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.