Effect of immediate and prolonged GLP‐1 receptor agonist administration on uric acid and kidney clearance: Post‐hoc analyses of four clinical trials

Aims To determine the effects of glucagon‐like peptide (GLP)‐1 receptor agonists (RA) on uric acid (UA) levels and kidney UA clearance. Material and methods This study involved post‐hoc analyses of 4 controlled clinical trials, which assessed actions of GLP‐1RA administration on kidney physiology. The immediate effects of GLP‐1RA exenatide infusion vs placebo were determined in 9 healthy overweight men (Study‐A) and in 52 overweight T2DM patients (Study‐B). The effects of 12 weeks of long‐acting GLP‐1RA liraglutide vs placebo in 36 overweight T2DM patients (Study‐C) and of 8 weeks of short‐acting GLP‐1RA lixisenatide vs once‐daily titrated insulin glulisine in 35 overweight T2DM patients (Study‐D) were also examined. Plasma UA, fractional (inulin‐corrected) and absolute urinary excretion of UA (UE UA ) and sodium (UE Na ), and urine pH were determined. Results Median baseline plasma UA level was 5.39 to 6.33 mg/dL across all studies (17%‐22% of subjects were hyperuricaemic). In Study‐A, exenatide infusion slightly increased plasma UA (+0.07 ± 0.02 mg/dL, P = .04), and raised absolute‐UE UA (+1.58 ± 0.65 mg/min/1.73 m 2 , P = .02), but did not affect fractional UE UA compared to placebo. Fractional UE UA and absolute UE UA correlated with increases in urine pH (r:0.86, P = .003 and r:0.92, P < .001, respectively). Fractional UE UA correlated with increased fractional UE Na (r:0.76, P = .02). In Study‐B, exenatide infusion did not affect plasma UA, but increased fractional UE UA (+0.76 ± 0.38%, P = .049) and absolute UE UA (+0.75 ± 0.27 mg/min/1.73 m 2 , P = .007), compared to placebo. In regression analyses, both parameters were explained by changes in urine pH and, in part, by changes in UE Na . In Study‐C, liraglutide treatment did not affect plasma UA, UE UA, UE Na or urine pH, compared to placebo. In Study‐D, lixisenatide treatment increased UE Na and urine pH from baseline, but did not affect plasma UA or UE UA . Conclusion Immediate exenatide infusion increases UE UA in overweight healthy men and in T2DM patients, probably by inhibiting Na + /H + ‐exchanger type‐3 in the renal proximal tubule. Prolonged treatment with a long‐acting or short‐acting GLP‐1RA does not affect plasma UA or UE UA in T2DM patients with normal plasma UA levels and at relatively low cardiovascular risk. Our results suggest that the cardio‐renal benefits of GLP‐1RA are not mediated through changes in UA.