http://orcid.org/0000-0002-4426-4644
Dear Editor
Mende described the role of sodium–glucose cotransporter-2 (SGLT2) and its inhibitors for diabetes and kidney diseaseCitation1. Min et al. discussed dapagliflozin and renal function in relation to this articleCitation2. I would like to present recent information with special reference to the mechanism of the association between SGLT2 inhibitors and serum uric acid (SUA).
Zhao et al. conducted a meta-analysis to evaluate the effects of SGLT2 inhibitors on SUA in patients with type 2 diabetes mellitus (T2DM)Citation3. Any of the SGLT2 inhibitors significantly decreased SUA levels compared with controls, and empagliflozin presented a superior reduction in SUA, presenting total weighted mean difference of −45.83 μmol/L. In addition, Davies et al. reported that the reduction of SUA by canagliflozin (both 100 and 300 mg) in the Canagliflozin Cardiovascular Assessment Study trial was 13% (or 0.7 mg/dl) compared to placeboCitation4. With respect to the mechanism of the association, increase of the urinary excretion of uric acid by SGLT2 inhibitors is not simply caused by the increased urinary volume. The inhibition of uric acid reabsorption by SGLT2 inhibitors occurs at the collecting duct in the renal tubule by activating the glucose transporter (GLUT) 9 isoform 2Citation5. I suspect that the urinary excretion rate of uric acid would be increased by SGLT2 inhibitor-induced glycosuria plus active uric acid reabsorption mechanism via insulin resistance. Namely, GLUT9 isoform 2 is expressed at the apical membrane of the kidney tubular cells and transports both uric acid (UA) and glucose. In addition, insulin increases urate transporter 1 and decreases ATP-binding cassette subfamily G member 2 levels, resulting in increased UA reabsorptionCitation6,Citation7.
Wanner et al. reported the prognostic effect of empagliflozin in patients with T2DM with special reference to established cardiovascular disease and chronic kidney disease (CKD)Citation8. The glomerular filtration rate and urine albumin–creatinine ratio did not modify the effect of empagliflozin on clinical outcomes, and this SGLT2 inhibitor improved clinical outcomes and reduced mortality in patients with T2DM. Taken together, the effects of SGLT2 inhibitors on SUA should be considered in combination with diabetes, kidney disease and cardiovascular disease.
There are benefits of SUA lowering therapy for improving endothelial dysfunction and systemic inflammation, which would also lead to the prevention of cardiovascular diseasesCitation9. In addition, genetic evidence regarding the effect of SUA concentration on the development of cardiovascular disease is requiredCitation10.
Finally, there has been no report of nephrolithiasis with SGLT2 inhibitors, despite the increased uric acid excretion. I suspect that the increased osmotic diuresis would partly prevent nephrolithiasis. In addition, hyperuricemia in CKD affects renal arterial wall thickness and arteriolar hyalinosis, which should be monitored with caution as a non-crystalline complicationCitation11.
Transparency
Declaration of funding
No funding was received for this letter.
Declaration of financial/other relationships
T.K. has disclosed that he has no significant relationships with or financial interests in any commercial companies related to this study or article.
CMRO peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
References
- Mende CW. Diabetes and kidney disease: the role of sodium-glucose cotransporter-2 (SGLT-2) and SGLT-2 inhibitors in modifying disease outcomes. Curr Med Res Opin 2017;33:541-51.
- Min T, Wali L, Williams DM, et al. Dapagliflozin and renal function. Re: Diabetes and kidney disease: the role of sodium-glucose cotransporter-2 (SGLT-2) and SGLT-2 inhibitors in modifying disease outcomes. Mende CW. Curr Med Res Opin 2017;33:541-551. Curr Med Res Opin 2017;33:1715-6.
- Zhao Y, Xu L, Tian D, et al. Effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on serum uric acid level: a meta-analysis of randomized controlled trials. Diabetes Obes Metab 2018;20:458-62.
- Davies MJ, Trujillo A, Vijapurkar U, et al. Effect of canagliflozin on serum uric acid in patients with type 2 diabetes mellitus. Diabetes Obes Metab 2015;17:426-9.
- Ahmadieh H, Azar S. Effects of sodium glucose cotransporter-2 inhibitors on serum uric acid in type 2 diabetes mellitus. Diabetes Technol Ther 2017;19:507-12.
- Chino Y, Samukawa Y, Sakai S, et al. SGLT2 inhibitor lowers serum uric acid through alteration of uric acid transport activity in renal tubule by increased glycosuria. Biopharm Drug Dispos 2014;35:391-404.
- Toyoki D, Shibata S, Kuribayashi-Okuma E, et al. Insulin stimulates uric acid reabsorption via regulating urate transporter 1 and ATP-binding cassette subfamily G member 2. Am J Physiol Renal Physiol 2017;313:F826-34.
- Wanner C, Lachin JM, Inzucchi SE, et al. Empagliflozin and clinical outcomes in patients with type 2 diabetes mellitus, established cardiovascular disease, and chronic kidney disease. Circulation 2018;137:119-29.
- Volterrani M, Iellamo F, Sposato B, et al. Uric acid lowering therapy in cardiovascular diseases. Int J Cardiol 2016;213:20-2.
- Borghi C, Verardi FM, Pareo I, et al. Hyperuricemia and cardiovascular disease risk. Expert Rev Cardiovasc Ther 2014;12:1219-25.
- Kohagura K, Kochi M, Miyagi T, et al. An association between uric acid levels and renal arteriolopathy in chronic kidney disease: a biopsy-based study. Hypertens Res 2013;36:43-9.