Can Angiotensin Receptor Neprilysin Inhibitors (ARNi) produce hyperuricemia?

From the Guidelines

Yes, angiotensin receptor-neprilysin inhibitors (ARNi) can cause hyperuricemia. The mechanism involves interference with uric acid transporters in the renal tubules, leading to decreased uric acid clearance, as noted in the context of neprilysin inhibition effects 1. The risk appears to be dose-dependent, with higher doses more likely to affect uric acid levels. Patients with pre-existing gout or elevated baseline uric acid levels may be at higher risk for this side effect. While hyperuricemia from ARNi therapy is generally mild to moderate, it's essential to monitor uric acid levels in patients on these medications, particularly those with a history of gout or kidney disease, as suggested by the management of cardiovascular diseases treated with renin-angiotensin-aldosterone system inhibitors 1. If a patient develops symptomatic hyperuricemia or gout while on ARNi therapy, treatment with urate-lowering medications may be necessary while continuing the ARNi if it provides significant cardiovascular benefits. Key considerations include the potential for increased serum uric acid levels with sacubitril/valsartan (Entresto), the main ARNi medication currently available, and the importance of managing hyperkalemia, which can be a concern with renin-angiotensin-aldosterone system inhibitors, as outlined in guidelines for the management of heart failure 1. Monitoring and appropriate management are crucial to balance the cardiovascular benefits of ARNi therapy with the potential risks of hyperuricemia.

From the Research

ARNi and Hyperuricemia

• The effect of ARNi (Angiotensin Receptor-Neprilysin Inhibitor) on serum uric acid levels has been studied in several trials 2, 3.
• In the PARAGON-HF trial, sacubitril-valsartan (an ARNi) reduced serum uric acid (SUA) levels by 0.38 mg/dL compared to valsartan at 4 months 2.
• Similarly, in the PARADIGM-HF trial, sacubitril/valsartan reduced SUA levels by 0.24 mg/dL over 12 months compared to enalapril 3.
• These studies suggest that ARNi may actually decrease serum uric acid levels, rather than producing hyperuricemia.

Renal Function and ARNi

• The effect of ARNi on renal function has been evaluated in several studies 4, 5, 6.
• In a real-world 12-week study, sacubitril/valsartan slowed down renal function decline and reversed myocardial remodeling in patients with chronic kidney disease (CKD) and heart failure with preserved ejection fraction (HFpEF) 4.
• A systematic review and meta-analysis found that sacubitril/valsartan improved renal function and conferred effective cardiovascular benefits in patients with CKD, without serious safety issues being observed 6.
• These studies suggest that ARNi may have a beneficial effect on renal function, rather than producing hyperuricemia.

Hyperuricemia and ARNi

• There is no evidence to suggest that ARNi produces hyperuricemia.
• In fact, the available evidence suggests that ARNi may actually decrease serum uric acid levels and improve renal function.
• Therefore, it is unlikely that ARNi would produce hyperuricemia 2, 4, 5, 3, 6.