examination Survey.
-- there are an array of risk factors associated with increased uric acid levels:
    -- several foods/drinks lead to hyperuricemia: alcohol, high purine diet (meat/seafoods), as well as obesity.
    -- one other major dietary factor leading to hyperuricemia is fructose.
        --I’ve seen several patients stop drinking sodas (a large source of high fructose corn syrup) and have their serum uric acid levels decrease by 1-1.5 mg/dL (as commented on in http://gmodestmedblogs.blogspot.com/2016/12/new-gout-management-guidelines.html  .
        --Another blog (http://gmodestmedblogs.blogspot.com/2015/11/fructose-restriction-and.html ) did not find a lowering of uric acid by diet in a small study of kids, though this blog reviews some of the epidemiologic studies.
        --Also http://gmodestmedblogs.blogspot.com/2016/08/non-alcoholic-fatty-liver-disease-2.html  has a review of fructose metabolism (different than other sugars) and suggestions that it may directly lead to non-alcoholic fatty liver disease.
     -- Medications: a study of 25K pts in general practices in UK found a 19% decreased risk of clinical gout with losartan (compared to other hypertensive pts), 13% with ccbs (21% decreased with amlodipine, 13% with nifedipine, and 14% with diltiazem), and increased gout risk with diuretics, b-blockers, ACE-I's, other ARBs besides losartan.  They note in their discussion some studies (which I looked at, and are pretty small…) find that ccbs (esp nifedipine and amlodipine) and losartan are uricosuric and decrease serum uric acid levels.  See https://www.bmj.com/content/bmj/344/bmj.d8190.full.pdf . 
-- as per the authors, the current study was limited by lack of environmental risk factors which could have influenced gout or the inflammatory response to hyperuricemia (since only half the patients with very high uric acid levels develop clinical gout, were there some moderators for inciting or depressing clinical gout?). and there were variable differences in the definitions and ascertainment of the gout diagnosis; there was only one baseline serum urate concentration measured (this might have changed over time), and this study looked only at gout as the clinical outcome and not other perhaps more important endpoints such as hypertension, chronic kidney disease, or cardiovascular disease
--and there are a lot of relevant blogs reviewing studies, some related to the potential effects of hyperuricemia on heart disease and hypertension, and some suggesting that gout therapies may lower the risk.
    --see http://gmodestmedblogs.blogspot.com/2017/07/hyperuricemia-and-cardiometabolic.html : a Japanese study suggesting that hyperuricemia predated the development of hypertension, hyperlipidemia, chronic kidney disease, overweight/obesity, diabetes
    --see http://gmodestmedblogs.blogspot.com/2016/03/hyperuricemia-allopurinol-decreases.html for a Danish study suggesting that treating hyperuricemia in those with allopurinol led to fewer cardiovascular events
    --see http://gmodestmedblogs.blogspot.com/search/label/gout%2Fhyperuricemia   which includes blog on an interesting evolutionary perspective on hyperuricemia (see  http://gmodestmedblogs.blogspot.com/2019/04/uric-acid-lowering-cardiovasc-benefit.html  ), as well as several on gout (guidelines, even a study suggesting that colchicine lowers cardiovascular risk)

So, I have become more convinced that hyperuricemia may well be a bad actor for a lot of chronic medical problems, as well as clinical gout.  It may be useful to occasionally check uric acid levels on patients (I do, but this is certainly not routine clinical practice), with an eye to decreasing causative agents if the uric acid is elevated (dietary changes, with a focus on high fructose corn syrup), perhaps switching antihypertensive agents to using more losartan, ccb’s. and strongly considering allopurinol if very elevated levels.

geoff​

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