Volume 20, Issue 5 p. 1235-1245
ORIGINAL ARTICLE

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

Lennart Tonneijck MD

Corresponding Author

Lennart Tonneijck MD

Department of Internal Medicine, Diabetes Center, VU University Medical Center, Amsterdam, The Netherlands

Correspondence

Lennart Tonneijck, MD, Department of Internal Medicine, Diabetes Center, VU University Medical Center Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.

Email: l.tonneijck@vumc.nl

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Marcel H. A. Muskiet MD

Marcel H. A. Muskiet MD

Department of Internal Medicine, Diabetes Center, VU University Medical Center, Amsterdam, The Netherlands

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Mark M. Smits MD

Mark M. Smits MD

Department of Internal Medicine, Diabetes Center, VU University Medical Center, Amsterdam, The Netherlands

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Petter Bjornstad MD

Petter Bjornstad MD

Department of Pediatric Endocrinology, University of Colorado School of Medicine and Barbara Davis Center for Diabetes, University of Colorado Denver, Aurora, Colorado

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Mark H. H. Kramer MD

Mark H. H. Kramer MD

Department of Internal Medicine, Diabetes Center, VU University Medical Center, Amsterdam, The Netherlands

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Michaela Diamant

Michaela Diamant

Department of Internal Medicine, Diabetes Center, VU University Medical Center, Amsterdam, The Netherlands

Deceased.Search for more papers by this author
Ewout J. Hoorn MD

Ewout J. Hoorn MD

Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus Medical Center, Rotterdam, The Netherlands

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Jaap A. Joles MD

Jaap A. Joles MD

Department of Nephrology and Hypertension, University Medical Center, Utrecht, The Netherlands

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Daniël H. van Raalte MD

Daniël H. van Raalte MD

Department of Internal Medicine, Diabetes Center, VU University Medical Center, Amsterdam, The Netherlands

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First published: 17 January 2018
Citations: 22
Funding information The research leading to the results of Studies A to C received funding from the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement 282521–the SAFEGUARD project, and from the Dutch Kidney Foundation under grant agreement IP12.87. For Study-C Novo Nordisk provided liraglutide and liraglutide-placebo pens. Study-D was an investigator-initiated study, planned and conducted entirely under the scientific supervision of M.D. and, after her passing in 2014, of D.H.v.R. and M.H.H.K. Funding for the study was provided by Sanofi-Aventis. Sanofi-Aventis provided prefilled lixisenatide and insulin glulisine pens for subcutaneous use. Self-monitoring blood glucose devices were provided by Menarini Diagnostics. The funders of all studies had no role in study design or in collection, analysis and interpretation of data, in writing of the report or in the decision to submit the article for publication.
Lennart Tonneijck and Marcel H. A. Muskiet contributed equally to this work.

Abstract

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 (UEUA) and sodium (UENa), 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-UEUA (+1.58 ± 0.65 mg/min/1.73 m2, P = .02), but did not affect fractional UEUA compared to placebo. Fractional UEUA and absolute UEUA correlated with increases in urine pH (r:0.86, P = .003 and r:0.92, P < .001, respectively). Fractional UEUA correlated with increased fractional UENa (r:0.76, P = .02). In Study-B, exenatide infusion did not affect plasma UA, but increased fractional UEUA (+0.76 ± 0.38%, P = .049) and absolute UEUA (+0.75 ± 0.27 mg/min/1.73 m2, P = .007), compared to placebo. In regression analyses, both parameters were explained by changes in urine pH and, in part, by changes in UENa. In Study-C, liraglutide treatment did not affect plasma UA, UEUA, UENa or urine pH, compared to placebo. In Study-D, lixisenatide treatment increased UENa and urine pH from baseline, but did not affect plasma UA or UEUA.

Conclusion

Immediate exenatide infusion increases UEUA 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 UEUA 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.