Does treatment status relate to other diseases in gout patients?

Gout is a growing threat to the world population. Moreover, the prevalence of comorbidities is higher in gout patients.

A new study shows how urate-lowering therapy (ULT) is related to such conditions as chronic kidney disease (CKD) and cardiovascular disease (CVD).

Introduction

Gout affects more males than females and is known to be due to the accumulation of uric acid in the body. High levels of serum uric acid (SUA, hyperuricemia) cause urate crystals to deposit in the joints, causing the classical picture of gout.

Gout is a remitting-relapsing condition, and reduction of SUA is key to its best management. This encourages already-formed urate crystals to dissolve, alleviating the injury and the symptoms.

ULT is the recommended treatment for this condition, according to the American College of Rheumatology. The preferred drugs include allopurinol and febuxostat, which prevent the formation of uric acid from digested purines. Probenecid is a second-line agent and may be added to the former drugs as required.

Most patients are not on ULT, however, but on anti-inflammatories to control the pain. This does not modify the disease process, however, predisposing to continuing joint damage and eventually to tophi (granulomas formed beneath the skin as part of the body’s reaction to the urate crystals), and renal stones.

Other long-term outcomes include a higher risk of CVD, including heart attacks, arrhythmias, and strokes. Diabetes and hypertension are also more common among gout patients. The question is whether better control of SUA with ULT will mitigate or prevent such complications.

Earlier research showed a better outcome following treatment of heart failure when allopurinol or febuxostat was added, with a lower risk of acute cardiovascular events. Some indications exist of an association between allopurinol and blood glucose levels. Not much is known about how ULT affects inflammatory markers and of lipid or glucose levels.

The current study, published in Rheumato, explored the association between ULT status and the following conditions: CKD, high serum cholesterol and other lipids, coronary heart disease (CHD), heart failure, and hypertension, as well as with specific laboratory markers.

The study had an observational design and was based on data from the National Health and Nutrition Examination Survey (NHANES), covering the period 2013-2018. There were 835 patients, all adults aged 30 years or older, with a history of gout for a mean of 13 years.

What did the study show?

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The scientists found that about 30% of gout patients were on ULT. Most of these patients were educated to college level or higher, had insurance, were somewhat older (~65 years vs. 61 years for non-ULT patients), were more commonly male (~76% vs. 64%, respectively), and were obese.

The most common ULT was allopurinol, used by 91%. SUA levels were lower with those on treatment, at 5.8 mg/dL vs. 6.6 mg/dL for the others. SUA levels were within the therapeutic target for 64% and 39% of ULT and non-ULT users, respectively.

CKD was more than twice as common among ULT users,  even after adjusting for other confounding factors, including diabetes. Interestingly, these patients had lower levels of the inflammatory marker C-reactive protein (CRP), at 4.8 mg/L vs. 7.2 mg/L in non-ULT users. Cholesterol levels, both total and low-density lipoprotein (LDL), were also lower.

However, other medical conditions were rare among patients on ULT.

What are the implications?

This is the first study to use epidemiologic methods to explore the prevalence of some chronic conditions against a background of medical treatment for gout. The findings show that the use of ULT is low among American adults with gout, and may depend on financial and educational status to some extent. Patients with typical risk factors for gout, such as males, those with obesity and CKD patients, are more likely to be on ULT.

“Gout remains suboptimally managed in a sizable proportion of patients,” warn the researchers. This increases the risk that these patients will develop kidney stones, high blood pressure and acute cardiovascular events.

ULT uptake should be encouraged among gout patients, leveraging the influence of nurses and pharmacists, especially in the primary care setting where most of these patients are seen. Educating patients on the role of these medications in mitigating the disease pathophysiology is a cost-effective step that could help achieve better SUA control.

A third of those on ULT fail to normalize their SUA levels, perhaps because of irregular monitoring, poor compliance, or failure on the part of the physician to adjust the dose as necessary. Genetic factors may also come into play to influence the response to ULT.

The scientists downplay the risk of worsening renal function while on ULT, since another study showed a 13% lower risk of stage 3 CKD among allopurinol users over five years compared to non-users.

Allopurinol is converted to a compound that is excreted by the kidney, and CKD could cause the latter to build up, perhaps damaging the kidneys further. This does not seem to be the case, judging by currently available evidence; in fact, the reverse may be true. ULT use has also been associated with better outcomes in heart failure patients.

Meanwhile, ULT is linked to lower cholesterol levels, both because of the reduced production of fat in the body, and perhaps genetic factors. The latter, while making individuals more prone to develop gout may sensitize them to anti-gout treatment as well.

The researchers point out that “gout patients receiving ULT may garner added health benefits beyond lower urate levels.” However, more research will be necessary to understand how these drugs could affect serum lipids, renal function and the cardiovascular system if used over the long term.

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.