Serum uric acid lowering and effects of sodium‐glucose cotransporter‐2 inhibitors on gout: A meta‐analysis and meta‐regression of randomized controlled trials

Abstract Aims To pool the effects of sodium‐glucose cotransporter‐2 (SGLT2) inhibitors on gout and to investigate the association of these effects with baseline serum uric acid (SUA), SUA lowering, and underlying conditions, such as type 2 diabetes mellitus (T2DM)/heart failure (HF). Methods PubMed, Embase, Web of Science, Cochrane Library and clinical trial registry websites were searched for randomized controlled trials (RCTs) or post hoc analyses (≥1‐year duration; PROSPERO:CRD42023418525). The primary outcome was a composite of gouty arthritis/gout flares and commencement of anti‐gout drugs (SUA‐lowering drugs/colchicine). Hazard ratios (HRs) with 95% confidence interval (CI) were pooled using a generic inverse‐variance method with a random‐effects model. Mixed‐effects model univariate meta‐regression analysis was performed. Results Five RCTs involving 29 776 patients (T2DM, n = 23 780) and 1052 gout‐related events were identified. Compared to placebo, SGLT2 inhibitor use was significantly associated with reduced risk of composite gout outcomes (HR 0.55, 95% CI 0.45‐0.67; I 2 = 61%, P < 0.001). Treatment benefits did not differ between trials being conducted exclusively in baseline HF versus those conducted in patients with T2DM ( P ‐interaction = 0.37), but were greater with dapagliflozin 10 mg and canagliflozin 100/300 mg ( P < 0.01 for subgroup differences). Sensitivity analysis excluding trials that evaluated the effects of empagliflozin 10/25 mg (HR 0.68, 95% CI 0.57‐0.81; I 2 = 0%) accentuated the benefits of SGLT2 inhibitors with no between‐trial heterogeneity (HR 0.46, 95% CI 0.39‐0.55; I 2 = 0%). Univariate meta‐regression found no impact of baseline SUA, SUA lowering on follow‐up, diuretic use, or other variables on their anti‐gout effects. Conclusion We found that SGLT2 inhibitors significantly reduced the risk of gout in individuals with T2DM/HF. Lack of an association with SUA‐lowering effects suggests that metabolic and anti‐inflammatory effects of SGLT2 inhibitors may predominantly mediate their anti‐gout benefits.