Combination treatment for the management of chronic kidney disease and type 2 diabetes: a review and practical guidance

CONTEXT: Renin-angiotensin system inhibitors (RASi), sodium glucose cotransporter-2 inhibitors (SGLT2i), nonsteroidal mineralocorticoid receptor antagonists (nsMRA), and glucagon-like peptide-1 receptor agonists (GLP-1RA) are key components of guideline-directed medical treatments (GDMT) for chronic kidney disease (CKD) with type 2 diabetes (T2D). However, the combined use of these medications remains uncommon in clinical practice, in part, due to the absence of specific guidance on implementing combination treatment. Herein, we aim to 1) summarize the evidence supporting combination GDMT in CKD with T2D, 2) propose a practical algorithm to guide the accelerated implementation of quadruple treatment, and 3) discuss strategies to improve uptake of combination treatment. EVIDENCE ACQUISITION: We searched PubMed from inception to present for English-speaking studies using the search terms "renin-angiotensin system inhibitor", "sodium glucose cotransporter-2 inhibitor", "nonsteroidal mineralocorticoid receptor antagonist", "glucagon-like peptide-1 receptor agonist", and "diabetes". We focused on clinical guidelines, randomized controlled trials (RCTs), and if necessary, large observational studies. EVIDENCE SYNTHESIS: SGLT2i, nsMRA, and GLP-1RA confer early cardiovascular and kidney protection through independent mechanisms, allowing them to be combined. RCTs support use of each agent on top of "standard care" and multiple clinical guidelines endorse combination treatment. However, the optimal order and timing for medication initiation, and the approach to managing treatment-related side effects remain uncertain, thereby limiting uptake of combination treatment. CONCLUSIONS: Current evidence supports the use of combination GDMT in CKD with T2D. We propose a combination treatment algorithm that may combat clinical inertia and achieve greater cardiorenal risk reduction in high-risk patients with CKD and T2D.