SGLT2 Inhibitors and Kidney and Cardiac Outcomes According to Estimated GFR and Albuminuria Levels: A Meta-analysis of Randomized Controlled Trials

Abstract

Rationale & ObjectiveThere are few data on the absolute effects of sodium/glucose cotransporter 2 (SGLT2) inhibitors, despite their importance in treatment decision making. We investigated absolute treatment effects according to baseline kidney disease status.Study DesignMeta-analysis.Study PopulationsAdults with type 2 diabetes, chronic kidney disease, or heart failure.Selection Criteria for StudiesRandomized controlled trials of SGLT2 inhibitors (10 trials to November 20, 2020) for clinical outcomes of kidney disease progression, heart failure events, and major cardiovascular events.Data ExtractionPublications of 10 trials to November 20, 2020.Analytical ApproachThe incidence rate difference (IRD) between SGLT2 inhibitor and placebo was compared across estimated glomerular filtration rate (eGFR) or urinary albumin-creatinine ratio (UACR) subgroups.ResultsSubgroup analyses included data from seven trials (61,821 participants with diabetes or chronic kidney disease). SGLT2 inhibitor treatment, in eGFR subgroups of <45, 45 to <60, and ≥60 mL/min/1.73 m2, reduced 16.0, 9.5, and 1.9 heart failure events per 1,000 patient-year, respectively (P < 0.001 for heterogeneity). In urine UACR subgroups of >300, 30 to 300, and <30 mg/g, SGLT2 inhibitors reduced 17.3, 1.4, and 2.2 kidney disease events per 1,000 patient-year, respectively (P < 0.001 for heterogeneity), and 14.8, 8.7, and 2.1 heart failure events per 1,000 patient-year, respectively (P = 0.006 for heterogeneity). The pooled IRDs for major cardiovascular events were also greater in lower eGFR or overt albuminuria subgroups. In secondary analyses, risk differences calculated using pooled baseline and relative risks were comparable to the pooled IRDs, while the relative risk reductions for kidney and heart failure outcomes were consistent across the subgroups. For treatment-related harms, IRDs were similar between eGFR subgroups.LimitationsStudy-level data rather than individual patient data were used.ConclusionsSGLT2 inhibitor treatment resulted in greater reductions of cardiovascular events in patients with lower eGFR and higher albuminuria and had substantially greater absolute benefits of renoprotection in patients with overt albuminuria than in their counterparts.