Semaglutide 2.4 mg Cuts Heart Events in Broader ASCVD Patients
What You’ll Learn From This Review:
- How semaglutide 2.4 mg performed against a matched real-world comparator in a population that spans the full clinical ASCVD spectrum, not just prior MI or stroke
- Which specific MACE components drove the reductions, and which did not reach significance
- What the study’s design limitations mean for how confidently you should apply these findings to your patients
- How this observational dataset compares to SELECT and the earlier SCORE study, and why the effect sizes differ
TL;DR: In a propensity-score-matched real-world U.S. cohort of 38,308 adults with clinical ASCVD and overweight or obesity without diabetes, initiating semaglutide 2.4 mg was associated with a 45% lower hazard of the composite of MI, stroke, and all-cause mortality (HR 0.55; 95% CI 0.47–0.65) over a mean follow-up of 8.6 months.
Abstract
Aims: To evaluate the association between semaglutide 2.4 mg and major adverse cardiovascular events (MACE) among adults with clinical atherosclerotic cardiovascular disease (ASCVD) and overweight or obesity without diabetes in real-world clinical practice.
Materials and Methods: Adults aged ≥45 years with overweight or obesity and clinical ASCVD were identified from a United States database (2016–2024). Patients initiating semaglutide 2.4 mg were matched 1:2 with individuals not treated with semaglutide 2.4 mg through a propensity score model including more than 70 demographic and clinical covariates. Primary outcomes were revised 3-point MACE (rMACE-3: myocardial infarction, stroke, all-cause mortality) and revised 5-point MACE (rMACE-5: rMACE-3, heart failure hospitalization, coronary revascularization). Secondary outcomes included 3-point MACE and 5-point MACE replacing all-cause mortality with cardiovascular-related mortality, and heart failure composite outcomes. Exploratory outcomes were incident type 2 diabetes (T2D), major adverse kidney events (MAKE), and major obesity-related adverse events (MORAE). Hazard ratios and 95% confidence intervals were estimated using Cox proportional hazards models.
Results: The final sample comprised 38,308 patients with semaglutide 2.4 mg use propensity-score matched to 76,615 patients without. Over a mean follow-up of 8.6 months, semaglutide 2.4 mg significantly reduced the risk of rMACE-3 (HR 0.55; 95% CI 0.47–0.65), rMACE-5 (0.63; 0.56–0.71), MACE-3 (0.66; 0.56–0.78), and MACE-5 (0.69; 0.62–0.77). Semaglutide 2.4 mg also significantly reduced the risk of HF composite outcomes, T2D, MAKE, and MORAE.
Conclusions: Semaglutide 2.4 mg was associated with a significantly reduced risk of MACE and other obesity-related outcomes, extending prior evidence of benefits to a broader clinical ASCVD population.
Source: Diabetes, Obesity and Metabolism, 2026; 28:4975–4990
DOI: https://doi.org/10.1111/dom.70686
Trial Registration: NCT07141914 (SCORE — Clinical ASCVD Study)
Open Access: Yes (Creative Commons Attribution-NonCommercial)
Study at a Glance
| Design | Retrospective, longitudinal, observational cohort with 1:2 propensity-score matching |
| Population | U.S. adults aged ≥45 years with clinical ASCVD and overweight or obesity, without diabetes |
| Total N (matched) | 114,923 (38,308 semaglutide 2.4 mg; 76,615 non-use) |
| Intervention | Semaglutide 2.4 mg (Wegovy), any dose, initiated on or after June 4, 2021 |
| Comparator | No semaglutide 2.4 mg use (propensity-score matched) |
| Primary Endpoint | rMACE-3 (MI, stroke, all-cause mortality) and rMACE-5 (rMACE-3 + HF hospitalization + coronary revascularization) |
| Mean Follow-Up | 8.6 months (SD 7.4 months in semaglutide group; 7.3 months in non-use group) |
| Key Finding | rMACE-3 HR 0.55 (95% CI 0.47–0.65); rMACE-5 HR 0.63 (95% CI 0.56–0.71); both p<0.001 |
Study Snapshot: Key Statistics
| Outcome | Semaglutide 2.4 mg Events (IR/1000 PY) | Non-Use Events (IR/1000 PY) | HR (95% CI) | p-value |
|---|---|---|---|---|
| rMACE-3 (primary) | 194 (7.0) | 699 (12.7) | 0.55 (0.47–0.65) | <0.001 |
