Introduction
The increasing prevalence of type 2 diabetes mellitus (T2DM) and obesity highlights the urgent clinical need for pharmacotherapies with substantial weight loss and optimal glycemic control (1). Incretin-based therapies, specifically agonists of glucagon-like peptide-1 receptors (GLP-1 RAs) and glucose-dependent insulinotropic polypeptide (GIP) receptors, have demonstrated benefits for regulating appetite, improving glucose homeostasis, and reducing cardiovascular risk (2, 3).
Semaglutide is a GLP-1 RA that has shown significant clinical advantages in both diabetic and non-diabetic populations. Landmark trials such as SUSTAIN and STEP demonstrated significant reductions in HbA1c levels and body weight in T2DM and obesity (4, 5). Tirzepatide represents the next generation of incretin-based therapy and is considered a novel dual agonist of GLP-1 and GIP receptors. This unique mechanism of action has been shown to produce greater reductions in body weight and HbA1c compared with traditional GLP-1 RAs in trials involving individuals with obesity or T2DM. These findings have generated significant interest regarding the comparative effectiveness of tirzepatide and semaglutide across metabolic, cardiovascular, and patient-centered outcomes (6, 7).
Although direct head-to-head evidence robustly favors tirzepatide for weight loss and glycemic control, comparative cardiovascular outcomes currently rely on contextual data from independent cardiovascular outcome trials and real-world observational studies. As this evidence base rapidly expands, a contemporary synthesis is required to inform clinical decision-making. Consequently, this structured narrative review evaluates the comparative effects of tirzepatide vs. semaglutide on weight, glycemic control, cardiovascular outcomes, and safety profiles in adults with obesity or T2DM.
Methodological framework and research design
Search strategy and inclusion criteria
This study is explicitly designed as a structured narrative review. To ensure methodological clarity, avoid overstating analytical rigor and to address the inherent heterogeneity of comparing controlled clinical trials with observational real-world evidence, no original quantitative meta-analysis or formal risk-of-bias assessments were conducted. A study selection flow diagram is provided to enhance transparency of the literature identification and screening process. This approach maintains a transparent structure for identifying and synthesizing the literature without claiming the strict reproducibility of a systematic review.
PICOS framework and eligibility criteria to provide methodological clarity, the research scope and eligibility criteria were strictly defined using the PICOS framework:
Studies were excluded if they focused on investigational therapies other than semaglutide, compared tirzepatide to combination therapies (e.g., CagriSema) rather than semaglutide directly, or investigated non-clinical outcomes (e.g., gastric motility) without reporting weight or glycemic endpoints. Furthermore, to ensure the outcome synthesis relied only on analyzable data, ongoing studies without published primary results are noted in the summary tables solely to provide context regarding the future research landscape; they are excluded from the main comparative data synthesis.
Data sources and search strategy
To identify relevant literature, searches were conducted using the ClinicalTrials.gov database and PubMed. The search strategy utilized the following primary terms: (tirzepatide OR Mounjaro OR Zepbound) AND (semaglutide OR Ozempic OR Wegovy). These keywords were combined with condition-specific terms and filters, including “obesity”, “overweight”, “weight loss”, “type 2 diabetes”, “glycemic control”, and “metabolic syndrome”. The search included studies with results available up to June 10, 2025, and was restricted to completed trial records and full-text articles available in English. Reference lists of relevant published reviews and clinical guidelines were also manually screened to capture additional real-world comparative cohorts.
Data extraction and synthesis
From the eligible studies, detailed variables were extracted to facilitate a structured narrative comparison. Extracted data included trial identifiers (NCT number, phase, duration), baseline population characteristics (baseline BMI, diabetes status), specific intervention arms and dosages, primary and secondary metabolic outcomes, and safety parameters. The extracted outcomes were synthesized narratively to evaluate comparative clinical effectiveness across the respective patient populations.
