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

Diabetes Obes Metab. 2023 Sep;25(9):2697-2703. doi: 10.1111/dom.15157. Epub 2023 Jun 19.

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; I2 = 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; I2 = 0%) accentuated the benefits of SGLT2 inhibitors with no between-trial heterogeneity (HR 0.46, 95% CI 0.39-0.55; I2 = 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.

Keywords: SGLT2 inhibitors; T2DM; anti-inflammatory; gout; heart failure; uric acid.

Publication types

  • Meta-Analysis

MeSH terms

  • Canagliflozin / therapeutic use
  • Diabetes Mellitus, Type 2* / complications
  • Diabetes Mellitus, Type 2* / drug therapy
  • Glucose / therapeutic use
  • Gout* / chemically induced
  • Gout* / complications
  • Gout* / drug therapy
  • Heart Failure* / complications
  • Humans
  • Randomized Controlled Trials as Topic
  • Sodium
  • Sodium-Glucose Transporter 2 Inhibitors* / therapeutic use
  • Uric Acid

Substances

  • Sodium-Glucose Transporter 2 Inhibitors
  • Uric Acid
  • Canagliflozin
  • empagliflozin
  • Glucose
  • Sodium