Study analysis · Diabetes, Obesity & Metabolism · 2025
Semaglutide linked to 45% lower relative heart risk in real-world study — but that meant only about 7 fewer events per 1,000 people over 200 days.
In people with heart disease and extra weight but no diabetes, taking semaglutide 2.4 mg was linked to fewer heart attacks, strokes, and deaths over about 6–7 months, but the study can't prove it caused the improvement.
Overview
What the study found
The study in plain English — the bottom line, every takeaway we extracted, and what to do with them.
In simple terms
This study looked back at health records of people who took semaglutide 2.4 mg and similar people who did not, and found that those taking it had fewer heart attacks, strokes, and deaths. But because people were not randomly assigned to take the drug, it can only show a link, not prove that the drug caused the better outcomes. It's like noticing that people who eat breakfast tend to be healthier, but not proving breakfast is the reason.
What’s the bottom line?
Researchers looked at health records of US adults with heart disease and overweight/obesity but no diabetes. People who started semaglutide 2.4 mg were compared with similar people who did not. Over about 200 days, those on semaglutide had fewer heart attacks, strokes, and deaths.
How strong is this study?
The study is quite strong for an observational study because it included many people, carefully matched the two groups on many characteristics, and did several checks to see if hidden factors could explain the results. Still, because it was not a randomized experiment, there could be unmeasured differences between people who chose semaglutide and those who did not, so we cannot be fully certain the drug is responsible for the lower risks.
40 / 100
- COI disclosure+40/40
- Data availabilitydata not shared
- Code availabilitycode not shared
56 / 100
- Randomizationnot randomized
- Blindingnot blinded
- Control group+15/15
- Sample size (n=27963)+20/20
- Follow-up+10/10
100 / 100
100 / 100
- P-values+15/15
- Effect size+20/20
- Confidence intervals+15/15
- Pre-registration+15/15
Each component is scored out of 100 and then capped by the study design — a case series cannot reach the ceiling a randomised trial can, however well it is reported.
Where it sits
RCT reviewsReviews of RCTs (Meta-analyses)
Max 100Randomized TrialsRandomized Trials
Max 90Reviews of Cohort StudiesReviews of Cohort Studies
Max 85Cohort StudiesCohort Studies
Max 72Reviews of Case-Control StudiesReviews of Case-Control Studies
Max 63Case-Control StudiesCase-Control Studies
Max 58Cross-Sectional & Case SeriesCross-Sectional & Case Series
Max 50Expert OpinionExpert Opinion
Max 572 / 100
Probability of being correct
Groups of people are followed over time to see who develops an outcome. Strong for identifying risk factors and associations, but cannot prove causation as firmly as RCTs.
This design cannot establish causation — the findings describe an association, not a cause. This is a retrospective observational cohort study using administrative claims data with propensity-score matching. Although it found strong associations between semaglutide 2.4 mg initiation and lower cardiovascular event risks, treatment was not randomly assigned. Therefore, residual confounding, selection bias, healthy-user/adherer effects, and unmeasured differences between groups cannot be excluded. The short mean follow-up (~200 days) and claims-based outcome ascertainment further limit causal inference.
COI Unknown
Could not determine conflict of interest status
No conflicts of interest or funding sources were disclosed in the provided text, leaving potential industry ties unassessed.
The provided text does not include a conflict of interest, funding, or author disclosure section. The study evaluates semaglutide 2.4 mg (a Novo Nordisk product), but no funding source or author affiliations are present in the excerpt, so potential conflicts cannot be ruled out.
Key takeaways
- 01
For the main 5-point heart outcome, semaglutide was linked to a 45% lower relative risk (HR 0.55).
- 02
That was 16.0 vs 29.4 events per 1,000 person-years, or about 7 fewer events per 1,000 people over ~200 days.
- 03
For the narrower 3-point outcome, it was a 57% lower relative risk (HR 0.43), or about 6 fewer events per 1,000 people over ~200 days.
- 04
For other heart outcomes, relative risk reductions were 35% and 42%.
- 05
For diabetes, kidney events, and obesity-related events, relative risks were 16% to 70% lower, but absolute risks were not reported.
- 06
In absolute terms: without semaglutide, about 29 of every 1,000 people had a main heart event per year; with semaglutide, about 16 per 1,000.
