SOUL: effects of oral semaglutide and cardiovascular outcomes independent of SGLT2 inhibitor use
The benefits on cardiovascular (CV) outcomes of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and of sodium–glucose co-transporter-1 inhibitors (SGLT2is) in people with type 2 diabetes and high CV risk and/or chronic kidney disease (CKD) have been independently demonstrated. While both classes are recommended in guidelines, there is limited evidence about the effects of combining them.
The SOUL trial randomised 9650 participants with type 2 diabetes and established atherosclerotic cardiovascular disease (ASCVD) and/or CKD to receive oral semaglutide (up to 14 mg once-daily) or placebo (1:1). Within this cohort, 26.9% were using an SGLT2i at baseline, providing a large dataset on the combined use of a GLP-1 RA and SGLT2i.
In pre-specified analyses, investigators examined the effect of oral semaglutide on CV outcomes, according to baseline use of SGLT2i (Yes, n=2596; No, n=7054) and, subsequently for any use of SGLT2i during the trial (Yes, n=4718; No, n=4932).
Participants were followed over a mean time of 47.5±10.9 months. For the overall study population, the primary efficacy outcome of time from randomisation to first occurrence of major adverse CV event (MACE; a composite of time to CV death, time to non-fatal myocardial infraction or time to non-fatal stroke) was 14% lower for oral semaglutide compared to placebo (HR, 0.86 [95% CI, 0.77–0.96]).
In the subgroup of participants taking an SGLT2i at baseline, there were 143/1296 (11.0%) primary outcome events in the oral semaglutide group versus 158/1300 (12.2%) in the placebo group (HR, 0.89 [95% CI, 0.71–1.11). Amongst those not taking an SGLT2i at baseline, there were 436/3529 (12.4%) primary outcome events with semaglutide versus 510/3525 (14.5%) in those taking a placebo (HR, 0.84 [95% CI, 0.74–0.95; P-interaction, 0.66).
An analysis of MACE by any in-trial SGLT2i use compared to no use did not show evidence of a difference in the effects of oral semaglutide.
Serious adverse events in those with SGLT2i use at baseline were reported in 48.3% versus 48.6% of participants receiving oral semaglutide versus placebo, and 47.8% versus 50.9%, respectively, in those without SGLT2i use at baseline. This suggests that the adverse event profiles for oral semaglutide with or without an SGLT2i were similar.
The investigators conclude that the beneficial effects of oral semaglutide on CV outcomes in this population were independent of concomitant SGLT2i use, and that the combination appeared to be safe. These findings underscore current guideline recommendations for the additive use of both agents in people with type 2 diabetes and ASCVD.
The full article can be read here.
