Effects of GLP-1RA and SGLT2i combination therapy in high-risk T2D

In a prespecified analysis of SOUL, the efficacy and safety of oral semaglutide versus placebo in reducing MACE in patients with T2D and ASCVD and/or CKD were not affected by concomitant SGLT2 inhibitor use.

This summary is based on the publication of Marx N, Deanfield JE, Mann JFE, et al. - Oral Semaglutide and Cardiovascular Outcomes in Persons With Type 2 Diabetes, According to SGLT2i Use: Prespecified Analyses of the SOUL Randomized Trial. Circulation. 2025 Mar 29 [Online ahead of print]. doi: 10.1161/CIRCULATIONAHA.125.074545.

Introduction and methods

Background

To reduce CVD risk in patients with T2D and ASCVD, current guidelines recommend treatment with GLP-1RAs and SGLT2 inhibitors [1,2]. However, data on the effects of combining these 2 drug classes on CV and safety outcomes are limited. Recently, the SOUL (Semaglutide cardiOvascular oUtcomes triaL) trial showed that treatment with the oral GLP-1RA semaglutide reduced the risk of MACE by 14% compared with placebo in T2D patients with established ASCVD and/or CKD [3]. As 26.9% of the study patients were treated with SGLT2 inhibitors at baseline, this RCT provides the largest dataset from a single CV outcome trial on the combined use of GLP-1RAs and SGLT2 inhibitors.

Aim of the study

In a prespecified analysis of the SOUL trial, the authors investigated the efficacy and safety of oral semaglutide on CV outcomes in patients with T2D and ASCVD and/or CKD stratified by SGLT2 inhibitor use at baseline or during the trial.

Methods

The SOUL trial was an international, double-blind, placebo-controlled, event-driven, phase 3b RCT in which 9650 patients (aged ≥50 years) with T2D (HbA1c 6.5%–10.0%) and either ASCVD (coronary artery disease, cerebrovascular disease, and/or symptomatic peripheral artery disease), CKD (eGFR <60 mL/min/1.73 m²), or both were randomized to oral semaglutide (maximum dose: 14 mg) or placebo, in addition to standard care [4]. Mean ± SD follow-up duration was 47.5 ± 10.9 months.

At baseline, 2596 patients (26.9%) were taking SGLT2 inhibitors, whereas 4718 (48.9%) were treated with SGLT2 inhibitors at baseline or during the trial.

Outcomes

The primary efficacy endpoint was the time to first MACE, a composite outcome of CV death, nonfatal MI, or nonfatal stroke. Secondary efficacy endpoints included the individual components of the primary endpoint, all-cause mortality, and changes in blood pressure, body weight, and levels of HbA1c, LDL-c, eGFR, and hs-CRP. Safety assessment included the incidence of serious adverse events.

Main results

CV outcomes by baseline SGLT2 inhibitor use

• In the subgroup of patients on SGLT2 inhibitors at baseline, 143 of the 1296 participants treated with semaglutide (11.0%) experienced a first MACE (primary endpoint) compared with 158 of the 1300 placebo-treated participants (12.2%) (HR: 0.89; 95%CI: 0.71–1.11).
• Among patients not taking SGLT2 inhibitors at baseline, the rates of the primary endpoint were 12.4% (436/3529) and 14.5% (510/3525), respectively (HR: 0.84; 95%CI: 0.74–0.95; P for interaction=0.66).
• Regarding the incidence rates of the secondary endpoints, there were also no significant interactions by baseline SGLT2 inhibitor use (all P for interaction>0.05).
• The frequencies of serious adverse events were 48.3% in semaglutide-treated patients and 48.6% in placebo-treated patients in the subgroup with SGLT2 inhibitor use at baseline and 47.8% and 50.9%, respectively, in the subgroup with no baseline SGLT2 inhibitor use.
• In particular, there were no apparent differences in the incidence of severe hypoglycemia or ketoacidosis between the 2 treatment groups when patients were stratified by baseline SGLT2 inhibitor use.

CV outcomes by SGLT2 inhibitor use during trial

• Among participants who received SGLT2 inhibitors at baseline or during the trial, a primary endpoint event occurred in 250 of the 2168 semaglutide-treated patients (11.5%) and 326 of 2550 the placebo-treated patients (12.8%) (HR: 0.89; 95%CI: 0.76–1.05).
• For participants with no SGLT2 inhibitor use at baseline and no initiation of this medication during the trial, the rates of the primary endpoint were 12.4% (329/2657) and 15.0% (342/2275), respectively (HR: 0.79; 95%CI: 0.68–0.92; P for interaction=0.31).

Conclusion

In this prespecified analysis of the SOUL trial, oral semaglutide reduced the rate of MACE compared with placebo in patients with T2D and ASCVD and/or CKD irrespective of concomitant SGLT2 inhibitor treatment at baseline or during the trial. The safety profile of semaglutide was also unaffected by SGLT2 inhibitor use.

The authors conclude that their results “provide clinicians further confidence to combine GLP-1RA and SGLT2 inhibitor treatment with the aim of reducing CV events in patients with T2D at high CVD risk and underscore current guideline recommendations for the additive use of both agents in patients with T2D and ASCVD.”

Find this article online at Circulation.

References

1. Marx N, Federici M, Schütt K, Müller-Wieland D, Ajjan RA, Antunes MJ, Christodorescu RM, Crawford C, Di Angelantonio E, Eliasson B, et al. 2023 ESC Guidelines for the management of cardiovascular disease in patients with diabetes. Eur Heart J. 2023;44:4043-4140.
2. American Diabetes Association Professional Practice Committee. 10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes-2024. Diabetes Care. 2024;47:S179-218.
3. McGuire DK, Marx N, Mulvagh SL, Deanfield J, Inzucchi SE, Busui RP, Mann JFE, Emerson SS, Poulter NR, Engelmann MDM, et al. Oral semaglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2025;DOI:10.1056/NEJMoa2501006
4. McGuire DK, Busui RP, Deanfield J, Inzucchi SE, Mann JFE, Marx N, Mulvagh SL, Poulter N, Engelmann MDM, Hovingh GK, et al. Effects of oral semaglutide on cardiovascular outcomes in individuals with type 2 diabetes and established atherosclerotic cardiovascular disease and/or chronic kidney disease: Design and baseline characteristics of SOUL, a randomized trial. Diabetes Obes Metab. 2023;25:1932-1941.