- 07
Over ~200 days, that is about 7 fewer events per 1,000 people.
- 08
For the narrower 3-point outcome, about 6 fewer per 1,000 over ~200 days.
- 09
For the other outcomes, the study did not report enough data to calculate absolute risk, so the absolute benefit remains unknown.
Surprising findings
- The absolute benefit was much smaller than the relative risk reduction suggested: 45% lower relative risk translated to about 7 fewer rMACE-5 events per 1,000 people over ~200 days.Most people assume a 45% risk reduction means a large personal benefit; absolute numbers reveal the baseline risk matters.
- About 80% of the MACE risk reduction may be mediated by factors other than body weight loss.Semaglutide is known as a weight-loss drug, so many assume heart benefits come from weight loss alone.
- Kidney outcomes showed a 70% lower relative risk for major adverse kidney events, but absolute risks were not reported.Such a large relative reduction would usually be headline news, but without absolute numbers its real-world impact is unclear.
- Real-world results closely matched a randomized trial despite a very different, more diverse population.Real-world data often diverge from trials because of adherence, comorbidities, and patient differences.
Practical takeaways
If you have ASCVD and overweight/obesity without diabetes, ask your doctor whether semaglutide 2.4 mg is appropriate for cardiovascular risk reduction.
This study is observational and cannot prove that semaglutide caused the lower risk; decisions should consider cost, side effects, and individual risk.
medium confidenceWhen you see a relative risk reduction like 45%, ask for the absolute risk difference.
The absolute benefit here was about 7 fewer rMACE-5 events per 1,000 people over ~200 days; longer-term absolute benefit is unknown.
high confidenceDon't assume the heart benefit is only from weight loss.
The mediation analysis is exploratory and not definitive; weight loss still matters for overall health.
low confidencePay attention to kidney and diabetes outcomes, but wait for absolute-risk data before drawing conclusions.
Exploratory outcomes did not report absolute risks, and the study was short and industry funded.
low confidenceWhy this study matters
The 45% headline — and the absolute reality
For the primary rMACE-5 outcome (heart attack, stroke, heart-failure hospitalization, coronary revascularization, or all-cause death), semaglutide was associated with a 45% lower relative risk (HR 0.55, 95% CI 0.43–0.69). Absolute incidence was 16.0 vs 29.4 events per 1,000 person-years, or about 7 fewer events per 1,000 people over ~200 days. For rMACE-3, it was a 57% lower relative risk (HR 0.43), with absolute incidence 7.6 vs 17.8 per 1,000 person-years, about 6 fewer per 1,000 over ~200 days.
People hear '45% lower risk' and think it means 45 out of 100 are protected. The absolute numbers show a real but much smaller personal benefit over 6–7 months.
Real-world results mirror the SELECT trial
This observational SCORE study found MACE-3 HR 0.58 at ~200 days, while a secondary analysis of the randomized SELECT trial reported MACE-3 HR 0.59 at 6 months. The population was also different: mean age 57, 67.8% female, and more than half non-white, unlike many trial cohorts.
It suggests the trial benefits may hold in everyday, more diverse patients — not just in tightly controlled research settings.
Most heart benefit may not come from weight loss
The discussion states: 'A mediation analysis suggested that about 80% of the MACE risk reduction with semaglutide is mediated by factors other than body weight loss.' The authors propose vascular, inflammatory, insulin-resistance, and metabolic mechanisms.
It challenges the idea that you must lose a lot of weight to protect your heart; the drug may have direct cardiovascular effects.
Kidney and diabetes signals — but absolute risks missing
Exploratory outcomes showed lower relative risks: incident type 2 diabetes HR 0.80 (20% lower relative risk; absolute not reported), major adverse kidney events HR 0.30 (70% lower relative risk; absolute not reported), acute kidney injury HR 0.38 (62% lower relative risk; absolute not reported), and major obesity-related adverse events HR 0.84 (16% lower relative risk; absolute not reported).
Kidney protection and diabetes prevention would be huge for patients, but without absolute numbers we don't know how many people actually benefited.
The fine print: industry funding and observational limits
The study was funded by Novo Nordisk, the maker of semaglutide; authors include Novo Nordisk employees. It is retrospective and observational, with mean follow-up ~200 days and claims-based outcome/exposure misclassification. E-values were 3.0–4.1, and a negative control outcome (sensorineural hearing loss) showed no difference (HR 1.03).
