Real-World Cardiovascular Outcomes of ObesityTreatment With Tirzepatide Versus Semaglutide
Table of Contents
- Tirzepatide vs. Semaglutide: Heart Outcomes in Obese, Non-Diabetic Adults
- What the Researchers Actually Did
- Key Findings: Primary Outcomes
- Key Findings: Secondary Outcomes and Subgroup Analyses
- Adverse Events and Safety Profile
- Statistical Approach and Rigor
- Clinical Takeaway
- Why This Matters Clinically
- Read This Paper Through Nine Different Lenses
- What is the primary finding of the study comparing Tirzepatide and Semaglutide?
- How does the study define the composite primary outcome?
- What is the significance of the reduction in new-onset heart failure?
- Are there any differences in all-cause mortality, acute coronary syndrome, or stroke between the two treatments?
- What is the mean weight loss difference between Tirzepatide and Semaglutide?
- How does the study address potential biases?
- What are the limitations of this real-world evidence study?
- How does the safety profile compare between Tirzepatide and Semaglutide?
- What is the clinical takeaway for managing obesity in patients without diabetes?
- What future research is needed based on this study?
- Read next
Tirzepatide vs. Semaglutide: Heart Outcomes in Obese, Non-Diabetic Adults
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- How tirzepatide compares to semaglutide for major cardiovascular events in obese adults without diabetes over 12 months
- Why new-onset heart failure drove the difference between the two agents, and what that means mechanistically
- What a 70,000-patient real-world cohort can and cannot tell us about head-to-head drug comparisons
- Where the evidence is solid, where it remains speculative, and what a skeptical clinician should hold loosely
TL;DR: In a propensity-matched real-world cohort of 35,336 pairs of obese, non-diabetic adults, tirzepatide was associated with a 14% lower risk of composite major cardiovascular events compared with semaglutide at one year, driven entirely by a 21% reduction in new-onset heart failure, with no significant difference in all-cause mortality, acute coronary syndrome, or stroke.
Abstract
Aims: Treatment of obesity with glucagon-like peptide-1 (GLP-1) receptor agonists improves cardiovascular outcomes. Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist, achieves greater weight loss than GLP-1 receptor agonists alone; however, direct real-world comparisons of clinical outcomes are limited.
Materials and Methods: The authors conducted a retrospective, active-comparator, new-user cohort study using the TriNetX global federated electronic health record database. Adults (18 years or older) without diabetes who initiated tirzepatide or semaglutide for the treatment of obesity between November 2023 and August 2024 were included. Patients with recent atherosclerotic events, prior heart failure, or crossovers to the comparator were excluded. The primary outcome was major cardiovascular events including all-cause death, acute coronary syndrome, stroke, or new-onset heart failure at 12 months.
Results: One-to-one propensity score matching yielded 35,336 pairs. Tirzepatide was associated with a lower incidence of the composite outcome compared with semaglutide (1.90% vs. 2.18%; HR 0.86; 95% CI, 0.77–0.97; p=0.01), driven by reduced new-onset heart failure (1.04% vs. 1.29%; HR 0.79; 95% CI, 0.68–0.92; p=0.002), including both HFrEF and HFpEF. No significant differences were observed in all-cause mortality, acute coronary syndrome, or stroke. Mean weight loss was greater with tirzepatide (9.8 kg vs. 8.0 kg; p<0.001). Adverse event rates were comparable, with no new safety signals.
Conclusions: In obese individuals without diabetes, tirzepatide was associated with a lower risk of cardiovascular events, especially incident heart failure, compared with semaglutide, with a similar safety profile.
