Larger effect size in composite kidney outcomes than in major cardiovascular events associated with sodium‐glucose cotransporter‐2 (SGLT2) inhibitors compared with glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs): A pooled analysis of type 2 diabetes trials

AIM: To compare treatment effect sizes between a composite kidney outcome (CKO) and three‐point major adverse cardiovascular event (MACE‐3) outcomes with use of sodium‐glucose cotransporter‐2 (SGLT2) inhibitors and glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs), and to investigate the relationship between treatment effects on CKO and MACE‐3 in patients with type 2 diabetes (T2D). MATERIALS AND METHODS: We performed a MEDLINE database search up to December 31, 2021 to identify all placebo‐controlled Phase 3 trials which investigated the efficacy of glucose‐lowering interventions, and selected those reporting results for CKO and MACE‐3. Hazard ratios (HRs) with 95% confidence intervals (CIs) for both outcomes were extracted for each trial, and we evaluated differences in treatment effect sizes by using a ratio of HRs (rHR): the HR for CKO to the HR for MACE‐3. A random‐effects meta‐analysis was used to obtain the overall rHR across trials and according to subgroup. We investigated the relationship between treatment effects on CKO and MACE‐3 using the coefficient of determination (R(2)) with weighted meta‐regression. The study protocol was registered on PROSPERO (CRD42022299690). RESULTS: A total of 12 studies fulfilled the prespecified criteria, and comprised a total of 104 987 patients with T2D. On average, treatment effect sizes were 17% greater for CKO than for MACE‐3 (rHR 0.83, 95% CI 0.74 to 0.92; I ( 2 ) = 50%; P = 0.03; τ ( 2 ) = 0.0161), especially for trials of SGLT2 inhibitors compared with GLP‐1RAs. For secondary outcomes, treatment effect size was 22%, 21%, 16% and 9% greater for CKO than for myocardial infarction, stroke, death from cardiovascular causes, and hospitalization for heart disease, respectively. MACE‐3 and CKO were moderately correlated (ρ = 0.40; P = 0.21), and only 11% (95% CI 1% to 54%) of the variability in the MACE‐3 effect could be explained by the variability in the CKO effect. CONCLUSION: In T2D patients, treatment effect sizes were greater for kidney than for macrovascular (MACE‐3) outcomes, with important differences according to the drugs considered. CKO and MACE‐3 are independent. Caution must be taken when interpreting CKO in the absence of MACE‐3 data.