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 ) 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  = 50%; P = 0.03; τ  = 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.