SGLT2i lowers serum urate regardless of diabetes status

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) can keep serum urate levels low in patients with and without diabetes, according to a recent Singapore study.

“To the best of our knowledge, this is the first and largest meta-analysis investigating the effects of SGLT2 inhibitors on serum urate in patients with and without diabetes,” the researchers said.

The present meta-analysis included 43 randomized controlled trials (combined cohort n=31,921 patients) retrieved from the online databases of PubMed, Embase, SCOPUS, and Cochrane. Pooled analysis revealed that SGLT2is could significantly reduce serum urate levels by 33.03 µmol/L (95 percent confidence interval [CI], –37.38 to –28.69; p<0.001). [Ther Adv Chronic Dis 2022;doi:10.1177/20406223221083509]

Subgroup analyses found that of all SGLT2is administered, luseogliflozin had the strongest effect on serum urate, reducing mean levels by 47.73 µmol/L (95 percent CI, –79.50 to –15.96; p=0.003). This was followed by canagliflozin (mean reduction, 36.62 µmol/L, 95 percent CI, –42.67 to –30.56; p<0.001) and empagliflozin (mean reduction, 35.19 µmol/L; 95 percent CI, –42.61 to –27.78).

Of note, SGLT2is remained significantly effective at decreasing serum urate levels both in patients with (mean reduction, 31.48 µmol/L, 95 percent CI, –37.35 to –25.60; p<0.001) and without (mean reduction, 91.38 µmol/L, 95 percent CI, –126.53 to –56.24; p<0.001) type 2 diabetes mellitus (T2DM), though its effects were much stronger in the latter subgroup.

In contrast, SGLT2is could not suppress serum urate in T2DM patients with concomitant chronic kidney disease.

The researchers then performed random-effects meta-regression analysis to determine whether the dose of three SGLT2is (dapagliflozin, canagliflozin, and empagliflozin) affected the degree of serum urate reduction. Data were insufficient for a meta-regression analysis of ipragliflozin and luseogliflozin.

They found no such interaction: dapagliflozin (beta, –0.478, 95 percent CI, –3.04 to 2.09; p=0.704), canagliflozin (beta, –0.0073, 95 percent CI, –0.064 to 0.05; p=0.79), and empagliflozin (beta, 0.267, 95 percent CI, –0.654 to 1.19; p=0.559). These findings indicated no dose-dependence effect of the urate-lowering properties of SGLT2is.

“While lowering serum urate levels may have benefits, this effect has been difficult to characterize. Nevertheless, lowering serum urate has not been shown to be harmful,” the researchers said.

“Given the strong association between urate levels and many other comorbidities, the urate-lowering properties of SGLT2 inhibitors should be viewed as an additional benefit in the management of the overall morbidity in patients with diabetes,” they added. [Eur J Intern Med 2016;29:3-8; Clin J Am Soc Nephrol 2020;15:1576-1586]

“Adequately powered randomized controlled trials are also required to formally interrogate the use of SGLT2 inhibitors in patients without diabetes,” the researchers said. “Future studies should also consider SGLT2 inhibitors in patients with gout, who have an absolute indication for urate-lowering therapy.”