| rMACE-5 (primary) | 407 (14.8) | 1285 (23.5) | 0.63 (0.56–0.71) | <0.001 |
| MACE-3 (secondary) | 184 (6.7) | 556 (10.1) | 0.66 (0.56–0.78) | <0.001 |
| MACE-5 (secondary) | 397 (14.5) | 1147 (21.0) | 0.69 (0.62–0.77) | <0.001 |
| Stroke | 77 (2.8) | 243 (4.4) | 0.63 (0.49–0.82) | <0.001 |
| Hospitalization for HF | 112 (4.1) | 402 (7.3) | 0.56 (0.45–0.69) | <0.001 |
| All-cause mortality | 29 (1.05) | 299 (5.4) | 0.19 (0.13–0.28) | <0.001 |
| Cardiovascular-related mortality | 17 (0.61) | 153 (2.8) | 0.22 (0.13–0.37) | <0.001 |
| MI (component) | 94 (3.4) | 195 (3.5) | 0.96 (0.75–1.23) | 0.765 (NS) |
| Coronary revascularization | 173 (6.3) | 372 (6.8) | 0.93 (0.77–1.11) | 0.407 (NS) |
| 2-point HF composite | 151 (5.5) | 494 (9.0) | 0.61 (0.51–0.73) | <0.001 |
| 3-point HF composite | 165 (6.0) | 621 (11.3) | 0.53 (0.45–0.63) | <0.001 |
| Incident T2D (exploratory) | 811 (29.9) | 2406 (45.0) | 0.67 (0.62–0.72) | <0.001 |
| MAKE (exploratory) | 166 (6.0) | 641 (11.7) | 0.52 (0.44–0.61) | <0.001 |
| MORAE (exploratory) | 2610 (99.9) | 6622 (129.4) | 0.77 (0.74–0.81) | <0.001 |
IR = incidence rate per 1,000 person-years; PY = person-years; NS = not statistically significant; HF = heart failure; MAKE = major adverse kidney events; MORAE = major obesity-related adverse events.
Study Facts Table
| Authors | Nanna MG, Mena-Hurtado C, Divino V, Zhao Z, Chen Y, Boland J, Song J, Traina A, Ozer K, Knop FK, Smolderen KG |
| Journal | Diabetes, Obesity and Metabolism |
| Year | 2026 |
| Design | Retrospective longitudinal observational cohort; 1:2 propensity-score matching; Cox proportional hazards modeling |
| Database | Komodo Research Database (KRD); U.S. administrative medical and pharmacy claims linked with clinical/lab data; 2016–2024 |
| N (matched sample) | 38,308 (semaglutide 2.4 mg) vs. 76,615 (non-use) |
| Intervention | Semaglutide 2.4 mg (Wegovy), any dose, first pharmacy claim on or after June 4, 2021 |
| Comparator | No semaglutide 2.4 mg use; propensity-score matched on more than 70 baseline variables |
| Primary Endpoints | rMACE-3 (MI + stroke + all-cause mortality); rMACE-5 (rMACE-3 + HF hospitalization + coronary revascularization) |
| Key Results | rMACE-3 HR 0.55 (0.47–0.65); rMACE-5 HR 0.63 (0.56–0.71); both p<0.001. All-cause mortality HR 0.19 (0.13–0.28). MI HR 0.96 (NS). Coronary revascularization HR 0.93 (NS). |
| Adverse Events | Not reported in this observational claims-based analysis |
| Funding | Novo Nordisk Inc. |
| Conflicts of Interest | Multiple authors are Novo Nordisk employees or stockholders. Statistical analysis conducted by Analysis Group Inc., which received consulting fees from Novo Nordisk Inc. Academic authors (Nanna, Smolderen, Mena-Hurtado) report consulting relationships with Novo Nordisk. |
What Researchers Actually Did
Investigators extracted de-identified administrative claims and linked laboratory data from the Komodo Research Database, a nationally representative U.S. repository spanning January 2016 through December 2024. Eligible participants were adults aged 45 years or older with documented overweight or obesity — confirmed by ICD-10-CM codes or anthropometric records reflecting BMI ≥27.0 kg/m² — and with prior evidence of clinical ASCVD according to the 2018 AHA/ACC definition. That definition is broader than the one used in the SELECT trial: it encompasses not only prior MI, ischemic stroke, and peripheral arterial disease, but also stable angina, unstable angina, transient ischemic attack (TIA), carotid stenosis, and aortic aneurysm. Patients with any history of diabetes, end-stage kidney or heart failure, pancreatitis, bariatric surgery, or prior GLP-1 or GIP/GLP-1 receptor agonist use for weight management were excluded. The index date for the semaglutide 2.4 mg cohort was the date of the first qualifying pharmacy claim; for the non-use cohort, an index date was randomly assigned from the post-approval period. A minimum of 12 months of continuous insurance enrollment before the index date was required.
