Net Effects of SGLT2 Inhibitors by Diabetes Status and Albuminuria

Background: KDIGO 2024 guidelines have different levels of recommendation for use of SGLT2i depending on diabetes status and urine albumin:creatinine ratio (uACR). Methods: We used inverse variance-weighted meta-analysis to assess effects of SGLT2i on efficacy and safety outcomes and eGFR slopes in 8 large placebo control trials. We assessed heterogeneity (het) by baseline uACR <200 vs ≥200mg/g separately by diabetes status. Group-specific absolute effects were estimated by applying diabetes subgroup-specific relative risks to the event rate in placebo arms. Results: Among 58,816 participants (48,946 with diabetes and 9870 without), compared to placebo, allocation to SGLT2i slowed chronic rate of eGFR decline in people with or without diabetes (by 57% [95%CI 54-60%] and 41% [33-49%] respectively; P-het<0.001), irrespective of baseline uACR (both P-het>0.20). Allocation to SGLT2i reduced risk of kidney disease progression (KDP) by 32% (hazard ratio [HR] 0.68, 0.63-0.74), acute kidney injury by 21% (0.79, 0.70-0.90), any death by 13% (0.87, 0.80-0.95) and any hospitalization by 11% (0.89, 0.85-0.93). HRs for these efficacy outcomes were similar when stratified by diabetes status and by baseline uACR (Fig.1). For KDP, larger absolute benefits were evident at uACR ≥200 vs. <200 mg/g, due to higher risk at uACR≥200 mg/g. However, substantial net benefits were seen for other efficacy outcomes even for those with uACR<200 mg/g (Fig.2). Conclusion: There are clear benefits of SGLT2i on a range of efficacy outcomes (substantially exceeding any harms) in people with or without diabetes, irrespective of uACR.Fig.1 Relative effects of SGLT2i on selected key efficacy outcomesFig.2 Absolute effects of SGLT2i on outcomes