Cardiorenal benefits of sodium‐glucose co‐transporter‐2 inhibitors versus dipeptidyl peptidase‐4 inhibitors in type 2 diabetes without cardiovascular and renal diseases

Dear Editor, We read with great interest the study by Idris et al. recently published in Diabetes, Obesity and Metabolism. In the study, the authors compared the cardiorenal efficacies of sodium-glucose cotransporter-2 inhibitors (SGLT2is) and dipeptidyl peptidase-4 inhibitors (DPP4is) in type 2 diabetes (T2D) patients with and without cardiovascular and renal diseases (CVRD). However, the relative effects of SGLT2is and DPP4is on cardiorenal outcomes in T2D without CVRD revealed in the study conducted by Idris et al. are inconsistent with those revealed in previous studies. For example, Idris et al. found that SGLT2is were associated with a significantly lower risk of heart failure (HF) but had similar risks of stroke and cardiovascular mortality (CVM) compared with DPP4is in CVRD-free T2D patients, whereas previous studies found that SGLT2is were associated with significantly lower risks of stroke and CVM, but had a similar risk of HF compared with DPP4is in this population. Hence, to resolve the conflicting data, we conducted a meta-analysis to analyse the relative efficacy of SGLT2is versus DPP4is on cardiorenal endpoints in CVRDfree T2D patients. In the absence of randomized controlled trials (RCTs) focusing on cardiorenal outcomes in T2D patients treated with SGLT2is or DPP4is, we identified cohort studies directly comparing the effects of SGLT2is and DPP4is on cardiorenal outcomes in CVRD-free T2D patients by searching Embase and PubMed from the date of inception of the databases to 22 September 2021 (the search strategy is detailed in Table S1). Outcomes of interest were HF, chronic kidney disease (CKD), stroke, myocardial infarction (MI), all-cause mortality (ACM), and CVM. Three studies met the inclusion criteria. Using both survival data (i.e. hazard ratios [HRs] with 95% confidence intervals [CIs]) and dichotomous data (i.e. the numbers of events and total subjects in each study group, with results expressed through risk ratios [RRs] with 95% CIs), we performed both random-effects and fixed-effects meta-analyses. We reported random-effects results (I > 50%) or fixed-effects results (I ≤ 50%). Statistical analyses were performed using Stata/MP (16.0). Among the three studies that met the inclusion criteria, the study conducted by Idris et al. enrolled T2D patients both with and without CVRD, while the other two studies only enrolled T2D patients without CVRD. We extracted the corresponding outcome data of CVRD-free T2D patients from the three studies for this meta-analysis. The extracted data and characteristics of the included studies are shown in Table S2. The cohorts from the included studies were similar in terms of mean age and proportion of females and involved a total of 139 715 SGLT2i users and 139 715 DPP4i users. Meta-analysis of the survival data showed that SGLT2is, in comparison with DPP4is, were associated with a 25% greater reduction in HF (HR 0.75, 95% CI 0.66-0.86; Figure 1A), a 54% greater reduction in CKD (HR 0.46, 95% CI 0.24-0.90; Figure 1B), and a 33% greater reduction in ACM (HR 0.67, 95% CI 0.61-0.74; Figure 1E); however, the two drug classes had similar risks of stroke (HR 0.75, 95% CI 0.55-1.02; Figure 1C), MI (HR 0.96, 95% CI 0.84-1.10; Figure 1D), and CVM (HR 0.74, 95% CI 0.50-1.08; Figure 1F). Meta-analysis of the dichotomous data showed that SGLT2is, in comparison with DPP4is, were associated with a 29% greater reduction in HF (RR 0.71, 95% CI 0.63-0.80; Figure 1G), a 54% greater reduction in CKD (RR 0.46, 95% CI 0.29-0.74; Figure 1H), and a 34% greater reduction in ACM (RR 0.66, 95% CI 0.59-0.72; Figure 1K); however, the two drug classes had similar risks of stroke (RR 0.76, 95% CI 0.58-1.01; Figure 1I), MI (RR 0.98, 95% CI 0.76-1.27; Figure 1J), and CVM (RR 0.71, 95% CI 0.481.05; Figure 1L). The results of meta-analysis of the survival data (Figure 1A-F) were consistent with those of the dichotomous data (Figure 1G-L), showing the robustness of pooled results. We found that, compared with DPP4is, SGLT2is were associated with significantly lower risks of HF, CKD, and ACM in CVRD-free T2D patients, but that the two drug classes had similar risks of stroke, MI, and CVM. Similarly, three recent meta-analyses based on RCTs suggested that SGLT2is could yield better HF, renal failure, and mortality outcomes. Inconsistent with our findings, two other meta-analyses based on cardiorenal outcome trials showed that SGLT2is led to clear and consistent reductions in major adverse cardiovascular events (MACE, a composite of non-fatal stroke, non-fatal MI, or CVM) regardless of baseline metformin use and history of cardiovascular disease. There are a few possible reasons for these inconsistent findings. First, the previous metaanalyses included patients with T2D or CVRD, whereas ours included only patients with T2D without CVRD. Second, the previous meta-analyses compared SGLT2is with a placebo, whereas ours compared SGLT2is with DPP4is. Finally, the previous meta-analyses were conducted based on RCTs, whereas ours was based on cohort studies because of the lack of relevant active-controlled trials. Three other meta-analyses based on cohort studies, among which the study conducted by Longato et al. involved both original data analysis and meta-analysis, assessed the cardiorenal efficacy of SGLT2is compared with DPP4is in T2D patients overall, but failed to Received: 1 October 2021 Revised: 26 October 2021 Accepted: 31 October 2021