To address confounding, investigators built a non-parsimonious propensity score model incorporating more than 70 baseline demographic and clinical variables — including ASCVD phenotype, comorbidities, medications, healthcare utilization, and insurance type — and matched each semaglutide 2.4 mg user to up to two non-users via greedy nearest-neighbor matching within a caliper of 0.2 standard deviations of the logit of the propensity score. After matching, all standardized mean differences were below 0.1, indicating adequate covariate balance. Outcomes were identified using ICD-10-CM diagnosis codes (primary position on inpatient visits for MI, stroke, and HF hospitalization) and procedure codes for revascularization. All-cause mortality was captured by month and year, with the date assigned as the last day of the recorded month. Competing risks were handled using Aalen-Johansen
Read This Paper Through Nine Different Lenses
The same evidence can produce very different conclusions depending on the question being asked. Explore this study through multiple physician-guided interpretive frameworks.
Overview
This study demonstrates that semaglutide 2.4 mg is effective in reducing major adverse cardiovascular events, including myocardial infarction, stroke, and all-cause mortality, among adults with atherosclerotic cardiovascular disease (ASCVD) who are overweight or obese but do not have diabetes.
The research leverages real-world data from over 38,000 patients, providing insights into the drug’s performance in diverse clinical settings beyond those typically seen in randomized controlled trials.
- Semaglutide 2.4 mg reduces rMACE-3 by 45% and rMACE-5 by 37%.
- Benefits extend to heart failure hospitalization and major adverse kidney events.
- Study includes a broad ASCVD spectrum, not limited to prior MI or stroke.
Patient Takeaway
For patients with atherosclerotic cardiovascular disease (ASCVD) who are overweight or obese, semaglutide 2.4 mg can significantly reduce the risk of major adverse cardiovascular events such as heart attacks and strokes.
This treatment also lowers the likelihood of hospitalization for heart failure and other serious health issues, providing a comprehensive approach to managing cardiovascular risk.
- Reduces risk of myocardial infarction, stroke, and all-cause mortality.
- Improves outcomes related to heart failure and kidney events.
- Effective in a broad ASCVD population without diabetes.
Clinician’s POV
Clinicians can use semaglutide 2.4 mg to reduce cardiovascular risk in patients with atherosclerotic cardiovascular disease (ASCVD) who are overweight or obese, based on real-world evidence from over 38,000 patients.
The treatment is effective across a broad spectrum of ASCVD conditions and provides significant reductions in major adverse cardiovascular events.
- Reduces rMACE-3 by 45% and rMACE-5 by 37%.
- Effective for heart failure hospitalization and kidney events.
- Broad applicability to various ASCVD phenotypes.
A Skeptical Read
While semaglutide 2.4 mg shows promising results in reducing cardiovascular risk among patients with atherosclerotic cardiovascular disease (ASCVD) who are overweight or obese, the study is observational and may have biases not captured by randomized controlled trials.
