Sodium glucose co-transporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1 RA), and the non-steroidal mineralocorticoid receptor antagonist (MRA) finerenone all individually reduce cardiovascular, kidney and mortality outcomes in patients with type 2 diabetes and albuminuria. However, the lifetime benefits of combination therapy with these medicines are not known. We used data from 2 SGLT2i trials (CANVAS and CREDENCE), 2 non-steroidal MRA trials (FIDELIO-DKD and FIGARO-DKD) and 8 GLP-1 RA trials to estimate the relative effects of combination therapy versus conventional care (renin-angiotensin system blockade and traditional risk factor control) on cardiovascular, kidney and mortality outcomes. Using actuarial methods, we then estimated absolute risk reductions with combination SGLT2i, GLP-1 RA and non-steroidal MRA in patients with type 2 diabetes and at lease moderately increased albuminuria (urinary albumin:creatinine ratio ≥30 mg/g) by applying estimated combination treatment effects to participants receiving conventional care in CANVAS and CREDENCE. Compared to conventional care, combination SGLT2i, GLP-1 RA and non-steroidal MRA was associated with a hazard ratio of 0.65 (95% CI 0.55-0.76) for major adverse cardiovascular events (MACE; nonfatal myocardial infarction, nonfatal stroke or cardiovascular death). The corresponding estimated absolute risk reduction over 3 years was 4.4% (95% CI 3.0-5.7) with a number-needed-to-treat of 23 (95% CI 18-33). For a 50-year-old commencing combination therapy, estimated MACE event-free survival was 21.1 years compared to 17.9 years for conventional care (3.2 years gained, 95% CI 2.1-4.3). There were also projected gains in survival free from hospitalized heart failure (3.2 years, 95% CI 2.4-4.0), CKD progression (5.5 years, 95% CI 4.0-6.7), cardiovascular death (2.2 years, 95% CI 1.2-3.0) and all-cause death (2.4 years, 95% CI 1.4-3.4). Attenuated but clinically relevant gains in event-free survival were observed in analyses assuming 50% additive effects of combination therapy, including for MACE (2.4 years, 95% CI 1.1-3.5), CKD progression (4.5 years, 95% CI 2.8-5.9),) and all-cause death (1.8 years, 95% CI 0.7-2.8). In patients with type 2 diabetes and at least moderately increased albuminuria, combination treatment with SGLT2i, GLP-1 RA and non-steroidal MRA has the potential to afford relevant gains in cardiovascular and kidney event-free and overall survival.
