Combination therapy: an upcoming paradigm to improve kidney and cardiovascular outcomes in chronic kidney disease

In this article the authors review recent advances in the treatment of chronic kidney disease (CKD) with diabetes, and summarize evidence supporting combination therapy approaches to improve patient outcomes. Driven by the global rise in diabetes, the worldwide burden of CKD has nearly doubled since the 1990s. People with CKD have notably increased risks for premature cardiovascular disease (heart and blood vessels disease), kidney failure and death. CKD, diabetes, obesity and cardiovascular disease are closely interrelated and share common risk factors. These health conditions therefore comprise what is now known as cardiovascular-kidney-metabolic (CKM) syndrome. Recently approved medications, including sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs) and the non-steroidal mineralocorticoid receptor antagonist (ns-MRA) finerenone, represent agents capable of reducing metabolic, kidney and cardiovascular risk through complementary mechanisms of action. Current evidence supports use of these therapies in combination. Besides providing additive protective effects, combination therapy may also help reduce side effects. For instance, using an SGLT2 inhibitor in combination with finerenone helps decrease the risk for high potassium levels. Through the multipronged approach, combination therapy allows tailoring treatment for the individual patient characteristics and needs. Several planned and ongoing clinical trials continue to study the benefits of combination therapy in people with CKM syndrome. With building evidence supporting the use of combination therapy, it is crucial to raise awareness of the importance of this treatment approach and develop processes to incorporate new therapies into every day practice to support optimal care and improved outcomes.ABSTRACT The global burden of chronic kidney disease (CKD) increased by nearly 90% in the period spanning 1990 to 2016, mostly attributed to an increase in the prevalence of CKD in diabetes. People living with CKD have an elevated lifetime risk for cardiovascular disease (CVD) when compared with the general population, with risk increasing in parallel with albuminuria and kidney function decline. Metabolic disease, CKD and CVD share common risk factors including neurohumoral activation, systemic inflammation and oxidative stress, thus prompting the introduction of a broader construct of cardiovascular-kidney-metabolic (CKM) syndrome. An important rationale for the introduction of this concept are recent and ongoing therapeutic advancements fundamentally changing CKM management. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs) and the non-steroidal mineralocorticoid receptor antagonist (ns-MRA) finerenone have shifted the therapeutic paradigm for patients with CKD and have emerged in rapid succession as cornerstones of guideline-directed medical therapy (GDMT). Recently completed clinical trials of aldosterone synthase inhibitors and endothelin receptor antagonists have additionally reported additive antiproteinuric effects on the background of renin-angiotensin system and SGLT2 inhibition, with acceptable safety profiles. The sum of current evidence from both preclinical and clinical studies support combination therapy in the setting of CKD to achieve additive and potentially synergistic kidney and heart protection by addressing metabolic, hemodynamic, and pro-inflammatory and pro-fibrotic mechanistic pathways. This narrative review will discuss available evidence supporting combination GDMT in CKD with diabetes and additionally discuss ongoing and future trials evaluating the efficacy and safety of combination therapies for CKD with or without diabetes.