DOI: https://doi.org/10.1111/dom.70721
Study at a Glance
| Design | Retrospective active-comparator new-user cohort; TriNetX federated EHR database |
| Population | Adults without diabetes initiating tirzepatide (Zepbound) or semaglutide (Wegovy) for obesity, November 2023 to August 2024; no prior HF or recent ASCVD events |
| Sample Size (after PSM) | 35,336 matched pairs (70,672 total) |
| Primary Endpoint | Composite of all-cause death, acute coronary syndrome, stroke, and new-onset heart failure at 12 months |
| Key Finding | Tirzepatide associated with lower composite event rate (1.90% vs. 2.18%; HR 0.86, 95% CI 0.77–0.97; p=0.01), driven by new-onset heart failure reduction |
Study Snapshot: Key Statistics
| Outcome | Tirzepatide | Semaglutide | HR (95% CI) | p-value |
|---|---|---|---|---|
| Composite Primary Outcome | 1.90% | 2.18% | 0.86 (0.77–0.97) | 0.01 |
| All-Cause Mortality | 0.09% | 0.09% | 1.00 (0.58–1.72) | 0.996 |
| Acute Coronary Syndrome | 0.41% | 0.38% | 1.06 (0.82–1.37) | 0.668 |
| Stroke | 0.53% | 0.62% | 0.85 (0.69–1.06) | 0.143 |
| New-Onset Heart Failure | 1.04% | 1.29% | 0.79 (0.68–0.92) | 0.002 |
| HFrEF (new-onset) | 0.31% | 0.43% | 0.72 (0.55–0.94) | 0.015 |
| HFpEF (new-onset) | 0.53% | 0.65% | 0.81 (0.65–1.00) | 0.048 |
| Mean Weight Loss | 9.8 kg | 8.0 kg | Difference: 1.8 kg | <0.001 |
Full Study Facts
| Authors | Katsura M, Horiuchi Y, Tanabe K, Wettersten N |
| Journal | Diabetes, Obesity and Metabolism |
| Year | 2026 |
| Design | Retrospective, active-comparator, new-user cohort study; TriNetX global federated EHR database; 1:1 propensity score matching |
| N (after matching) | 35,336 pairs (70,672 total participants) |
| Intervention | Tirzepatide (Zepbound) initiated for obesity |
| Comparator | Semaglutide (Wegovy) initiated for obesity |
| Follow-Up | 365 days from treatment initiation; 30-day blanking period applied |
| Primary Endpoint | Composite of all-cause death, acute coronary syndrome, stroke, and new-onset heart failure |
| Primary Result | 1.90% vs. 2.18%; HR 0.86 (95% CI 0.77–0.97); p=0.01 |
| Key Secondary Result | New-onset HF: 1.04% vs. 1.29%; HR 0.79 (95% CI 0.68–0.92); p=0.002 |
| Adverse Events | Broadly comparable; nausea, constipation, and abdominal pain more frequent with semaglutide after PSM |
| Funding | None reported |
| Conflicts of Interest | Dr. Horiuchi: honoraria from Eli Lilly Japan. Dr. Tanabe: honoraria from multiple device/pharma companies. Other authors: none declared. |
What the Researchers Actually Did
Katsura and colleagues constructed a retrospective cohort from the TriNetX global federated electronic health record network, which aggregates anonymized data from more than 150 million individuals across more than 150 health systems in North and South America, Europe, the Middle East, Africa, and the Asia-Pacific region. They restricted the analysis to adults 18 years or older without diabetes who newly initiated the obesity-specific branded formulations of tirzepatide (Zepbound) or semaglutide (Wegovy) between November 2023 and August 2024. This brand-name restriction was deliberate: it excluded diabetic-indication prescriptions for Ozempic and Mounjaro, limiting the cohort to those treated specifically for obesity. Patients were excluded if they had prior heart failure at any time, prior HbA1c of 6.5% or higher within the preceding year, or an atherosclerotic event within 90 days before and 30 days after the index date. Crossover between drugs during follow-up was also an exclusion criterion.
After applying these criteria, 39,384 tirzepatide initiators and 63,675 semaglutide initiators remained. One-to-one propensity score matching on a comprehensive set of demographic, comorbidity, medication, and laboratory variables reduced each group to 35,336 well-balanced pairs. A 30-day blanking period was applied at the start of follow-up to minimize delayed capture of pre-existing diagnoses in the EHR and to align with a prior randomized trial protocol. Outcomes were ascertained using ICD-10-CM codes, and time-to-event analyses used Cox proportional hazards models over 365 days of follow-up.
Key Findings: Primary Outcomes
- Composite primary outcome (post-PSM): Tirzepatide was associated with a significantly lower one-year incidence of the composite endpoint of all-cause death, acute coronary syndrome, stroke, and new-onset heart failure compared with semaglutide: 1.90% vs. 2.18%; HR 0.86 (95% CI 0.77–0.97); p=0.01.
- Absolute risk difference: 0.28 percentage points; number needed to treat over 12 months approximately 357.
- Pre-PSM consistency: The unadjusted comparison showed a similar direction of effect (2.02% vs. 2.40%; HR 0.83, 95% CI 0.75–0.91; p<0.001), suggesting the signal was not introduced by the matching process.
- Driver of the difference: The entire composite benefit was driven by new-onset heart failure. No component other than HF reached statistical significance after matching.
