Kidney and cardiovascular-protective benefits of combination drug therapies in chronic kidney disease associated with type 2 diabetes

Abstract

Given the substantial burden of chronic kidney disease associated with type 2 diabetes, an aggressive approach to treatment is required. Despite the benefits of guideline-directed therapy, there remains a high residual risk of continuing progression of chronic kidney disease and of cardiovascular events. Historically, a linear approach to pharmacologic management of chronic kidney disease has been used, in which drugs are added, then adjusted, optimized, or stopped in a stepwise manner based on their efficacy, toxicity, effects on a patient's quality of life, and cost. However, there are disadvantages to this approach, which may result in missing a window of opportunity to slow chronic kidney disease progression. Instead, a pillar approach has been proposed to enable earlier treatment that simultaneously targets multiple pathways involved in disease progression. Combination therapy in patients with chronic kidney disease associated with type 2 diabetes is being investigated in several clinical trials. In this article, we discuss current treatment options for patients with chronic kidney disease associated with type 2 diabetes and provide a rationale for tailored combinations of therapies with complementary mechanisms of action to optimize therapy using a pillar-based treatment strategy. [This article includes a plain language summary as an additional file].

Keywords: Chronic kidney disease; Combination therapy; Finerenone; Glucagon-like peptide-1 receptor agonist; Sodium-glucose cotransporter-2 inhibitor.

Fig. 1

Overview of the MOAs of the main drug classes used in CKD associated with T2D. The figure shows how these main drug classes tackle the three main contributing pathways of CKD. These drugs may be used in combination depending on factors such as baseline clinical factors/treatment aims, patient preference and clinician familiarity [, –20, 32, 33]. GLP-1 RA, glucagon-like peptide-1 receptor agonist; RAAS, renin-angiotensin‐aldosterone system; ns-MRA, nonsteroidal mineralocorticoid receptor antagonist; SGLT2, sodium-glucose cotransporter-2

Fig. 2

Summary of the advantages and disadvantages of combination (pillar-based) therapy compared with linear therapy approaches in CKD associated with T2D

Fig. 3

Current practice guideline recommendations for combination therapies in patients with T2D at risk of CKD. KDIGO 2022 [18], ADA 2024 Chap. 11, [20] and AACE 2022 [84] and KDIGO 2024 [6] S/R = strong support/recommended by at least one of the practice guidelines; PP = Practice Point (by KDIGO, not a formal recommendation); NG = not graded AACE, American Association of Clinical Endocrinology; ADA, American Diabetes Association; CKD, chronic kidney disease; CV, cardiovascular; eGFR, estimated glomerular filtration rate; GLP-1 RA, glucagon-like peptide-1 receptor agonist; KDIGO, Kidney Disease: Improving Global Outcomes; ns-MRA, nonsteroidal mineralocorticoid receptor antagonist; SGLT2i, sodium-glucose cotransporter-2 inhibitor; T2D, type 2 diabetes