Premature Conclusion that Sodium-Glucose Cotransporter-2 Inhibitors Improve Kidney Outcomes in Patients with Heart Failure

We read with great interest the meta-analysis by Siddiqi et al.,1 recently published in JASN, on the effects of sodium-glucose cotransporter-2 (SGLT-2) inhibitors on kidney outcomes in patients with heart failure, CKD, and type 2 diabetes. We would like to congratulate the authors on their tremendous effort in conducting a comprehensive systematic review, synthesizing data from 11 high-quality randomized control trials to evaluate this crucial question regarding SGLT-2 inhibitors. The main findings of the article suggest that, compared with placebo, SGLT-2 inhibitors improve kidney outcomes in the abovementioned three patient populations, and these effects are consistent across patients with different comorbidities. However, there are some questions we would like to discuss with the authors. First, meta-analysis is widely used as a powerful tool to synthesize data from different studies. However, when the number of included studies is small (≤5 studies) (e.g., heart failure with reduced ejection fraction), we need to interpret the results with caution.2 In such small-sample meta-analyses, traditional statistical methods (e.g., generic inverse variance method in Revman software) may not be sufficient to provide accurate estimates. Alternative methods, such as the Hartung–Knapp–Sidik–Jonkman method, have been devised specifically for meta-analyses with fewer studies to improve between-study variance estimates.3 Based on this consideration, we reanalyzed the data from Siddiqi et al.1 and found that the pooled effect sizes beyond the null line (Figure 1A). This result suggests that the original article on the benefits of SGLT-2 inhibitors on kidney outcomes in patients with heart failure may have been overestimated.Figure 1: Reanalysis of kidney composite outcome in heart failure patients with reduced ejection fraction by SGLT-2 inhibitors. (A) Forest plot. (B) Trial sequential analysis for kidney composite outcome in patients with heart failure. CI, confidence interval; DAPA-HF, Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure; EMPEROR-Reduced, Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction; HR, hazard ratio; SGLT-2, sodium-glucose cotransporter 2.Second, to further assess the reliability of the results, we conducted a trial sequential analysis with the following parameters set: α=0.05 (bilateral), β=0.20 (power 80%), and relative risk reduction=40%. Considering the small number of studies, we chose the Sidik and Jonkman random-effects model. Our results showed that the cumulative Z-curve exceeded the conventional test boundary but still did not breach the O'Brien–Fleming monitoring boundary (Figure 1B). This finding suggests a possible risk of false-positive results.4 In addition, the cumulative sample size (5387) fell far short of the required informative sample size (13,810), suggesting that the available evidence is not yet sufficient to conclusively demonstrate the benefit of SGLT-2 inhibitors on kidney composite outcomes in patients with heart failure. Based on the above analysis, we believe it is necessary to take the conclusions of the original article with a greater degree of caution. Although the available data suggest possible benefits of SGLT-2 inhibitors, the strength of the evidence is not yet strong enough to support definitive conclusions.