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Combination Therapy for Diabetes and Albuminuria
Quick Takes
- Combination treatment with SGLT2 inhibitors, GLP-1 receptor agonists, and nonsteroidal MRA was projected to result in relevant gains in CV and kidney event-free survival, as well as overall survival in patients with type 2 diabetes and albuminuria.
- Furthermore, lifetime gains in event-free and overall survival were observed across the range of ages studied.
- Optimal use of the “4 pillars” of therapy for diabetes and CKD, RAS blockade, SGLT2 inhibitors, GLP-1 receptor agonists, and nonsteroidal MRA has the potential to offer major benefits to these individuals.
Study Questions:
What are the lifetime gains in cardiorenal event-free and overall survival with a combination treatment of sodium glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1 RA), and the nonsteroidal mineralocorticoid receptor antagonist (ns-MRA) finerenone compared with conventional care in patients with type 2 diabetes and albuminuria?
Methods:
The investigators used data from two SGLT2i trials (CANVAS [Canagliflozin Cardiovascular Assessment] and CREDENCE [Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation]), two ns-MRA trials (FIDELIO-DKD [Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease] and FIGARO-DKD [Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and the Clinical Diagnosis of Diabetic Kidney Disease]), and eight GLP-1 RA trials to estimate the relative effects of combination therapy versus conventional care (renin-angiotensin system [RAS] blockade and traditional risk factor control) on cardiovascular (CV), kidney, and mortality outcomes. Using actuarial methods, they estimated absolute risk reductions with combination SGLT2i, GLP-1 RA, and ns-MRA in patients with type 2 diabetes and at least 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. The main combination treatment effect is estimated from the multiplicative product of the treatment effects from each derivative trial (i.e., treatment effects additive on the log [hazard ratio] scale).
Results:
Compared with conventional care, the combination of SGLT2i, GLP-1 RA, and ns-MRA was associated with a hazard ratio of 0.65 (95% confidence interval [CI], 0.55-0.76) for major adverse cardiovascular events (MACE) (nonfatal myocardial infarction, nonfatal stroke, or CV 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 patient commencing combination therapy, estimated MACE-free survival was 21.1 years compared with 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]), chronic kidney disease (CKD) progression (5.5 years [95% CI, 4.0-6.7]), CV 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]).
Conclusions:
The authors report that combination treatment of SGLT2i, GLP-1 RA, and ns-MRA has the potential to afford relevant gains in CV and kidney event-free and overall survival in patients with type 2 diabetes and at least moderately increased albuminuria.
Perspective:
This cross-trial analysis reports that combination treatment with SGLT2i, GLP-1 RA, and ns-MRA was projected to result in relevant gains in CV and kidney event-free survival, as well as overall survival in patients with type 2 diabetes and at least moderately increased albuminuria. Furthermore, lifetime gains in event-free and overall survival were observed across the range of ages studied. These findings highlight potential major opportunities to delay or potentially avert CV events and premature death with combined use of SGLT2i, GLP-1RA, and ns-MRA for patients with type 2 diabetes at high cardiorenal risk. Optimal use of the “4 pillars” of therapy for diabetes and CKD, RAS blockade, SGLT2i, GLP-1 RA, and ns-MRA has the potential to offer major benefits to these individuals.
Clinical Topics: Diabetes and Cardiometabolic Disease, Prevention
Keywords: Diabetes Mellitus, Type 2, Pharmaceutical Preparations, Renal Insufficiency, Chronic
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