Why the SOUL Trial Represents a Breakthrough for Oral GLP-1 Therapy
The SOUL trial positions oral semaglutide in an entirely new therapeutic category. Until now, every GLP-1 receptor agonist with proven cardiovascular protection had been administered by injection. Liraglutide, injectable semaglutide, dulaglutide – each demonstrated reductions in major adverse cardiovascular events, establishing GLP-1 RAs as a cornerstone of cardiometabolic care. Oral semaglutide, however, was generally viewed as a glucose-lowering agent whose strengths lay in convenience, not cardioprotection. Many clinicians doubted whether an oral formulation could reproduce the cardiometabolic benefits of injectables, given the challenges of bioavailability and the narrower therapeutic window of a daily pill.
SOUL fundamentally changes that assumption. Enrolling 9,650 patients aged fifty and older with type 2 diabetes and confirmed atherosclerotic cardiovascular disease, chronic kidney disease, or both, it represents one of the largest and longest GLP-1 cardiovascular outcome trials to date. Participants were followed for nearly four years a duration that allows adequate time for atherosclerosis-modifying effects to emerge. The headline finding, a 14% reduction in MACE with a hazard ratio of 0.86 (95% CI 0.77–0.96), confirms that oral semaglutide can meaningfully alter cardiovascular risk trajectories in a population tailored to guideline-level prevention. What makes this especially significant is the patient population for whom oral therapy fills an unmet need. A substantial proportion of individuals with diabetes express reluctance toward injections, whether due to needle aversion, stigma, lifestyle barriers, or a desire for simpler routines. For these patients, the absence of proven cardiovascular benefit from an oral GLP-1 created a therapeutic gap: clinicians either encouraged injections or relied on SGLT2 inhibitors alone for cardioprotection. SOUL closes that gap. It demonstrates that an oral GLP-1 can deliver not just metabolic advantages but tangible macrovascular benefit, reshaping expectations about what a once-daily pill can achieve.
The implications reach beyond patient preference. They challenge long-standing assumptions about the necessity of injectable delivery for achieving sustained GLP-1 receptor activation and place oral semaglutide alongside its injectable counterparts as a legitimate cardiovascular drug rather than an intermediate option.
What the SOUL Results Actually Show: Efficacy, Hazard Ratios, and Patient Subgroups
The SOUL trial demonstrates with unusual clarity that oral semaglutide has cardiovascular impact beyond glycemic control. The primary composite endpoint, such as nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death, occurred significantly less often in the semaglutide group than in the placebo group. The hazard ratio of 0.86 (95% CI 0.77–0.96) corresponds to a 14% relative risk reduction, a margin entirely consistent with what has been seen for injectable GLP-1 receptor agonists. Given that the study population carried heavy baseline risk (established atherosclerotic cardiovascular disease, chronic kidney disease, or both), the absolute reduction becomes clinically meaningful over the course of nearly four years.
The depth of the dataset lies in its representation of real-world high-risk patients. Participants were older, with long-standing diabetes and established organ complications, which tends to attenuate treatment effects in many cardiometabolic trials. Yet the benefit persisted across prespecified subgroups with no major attenuation in those with kidney disease, prior myocardial infarction, or long diabetes duration. This internal consistency reinforces the credibility of the finding and reduces the likelihood that the result reflects random variation within a single demographic slice.
Safety outcomes also mirror what clinicians have come to expect from GLP-1 biology. Serious adverse events were comparable between oral semaglutide and placebo, demonstrating that cardiovascular benefit was not offset by systemic harms. Gastrointestinal effects, such as nausea, vomiting, decreased appetite, diarrhea, occurred more frequently in the treatment group, but these were overwhelmingly mild to moderate and aligned with the established class profile. Importantly, the long trial duration allowed investigators to observe whether persistent daily dosing would produce any late-emerging safety issues; none materialized.
One of the nuanced interpretations of SOUL lies in how the effect size compares with other GLP-1 therapies. Injectable semaglutide has shown even larger reductions in certain cardiovascular endpoints, and SGLT2 inhibitors exert complementary effects on heart failure and renal progression. Oral semaglutide’s results do not replace these therapies but expand the palette of evidence-based options. For patients who previously received an oral GLP-1 solely for glycemic control, the trial elevates the therapy into the domain of cardiovascular risk reduction, which is a shift that has practical implications for prescribing patterns.
