Letter to the Editor: re-evaluating comparative efficacy of SGLT2 inhibitors in heart failure

Dear Editor, I read with interest the network meta-analysis by Abuhashem et al entitled, “A network meta-analysis of safety and efficacy of sodium-glucose cotransporter 2 inhibitors in heart failure patients.”1 The authors should be commended for synthesizing evidence from a large cohort of randomized controlled trials (RCTs). However, several methodological and clinical considerations merit further discussion. First, although network meta-analysis enables indirect comparisons across multiple interventions, the absence of direct head-to-head trials between SGLT2 inhibitors limits the robustness of comparative efficacy conclusions. Prior landmark trials such as DAPA-HF and EMPEROR-Reduced evaluated individual agents against placebo rather than against each other, making cross-trial comparisons inherently susceptible to bias2,3. Second, the unequal representation of individual agents, particularly the predominance of empagliflozin and dapagliflozin trials may skew comparative rankings. Agents such as sotagliflozin and ertugliflozin are supported by fewer trials, reducing confidence in their relative positioning despite promising results, including the notable reduction in heart failure hospitalization observed with sotagliflozin4. Third, heterogeneity across included studies poses an additional limitation. Variations in patient populations, including differences in heart failure phenotype (HFrEF vs HFpEF), diabetic status, and baseline cardiovascular risk, may confound pooled estimates. Evidence suggests that treatment effects of SGLT2 inhibitors may vary across these subgroups, emphasizing the need for more stratified analyses5. Fourth, although empagliflozin demonstrated statistically significant reductions in cardiovascular mortality and serious adverse events, the clinical significance of these differences compared with other agents remains uncertain. Prior meta-analyses have consistently shown a class effect of SGLT2 inhibitors in reducing cardiovascular outcomes, suggesting that differences between agents may be less pronounced in real-world settings6. Finally, the exclusion of observational and real-world data limits external validity. Given the growing body of real-world evidence supporting the effectiveness and safety of SGLT2 inhibitors across diverse populations, integrating such data could enhance the generalizability of findings and inform individualized treatment strategies. In conclusion, although this network meta-analysis provides valuable comparative insights, caution is warranted in interpreting drug-specific superiority. Future head-to-head RCTs and real-world studies are essential to establish definitive comparative effectiveness and guide optimal therapeutic selection in HF management.