SOUL trial: HbA1c predicts heart benefit

A post-hoc analysis of the SOUL cardiovascular outcomes trial, published 21 July 2026 in the Journal of Clinical Endocrinology and Metabolism, found that the heart benefits of oral semaglutide were more pronounced in participants with higher baseline HbA1c and in those who achieved greater HbA1c reductions during the trial^[1]. Body weight change, by contrast, showed no meaningful relationship with cardiovascular protection.

The SOUL trial: what it established

SOUL (NCT03914326) was a randomised, double-blind, placebo-controlled trial that enrolled 9,650 adults aged 50 or older with type 2 diabetes and established atherosclerotic cardiovascular disease, chronic kidney disease, or both^[2]. Participants received oral semaglutide 14 mg once daily or placebo on top of standard care. Median follow-up was 49.5 months.

The primary outcome was major adverse cardiovascular events (MACE), defined as cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Oral semaglutide reduced the rate of MACE from 13.8% on placebo to 12.0%, a hazard ratio of 0.86 (95% CI 0.77 to 0.96; p = 0.006)^[2]. That result, reported in the New England Journal of Medicine in May 2025, made SOUL the first large cardiovascular outcomes trial to confirm benefit for an oral GLP-1 receptor agonist.

What the subgroup analysis adds

The JCEM analysis, led by Silvio E. Inzucchi (Yale University School of Medicine), examined whether the cardiovascular benefit varied according to glycaemic control at baseline or glycaemic response during treatment^[1]. Baseline characteristics in SOUL give context: mean HbA1c across the 9,650 participants was 8.0% (63.5 mmol/mol) and mean BMI was 31.1 kg/m2.

The paper reports a statistically significant interaction between baseline HbA1c category and the MACE benefit of oral semaglutide (p-interaction = 0.04): participants with higher baseline HbA1c appeared to derive greater relative risk reduction. The relationship was even clearer for in-trial glycaemic response: larger HbA1c reductions at both 13 weeks (p-interaction = 0.005) and 52 weeks (p-interaction < 0.001) were associated with greater cardiovascular protection^[1].

The authors describe the cardiovascular benefits of oral semaglutide as appearing "glycemic-dependent" within this population. That framing is careful: it does not mean the drug only works through glucose lowering, but it does suggest that the magnitude of HbA1c improvement tracks with the magnitude of heart-risk reduction in SOUL participants.

The BMI finding: consistent across categories

When the same analysis was applied to body weight, the pattern did not hold. Baseline BMI category showed no significant interaction with MACE outcomes across the trial, and in-trial BMI changes at 13 weeks (p-interaction = 0.88) and 52 weeks (p-interaction = 0.64) showed similar consistency^[1]. Whether a participant lost a little or a lot of body weight during SOUL, the cardiovascular benefit of oral semaglutide appeared roughly the same.

This is in some tension with results from the SELECT trial, where semaglutide 2.4 mg weekly demonstrated a 20% MACE reduction in people with cardiovascular disease but without type 2 diabetes. SELECT enrolled a non-diabetic population, meaning glycaemic improvement was not a feature of that benefit. The two trials ask related but distinct questions, and the SOUL subgroup analysis does not invalidate the SELECT finding. It narrows the picture for the specific population with type 2 diabetes and high cardiovascular risk who were enrolled in SOUL.

What this does not mean

A post-hoc subgroup analysis carries well-known limitations. Subgroup findings are hypothesis-generating, not confirmatory. The interaction p-value for baseline HbA1c sits at 0.04, a threshold that calls for replication before drawing strong clinical conclusions. The analysis cannot rule out confounding: participants with higher baseline HbA1c and greater in-trial HbA1c response may differ in other ways that independently affect cardiovascular risk.

The paper does not advise clinicians to target a specific HbA1c threshold to guarantee cardiovascular protection, nor does it suggest oral semaglutide should be reserved for patients with poorer glycaemic control at baseline. Prescribing decisions should continue to follow the authorised label, which specifies oral semaglutide 14 mg once daily for adults with type 2 diabetes with cardiovascular or kidney disease.

Where this lands

For clinicians and patients following the evidence on oral semaglutide, the SOUL subgroup analysis adds a clinically plausible layer to a result that was already well-established^[3]. The headline from SOUL remains: oral semaglutide reduced MACE by 14% in high-risk type 2 diabetes. The Inzucchi et al. analysis refines that picture by showing the benefit appears stronger in people with higher baseline glucose levels and better glycaemic response. What it does not show is that weight loss was irrelevant to other outcomes, or that SOUL participants who lost more weight gained nothing. The paper focuses narrowly on MACE, and the broader picture of what semaglutide does across metabolic, renal, and cardiovascular endpoints is still emerging from the full SOUL dataset.

This article is for educational purposes. It does not constitute medical advice. Consult a qualified healthcare professional before making any treatment decision.