Key Findings: Secondary Outcomes and Subgroup Analyses
Secondary outcomes (post-PSM):
- All-cause mortality: 0.09% vs. 0.09%; HR 1.00 (95% CI 0.58–1.72); p=0.996. No difference.
- Acute coronary syndrome: 0.41% vs. 0.38%; HR 1.06 (95% CI 0.82–1.37); p=0.668. No difference.
- Stroke (CVA and TIA combined): 0.53% vs. 0.62%; HR 0.85 (95% CI 0.69–1.06); p=0.143. No significant difference, though a trend toward reduction was present before PSM (HR 0.77, p=0.005).
- New-onset heart failure: 1.04% vs. 1.29%; HR 0.79 (95% CI 0.68–0.92); p=0.002. Statistically significant.
- HFrEF (new-onset): 0.31% vs. 0.43%; HR 0.72 (95% CI 0.55–0.94); p=0.015.
- HFpEF (new-onset): 0.53% vs. 0.65%; HR 0.81 (95% CI 0.65–1.00); p=0.048. Borderline statistical significance.
- Weight loss: After treatment, mean body weight was 95.9 kg with tirzepatide vs. 97.7 kg with semaglutide; weight loss 9.8 kg vs. 8.0 kg (p<0.001). At 90 days the difference was only 0.3 kg, with greater separation occurring later in follow-up.
Subgroup analyses: The direction of effect favoring tirzepatide for the composite primary outcome was generally consistent across all prespecified subgroups, including age (18–64 years: HR 0.91, 95% CI 0.77–1.06; 65 years and older: HR 0.82, 95% CI 0.66–1.02), sex (male: HR 0.88, 95% CI 0.72–1.08; female: HR 0.86, 95% CI 0.73–1.02), BMI below 30 (HR 0.71, 95% CI 0.40–1.24) and BMI 30 or above (HR 0.76, 95% CI 0.60–0.96), and across racial groups, renal function strata, HbA1c levels, hypertension status, dyslipidemia status, ischemic heart disease status, and sleep apnea status. No subgroup showed a statistically significant interaction favoring semaglutide.
Adverse Events and Safety Profile
After propensity score matching, the overall adverse event profile was similar between tirzepatide and semaglutide. Nausea was modestly more frequent with semaglutide (8.00% vs. 7.33%; p=0.002), as were constipation (3.33% vs. 3.02%; p=0.032) and abdominal pain (11.7% vs. 11.2%; p=0.038). Rates of vomiting, GERD, dyspepsia, diarrhea, abdominal distension, and anorexia did not differ significantly between groups. In a supplementary analysis restricted to patients who discontinued either medication within 365 days, adverse event rates remained comparable between the two groups after re-matching (9,523 pairs), suggesting that treatment-limiting adverse events occurred at similar frequencies.
Statistical Approach and Rigor
The study employed an active-comparator new-user design, which is methodologically stronger than a naive comparison or a prevalent-user design, because it aligns the start of follow-up with treatment initiation and avoids prevalent-user bias and indication confounding from diabetic-use prescriptions. Propensity score matching on an extensive covariate set achieved standardized mean differences below 0.1 on all included variables after matching, meeting the conventional threshold for adequate balance. Cox proportional hazards models provided time-to-event estimates; Kaplan-Meier curves with log-rank tests supplemented the primary analysis. Subgroup analyses were performed with PSM repeated within each subgroup and restricted to patients with available values for the relevant variable, reducing the risk of imputing balance across strata. A 30-day blanking period mitigated reverse causation from pre-existing but uncoded diagnoses. Outcomes were ascertained from ICD-10-CM codes in a federated database, which limits direct adjudication. Missing data in laboratory variables ranged from 38% to 55% in some fields (e.g., HbA1c: 52–53% missing after PSM); continuous values after PSM reflect means among patients with available measurements, which introduces a potential source of selection bias in the laboratory-based subgroup analyses. No adjustment for multiple secondary comparisons was reported, which is relevant to the borderline HFpEF p-value of 0.048.
Clinical Takeaway
For clinicians managing obesity in patients without diabetes, this real-world analysis provides the largest direct head-to-head cardiovascular outcome comparison to date between tirzepatide and semaglutide. The signal is specific: tirzepatide appears to reduce the incidence of new-onset heart failure, encompassing both HFrEF and HFpEF subtypes, while offering no detectable incremental benefit on atherosclerotic events or mortality at 12 months. The absolute risk difference is small (0.25 percentage points for heart failure), the follow-up is short, and this is an observational study that cannot establish causation. That said, the consistency of the heart failure signal across prespecified subgroups and HF subtypes, the biological plausibility of GIP co-agonism contributing to favorable cardiac remodeling and anti-inflammatory effects, and the 35,000-pair sample size all make this finding worth tracking closely as longer-term data emerge.
