Oral Semaglutide and Cardiovascular Benefits in the SOUL Trial: Impact of Baseline and Changes in HbA1c and BMI on Clinical Outcomes

Introduction

The SOUL trial, a major international study, evaluated the cardiovascular (CV) safety and efficacy of oral semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), in adults aged 50 years or older with type 2 diabetes complicated by atherosclerotic cardiovascular disease and/or chronic kidney disease. Previous research established GLP-1 RAs as beneficial not only in glycemic control but also in reducing cardiovascular events. However, the relationship between initial patient characteristics—specifically baseline HbA1c and body mass index (BMI)—or their changes during the trial, with the cardiovascular benefits of oral semaglutide remained unclear. This post hoc analysis aimed to clarify these associations.

Study Design and Methods

The SOUL trial (NCT03914326) was a double-blind, placebo-controlled randomized clinical trial conducted at 444 international sites from 2019 to 2024. A total of 9,650 participants were randomized in a 1:1 ratio to receive either oral semaglutide or placebo and were followed for a median duration of 47.5 months. Key inclusion criteria included adults 50 years or older with diagnosed type 2 diabetes and established atherosclerotic cardiovascular disease and/or chronic kidney disease. The primary endpoint was a 3-point major adverse cardiovascular event (MACE) composite consisting of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. HbA1c and BMI were measured at baseline and then at weeks 13 and 52 to evaluate both initial levels and in-trial changes.

Results

The median age of participants was 66 years, with an interquartile range of 61 to 72 years. Baseline mean HbA1c was 8.0% (±1.1%), corresponding to 63.5 mmol/mol, and mean BMI was 31.1 kg/m2 (±5.8), indicating an obese population on average. Oral semaglutide demonstrated a significant 14% reduction in MACE risk compared to placebo.

Notably, subgroup analyses revealed that the MACE risk reduction with oral semaglutide varied significantly by baseline HbA1c category (P-interaction = .04). Participants with higher baseline HbA1c levels experienced greater cardiovascular risk reduction. Conversely, the beneficial effects were consistent across different baseline BMI categories with no significant interaction (P-interaction not significant).

Examining the in-trial changes, greater HbA1c reduction at both 13 and 52 weeks was strongly associated with larger decreases in MACE risk (P-interactions .005 and <.001, respectively). This suggests that the degree of glycemic improvement during treatment mediates cardiovascular benefit. In contrast, changes in BMI during the trial did not significantly affect cardiovascular outcomes (P-interactions .88 and .64, respectively), indicating that weight changes alone were not predictive of cardiovascular risk reduction in this context.

Discussion

This detailed post hoc evaluation of the SOUL trial data underscores important clinical insights regarding predictors of cardiovascular benefit from oral semaglutide treatment in a high-risk population with type 2 diabetes. The amplified benefit among those with higher baseline HbA1c suggests that patients with poorer glycemic control at treatment initiation may derive greater cardiovascular protection. Furthermore, the strong link between on-treatment HbA1c reduction and reduction in MACE supports the therapeutic goal of achieving meaningful glycemic lowering for cardiovascular risk mitigation.

The lack of significant influence from baseline BMI or its changes implies that the cardiovascular benefits of semaglutide are largely independent of weight loss effects. This differentiates the drug’s glucose-lowering and potential pleiotropic cardiovascular effects from weight reduction alone.

Given the complex pathophysiology of type 2 diabetes and its cardiovascular complications, these findings help refine patient selection and emphasize the importance of monitoring glycemic response to optimize outcomes when prescribing oral semaglutide.

Clinical Implications

For clinicians managing type 2 diabetes patients at high cardiovascular risk, these results reinforce the value of oral semaglutide as a therapeutic option. Patients presenting with elevated HbA1c may gain the most pronounced cardiovascular protection. Although weight management remains important for overall health, improvements in BMI during treatment are not primary determinants of cardiovascular benefit with oral semaglutide.

Thus, treatment strategies should prioritize achieving optimal glycemic control and regularly assess HbA1c responses to maximize cardiovascular risk reduction.

Limitations and Future Research

Being a post hoc analysis, these findings are exploratory and hypothesis-generating rather than definitive proof of causality. The trial population predominantly comprised older adults with established cardiovascular disease, which may limit generalizability to younger or lower-risk individuals. Future studies could explore mechanisms underlying the differential cardiovascular benefit with glycemic improvement and investigate whether these findings extend to diverse populations and other GLP-1 receptor agonists.

Conclusion

In summary, the SOUL trial analysis demonstrates that cardiovascular benefits of oral semaglutide are significantly influenced by baseline glycemic status and subsequent HbA1c reductions, whereas BMI and its changes do not markedly affect these outcomes. This reinforces the critical role of effective glucose control in reducing cardiovascular events among patients with type 2 diabetes and informs clinical decisions to optimize treatment with oral semaglutide.