Tirzepatide superior to Semaglutide- SURMOUNT-5 Trial Results
TRIAL HIGHLIGHTS:
- The SURMOUNT 5 trial compared the efficacy and safety of tirzepatide maximum tolerated dose(MTD) (10mg or 15mg) to semaglutide MTD (1.7 mg or 2.4 mg) in adults with obesity.
- In a 72-week open-label study, tirzepatide — a dual GIP and GLP-1 receptor agonist — demonstrated superior efficacy in reducing body weight (−21.6% a) compared to semaglutide, a selective GLP-1 RA (−15.4% a). It also showed greater reduction in waist circumference (−20 cm vs −14.7 cm), reinforcing its additional benefits on secondary metabolic parameters1.
aData are least-squares mean with 95% confidence intervals or no. (%). Only the Week 72 timepoint was pre-specified and controlled for multiplicity1
Tirzepatide is a long-acting glucose-dependent insulinotropic polypeptide (GIP) receptor and glucagon-like peptide-1 (GLP-1) receptor agonist.1 It is the first and only GIP and GLP-1 receptor agonist approved for weight management. 2,3 In SURMOUNT-1, tirzepatide 15 mg led to significant mean weight reductions of 22.5% (23.6 kg) at 72 weeks.4,†,§,¶
ENDPOINTS
Primary endpoint1:
Mean percentage change in body weight from baseline to 72 weeks.1
Key secondary endpoints included1:
- Weight reduction targets of ≥10%, ≥15%, ≥20%, and ≥25% from baseline to 72 weeks
- Change in waist circumference from baseline to 72 weeks
Additional secondary endpoints included1:
- Weight reduction targets of 30%
- Change from baseline in body weight in kg
Tertiary endpoints included1:
- Blood pressure
- Hemoglobin A1c (HbA1c)
- Lipid parameters
PARTICIPANTS ENROLLED IN SURMOUNT-51
The SURMOUNT-5 trial included 750 participants. The mean age was 44.7 years; 64.7% were female, and 76.1% were white. At baseline, the mean body weight and mean waist circumference were 113.0 kg and 118.3 cm, respectively, and most participants (75.9%) had one or more Obesity-related complications.1,#
PARTICIPANT DISPOSITION1
Overall 85.0% of participants completed the trial (85.1% in the tirzepatide group and 84.8% in the semaglutide group) and 80.2% completed the 72 weeks of study treatment.1
PRIMARY ENDPOINT
Tirzepatide demonstrated superior reduction in body weight compared to semaglutide 1,*,†,‡
At 72 weeks, participants taking tirzepatide MTD (10 mg or 15 mg) experienced a superior mean percentage body weight reduction of -21.6%a vs -15.4%a in those taking semaglutide MTD (1.7 mg or 2.4 mg) (Figure 2.).1,*,†,‡
Tirezepatide, while a single molecule, pharmacologically activates two metabolic receptors, GIP and GLP-1, which have both overlapping and non-overlapping expression and function. This dual agonism of tirzepatide may contribute to the higher weight reduction observed in the current study compared to semaglutide, a selective GLP 1 receptor agonist.1
KEY SECONDARY ENDPOINTS
1 in 3 participants taking tirzepatide 15 mg or MTD (10 mg or 15 mg) achieved 25% mean reduction in body weight vs 1 in 5 taking semaglutide 2.4 mg or MTD (1.7 mg or 2.4mg) at Week 72.1*,†,‡
More participants in the tirzepatide group attained body weight reduction targets of ≥10%, ≥15%, ≥20%, and ≥25% from baseline compared to the semaglutide group (Figure 3).1
Tirzepatide was superior to semaglutide with respect to waist circumference1
Participants taking tirzepatide experienced superior reduction in waist circumference (cm) vs participants taking semaglutide at Week 72 (Figure 4).1,*,†,‡
Tertiary Endpoints
In addition to weight reduction and decreases in waist circumference, improvements in systolic and diastolic blood pressure were seen in participants taking both tirzepatide and semaglutide (Table 2).1 In addition, consistent with previous trials, improvements were seen in HbA1c and lipids with both study treatments (Table 2).1
Safety:
The overall safety profile of tirzepatide in SURMOUNT-5 was similar to previously reported SURMOUNT trials.1,*
In SURMOUNT-5, the most frequently reported adverse events were gastrointestinal (e.g. nausea, constipation, diarrhea, and vomiting). Most were mild to moderate in severity and occurred primarily during dose escalation, with some pattern variation for incidence and prevalence between the two study treatments (Table 3).1
Conclusion:
- In the current trial, treatment with tirzepatide, a dual GIP and GLP-1 receptor agonist was superior to semaglutide, a selective GLP-1 receptor agonist, in respect to reduction in body weight and waist circumference 1,*,†,‡
- The safety profile of Trizepatide in this trial was consistent with the safety data reported in previous SURMOUNT trials1,*
THERAPEUTIC INDICATION1:
Type 2 diabetes mellitus
MOUNJARO® is indicated for the treatment of adults with insufficiently controlled type 2 diabetes mellitus as an adjunct to diet and exercise
• as monotherapy when metformin is considered inappropriate due to intolerance or contraindications
• in addition to other medicinal products for the treatment of diabetes.
