Danii L S Suijk1, Michaël J B van Baar2, Erik J M van Bommel2, Zainab Iqbal2, Merle M Krebber3, Volker Vallon4, Daan Touw5, Ewout J Hoorn6, Max Nieuwdorp7, Mark M H Kramer2, Jaap A Joles3, Petter Bjornstad8, Daniël H van Raalte2,7. 1. Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands d.suijk@amsterdamumc.nl. 2. Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands. 3. Department of Nephrology and Hypertension, University Medical Center, Utrecht, The Netherlands. 4. Division of Nephrology and Hypertension, Department of Medicine, University of California San Diego, La Jolla, California. 5. Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, Groningen, The Netherlands. 6. Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus Medical Center, Rotterdam, The Netherlands. 7. Department of Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands. 8. Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
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.
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.
Authors: Laura G Sánchez-Lozada; Edilia Tapia; José Santamaría; Carmen Avila-Casado; Virgilia Soto; Tomás Nepomuceno; Bernardo Rodríguez-Iturbe; Richard J Johnson; Jaime Herrera-Acosta Journal: Kidney Int Date: 2005-01 Impact factor: 10.612
Authors: Richard J Johnson; Mark S Segal; Titte Srinivas; Ahsan Ejaz; Wei Mu; Carlos Roncal; Laura G Sánchez-Lozada; Michael Gersch; Bernardo Rodriguez-Iturbe; Duk-Hee Kang; Jaime Herrera Acosta Journal: J Am Soc Nephrol Date: 2005-04-20 Impact factor: 10.121
Authors: Sunil V Badve; Elaine M Pascoe; Anushree Tiku; Neil Boudville; Fiona G Brown; Alan Cass; Philip Clarke; Nicola Dalbeth; Richard O Day; Janak R de Zoysa; Bettina Douglas; Randall Faull; David C Harris; Carmel M Hawley; Graham R D Jones; John Kanellis; Suetonia C Palmer; Vlado Perkovic; Gopala K Rangan; Donna Reidlinger; Laura Robison; Robert J Walker; Giles Walters; David W Johnson Journal: N Engl J Med Date: 2020-06-25 Impact factor: 91.245
Authors: Vlado Perkovic; Meg J Jardine; Bruce Neal; Severine Bompoint; Hiddo J L Heerspink; David M Charytan; Robert Edwards; Rajiv Agarwal; George Bakris; Scott Bull; Christopher P Cannon; George Capuano; Pei-Ling Chu; Dick de Zeeuw; Tom Greene; Adeera Levin; Carol Pollock; David C Wheeler; Yshai Yavin; Hong Zhang; Bernard Zinman; Gary Meininger; Barry M Brenner; Kenneth W Mahaffey Journal: N Engl J Med Date: 2019-04-14 Impact factor: 91.245