Why Oral Semaglutide Performs This Way: Pharmacologic Considerations and Clinical Interpretation
Understanding why oral semaglutide demonstrated cardiovascular benefit in SOUL requires revisiting the pharmacology of GLP-1 receptor agonists and the unique challenges posed by oral peptide delivery. The success of injectable semaglutide led many clinicians to assume that a tablet formulation, limited by gastrointestinal degradation, variable absorption, and lower plasma levels, might not reach the therapeutic intensity necessary to influence cardiovascular biology. Oral semaglutide’s absorption relies on co-formulation with sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC), which transiently elevates local gastric pH and enhances transcellular uptake. Even with this technology, only a small fraction of the administered dose reaches systemic circulation, and this led to skepticism about whether sustained cardiometabolic signaling comparable to injectables could be achieved.
The SOUL data suggest that the daily oral regimen compensates for its lower bioavailability through continuous receptor engagement. Unlike weekly injectables that achieve high peaks and gradual troughs, daily oral semaglutide maintains regular GLP-1 exposure, which may be sufficient to trigger long-term vascular and metabolic adaptations. GLP-1 receptor activation influences endothelial function, inflammatory pathways, and atherosclerotic plaque stability – i.e., domains that respond not only to peak concentration but also to cumulative exposure. Over nearly four years of treatment, these incremental effects may have accumulated to produce the observed 14% reduction in major cardiovascular events.
Biological plausibility strengthens this interpretation. GLP-1 signaling modulates oxidative stress, improves nitric oxide availability, enhances lipid handling, and reduces postprandial glycemic excursions that contribute to vascular injury. In patients with diabetes complicated by chronic kidney disease or established atherosclerotic disease, even modest improvements in these pathways can translate into meaningful cardiovascular protection. The consistency of benefit across subgroups in SOUL suggests that oral semaglutide’s mechanism aligns with the broader class effects of GLP-1 RAs rather than representing an isolated statistical finding.
The trial therefore provides affirmation that the pharmacologic ceiling for oral semaglutide is higher than previously assumed. It demonstrates that cardiovascular benefit is achievable without injectable delivery, challenging long-standing assumptions about the necessity of high systemic exposures. In doing so, it broadens therapeutic options while reinforcing the biological coherence of GLP-1–mediated cardioprotection.
Therapy Stratification: How SOUL May Change Real-World Treatment Selection
The SOUL results require clinicians to reconsider how they position oral versus injectable GLP-1 therapies within treatment algorithms for type 2 diabetes and cardiovascular risk management. Until now, oral semaglutide has typically been reserved for patients seeking an alternative to daily or weekly injections, with the understanding that they were trading some cardiometabolic potency for convenience. The demonstration of a significant reduction in major cardiovascular events challenges this hierarchy and invites a more flexible approach in which oral therapy is not merely a compromise but a legitimate starting point for high-risk individuals.
One of the most meaningful shifts concerns patients who are unwilling or unable to use injectable medications. Fear of needles, concerns about stigma, occupational barriers, and lifestyle constraints have historically excluded many from receiving GLP-1 therapies with proven cardiovascular benefit. Prior to SOUL, these patients were steered toward SGLT2 inhibitors or intensified statin therapy for risk reduction, with oral semaglutide offering glycemic and weight advantages but not meeting the threshold for cardiovascular protection. The new evidence removes that limitation. It allows clinicians to offer a fully oral cardioprotective regimen to a population that often struggles with adherence to injectable therapies. At the same time, treatment stratification will continue to rely on individualized goals. For patients prioritizing substantial weight loss or requiring aggressive glycemic control, injectable semaglutide or dual agonists such as tirzepatide still provide unmatched metabolic benefits. These agents are likely to remain first-line choices when the therapeutic target extends beyond cardiovascular protection. Oral semaglutide, in contrast, may serve as the preferred option for those who value simplicity, who wish to start with a less intensive regimen, or who require combination therapy with existing agents such as metformin, SGLT2 inhibitors, or basal insulin.