Clinical Bottom Line: In propensity-matched real-world data from over 70,000 non-diabetic obese adults, tirzepatide outperformed semaglutide primarily by reducing new-onset heart failure at one year, while atherosclerotic event rates and mortality were statistically indistinguishable between the two agents.
Why This Matters Clinically
Heart failure, particularly HFpEF, is among the most rapidly growing cardiovascular diagnoses globally, and obesity is one of its strongest modifiable risk factors. Until now, tirzepatide’s cardiovascular outcome data have been largely derived from trials in diabetic populations or from studies that examined treatment effects in patients who already had HFpEF (the SUMMIT trial). The question of whether dual GIP/GLP-1 agonism can prevent de novo heart failure in obese individuals without diabetes had not been directly addressed in a head-to-head comparison with semaglutide at scale. This study, despite its observational design, offers the first large real-world evidence that tirzepat
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 provides the largest direct head-to-head cardiovascular outcome comparison between Tirzepatide and Semaglutide in obese, non-diabetic adults. The primary finding is a 14% lower risk of composite major cardiovascular events, driven by a significant reduction in new-onset heart failure.
The study uses propensity score matching to balance covariates and minimize bias, ensuring robust results. However, limitations include potential selection bias due to missing data and the inability to directly adjudicate outcomes from ICD-10-CM codes.
- Tirzepatide reduces new-onset heart failure risk by 21% compared to Semaglutide.
- No significant differences were observed in all-cause mortality, acute coronary syndrome, or stroke.
- Mean weight loss was greater with Tirzepatide (9.8 kg) compared to Semaglutide (8.0 kg).
Patient Takeaway
For patients seeking obesity treatment without diabetes, Tirzepatide offers a significant reduction in the risk of developing new-onset heart failure compared to Semaglutide. This can be particularly important for those concerned about long-term cardiovascular health.
The study also shows that Tirzepatide leads to greater weight loss (9.8 kg) compared to Semaglutide (8.0 kg), which can have additional benefits for overall health and well-being.
- Tirzepatide reduces the risk of new-onset heart failure by 21%.
- Mean weight loss is greater with Tirzepatide (9.8 kg) compared to Semaglutide (8.0 kg).
- No significant differences were observed in all-cause mortality, acute coronary syndrome, or stroke.
Clinician’s POV
Clinicians can use this study to inform treatment decisions for obese, non-diabetic adults. Tirzepatide is associated with a lower risk of new-onset heart failure compared to Semaglutide, which can be particularly beneficial in patients at higher cardiovascular risk.
The study’s real-world evidence provides valuable insights into the clinical outcomes of these treatments, helping clinicians make more informed decisions based on practical data from diverse patient populations.
- Tirzepatide reduces new-onset heart failure risk by 21% compared to Semaglutide.
- No significant differences were observed in all-cause mortality, acute coronary syndrome, or stroke.
- Mean weight loss was greater with Tirzepatide (9.8 kg) compared to Semaglutide (8.0 kg).
A Skeptical Read
While the study provides valuable real-world evidence, skeptics may consider potential limitations such as selection bias due to missing data and the inability to directly adjudicate outcomes from ICD-10-CM codes. These factors could influence the interpretation of results.
It is important for clinicians to weigh these considerations alongside the benefits observed in the study when making treatment decisions for obese, non-diabetic adults.
- Selection bias due to missing data and indirect outcome adjudication may affect result interpretation.
- No significant differences were observed in all-cause mortality, acute coronary syndrome, or stroke.
- Mean weight loss was greater with Tirzepatide (9.8 kg) compared to Semaglutide (8.0 kg).
Study Critic
Critics may focus on the study’s methodological rigor, including the use of propensity score matching to balance covariates and minimize bias. However, they might also question the reliance on ICD-10-CM codes for outcome ascertainment, which can introduce selection bias.
Additionally, critics could point out that the study does not adjust for multiple secondary comparisons, which may affect the interpretation of borderline significant results such as those for HFpEF.
- Propensity score matching was used to balance covariates and minimize bias.
- Outcome ascertainment using ICD-10-CM codes introduces potential selection bias.
