Factors Influencing Change in Serum Uric Acid After Administration of the Sodium‐Glucose Cotransporter 2 Inhibitor Luseogliflozin in Patients With Type 2 Diabetes Mellitus

Abstract

Although sodium-glucose cotransporter 2 (SGLT2) inhibitors lower serum uric acid, their long-term effect on uric acid metabolism is not well understood. We analyzed pooled data from studies wherein patients with type 2 diabetes mellitus received luseogliflozin, an SGLT2 inhibitor. Upon stratifying patients by baseline glycated hemoglobin (HbA 1c ) or serum uric acid, lower HbA 1c or higher serum uric acid level was associated with a greater reduction in serum uric acid after treatment. At week 12 of treatment, significant increases in urinary glucose/creatinine (Cr) ratio and urinary uric acid clearance/Cr clearance ratio (C UA /C Cr ratio) and a significant reduction in serum uric acid were observed. Comparison of the subgroups of patients with a reduction or an increase in serum uric acid showed that the increase subgroup had a higher estimated glomerular filtration rate (eGFR) at baseline, and the eGFR was significantly reduced, associated with a significant reduction in the C UA /C Cr ratio. Multiple regression analysis showed that the reduction in serum uric acid in the luseogliflozin group was strongly associated with baseline high serum uric acid, low HbA 1c levels, and an increase in eGFR. Luseogliflozin was shown to reduce serum uric acid by enhancing urinary uric acid excretion in association with increased urinary glucose. Treatment with luseogliflozin resulted in increased serum uric acid in some patients, which may be due to reduced glomerular filtration of uric acid via the tubuloglomerular feedback. SGLT2 inhibitors reduced serum uric acid desirably in patients with type 2 diabetes mellitus with low HbA 1c and high serum uric acid.

Uric Acid and Oxidative Stress—Relationship with Cardiovascular, Metabolic, and Renal Impairment

“…Other control factors in the balance of serum UA can be volume status (enhances reabsorption) [ 46 , 47 ], low-salt diet (enhances reabsorption) [ 48 , 49 ], insulin [ 50 , 51 , 52 ], angiotensin II [ 53 ], epinephrine, and PTH, which raises serum UA through unknown mechanisms [ 54 ]. In addition, an important factor in controlling serum UA is oxidative stress, which modulates production, excretion, and reabsorption of urate [ 55 ].…”

A Description of Acute Renal Failure and Nephrolithiasis Associated With Sodium–Glucose Co-Transporter 2 Inhibitor Use: A VigiBase Study

“…However, it was also suggested that SGLT2i can cause hyperuricosuria ( Chino et al, 2014 ; Novikov et al, 2019 ), which may confer a greater risk for specific types of kidney stones. Moreover, a recent study of pooled analysis of data from clinical studies found that in 19% of patients, treatment with luseogliflozin resulted in increased serum uric acid, which may be due to reduced glomerular filtration of uric acid via the tubuloglomerular feedback ( Chino et al, 2022 ). Yet, another meta-analysis found no association of SGLT-2 inhibitors with nephrolithiasis ( Cosentino et al, 2019 ).…”

Sodium Glucose Cotransporter-2 Inhibitors: Spotlight on Favorable Effects on Clinical Outcomes beyond Diabetes

“…Uricosuria is a class effect; however, individual compounds were not found equal in this study. A Japanese analysis of three studies with luseogliflozin found both decreased and increased uric acid after 12 weeks, and this effect was dependent on the baseline uric acid concentration, glycosylated hemoglobin and glomerular filtration [ 89 ]. Thus, more research elucidating these differences is necessary.…”