These limitations don't erase the finding, but they mean we should not treat it as definitive proof.
Want the whole report?
Detailed mode opens the full scientific breakdown — every score component, the methodology, conflicts of interest, the evidence analysis behind each claim, and the raw study data.
Overview
What the study found
The study in plain English — the bottom line, every takeaway we extracted, and what to do with them.
Not medical advice. For informational purposes only. Always consult a healthcare professional. Terms
Researchers looked at health records of US adults with heart disease and overweight/obesity but no diabetes. People who started semaglutide 2.4 mg were compared with similar people who did not. Over about 200 days, those on semaglutide had fewer heart attacks, strokes, and deaths.
Research results
For the main 5-point heart outcome, semaglutide was linked to a 45% lower relative risk (HR 0.55). That was 16.0 vs 29.4 events per 1,000 person-years, or about 7 fewer events per 1,000 people over ~200 days. For the narrower 3-point outcome, it was a 57% lower relative risk (HR 0.43), or about 6 fewer events per 1,000 people over ~200 days. For other heart outcomes, relative risk reductions were 35% and 42%. For diabetes, kidney events, and obesity-related events, relative risks were 16% to 70% lower, but absolute risks were not reported.
What this means - more context
In absolute terms: without semaglutide, about 29 of every 1,000 people had a main heart event per year; with semaglutide, about 16 per 1,000. Over ~200 days, that is about 7 fewer events per 1,000 people. For the narrower 3-point outcome, about 6 fewer per 1,000 over ~200 days. For the other outcomes, the study did not report enough data to calculate absolute risk, so the absolute benefit remains unknown.
First interim analysis of the SCORE study, a retrospective real-world cohort, aimed to assess the risk of major adverse cardiovascular events (MACE) among US adults with atherosclerotic cardiovascular disease (ASCVD) and overweight/obesity but without diabetes who initiated semaglutide 2.4 mg versus non-use.
Over a mean 200 days, semaglutide 2.4 mg was associated with lower relative risks of cardiovascular outcomes. For the primary rMACE-5 outcome, the hazard ratio was 0.55 (45% lower relative risk); absolute incidence was 16.0 vs 29.4 events per 1,000 person-years, corresponding to about 7 fewer events per 1,000 people over ~200 days. For rMACE-3, HR 0.43 (57% lower relative risk); absolute incidence 7.6 vs 17.8 per 1,000 person-years, about 6 fewer per 1,000 over ~200 days. Secondary MACE-5 HR 0.65 (35% lower relative risk; 15.8 vs 24.7 per 1,000 person-years, about 5 fewer per 1,000 over ~200 days) and MACE-3 HR 0.58 (42% lower relative risk; 7.4 vs 13.0 per 1,000 person-years, about 3 fewer per 1,000 over ~200 days) were also lower. Exploratory outcomes showed lower relative risks: incident type 2 diabetes HR 0.80 (20% lower relative risk; absolute risk not reported), major adverse kidney events HR 0.30 (70% lower relative risk; absolute risk not reported), acute kidney injury HR 0.38 (62% lower relative risk; absolute risk not reported), and major obesity-related adverse events HR 0.84 (16% lower relative risk; absolute risk not reported).
Methods Used
Retrospective longitudinal observational study using Komodo Research Data, a US administrative claims database linked with clinical and laboratory measurements (2016–2023). Adults aged ≥45 years with overweight/obesity (BMI ≥27 kg/m² or diagnosis) and ASCVD but without diabetes were included. A total of 9,321 semaglutide 2.4 mg initiators were matched 1:2 to 18,642 non-users using a non-parsimonious propensity-score model. Cox proportional hazards models estimated hazard ratios over a mean follow-up of 200 days.
Main Finding
Semaglutide 2.4 mg was associated with a significantly lower relative risk of the primary composite outcomes versus non-use. rMACE-5: HR 0.55 (95% CI 0.43–0.69), a 45% lower relative risk; absolute incidence 16.0 vs 29.4 per 1,000 person-years, about 7 fewer events per 1,000 people over ~200 days. rMACE-3: HR 0.43 (95% CI 0.31–0.61), a 57% lower relative risk; absolute incidence 7.6 vs 17.8 per 1,000 person-years, about 6 fewer events per 1,000 over ~200 days. Secondary MACE-5 and MACE-3 were also lower, and exploratory outcomes including incident type 2 diabetes and kidney events showed lower relative risks. Authors conclude semaglutide was associated with significantly reduced risk of MACEs and other obesity-related morbidities.
