Effects of Sodium Glucose Cotransporter 2 Inhibitors by Diabetes Status and Level of Albuminuria

Importance: There is uncertainty about the effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors in participants with chronic kidney disease, with guidelines offering different strengths of recommendation based on diabetes status and urine albumin to creatinine ratio (UACR). Objective: To assess the relative and absolute effects of SGLT2 inhibitor use across efficacy and serious safety outcomes in participants stratified by diabetes status and UACR (≥200 mg/g or <200 mg/g). Data Sources and Study Selection: Included 8 randomized clinical trials that studied an SGLT2 inhibitor with a label indication for use in kidney disease and recorded longitudinal kidney outcomes and baseline data on albuminuria. Data Extraction and Synthesis: Data were combined using inverse variance-weighted meta-analysis; group-specific absolute effects were estimated by applying relevant relative risks to the event rates of the placebo groups. Main Outcomes and Measures: Assessed the effects of SGLT2 inhibitor use on clinical efficacy and safety outcomes. Heterogeneity by baseline level of UACR was assessed separately by diabetes status. Results: A total of 58 816 participants (mean age, 64 SD, 10 years; 35% were female; 48 946 with diabetes and 9870 without diabetes) were included from trials comparing an SGLT2 inhibitor vs placebo. Allocation to an SGLT2 inhibitor produced a lower rate of kidney disease progression (33 vs 48 for placebo per 1000 patient-years; hazard ratio HR, 0.65 95% CI, 0.60-0.70 in those with diabetes and 32 vs 46 per 1000; HR, 0.74 95% CI, 0.63-0.85 in those without diabetes), a lower rate of acute kidney injury (14 vs 18 per 1000 HR, 0.77; 95% CI, 0.69-0.87 with diabetes and 13 vs 18 per 1000 HR, 0.72; 95% CI, 0.56-0.92 without diabetes), a lower rate of any hospitalization (202 vs 231 per 1000 HR, 0.90; 95% CI, 0.87-0.92 with diabetes and 203 vs 237 per 1000 HR, 0.89; 95% CI, 0.83-0.95 without diabetes), and a lower rate of any death (42 vs 47 per 1000 HR, 0.86; 95% CI, 0.80-0.91 with diabetes and 42 vs 48 per 1000 HR, 0.91; 95% CI, 0.78-1.05 without diabetes). Diabetes-specific HRs were similar in participants (with a UACR ≥200 mg/g vs with a UACR <200 mg/g) considered separately. Higher absolute risk at a UACR of 200 mg/g or greater meant larger estimated absolute benefits on kidney disease progression were evident in this subgroup. Clear absolute benefits were evident for other efficacy outcomes, and particularly hospitalization, in participants with a UACR less than 200 mg/g. Net absolute benefits remained in the analyses of non-heart failure populations and when estimated glomerular filtration rate was less than 60 mL/min/1.73 m2. Conclusions and Relevance: Within the studied participants, there were clear absolute benefits of SGLT2 inhibitors on kidney, hospitalization, and mortality outcomes irrespective of diabetes status and level of UACR.