New findings from the landmark SOUL trial reveal that the cardiovascular benefits of oral semaglutide are most pronounced in patients with type 2 diabetes who have higher baseline hemoglobin A1c levels, while the drug’s heart-protective effects remain consistent across all body weight categories.
Dr. Silvio Inzucchi, director of the Yale Medicine Diabetes Center, presented these post-hoc analyses at the 85th Scientific Sessions of the American Diabetes Association, offering clinicians new insights into how baseline patient characteristics may influence treatment decisions with oral GLP-1 receptor agonists.
Background on SOUL Trial
The SOUL trial enrolled 9,650 patients with type 2 diabetes and established atherosclerotic cardiovascular disease or chronic kidney disease. The study previously demonstrated that oral semaglutide 14 mg daily reduced major adverse cardiovascular events by 14% compared to placebo over a mean follow-up of 47.5 months.
GLP-1 receptor agonists have traditionally been injectable medications, primarily used for glucose control and weight management in patients with diabetes. However, several injectable formulations have shown cardiovascular benefits beyond glycemic control in high-risk patients. SOUL was the first cardiovascular outcomes trial to evaluate an oral GLP-1 receptor agonist in this population, Dr. Inzucchi noted in his presentation.
Key Findings on A1c Levels
The new analysis revealed significant differences in cardiovascular outcomes based on baseline A1c levels. Participants with A1c levels above 8% showed a 27% relative risk reduction in major adverse cardiovascular events, with a hazard ratio (HR) of 0.73 (95% confidence interval [CI] 0.62-0.86; P-value for interaction .017), while those with A1c levels at or below 8% showed no significant benefit (HR 0.96; 95% CI 0.82-1.12).
When researchers examined cardiovascular benefits in four A1c strata, the cardiovascular benefits appeared to apply to patients with A1c levels above 7%. Those with A1c levels between 8% and 9% showed the most robust response, with a 32% relative risk reduction in major adverse cardiovascular events.
“The cardiovascular benefits of oral semaglutide appeared more pronounced with higher A1c levels at baseline,” Dr. Inzucchi noted in his presentation, suggesting that patients with poorer glycemic control may derive greater cardiovascular protection from the medication.
Consistent Benefits Across Weight Categories
Although the cardiovascular benefits of oral semaglutide varied depending on baseline A1c levels, the cardiovascular benefits of the treatment remained consistent regardless of the patients’ baseline body mass index (BMI). The drug showed similar efficacy in patients with BMI above and below 30 kg/m², as well as across all four BMI strata examined in the study.
Patients with BMI at or below 30 kg/m² experienced a 15% relative risk reduction in major adverse cardiovascular events (HR 0.85; 95% CI 0.72-1.00; P-value for interaction .933), while those with BMI above 30 kg/m² had a 16% reduction (HR 0.84; 95% CI 0.72-0.98). The consistency held true when researchers analyzed outcomes by baseline body weight above and below the study mean of 87.9 kg.
Cardiovascular Benefits Are Independent of Changes in BMI or A1c Levels
The researchers also examined whether changes in A1c or body weight during the trial influenced cardiovascular outcomes. The results suggested that neither the change in A1c nor the change in body weight during the trial influenced the cardiovascular benefits of oral semaglutide. According to Dr. Inzucchi, these findings suggest that the cardiovascular benefits of oral semaglutide may be independent of the metabolic effects of the treatment.
Clinical Implications and Future Directions
These findings may help clinicians make more informed decisions about prescribing oral semaglutide for cardiovascular protection. As Dr. Inzucchi noted in his presentation, the data suggest that patients with higher baseline A1c levels, particularly those above 8%, may be the most appropriate candidates for oral semaglutide when cardiovascular risk reduction is a primary goal. However, as this was a post hoc analysis, the findings require confirmation in prospectively designed studies.
Dr. Evangelou has no conflicts of interest to report.
Collage by Diana Connolly
