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Review: Cardiometabolic–Renal Comorbidities in Gout

Key findings

  • A number of cardiometabolic-renal (CMR) comorbidities are highly prevalent in individuals with gout, notably hypertension, obesity, type 2 diabetes, chronic kidney disease, myocardial infarction and stroke
  • Randomized controlled trials and Mendelian randomization studies give no indication that serum urate causes CMR risk factors or outcomes (e.g., metabolic syndrome, kidney function)
  • Thus, lowering serum urate, particularly with medications, is not expected to provide the CMR benefits that can be achieved through other means such as weight loss, increased physical activity and a healthful cardiometabolic diet
  • Some drugs used to treat the CMR comorbidities of gout also modestly lower serum urate: sodium–glucose cotransporter 2 inhibitors, calcium channel blockers, losartan and fenofibrate
  • Those agents should be considered for adjunctive treatment of gout or for its prevention

Gout is characterized not just by inflammatory arthritis but also by an increased burden of cardiometabolic-renal (CMR) comorbidities. The most prevalent are hypertension, obesity, type 2 diabetes, chronic kidney disease (CKD), myocardial infarction and stroke.

Hyon K. Choi, MD, program director of the Clinical Epidemiology Program and clinical rheumatologist with the Division of Rheumatology, Allergy and Immunology at Massachusetts General Hospital, Chio Yokose, MD, MS, a researcher and clinical rheumatologist in the division, and Natalie McCormick, PhD, another researcher in the division, recently reviewed in Nature Reviews Rheumatology some advances in the understanding and management of this life-threatening component of the disease burden of gout.

Mendelian Randomization Data

Just as people with gout have an increased risk of developing CMR comorbidities, people with renal or cardiovascular disease are more likely than others to develop gout. To clarify the relationships, five bidirectional Mendelian randomization studies have been conducted. Mendelian randomization is a method that enables researchers to better estimate potential causal effects by using genetic variants, something determined at conception and thus free of confounding or reverse causation, as the exposure.

In this research, genetically determined serum urate had no causal effect on body fat mass, triglyceride concentration or fasting insulin concentration, but those variables were positively associated with serum urate. The implication: Although urate-lowering therapy is unlikely to lower the risk of metabolic syndrome or CMR events, interventions to reduce insulin resistance and adiposity might lower serum urate.

Lifestyle Modification

Patients with gout should be screened for diabetes and cardiovascular risk factors, including obesity, dyslipidemia and hypertension. Some experts consider hyperuricemia itself a surrogate marker of metabolic syndrome, even in individuals without gout.

Like the Mendelian randomization studies, randomized controlled trials show no evidence that lowering serum urate with medications provides the CMR benefits that can be achieved through weight loss, increased physical activity and a healthful cardiometabolic diet.

A dietary approach that limits protein intake to reduce purine loading that is often recommended for individuals with gout has limited palatability and sustainability, and it tends to lead to increased consumption of refined carbohydrates, saturated fats and trans fats. Moreover, accumulating evidence suggests the diets shown to reduce the risk of cardiometabolic disease, including the Mediterranean and DASH (Dietary Approaches to Stop Hypertension) diets, can simultaneously reduce serum urate and risk of incident gout.

Double-duty Pharmacologic Therapy

Some drugs used to treat the CMR comorbidities of gout also lower serum urate. They should be considered for adjunctive treatment of gout, or for its prevention, in patients who already have certain CMR comorbidities:

Sodium–glucose cotransporter 2 (SGLT2) inhibitors have proven efficacy for patients with type 2 diabetes, as well as cardiovascular disease and CKD in individuals with or without comorbid diabetes. These agents reduce the risk of CKD worsening, and clinical trials of dapagliflozin and empagliflozin have shown cardiovascular benefits including significant reductions in the risk of heart failure hospitalization and premature mortality, even in patients who don't have diabetes.

The authors of this review propose considering SGLT2 inhibitors for patients who have gout plus type 2 diabetes, cardiovascular disease, and/or CKD, although evidence is more limited specifically in patients with gout.

The urate-lowering effects of SGLT2 inhibitors are probably most relevant to patients whose gout is relatively mild and infrequent, and thus typically being treated in primary care. However, supplementing conventional urate-lowering therapy with SGLT2 inhibitors or other urate-lowering CMR drugs might be promising for patients with advanced gout, particularly those who don't respond sufficiently to first-line urate-lowering therapy.

Calcium channel blockers and losartan—Prior use of these agents by patients with hypertension has been associated with a lower risk of gout in several population-based studies. In contrast, diuretics, beta-blockers, angiotensin-converting enzyme inhibitors and non-losartan angiotensin II receptor antagonists were associated with increased risk of gout.

Fenofibrate lowered serum urate concentrations by 20% in the randomized controlled FIELD trial and cut the risk of gout by 46% over five years of therapy, as reported in The Lancet Diabetes & Endocrinology. Fenofibrate may be particularly appropriate for preventing gout in patients who have hypertriglyceridemia and/or type 2 diabetes.

Looking Ahead

The review also discusses the pathogenesis of excess CMR comorbidities, including imaging studies suggesting monosodium urate crystals are deposited in coronary plaques and the renal medulla. If these reports are confirmed, further research might lead to a treat-to-target approach that uses serum urate reduction to improve CMR endpoints.

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Hyon K. Choi, MD, of the Division of Rheumatology, Allergy and Immunology, and colleagues report preliminary evidence that a dietitian-directed, DASH-patterned behavioral intervention lowers serum urate in gout patients not on urate-lowering drugs.