The broad spectrum of ASCVD conditions included in the study adds to its generalizability but also introduces variability that could affect results.
- Observational design with potential biases.
- Broad ASCVD spectrum increases generalizability.
- Real-world data provides insights beyond clinical trial settings.
Study Critic
Critics may point out that the study’s observational nature and reliance on real-world data introduce potential biases not present in randomized controlled trials. The broad spectrum of ASCVD conditions included also adds complexity to interpreting results.
However, the significant reductions in major adverse cardiovascular events provide compelling evidence for further investigation and clinical application.
- Observational study with inherent limitations.
- Broad ASCVD spectrum increases generalizability.
- Significant risk reduction supports clinical interest.
Compared to Past Research
This study builds on previous research showing the benefits of GLP-1 receptor agonists in reducing cardiovascular risk. Earlier studies, such as SELECT and SCORE, demonstrated significant reductions in major adverse cardiovascular events among patients with diabetes.
The current study extends these findings to a broader population of ASCVD patients without diabetes, highlighting the potential for semaglutide 2.4 mg in managing cardiovascular risk across different patient groups.
- Extends benefits beyond diabetic populations.
- Previous studies showed significant reductions in MACE.
- Historical context supports current findings.
Practical Considerations
Clinicians can integrate semaglutide 2.4 mg into their treatment plans for patients with atherosclerotic cardiovascular disease (ASCVD) who are overweight or obese, based on the real-world evidence presented in this study.
The broad spectrum of ASCVD conditions included suggests that the treatment may be effective across various clinical scenarios, providing practical value for managing cardiovascular risk.
- Practical application in diverse clinical settings.
- Broad applicability to different ASCVD phenotypes.
- Real-world data supports clinical use.
Future Directions
Future research should focus on long-term outcomes and the effects of semaglutide 2.4 mg in broader populations, including those with diabetes or other comorbidities.
Longitudinal studies can provide more comprehensive insights into the sustained benefits and potential side effects of this treatment over time.
- Future research needed for long-term outcomes.
- Explore effects in broader patient groups.
- Investigate sustained benefits and safety.
Misreadings & Bad-Faith Takes
Common misinterpretations of this study include assuming that the benefits are as strong in all ASCVD patients or that semaglutide 2.4 mg is a substitute for other cardiovascular treatments.
The observational nature of the study and its broad spectrum of ASCVD conditions highlight the need for cautious interpretation and further research to confirm findings.
- Avoid assuming uniform benefits across all ASCVD patients.
- Do not consider semaglutide 2.4 mg a substitute for other treatments.
- Cautious interpretation due to observational design.
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What is semaglutide 2.4 mg?
Semaglutide 2.4 mg is a GLP-1 receptor agonist used for weight management and diabetes treatment.
How does semaglutide 2.4 mg reduce cardiovascular risk in ASCVD patients?
Semaglutide 2.4 mg lowers the hazard of major adverse cardiovascular events, including myocardial infarction, stroke, and all-cause mortality.
Who were included in the study?
The study included U.S. adults aged 45 years or older with clinical ASCVD and overweight or obesity without diabetes.
What was the primary outcome of the study?
The primary outcomes were revised 3-point MACE (rMACE-3) and revised 5-point MACE (rMACE-5).
How long was the follow-up period in the study?
The mean follow-up period was 8.6 months.
What were some of the secondary outcomes measured?
Secondary outcomes included MACE-3, MACE-5, heart failure composite outcomes, and others.
Did semaglutide 2.4 mg reduce the risk of all types of cardiovascular events equally?
Semaglutide 2.4 mg significantly reduced stroke, hospitalization for heart failure, and all-cause mortality but did not reach significance for myocardial infarction or coronary revascularization.
What are the implications of this study for clinical practice?
This study supports the use of semaglutide 2.4 mg in reducing cardiovascular risk among ASCVD patients with overweight or obesity.
Are there any limitations to this study?
The study is observational and relies on real-world data, which may have biases not captured by randomized controlled trials.
How does this study compare to previous research?
This study extends prior evidence of semaglutide benefits to a broader clinical ASCVD population without diabetes.