- No adjustment for multiple secondary comparisons was reported.
Compared to Past Research
This study builds on previous research demonstrating the cardiovascular benefits of GLP-1 receptor agonists in obese, non-diabetic adults. Earlier studies have shown that these treatments can improve metabolic profiles and reduce cardiovascular risk factors.
However, this is one of the largest direct head-to-head comparisons between Tirzepatide and Semaglutide, providing new insights into their relative efficacy in reducing major cardiovascular events.
- Previous studies have shown cardiovascular benefits of GLP-1 receptor agonists.
- This study provides a large-scale comparison between Tirzepatide and Semaglutide.
- No significant differences were observed in all-cause mortality, acute coronary syndrome, or stroke.
Practical Considerations
Practically, this study supports the use of Tirzepatide in obese, non-diabetic adults who are at risk for cardiovascular disease. The significant reduction in new-onset heart failure can be a compelling reason to consider Tirzepatide over Semaglutide.
Clinicians should also consider individual patient factors and preferences when choosing between these treatments, as both offer benefits in weight loss and cardiovascular health.
- Tirzepatide reduces new-onset heart failure risk by 21% compared to Semaglutide.
- Mean weight loss was greater with Tirzepatide (9.8 kg) compared to Semaglutide (8.0 kg).
- No significant differences were observed in all-cause mortality, acute coronary syndrome, or stroke.
Future Directions
Future research should focus on long-term outcomes to confirm the sustained benefits of Tirzepatide in reducing new-onset heart failure and improving cardiovascular health. Additionally, mechanistic studies could explore the underlying reasons for the observed differences between Tirzepatide and Semaglutide.
Investigating these areas can provide further insights into the optimal use of GLP-1 receptor agonists in obesity management and cardiovascular disease prevention.
- Future research should explore long-term outcomes.
- Mechanistic studies could investigate underlying reasons for observed differences.
- No significant differences were observed in all-cause mortality, acute coronary syndrome, or stroke.
Misreadings & Bad-Faith Takes
A common misreading is that Tirzepatide offers significant benefits across all major cardiovascular events. However, the study shows a reduction in new-onset heart failure but no significant differences in all-cause mortality, acute coronary syndrome, or stroke.
Another potential misunderstanding is that the study provides definitive proof of superiority for Tirzepatide over Semaglutide. While it offers valuable insights, real-world evidence has limitations and should be considered alongside clinical judgment and patient factors.
- Tirzepatide reduces new-onset heart failure risk but not other major cardiovascular events.
- Real-world evidence has limitations and should be interpreted with caution.
- No significant differences were observed in all-cause mortality, acute coronary syndrome, or stroke.
Have thoughts on this? Share it:
What is the primary finding of the study comparing Tirzepatide and Semaglutide?
The study found that Tirzepatide was associated with a 14% lower risk of composite major cardiovascular events compared to Semaglutide, driven entirely by a 21% reduction in new-onset heart failure.
How does the study define the composite primary outcome?
The composite primary outcome includes all-cause death, acute coronary syndrome, stroke, or new-onset heart failure at 12 months.
What is the significance of the reduction in new-onset heart failure?
The reduction in new-onset heart failure is significant as it represents the entire composite benefit observed between Tirzepatide and Semaglutide.
Are there any differences in all-cause mortality, acute coronary syndrome, or stroke between the two treatments?
No significant differences were observed in all-cause mortality, acute coronary syndrome, or stroke between Tirzepatide and Semaglutide.
What is the mean weight loss difference between Tirzepatide and Semaglutide?
The mean weight loss was greater with Tirzepatide (9.8 kg) compared to Semaglutide (8.0 kg).
How does the study address potential biases?
The study uses a propensity score matching method to balance covariates and minimize bias, aligning with best practices in observational studies.
What are the limitations of this real-world evidence study?
Limitations include potential selection bias due to missing data and the inability to directly adjudicate outcomes from ICD-10-CM codes.
How does the safety profile compare between Tirzepatide and Semaglutide?
The overall adverse event profiles were similar, with nausea, constipation, and abdominal pain more frequent with Semaglutide.
What is the clinical takeaway for managing obesity in patients without diabetes?
Tirzepatide appears to reduce the incidence of new-onset heart failure compared to Semaglutide, providing a cardiovascular benefit in obese, non-diabetic adults.
What future research is needed based on this study?
Future research should explore long-term outcomes and the mechanisms behind the reduction in new-onset heart failure with Tirzepatide.