Results
Study identification and selection
A comprehensive search of ClinicalTrials.gov and relevant databases was conducted to identify studies evaluating tirzepatide and semaglutide. Initially, 32 clinical study records were retrieved. After applying the defined PICOS inclusion and exclusion criteria to select studies directly comparing tirzepatide and semaglutide, a total of 10 studies were deemed eligible for this review. These consisted of five clinical trials, four real-world observational studies and the completed trial (SURPASS-CVOT) was included separately to serve as a contextual cardiovascular outcomes study. This reconciled study count aligns with the study selection process outlined in Figure 1.
Study selection flow diagram for included studies (narrative review).
Characteristics of included studies
To ensure methodological clarity and appropriately weight the evidence, the included literature is organized into four distinct categories: completed head-to-head trials, contextual cardiovascular outcome trials, real-world observational studies, and ongoing (non-analytical) studies. Tables 1, 2 detail the study designs, populations, and primary outcomes of the included research.
| NCT ID | Title | Status/design | Condition(s) | Intervention(s) | Primary outcome(s) | Start date | Primary completion | Locations |
|---|---|---|---|---|---|---|---|---|
| NCT06980623 | Comparative effectiveness of Tirzepatide vs. Semaglutide in participants with type 2 diabetes and heart failure with preserved ejection fraction | Active not recruiting/interventional; 48-month follow-up | Type 2 diabetes|heart failure | Tirzepatide Semaglutide | Composite CV outcome, composite cardiovascular outcome includes hospitalization for HF or all-cause mortality, From treatment initiation to end of follow up, up to 48 months | 1/1/25 | 6/1/25 | United States |
| NCT06914141 | Comparative effectiveness of Tirzepatide vs. Semaglutide in individuals with heart failure with preserved ejection fraction (DUP-TIRZSEMA) | Active not recruiting/observational | Diabetes Mellitus, type 2|HFpEF—heart failure with preserved ejection fraction | Tirzepatide Semaglutide | Composite of all-cause mortality or heart failure hospitalization, to evaluate the comparative effect of tirzepatide vs. semaglutide on all-cause mortality or heart failure hospitalization in patients with heart failure with preserved ejection fraction., Through study completion (1 day after cohort entry date until the first of outcome or censoring) | 1/14/25 | 2025–05 | United States |
| NCT06803888 | Bariatric Surgery vs. Semaglutide vs. Tirzepatide | recruiting Randomized, parallel-group | Obesity and obesity-related medical conditions | PROCEDURE: bariatric surgery Semaglutide| Tirzepatide | The mean percentage weight loss, The mean percentage weight loss at 52 weeks for the following 2 comparisons:Bariatric surgery (RYGB and SG) vs. tirzepatideBariatric surgery (RYGB and SG) vs. semaglutide, first 52 weeks of the study** | 1/29/25 | 7/1/27 | United States |
| NCT03987919 | A Study of Tirzepatide (LY3298176) vs. Semaglutide once weekly as add-on therapy to metformin in participants with type 2 diabetes(SURPASS-2) | Completed phase 3 RCT | Type 2 diabetes | Tirzepatide 5, 10, 15 mg vs. Semaglutide 1 mg weekly | Change From Baseline in Hemoglobin A1c (HbA1c) (10 mg and 15 mg), HbA1c is the glycosylated fraction of hemoglobin A. HbA1c is measured primarily to identify average plasma glucose concentration over prolonged periods of time. Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with Baseline + Pooled Country + Treatment + Time + Treatment\Time (Type III sum of squares)., Baseline, Week 40* | 7/30/19 | 1/28/21 | United States |Argentina Australia| Brazil| Canada| Israel| Mexico| Puerto Rico| United Kingdom |
