Combining SGLT2is, GLP1-RAs and nsMRAs in Diabetes: A Scoping Review of Current and Future Perspectives.

Abstract

Combination therapy is a cornerstone of modern type 2 diabetes management, extending beyond traditional goals of glucose, blood pressure, and lipid control to focus on therapies protecting the heart and kidneys. The introduction of sodium-glucose cotransporter-2 inhibitors (SGLT2is), glucagon-like peptide receptor agonists (GLP-1RAs), and nonsteroidal mineralocorticoid receptor antagonists (nsMRAs) has reshaped clinical guidelines in recent decades. However, the effects of combining these drug classes remain uncertain. This review evaluates the current evidence on combination therapies involving SGLT2is, GLP-1RAs, and nsMRAs in type 1 and type 2 diabetes, thereby focusing on treatments that in type 2 diabetes have shown cardio-renal protection, while exploring future research directions. In type 2 diabetes, much of the evidence comes from post hoc analyses of trials that primarily examine the effects of single drugs compared with placebo. This limits the ability to draw definitive conclusions about the efficacy and safety of combination therapy. Nonetheless, observational studies indicate that combining SGLT2is and GLP-1RAs may offer superior cardiovascular and mortality benefits compared with monotherapy. Data on kidney outcomes remain limited, but SGLT2is appear particularly effective when kidney protection is the primary goal, regardless of concurrent treatment. The use of nsMRAs is still emerging, and studies investigating their combination with SGLT2is and GLP-1RAs are scarce. In type 1 diabetes, combination therapies have primarily focused on glucose control and safety, with several randomized controlled trials investigating the effects of combining treatments such as SGLT2is and GLP-1RAs with insulin. No current studies have estimated the effects on heart and kidneys. Ongoing and planned studies aim to fill critical gaps in our understanding of combination therapy for type 1 diabetes. These studies hold the promise of determining whether similar risk reductions, as observed in type 2 diabetes, can be achieved, offering hope for improved outcomes in this high-risk population. Currently, in type 2 diabetes, only one ongoing study is testing combination with an SGLT2i and a nsMRA.