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,†,§,¶

GIP and GLP-1 receptors are present in many tissues and organs, including brain regions that regulate appetite. GIP receptors are also present in adipose tissue and help regulate fat storage. GLP-1 regulates gastric emptying and feelings of satiety in the brain.²

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 (body mass index (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. Participants in both the tirzepatide and semaglutide treatment arms received lifestyle intervention, including a reduced-calorie diet and increased physical activity. ^1,* Figure 1 shows the design of the SURMOUNT- 5 trial.

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 trials^1,*