Confidence Level
Moderate. Large, propensity-matched real-world cohort with sensitivity analyses, a negative control outcome, and large E-values (3.0–4.1 for primary outcomes). Limitations include observational design with possible residual confounding, short mean follow-up (~200 days), claims-based outcome/exposure misclassification, and industry funding by Novo Nordisk. Not retracted; no corrections reported in available metadata.
Study Flags
Red Flags
- •Industry funded by Novo Nordisk, the maker of semaglutide
- •Observational design with possible residual confounding despite propensity-score matching
- •Short mean follow-up (~200 days) and claims-based outcome/exposure misclassification
Surprising Findings
The absolute benefit was much smaller than the relative risk reduction suggested: 45% lower relative risk translated to about 7 fewer rMACE-5 events per 1,000 people over ~200 days.
Most people assume a 45% risk reduction means a large personal benefit; absolute numbers reveal the baseline risk matters.
Practical Takeaways
If you have ASCVD and overweight/obesity without diabetes, ask your doctor whether semaglutide 2.4 mg is appropriate for cardiovascular risk reduction.
RCT reviewsReviews of RCTs (Meta-analyses)
Max 100Randomized TrialsRandomized Trials
Max 90Reviews of Cohort StudiesReviews of Cohort Studies
Max 85Cohort StudiesCohort Studies
Max 72Reviews of Case-Control StudiesReviews of Case-Control Studies
Max 63Case-Control StudiesCase-Control Studies
Max 58Cross-Sectional & Case SeriesCross-Sectional & Case Series
Max 50Expert OpinionExpert Opinion
Max 572 / 100
Probability of being correct
Groups of people are followed over time to see who develops an outcome. Strong for identifying risk factors and associations, but cannot prove causation as firmly as RCTs.
Human Cohort Study
Subject
High probability
on the GRADE evidence scale
This study looked back at health records of people who took semaglutide 2.4 mg and similar people who did not, and found that those taking it had fewer heart attacks, strokes, and deaths. But because people were not randomly assigned to take the drug, it can only show a link, not prove that the drug caused the better outcomes. It's like noticing that people who eat breakfast tend to be healthier, but not proving breakfast is the reason.
Strengths
- Large sample size (9,321 semaglutide users matched to 18,642 non-users).
- Propensity-score matching using a non-parsimonious model to balance measured confounders.
- Use of a negative control outcome (sensorineural hearing loss) to assess unmeasured confounding.
Weaknesses
- Observational design without randomization, so residual confounding cannot be excluded.
- Short mean follow-up (~200 days) limits assessment of long-term outcomes.
- Reliance on administrative claims data may lead to misclassification of exposure, outcomes, and covariates.
Methodology
Evidence Keywords
Statistical Reporting
Not medical advice. For informational purposes only. Always consult a healthcare professional. Terms
Researchers looked at health records of US adults with heart disease and overweight/obesity but no diabetes. People who started semaglutide 2.4 mg were compared with similar people who did not. Over about 200 days, those on semaglutide had fewer heart attacks, strokes, and deaths.
Research results
For the main 5-point heart outcome, semaglutide was linked to a 45% lower relative risk (HR 0.55). That was 16.0 vs 29.4 events per 1,000 person-years, or about 7 fewer events per 1,000 people over ~200 days. For the narrower 3-point outcome, it was a 57% lower relative risk (HR 0.43), or about 6 fewer events per 1,000 people over ~200 days. For other heart outcomes, relative risk reductions were 35% and 42%. For diabetes, kidney events, and obesity-related events, relative risks were 16% to 70% lower, but absolute risks were not reported.
What this means - more context
In absolute terms: without semaglutide, about 29 of every 1,000 people had a main heart event per year; with semaglutide, about 16 per 1,000. Over ~200 days, that is about 7 fewer events per 1,000 people. For the narrower 3-point outcome, about 6 fewer per 1,000 over ~200 days. For the other outcomes, the study did not report enough data to calculate absolute risk, so the absolute benefit remains unknown.
