Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Randomized Controlled Trial
. 2022 May;17(5):663-671.
doi: 10.2215/CJN.11480821. Epub 2022 Mar 23.

SGLT2 Inhibition and Uric Acid Excretion in Patients with Type 2 Diabetes and Normal Kidney Function

Danii L S Suijk  1 , Michaël J B van Baar  2 , Erik J M van Bommel  2 , Zainab Iqbal  2 , Merle M Krebber  3 , Volker Vallon  4 , Daan Touw  5 , Ewout J Hoorn  6 , Max Nieuwdorp  7 , Mark M H Kramer  2 , Jaap A Joles  3 , Petter Bjornstad  8 , Daniël H van Raalte  2   7
Affiliations
Randomized Controlled Trial

SGLT2 Inhibition and Uric Acid Excretion in Patients with Type 2 Diabetes and Normal Kidney Function

Danii L S Suijk et al. Clin J Am Soc Nephrol. 2022 May.

Abstract

Background and objectives: Sodium-glucose transporter 2 (SGLT2) inhibitor-induced uric acid lowering may contribute to kidney-protective effects of the drug class in people with type 2 diabetes. This study investigates mechanisms of plasma uric acid lowering by SGLT2 inhibitors in people with type 2 diabetes with a focus on urate transporter 1.

Design, setting, participants, & measurements: We conducted an analysis of two randomized clinical trials. First, in the Renoprotective Effects of Dapagliflozin in Type 2 Diabetes study, 44 people with type 2 diabetes were randomized to dapagliflozin or gliclazide for 12 weeks. Plasma uric acid, fractional uric acid excretion, and hemodynamic kidney function were measured in the fasted state and during clamped euglycemia or hyperglycemia. Second, in the Uric Acid Excretion study, ten people with type 2 diabetes received 1 week of empagliflozin, urate transporter 1 blocker benzbromarone, or their combination in a crossover design, and effects on plasma uric acid, fractional uric acid excretion, and 24-hour uric acid excretion were measured.

Results: In the Renoprotective Effects of Dapagliflozin in Type 2 Diabetes study, compared with the fasted state (5.3±1.1 mg/dl), acute hyperinsulinemia and hyperglycemia significantly reduced plasma uric acid by 0.2±0.3 and 0.4±0.3 mg/dl (both P<0.001) while increasing fractional uric acid excretion (by 3.2%±3.1% and 8.9%±4.5%, respectively; both P<0.001). Dapagliflozin reduced plasma uric acid by 0.8±0.8 during fasting, 1.0±1.0 in hyperinsulinemic-euglycemic state, and 0.8±0.7 mg/dl during hyperglycemic conditions (P<0.001), respectively, whereas fractional uric acid excretion in 24-hour urine increased by 3.0%±2.1% (P<0.001) and 2.6%±4.5% during hyperinsulinemic-euglycemic conditions (P=0.003). Fractional uric acid excretion strongly correlated to fractional glucose excretion (r=0.35; P=0.02). In the Uric Acid Excretion study, empagliflozin and benzbromarone both significantly reduced plasma uric acid and increased fractional uric acid excretion. Effects of combination therapy did not differ from benzbromarone monotherapy.

Conclusions: In conclusion, SGLT2 inhibitors induce uric acid excretion, which is strongly linked to urinary glucose excretion and is attenuated during concomitant pharmacologic blockade of urate transporter 1.

Clinical trial registry name and registration number: Renoprotective Effects of Dapagliflozin in Type 2 Diabetes (RED), NCT02682563; SGLT2 Inhibition: Uric Acid Excretion Study (UREX), NCT05210517.

Keywords: SGLT-2 inhibition; URAT-1; kidney; type 2 diabetes; uric acid.