| NCT05822830 | A Study of Tirzepatide (LY3298176) in participants with obesity or overweight with weight related comorbidities (SURMOUNT-5) | Completed phase 3 RCT | obesity Overweight | Tirzepatide 10 & 15 mg vs. Semaglutide up to 2.4 mg weekly Semaglutide | Percent change from baseline in body weight, baseline, week 72 | 4/21/23 | 11/13/24 | United States| Puerto Rico |
| Study first author, year (publisher) | Data source & population | Follow-up | Outcomes measured | Key findings (tirzepatide vs. Semaglutide) |
|---|---|---|---|---|
| Rodriguez et al., 2024 (JAMA Intern Med) () [30] | US EHR network; adults with obesity or T2DM | 6–12 months | Weight, BMI, HbA1c | Tirzepatide produced significantly greater weight loss vs. semaglutide; limitations: on-treatment weight only |
| Terrell et al., 2025 (ISPOR poster) () [26] | US claims data; T2DM and obesity | 12 months post-initiation (required continuous insurance enrollment). | HbA1c change, Weight change (subsets with lab/weight data) | Greater weight loss and higher persistence with tirzepatide; industry-sponsored |
| Chuang et al., 2024 (JAMA Net Open) () [31] | TriNetX; US cardiac-metabolic population | Median 10.5 months (IQR 5.2–15.7). | All-cause mortality; MACE (MI, stroke); MACE + mortality; Kidney outcomes (AKI, new kidney disease); HbA1c, weight change | Small CV differences between groups; tirzepatide had larger weight reductions |
| Dani et al., 2025 (JACC: Advances) () [14] | TriNetX subset; high CV-risk adults | 12 months | Composite CV outcome (MI, ischemic stroke, all-cause death); individual MACE components; safety outcomes not detailed | Lower MI, stroke, mortality with tirzepatide Limitation: small tirzepatide sample (< 800) limits power; GLP-1 RA comparator includes older agents; confounding by indication possible even with matching (tirzepatide users might differ in unmeasured ways)n |
| Outcome | Tirzepatide | Semaglutide | Significance/notes |
|---|---|---|---|
| HbA1c reduction (SURPASS-2) | −2.01 to −2.30% | −1.86% | Favoring tirzepatide (< 0.001)p |
| Weight loss (kg) (SURPASS-2) | −7.6 to −11.2 kg | −5.7 kg | Favoring tirzepatide (< 0.001)p |
| Weight loss % (SURMOUNT-5) | −20.2% | −13.7% | Favoring tirzepatide |
| ≥20% weight Loss Responders | 50% | 27% | Favoring tirzepatide |
| ≥25% weight loss responders | 33% | 16% | Favoring tirzepatide |
| GI adverse events | 17%−22% | ~18% | Similar |
| Hypoglycemia | 0.2%−1.7% | 0.4% | Slightly higher with tirzepatide |
| Primary CV outcome: 3-point MACE (CV Death, MI, Stroke) | non-inferior to dulaglutide; HR ~0.90–0.95 (directionally favoring tirzepatide butmeeting superiority)SURPASS-CVOT:not | 20% MACE reduction;significant CV benefit in T2DMSELECT (no diabetes):SUSTAIN-6/PIONEER-6: | Semaglutide has more mature randomized evidence for cardiovascular benefit |
| CV risk factors (BP, lipids, weight) | Significant reductions in SBP, triglycerides, weight, and waist circumference | Moderate improvements vs. placebo; less than tirzepatide | Tirzepatide shows stronger cardiometabolic risk-factor improvement |
| HF-related outcomes | No dedicated HF trial yet (+ RWE suggest benefit)post-hoc | improved symptoms, function, inflammationSTEP-HFpEF: | Semaglutide has dedicated HFpEF evidence |
Discussion
This narrative review synthesizes contemporary evidence comparing tirzepatide with semaglutide across glycemic, weight-related, and cardiometabolic domains. In completed randomized trials, tirzepatide consistently achieves greater reductions in body weight and HbA1c compared with semaglutide, demonstrating the synergistic metabolic benefits of simultaneous GIP and GLP-1 receptor stimulation.