The question of adherence will also become central to therapy selection. Oral semaglutide requires strict dosing conditions (taken on an empty stomach with limited fluid and followed by a fasting period), which some patients may find challenging. Conversely, others prefer the predictability of a daily pill. SOUL does not resolve this practical distinction but elevates both options to evidence-supported choices, allowing shared decision-making to play a larger role.
The trial expands the therapeutic landscape. Instead of a rigid injectable-first hierarchy, clinicians can now match GLP-1 therapy to patient preferences and clinical profiles without sacrificing cardiovascular protection. This flexibility represents a meaningful evolution in real-world diabetes care.
Integrating Rybelsus into Combination Therapy: SGLT2 Inhibitors, Statins, and Guideline-Level Cardiovascular Prevention
The SOUL trial positions oral semaglutide as a credible component of combination therapy for patients with type 2 diabetes and high cardiovascular risk. Many of these individuals are already prescribed SGLT2 inhibitors, statins, and antihypertensive agents as part of a layered approach to risk reduction. The emergence of an oral GLP-1 option with demonstrated MACE reduction simplifies the task of assembling a comprehensive cardiometabolic regimen. Rather than reserving GLP-1 receptor agonists for patients willing to accept injections, clinicians can now incorporate Rybelsus alongside SGLT2 inhibitors to address complementary mechanisms: GLP-1–mediated improvements in endothelial function and inflammation, combined with the robust heart failure and renal protection seen with SGLT2 blockade. (Efficacy, mechanisms, and clinical use of SGLT2 inhibitors compared to other diabetes drug classes)
The compatibility of these agents extends beyond physiology. Both drug classes exert favorable effects on weight, reduce postprandial glucose excursions, and improve markers of metabolic health. When used together, they create a multi-modal strategy that addresses the major drivers of cardiovascular risk in diabetes. Statins remain foundational for lipid management, and oral semaglutide’s demonstrated benefit in SOUL allows cardiometabolic teams to reinforce statin therapy rather than substitute for it. In practice, this means patients can now receive a fully oral, evidence-based combination that spans glycemic control, atherosclerotic risk reduction, and heart–kidney protection.
Implications for Guidelines and Clinical Practice: What Will Happen Next?
The cardiovascular benefit demonstrated in SOUL is likely to prompt a formal reassessment of how oral semaglutide is positioned in major diabetes and cardiology guidelines. Until now, the ADA, EASD, ESC, and ACC frameworks have emphasized injectable GLP-1 receptor agonists for atherosclerotic cardiovascular disease risk reduction, while oral semaglutide has been categorized primarily as a glucose-lowering option with secondary metabolic advantages. With a clearly documented reduction in MACE, that distinction becomes difficult to maintain. Guideline panels will need to consider whether oral semaglutide should join the ranks of recommended agents for patients with type 2 diabetes and established cardiovascular disease, particularly for those who decline injectable therapy or face barriers to its use.
The change may be especially impactful in primary care settings, where the majority of diabetes management occurs. Clinicians who hesitated to introduce injectable GLP-1s due to patient reluctance may find it easier to initiate cardioprotective therapy with an oral agent that aligns with existing prescribing habits. This shift could broaden the population receiving GLP-1–mediated cardiovascular protection, closing a gap created not by lack of efficacy but by practical limitations in real-world acceptance of injections.
Cardiologists, too, may reconsider their approach. With increasing collaboration between cardiology and endocrinology, the ability to prescribe an oral GLP-1 with proven MACE reduction simplifies integration into secondary prevention strategies. SOUL therefore represents not only a pharmacologic milestone, but an organizational one, expanding the tools available to diverse clinicians who manage cardiometabolic risk.
References
- Aroda, V. R., Bain, S. C., Buse, J. B., Pratley, R. E., Kushner, R. F., Nauck, M. A., & others. (2025). Oral semaglutide and cardiovascular outcomes in type 2 diabetes (SOUL): A randomized, double-blind, placebo-controlled trial. The New England Journal of Medicine. https://pubmed.ncbi.nlm.nih.gov/40162642/
