Letter by Awadhesh Kumar Singh Regarding Article, "Cardiovascular Outcomes Comparison of Dipeptidyl Peptidase-4 Inhibitors Versus Sulfonylurea as Add-on Therapy for Type 2 Diabetes Mellitus: A Meta-Analysis".

We read the manuscript by Jeon et al.1 on “Cardiovascular Outcomes Comparison of Dipeptidyl Peptidase-4 Inhibitors versus Sulfonylurea as Add-on Therapy for Type 2 Diabetes Mellitus: a Meta-Analysis” published in your esteemed journal with great interest and applaud the authors for conducting such a high-quality meta-analysis. However, we noticed few major errors in this meta-analysis that need correction, in order to assist the conclusion. First, regarding the interpretation of ischemic stroke or transient ischemic attack (TIA) outcome between DPP-4 inhibitors (DPP-4Is) and sulfonylureas (SUs)—while authors have reported that DPP-4Is were associated with a higher risk of ischemic stroke or TIA (random-effect risk ratio [RR], 2.78; 95% confidence interval [CI], 1.06–7.30; p=0.065; I2=51.9%) when compared to SUs from the analysis of 6 studies (5 randomized controlled trials [RCTs] and 1 prospective study), after the adjustment through the trim and fill method (excluding one small study that showed bias in ischemic stroke analysis) there was no significant difference in ischemic stroke between SUs and DPP4-Is (random-effect RR, 1.28; 95% CI, 0.50–3.29; p=0.612). Intriguingly, while title of this meta-analysis suggests a comparison of cardiovascular outcomes with DPP-4Is vs. SUs as an add-on therapy for type 2 diabetes mellitus, all analysis were done in reverse order i.e., SUs vs. DPP-4Is. In fact, the forest plot made by the authors itself suggests a rather 2.8-fold increase in relative risk of ischemic stroke or TIA in SUs recipients compared to DPP-4Is not the vice versa, as interpreted by the authors. Although reversing the order may not change the final results of any outcome, interpretations would be mistaken and funnel plot could be misleading, as in this case. Indeed, when we re-analyzed the ischemic stroke or TIA data from the same selected six studies (having exactly the same number of events and patients) using Comprehensive metaanalysis software version 3, Biostat Inc. Englewood, NJ, USA, we found a significantly 63% lesser relative risk amongst DPP-4Is recipients (random-effect RR, 0.37; 95% CI, 0.14–0.95; p=0.039) compared to SUs, with a similar insignificant albeit moderate heterogeneity (I2= 51.4%; p=0.068) (Fig. 1). Interestingly, in our analysis, funnel plot found no publication bias, and the Trim and Fill method computed the same result (Supplementary Fig. 1). These findings do suggest J Lipid Atheroscler. 2022 Jan;11(1):84-86 https://doi.org/10.12997/jla.2022.11.1.84 pISSN 2287-2892·eISSN 2288-2561