18d • Weekly Journal Club
SOUL Trial: Oral Semaglutide & Cardiovascular Outcomes (NEJM 2025)
1.) Why This Paper Matters
Type 2 diabetes is ubiquitous, and cardiovascular disease is the leading cause of morbidity and mortality in diabetic patients. GLP‑1 receptor agonists have consistently shown improvements in reducing cardiovascular risk, but oral formulations were unavailable until recently.
The SOUL trial examines whether oral semaglutide can reduce major adverse cardiovascular events (MACE) in high-risk adults.
Key learning points for members:
- How to identify what outcomes are clinically relevant
- How to interpret absolute vs relative risk
- How to approach papers yourself in a structured way
2.) Study Design & Population
- Design: Phase III, randomized, double-blind, placebo-controlled trial
- Participants: ~9,650 adults with type 2 diabetes and established cardiovascular disease, chronic kidney disease, or both
- Intervention: Oral semaglutide (tablet) vs placebo (in addition to standard of care)
- Follow-up: Median ~4 years
- Inclusion/Exclusion: Adults age 50 or greater, with HbA1c 6.5-10%, high CV risk; excluded severe GI disease or recent major CV events
3.) Methods & Statistics
- Primary outcome: Composite MACE (CV death, nonfatal MI, nonfatal stroke)
- Analysis: Intention-to-treat; hazard ratios (HR) with 95% confidence intervals
- Power: Designed to detect ~15% relative risk reduction
- Other outcomes: HbA1c, weight, safety/adverse events
- Why this matters: Learn how hazard ratios, confidence intervals, and absolute vs relative risk inform clinical interpretation
4.) Results
- MACE: HR 0.86 (14% relative reduction) vs placebo
- Absolute risk reduction: 1.8% over ~4 years
- Weight & glycemic control: Significant reductions with semaglutide
- Adverse events: Mostly mild/moderate GI events; serious events similar between groups
- Subgroups: Benefits observed broadly, slightly attenuated in lower-risk populations
5.) Strengths & Limitations
Strengths:
- Large sample size
- Double-blind, placebo-controlled
- Definitive and observable cardiovascular outcomes
- Long follow-up
Limitations:
- Composite endpoints can mask variability of individual components
- Absolute benefit is modest → shared decision-making is key
- Generalizability outside high-risk adults may be limited (remember; all patients had established CVD, CKD, or both)
- Trial participants highly monitored → may differ from real-world patients
6.) Clinical Bottom Line
- Oral semaglutide reduces MACE modestly in adults with T2DM and high CV risk
- Absolute benefit is small but clinically relevant
- Oral formulation may improve adherence and accessibility
- Shared decision-making is essential: consider patient-specific factors, tolerability, and cost
7.) Discussion & Key Takeaways
- Identifying relevance: Focus on the primary outcome (MACE) and what matters clinically. Secondary endpoints, subgroup analyses, and surrogate outcomes can be important, but always ask: “Will this change patient care?”
- Generalizability: While the difference in outcomes is clear, is it applicable to all of our patients? Given the higher risk at baseline, do we expect to have the same degree of impact in other populations? Further, make sure to understand what "standard of care" means in this context - given the wide variety of diabetes management options available, is the trial's standard the same as your own?
- Understanding absolute vs relative risk: While the HR shows a 14% relative risk reduction, the absolute reduction is ~1.8% over 4 years. Both are important: absolute risk frames real-world patient impact, relative risk shows effect size consistency.
- Approaching papers yourself: Break papers into sections: why it matters → study design → results → limitations → clinical implications. Skim abstracts and figures first to get the high-level picture, then dive deeper into statistics for nuance.
- Practice tips: Ask yourself: “What outcome affects my patients most?” and “What is the absolute benefit vs risk?” With repetition, you’ll quickly identify what’s relevant in any study.
8.) Discussion Prompts
- Would this trial change your approach for high-risk T2DM patients? What about low-risk?
- How does understanding absolute vs relative risk affect your interpretation of the findings?
- Think about what's actually relevant to the therapy as well - does MACE seem like an appropriate endpoint to associate with an oral GLP-1?
9.) References / Paper Link
- [SOUL Trial — NEJM 2025](https://pubmed.ncbi.nlm.nih.gov/40162642)
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SOUL Trial: Oral Semaglutide & Cardiovascular Outcomes (NEJM 2025)
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