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  • Cardiovascular and renal efficacy and safety of sodium-glucose cotransporter-2 inhibitors in patients without diabetes: a systematic review and meta-analysis of randomised placebo-controlled trials

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Cardiovascular and renal efficacy and safety of sodium-glucose cotransporter-2 inhibitors in patients without diabetes: a systematic review and meta-analysis of randomised placebo-controlled trials
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  • Published on: 29 January 2024
    RE: Cardiovascular and renal efficacy and safety of sodium-glucose cotransporter-2 inhibitors in patients without diabetes
    • Wan-Chuan Tsai, Nephrologist Far Eastern Memorial Hospital. No. 21, Section 2, Nanya South Rd, Banciao District, New Taipei City 220, Taiwan
    • Other Contributors:
      • Yu-Sen Peng, Nephrologist
      • Hon-Yen Wu, Nephrologist

    The hypothesized mechanisms for reduction of cardiovascular risk by sodium-glucose cotransporter-2 (SGLT2) inhibitors are multifactorial. Among these mechanisms, Professor Tomoyuki Kawada made a comment on the relative contribution of two clinically important markers, serum uric acid and kidney function, to SGLT2 inhibitors-driven risk reduction of cardiovascular disease.
    Inzucchi et al. explored the potential underlying mechanisms behind the empagliflozin on cardiovascular benefit by conducting post hoc mediation analysis of data from the EMPA-REG OUTCOME trial. 1 The authors demonstrated that changes in plasma volume status (hematocrit or hemoglobin) had the largest impact (mediated around 50% of the treatment effect) on the cardiovascular death with empagliflozin versus placebo. In line with Professor Tomoyuki Kawada’s point of view, the authors reported that changes in uric acid had a greater mediation effect on the treatment effect of empagliflozin on cardiovascular risk reduction, whereas changes in kidney function had no or negligible effects (percentage mediation was 24.6% for uric acid, 11.1% for logUACR, and 5.3% for eGFR). The uricosuric effect of the SGLT2 inhibitors is linked to urinary glucose excretion and caused by blockage of renal tubular uric acid transporters. 2
    The relationship between changes in albuminuria and reduction in cardiovascular risk with SGLT2 inhibitors therapy depends on baseline albuminuria status. Waijer el al. assessed whet...

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    Conflict of Interest:
    None declared.
  • Published on: 24 January 2024
    RE: Cardiovascular and renal efficacy and safety of sodium-glucose cotransporter-2 inhibitors in patients without diabetes

    Tsai et al. conducted a meta-analysis to evaluate the cardiovascular and renal efficacy and safety of sodium-glucose cotransporter-2 (SGLT2) inhibitors in patients without diabetes (1). Risk ratios (RRs) (95% confidence intervals [CIs]) of SGLT2 inhibitors for the composite cardiovascular outcome, cardiovascular death, hospitalization for heart failure, and the composite renal outcome were 0.79 (0.71 to 0.87), 0.85 (0.74 to 0.99), 0.72 (0.62 to 0.82), and 0.64 (0.48 to 0.85), respectively. The authors clarified that SGLT2 inhibitors had cardiorenal benefits and increased risk for urinary tract and genital infection in patients without diabetes. I present comments with special reference to the level of serum uric acid and kidney function.

    Zhao et al. conducted a meta-analysis to evaluate the effects of SGLT2 inhibitors on serum uric acid (SUA) in patients with type 2 diabetes mellitus (T2DM) (2). Any of the SGLT2 inhibitors significantly decreased SUA levels against controls, and empagliflozin presented a predominant reduction in SUA. Increase of the urinary excretion of uric acid by SGLT2 inhibitor is not simply caused by the increased urinary volume, but the inhibition of uric acid reabsorption by SGLT2 inhibitor would be made at the collecting duct in the renal tubule (3). 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.

    Tang e...

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    Conflict of Interest:
    None declared.