Cardiovascular outcomes: direct vs. contextual evidence
While metabolic outcomes strongly favor tirzepatide, the cardiovascular evidence base requires nuanced interpretation. Semaglutide possesses a well-established cardioprotective profile, supported by landmark trials (SUSTAIN-6, PIONEER-6, and SELECT) that demonstrate significant reductions in MACE (2, 9–13).
For tirzepatide, the SURPASS-CVOT trial provides robust contextual cardiovascular outcome data. Tirzepatide achieved non-inferiority to dulaglutide for three-point MACE in adults with T2DM, alongside superior improvements in glycemic control, body weight, blood pressure, and lipid parameters. Although superiority for the primary endpoint was not demonstrated against dulaglutide, the consistently favorable cardiometabolic risk-factor shifts suggest a potentially favorable cardiovascular profile (8).
Critical appraisal of real-world evidence
Real-world observational studies supplement clinical trial data but reveal highly population-dependent differences. Some large analyses report lower rates of myocardial infarction, stroke, and all-cause mortality with tirzepatide compared with GLP-1 receptor agonists, including semaglutide (14, 15). Conversely, a target-trial emulation found small and variable cardiovascular differences between the two agents, though both outperformed non-incretin therapies (16). It is imperative to interpret these observational findings cautiously; disparities in outcomes may be heavily influenced by residual confounding factors, treatment selection bias, titration patterns, and heterogeneity in comparator definitions. Additionally, certain real-world findings currently originate from conference abstracts rather than fully peer-reviewed literature (17–20).
Methodological limitations of comparative data
Several methodological limitations complicate direct comparisons between these agents. For instance, numerous semaglutide trials in diabetic cohorts utilized the 1.0 mg dosage rather than the 2.4 mg dosage approved for obesity, inherently skewing relative efficacy assessments (21, 22). Furthermore, trials exhibited significant variations in duration, intensity of lifestyle interventions, and background pharmacotherapy (4–7, 22, 23). Older subjects, non-White ethnic groups, and those with severe comorbidities are under-represented, which may limit the generalizability of the findings to real-world populations (24).
Both therapies exhibit favorable and comparable safety profiles, primarily characterized by transient gastrointestinal adverse events (4–7, 22, 25). However, discontinuation in real-world settings and submaximal titration rates significantly influence both real-world tolerability and sustained clinical effectiveness (26–28). Furthermore, recent withdrawal studies reveal significant weight regain following the cessation of therapy, highlighting the necessity for research focused on long-term maintenance strategies (25, 29).
Conclusion
Tirzepatide and semaglutide represent highly effective pharmacologic options for managing obesity and T2DM, with distinct clinical evidence profiles. Based on direct head-to-head clinical trials, tirzepatide consistently achieves superior metabolic efficacy, specifically regarding weight loss and HbA1c reduction. Conversely, supported by independent, dedicated outcome trials, semaglutide currently retains the most mature and robust evidence for cardiovascular risk reduction. While contextual data confirms cardiovascular safety for tirzepatide against dulaglutide, definitive head-to-head cardiovascular outcomes comparing the two agents directly remain unestablished. Therefore, clinical selection must be highly individualized: tirzepatide should be prioritized for patients requiring maximal weight and glycemic improvements, whereas semaglutide is currently optimal for those requiring proven cardiovascular event reduction. Future research must prioritize definitive comparative cardiovascular outcome trials and rigorous real-world analyses to address current observational limitations and fully elucidate long-term comparative effectiveness.
Funding Statement
The author(s) declared that financial support was not received for this work and/or its publication.
Footnotes
Data availability statement
Publicly available datasets were analyzed in this study. This data can be found here: Clinicaltrials.gov.
Author contributions
MH: Data curation, Conceptualization, Writing – original draft. AA: Writing – review & editing. NA: Writing – review & editing. MD: Methodology, Writing – review & editing. SW: Conceptualization, Writing – review & editing. YA: Conceptualization, Writing – review & editing.
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
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References
Associated Data
Data Availability Statement
Publicly available datasets were analyzed in this study. This data can be found here: Clinicaltrials.gov.