Combining SGLT2is, GLP1-RAs and nsMRAs in Diabetes: A Scoping Review of Current and Future Perspectives - PubMed (original) (raw)

Review

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

Elisabeth Buur Stougaard et al. Diabetes Ther. 2025 May.

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.

Keywords: Combination therapy; Heart and kidney protection; Type 1 diabetes; Type 2 diabetes.

© 2025. The Author(s).

PubMed Disclaimer

Conflict of interest statement

Declarations. Conflicts of Interest: Tine W. Hansen holds shares in Novo Nordisk A/S. Tine W. Hansen is an Editorial Board member of Diabetes Therapy. Tine W. Hansen was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions. Elisabeth B. Stougaard and Viktor R. Curovic have nothing to disclose. Ethical Approval: This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

References

    1. ElSayed NA, Aleppo G, Bannuru RR, Bruemmer D, Collins BS, Ekhlaspour L, et al. 9. Pharmacologic approaches to glycemic treatment: standards of care in diabetes—2024. Diabetes Care. 2024;47(Suppl 1):S158–78. - PMC - PubMed
    1. Cosentino F, Grant PJ, Aboyans V, Bailey CJ, Ceriello A, Delgado V, et al. 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J. 2020;41(2):255–323. - DOI - PubMed
    1. Mann JFE, Ørsted DD, Brown-Frandsen K, Marso SP, Poulter NR, Rasmussen S, et al. Liraglutide and renal outcomes in type 2 diabetes. N Engl J Med. 2017;377(9):839–48. - DOI - PubMed
    1. Mann JFE, Rossing P, Bakris G, Belmar N, Bosch-Traberg H, Busch R, et al. Effects of semaglutide with and without concomitant SGLT2 inhibitor use in participants with type 2 diabetes and chronic kidney disease in the FLOW trial. Nat Med. 2024;30:2849–56. - DOI - PMC - PubMed
    1. Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375(4):323–34. - DOI - PubMed

Publication types

LinkOut - more resources