PubMed Disclaimer

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Metabolic parameters and uric acid handling during clamp. Uric acid, insulin, and glucose handling at baseline. (A) Blood glucose. (B) Blood insulin. (C) Plasma uric acid. (D) Fractional excretion of uric acid. (E) Fractional excretion of glucose. (F) Fractional excretion of sodium. Data are mean ± SD.
Figure 2.
Figure 2.
Determinants of uric acid handling baseline. (A) The association between plasma uric acid and fractional excretion of glucose. (B) Data on the association between fractional uric acid excretion and fraction glucose excretion. (C) Association between fractional excretion of uric acid and fractional excretion of sodium.
Figure 3.
Figure 3.
Effect of dapagliflozin on kidney uric acid handling. Uric acid levels at baseline and after 12 weeks of treatment with dapagliflozin or gliclazide. (A) Plasma uric acid levels during fasting conditions. (B) Plasma uric acid levels during hyperinsulinemic euglycemia. (C) Plasma uric acid levels during hyperglycemia. (D) Within-group change in plasma uric acid. (E) Fractional excretion of uric acid levels derived from 24-hour urine samples. (F) Fractional excretion of uric acid levels during hyperinsulinemic euglycemia. (G) Fractional excretion of uric acid levels during hyperglycemia. (H) Within-group change from baseline in fractional excretion of uric acid. Data are mean ± SD. NS, not significant.
Figure 4.
Figure 4.
Effect of empagliflozin, benzbromarone, and combination therapy on uric acid. (A) Plasma uric acid. (B) Fractional excretion of uric acid. Data are mean ± SD. NS, not significant.
See this image and copyright information in PMC

References

    1. Johnson RJ, Bakris GL, Borghi C, Chonchol MB, Feldman D, Lanaspa MA, Merriman TR, Moe OW, Mount DB, Sanchez Lozada LG, Stahl E, Weiner DE, Chertow GM: Hyperuricemia, acute and chronic kidney disease, hypertension, and cardiovascular disease: Report of a scientific workshop organized by the National Kidney Foundation. Am J Kidney Dis 71: 851–865, 2018 - PMC - PubMed
    1. Sato Y, Feig DI, Stack AG, Kang DH, Lanaspa MA, Ejaz AA, Sánchez-Lozada LG, Kuwabara M, Borghi C, Johnson RJ: The case for uric acid-lowering treatment in patients with hyperuricaemia and CKD. Nat Rev Nephrol 15: 767–775, 2019 - PubMed
    1. Doria A, Galecki AT, Spino C, Pop-Busui R, Cherney DZ, Lingvay I, Parsa A, Rossing P, Sigal RJ, Afkarian M, Aronson R, Caramori ML, Crandall JP, de Boer IH, Elliott TG, Goldfine AB, Haw JS, Hirsch IB, Karger AB, Maahs DM, McGill JB, Molitch ME, Perkins BA, Polsky S, Pragnell M, Robiner WN, Rosas SE, Senior P, Tuttle KR, Umpierrez GE, Wallia A, Weinstock RS, Wu C, Mauer M; PERL Study Group : Serum urate lowering with allopurinol and kidney function in type 1 diabetes. N Engl J Med 382: 2493–2503, 2020 - PMC - PubMed
    1. Badve SV, Pascoe EM, Tiku A, Boudville N, Brown FG, Cass A, Clarke P, Dalbeth N, Day RO, de Zoysa JR, Douglas B, Faull R, Harris DC, Hawley CM, Jones GRD, Kanellis J, Palmer SC, Perkovic V, Rangan GK, Reidlinger D, Robison L, Walker RJ, Walters G, Johnson DW; CKD-FIX Study Investigators : Effects of allopurinol on the progression of chronic kidney disease. N Engl J Med 382: 2504–2513, 2020 - PubMed
    1. Zhao Y, Xu L, Tian D, Xia P, Zheng H, Wang L, Chen L: Effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on serum uric acid level: A meta-analysis of randomized controlled trials. Diabetes Obes Metab 20: 458–462, 2018 - PubMed

Publication types

MeSH terms

Associated data