The Long-Term Effects of the Selective Inhibitor of Urate Transporter 1, Dotinurad, on Metabolic Parameters and Renal...

Epidemiological studies have reported that hyperuricemia is associated with the development of metabolic syndrome, hypertension, dyslipidemia, type 2 diabetes, and chronic kidney disease (CKD). Renal uric acid (UA) reabsorption is mainly mediated by urate transporter 1 (URAT1) in renal proximal tubule epithelial cells. Recently, URAT1 was found to be expressed in the liver and adipose tissue in addition to the kidney. UA enters such organs via URAT1 and induces inflammation and oxidative stress, which may lead to metabolic disorders. We investigated the effects of long-term treatment with the novel uricosuric drug, a highly selective inhibitor of URAT1, dotinurad, on metabolic parameters and renal function.

We retrospectively picked up patients who had taken dotinurad for the treatment of asymptomatic hyperuricemia for more than 2 years. We compared metabolic parameters and renal function at baseline with the data at 6, 12, 18, and 24 months after starting dotinurad.

Pharmacologically, dotinurad decreases serum UA, by selectively inhibiting URAT1 and decreasing renal reabsorption of UA, which was supported by our result that dotinurad significantly increased urine UA and reduced serum UA. In addition to UA-lowering, dotinurad was associated with improvements in body weight, liver function, hepatic steatosis index as the marker for metabolic dysfunction-associated steatotic liver disease (MASLD), serum lipids, and albuminuria. The ATP-binding cassette transporter G2 (ABCG2) regulates renal and intestinal excretion of UA and uremic toxins and strongly affects renal function. Our study also indicates that switching from xanthine oxidase inhibitors, which inhibit ABCG2, to dotinurad, which does not inhibit ABCG2, was beneficial for albuminuria and maintaining the estimated glomerular filtration rate.

Dotinurad may improve obesity, MASLD, serum lipids, and CKD by blocking the entry of UA via URAT1 to the adipose tissue, liver, and kidney.