For study results with respect to combinations, effects on glycaemic control and the populations studied, see sections 4.4, 4.5 and 5.1.
Weight management
MOUNJARO® is indicated as an adjunct to a reduced-calorie diet and increased physical activity for weight management, including weight loss and weight maintenance, in adults with an initial Body Mass Index (BMI) of
• ≥ 30 kg/m² (obesity) or
• ≥ 27 kg/m² to < 30 kg/m² (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, dyslipidaemia, obstructive sleep apnoea, cardiovascular disease, prediabetes, or type 2 diabetes mellitus).
*SURMOUNT-5 was a 72-week, Phase 3b, multicenter, randomized, parallel-arm, open-label, comparator-controlled study that evaluated the efficacy and safety of Tirzepatide 15 mg or MTD (10 mg or 15 mg) compared with Semaglutide 2.4 mg or MTD (1.7 mg or 2.4 mg) in adults with Obesity (BMI ≥30 kg/m²) or overweight (BMI ≥27 kg/m²) with at least one Obesity-related complication (e.g., hypertension, dyslipidemia), excluding diabetes.** The study included a 2-week screening period. Mean baseline weight was 112.7 kg for Tirzepatide MTD (10 mg or 15 mg) and 113.4 kg for Semaglutide MTD (1.7 mg or 2.4 mg). Participants in both the Tirzepatide and Semaglutide treatment arms received lifestyle intervention, including a reduced-calorie diet and increased physical activity. Treatments were administered QW subcutaneously as an adjunct to a reduced-calorie diet and increased physical activity1.
For Tirzepatide Prescribing Information, please check: https://image.mc.lilly.com/lib/fe9312747462077971/m/1/0e04e051-5fa2-445b-850d-4f09ef66d35e.pdf
Efficacy estimand, mixed model for repeated measures (MMRM) analysis, modified intent-to-treat (mITT) population, (efficacy analysis set). Limitations of an open-label study may be related to a bias in evaluation of the outcomes, efficacy and/or safety, and analysis was not tested against a placebo-controlled comparison group1.
SURMOUNT-1 Phase 3 double-blind, randomized, placebo-controlled trial in adults with Obesity (BMI of ≥30 kg/m²) or with Overweight (BMI of ≥27 kg/m²) with at least one Obesity-related complication (e.g.,hypertension, dyslipidemia), excluding T2D. All participants received lifestyle interventions, including a reduced-calorie diet and increased physical activity.** All patients were randomly assigned in a 1:1:1:1 ratio to receive placebo, or tirzepatide at a dose of 5 mg, 10 mg, or 15 mg as an adjunct to lifestyle intervention4
¶p<0.001 vs baseline. Mean % change in weight vs baseline (co-primary end point) at 72 weeks was -16.0% and -21.4% for the 5 mg and 10 mg doses, respectively. Mean % change in weight vs placebo at 72 weeks was -13.5%, -18.9%, and -20.1% for the 5 mg, 10 mg, and 15 mg doses, respectively (p<0.001 vs placebo, adjusted for multiplicity). Mean kg change in weight vs baseline at 72 weeks was -16.1 kg and -22.2 kg for the 5 mg and 10 mg doses, respectively. Mean kg change in weight vs placebo at 72 weeks was -13.8 kg, -19.8 kg, and -21.2 kg for the 5 mg, 10 mg, and 15 mg doses, respectively (p<0.001 vs placebo, not adjusted for multiplicity). 2,4
# Adverse reaction development was not an endpoint for this study. Data presented here should not be used to make inferences.
**”Obesity-related complications” are used as synonymic to “weight-related complications and /or comorbidities”.
REFERENCES
1. Louis J. Aronne, M.D., et al. Tirzepatide as Compared with Semaglutide for the Treatment of Obesity, N Engl J Med. 2025; doi: 10.1056/NEJMoa2416394
2. Mounjaro® (tirzepatide), India Prescribing Information. Updated March 2025.
3. Fisman EZ, Tenenbaum A. Cardiovasc Diabetol. 2021;20(1):225.
4. Jastreboff AM, et al. N Engl J Med. 2022;387(3):205–16.
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