First interim analysis of the SCORE study, a retrospective real-world cohort, aimed to assess the risk of major adverse cardiovascular events (MACE) among US adults with atherosclerotic cardiovascular disease (ASCVD) and overweight/obesity but without diabetes who initiated semaglutide 2.4 mg versus non-use.
Over a mean 200 days, semaglutide 2.4 mg was associated with lower relative risks of cardiovascular outcomes. For the primary rMACE-5 outcome, the hazard ratio was 0.55 (45% lower relative risk); absolute incidence was 16.0 vs 29.4 events per 1,000 person-years, corresponding to about 7 fewer events per 1,000 people over ~200 days. For rMACE-3, HR 0.43 (57% lower relative risk); absolute incidence 7.6 vs 17.8 per 1,000 person-years, about 6 fewer per 1,000 over ~200 days. Secondary MACE-5 HR 0.65 (35% lower relative risk; 15.8 vs 24.7 per 1,000 person-years, about 5 fewer per 1,000 over ~200 days) and MACE-3 HR 0.58 (42% lower relative risk; 7.4 vs 13.0 per 1,000 person-years, about 3 fewer per 1,000 over ~200 days) were also lower. Exploratory outcomes showed lower relative risks: incident type 2 diabetes HR 0.80 (20% lower relative risk; absolute risk not reported), major adverse kidney events HR 0.30 (70% lower relative risk; absolute risk not reported), acute kidney injury HR 0.38 (62% lower relative risk; absolute risk not reported), and major obesity-related adverse events HR 0.84 (16% lower relative risk; absolute risk not reported).
Methods Used
Retrospective longitudinal observational study using Komodo Research Data, a US administrative claims database linked with clinical and laboratory measurements (2016–2023). Adults aged ≥45 years with overweight/obesity (BMI ≥27 kg/m² or diagnosis) and ASCVD but without diabetes were included. A total of 9,321 semaglutide 2.4 mg initiators were matched 1:2 to 18,642 non-users using a non-parsimonious propensity-score model. Cox proportional hazards models estimated hazard ratios over a mean follow-up of 200 days.
Main Finding
Semaglutide 2.4 mg was associated with a significantly lower relative risk of the primary composite outcomes versus non-use. rMACE-5: HR 0.55 (95% CI 0.43–0.69), a 45% lower relative risk; absolute incidence 16.0 vs 29.4 per 1,000 person-years, about 7 fewer events per 1,000 people over ~200 days. rMACE-3: HR 0.43 (95% CI 0.31–0.61), a 57% lower relative risk; absolute incidence 7.6 vs 17.8 per 1,000 person-years, about 6 fewer events per 1,000 over ~200 days. Secondary MACE-5 and MACE-3 were also lower, and exploratory outcomes including incident type 2 diabetes and kidney events showed lower relative risks. Authors conclude semaglutide was associated with significantly reduced risk of MACEs and other obesity-related morbidities.
Confidence Level
Moderate. Large, propensity-matched real-world cohort with sensitivity analyses, a negative control outcome, and large E-values (3.0–4.1 for primary outcomes). Limitations include observational design with possible residual confounding, short mean follow-up (~200 days), claims-based outcome/exposure misclassification, and industry funding by Novo Nordisk. Not retracted; no corrections reported in available metadata.
Study Flags
Red Flags
- •Industry funded by Novo Nordisk, the maker of semaglutide
- •Observational design with possible residual confounding despite propensity-score matching
- •Short mean follow-up (~200 days) and claims-based outcome/exposure misclassification
Surprising Findings
The absolute benefit was much smaller than the relative risk reduction suggested: 45% lower relative risk translated to about 7 fewer rMACE-5 events per 1,000 people over ~200 days.
Most people assume a 45% risk reduction means a large personal benefit; absolute numbers reveal the baseline risk matters.
Practical Takeaways
If you have ASCVD and overweight/obesity without diabetes, ask your doctor whether semaglutide 2.4 mg is appropriate for cardiovascular risk reduction.
RCT reviewsReviews of RCTs (Meta-analyses)
Max 100Randomized TrialsRandomized Trials
Max 90Reviews of Cohort StudiesReviews of Cohort Studies
Max 85Cohort StudiesCohort Studies
Max 72Reviews of Case-Control StudiesReviews of Case-Control Studies
Max 63Case-Control StudiesCase-Control Studies
Max 58Cross-Sectional & Case SeriesCross-Sectional & Case Series
Max 50Expert OpinionExpert Opinion
Max 572 / 100
Probability of being correct
Groups of people are followed over time to see who develops an outcome. Strong for identifying risk factors and associations, but cannot prove causation as firmly as RCTs.
Human Cohort Study
Subject
High probability
on the GRADE evidence scale
This study looked back at health records of people who took semaglutide 2.4 mg and similar people who did not, and found that those taking it had fewer heart attacks, strokes, and deaths. But because people were not randomly assigned to take the drug, it can only show a link, not prove that the drug caused the better outcomes. It's like noticing that people who eat breakfast tend to be healthier, but not proving breakfast is the reason.
Strengths
- Large sample size (9,321 semaglutide users matched to 18,642 non-users).
- Propensity-score matching using a non-parsimonious model to balance measured confounders.
- Use of a negative control outcome (sensorineural hearing loss) to assess unmeasured confounding.
Weaknesses
- Observational design without randomization, so residual confounding cannot be excluded.
- Short mean follow-up (~200 days) limits assessment of long-term outcomes.
- Reliance on administrative claims data may lead to misclassification of exposure, outcomes, and covariates.
Methodology
Evidence Keywords
Statistical Reporting
Scoring
How strong is this study?
The study is quite strong for an observational study because it included many people, carefully matched the two groups on many characteristics, and did several checks to see if hidden factors could explain the results. Still, because it was not a randomized experiment, there could be unmeasured differences between people who chose semaglutide and those who did not, so we cannot be fully certain the drug is responsible for the lower risks.
40 / 100
- COI disclosure+40/40
- Data availabilitydata not shared
- Code availabilitycode not shared
56 / 100
- Randomizationnot randomized
- Blindingnot blinded
- Control group+15/15
- Sample size (n=27963)+20/20
- Follow-up+10/10
100 / 100
100 / 100
- P-values+15/15
- Effect size+20/20
- Confidence intervals+15/15
- Pre-registration+15/15
Each component is scored out of 100 and then capped by the study design — a case series cannot reach the ceiling a randomised trial can, however well it is reported.
Where it sits
RCT reviewsReviews of RCTs (Meta-analyses)
Max 100Randomized TrialsRandomized Trials
Max 90Reviews of Cohort StudiesReviews of Cohort Studies
Max 85Cohort StudiesCohort Studies
Max 72Reviews of Case-Control StudiesReviews of Case-Control Studies
Max 63Case-Control StudiesCase-Control Studies
Max 58Cross-Sectional & Case SeriesCross-Sectional & Case Series
Max 50Expert OpinionExpert Opinion
Max 572 / 100
Probability of being correct
Groups of people are followed over time to see who develops an outcome. Strong for identifying risk factors and associations, but cannot prove causation as firmly as RCTs.
This design cannot establish causation — the findings describe an association, not a cause. This is a retrospective observational cohort study using administrative claims data with propensity-score matching. Although it found strong associations between semaglutide 2.4 mg initiation and lower cardiovascular event risks, treatment was not randomly assigned. Therefore, residual confounding, selection bias, healthy-user/adherer effects, and unmeasured differences between groups cannot be excluded. The short mean follow-up (~200 days) and claims-based outcome ascertainment further limit causal inference.
COI Unknown
Could not determine conflict of interest status
No conflicts of interest or funding sources were disclosed in the provided text, leaving potential industry ties unassessed.
The provided text does not include a conflict of interest, funding, or author disclosure section. The study evaluates semaglutide 2.4 mg (a Novo Nordisk product), but no funding source or author affiliations are present in the excerpt, so potential conflicts cannot be ruled out.
Standing
Who’s using this study?
The videos and claims on this site that lean on this study, and the researchers who wrote it.
1 video from Dr Brad Stanfield cite this study, drawing 1 claim from it.
- Very strong evidence
Randomized or controlled trials support this claim, alongside consistent supporting evidence.
Evidence
Authored by
10 researchersIf this is your work, this is how we attribute it on Fit Body Science. Kim G. Smolderen is listed as the lead author.