Release date:2023/6/16 11:33:57

The battle between Novo Nordisk's Semaglutide and Lilly's Tirzepatide is gradually heating up in the field of obesity. Both sides have recently published a Phase 3 clinical result.

Although both semaglutide and tirzepatide have been used in the treatment of type 2 diabetes, their mechanisms of action are not identical. Semaglutide is a GLP-1 (glucagon-like peptide 1) receptor agonist, while tirzepatide is a  dual agonist. dual GIP/GLP-1 receptor co-agonist.
Related Article: 
GLP-1R Agonists for Weight Loss


Figure 1. Structure of semaglutide and tirzepatide

Novo Nordisk pioneered the use of semaglutide (Wegovy) in the treatment of obesity and received FDA approval for the treatment of obesity in adults in June 2021. Another FDA approval was received in December 2022, expanding the use of Wegovy to adolescents aged 12 and older who meet the BMI (Body Mass Index) criteria. Wegovy® generated revenues of $913 million in 2022 and $673.7 million in the first quarter of 2023.

In May 2022, Tirzepatide was approved for marketing by the FDA for the treatment of type 2 diabetes in adults. On Nov. 8, 2023, the FDA approved Zepbound™ (tirzepatide) injection, the first and only obesity treatment of its kind that activates both GIP and GLP-1 hormone receptors. In less than nine months after its launch in 2022, tirzepatide generated sales of $483 million. In first quarter of 2023, tirzepatide has generated sales of $568 million. Based on the analysis, tirzepatide is expected to receive FDA approval for obesity by the end of 2023, and analysts predict that its sales could surpass those of Wegovy®, provided that Lilly can continue to build on the potentially superior efficacy of tirzepatide.

Tirzepatide - SURMOUNT-2, SURMOUNT-3 and SURMOUNT-4

On July 27, 2023, Eli Lilly and Company announced results of SURMOUNT-3 and SURMOUNT-4 in adults with obesity or overweight with weight-related comorbidities, excluding type 2 diabetes. SURMOUNT-3 and SURMOUNT-4 met all primary and key secondary objectives for tirzepatide compared to placebo. 


For the SURMOUNT-3 trial, patients who lost at least 5% of their body weight after a 12-week intensive lifestyle intervention lead-in period that included a low-calorie diet, exercise and weekly counseling sessions, were randomly assigned to receive either tirzepatide or placebo for 72 weeks to assess the efficacy and safety of the drug.

Tirzepatide met both co-primary endpoints during the 72-week double-blind treatment period, demonstrating the superiority of the drug over placebo. Patients treated with tirzepatide lost an average of 21.1% of their body weight since randomization (co-primary endpoint), compared to an average weight gain of 3.3% over 72 weeks for patients treated with placebo, for a placebo-adjusted net weight change of -24.5%. In addition, 94.4% of patients in the tirzepatide group reached an additional ≥5% weight loss after randomization (another co-primary endpoint), compared to 10.7% in the placebo group over 72 weeks. In the secondary endpoint, subjects treated with tirzepatide achieved an overall mean weight loss of 26.6% after 12 weeks of intensive lifestyle intervention followed by 72 weeks of tirzepatide treatment.


The SURMOUNT-4 trial design was divided into two periods. An open-label introductory period of the first 36 weeks, during which all subjects were treated with tirzepatide, followed by a 52-week double-blind treatment period, during which subjects were randomly assigned to receive either tirzepatide or placebo.

Analysis showed that the trial met its primary endpoint of achieving a superior mean percent change in body weight with tirzepatide versus placebo from week 36 to week 88, with patients sustaining weight loss. At week 88, patients receiving tirzepatide lost an additional 6.7% of their mean body weight from randomization, while patients receiving placebo gained 14.8% of their mean body weight, for a placebo-adjusted net weight change of -21.4%. On analysis of secondary endpoints, subjects who continued to receive tirzepatide after randomization had a mean weight loss totaling 26.0% from enrollment through the entire 88-week period of the trial.


SURMOUNT-2 is a multicenter, randomized, double-blind, placebo-controlled phase III clinical study designed to evaluate the efficacy and safety of once-weekly Tirzepatide (10mg , 15mg) in adult patients with type 2 diabetes who are obese or overweight.

A total of 938 subjects with a mean baseline body weight of 100.7 kg and a baseline A1C of 8.0% were enrolled in the study. Patients received Tirzepatide 10 mg, 15 mg or placebo on a 1:1:1 basis. The co-primary endpoints were the percentage change of weight reduction in the Tirzepatide 10mg and 15mg dose groups at week 72 and the percentage of participants achieving ≥5% body weight reduction at 72 weeks compared to placebo.

Results showed that Tirzepatide (10mg and 15mg) achieved superior weight loss to placebo at 72 weeks of treatment. The study met both the co-primary endpoint and all key secondary endpoints compared to placebo. Compared to placebo (3.3%, 3.2 kg), patients lost a mean of 13.4% (13.5 kg) of body weight in the 10 mg group and 15.7% (15.6 kg) of body weight in the 15 mg group.


Figure 2. SURMOUNT-2 ket efficacy results, source: reference [2]

Additionally, 81.6% (10 mg) and 86.4% (15 mg) of people taking tirzepatide achieved at least 5% body weight reduction, the other co-primary endpoint, compared to 30.5% of those taking placebo.


Figure 3. SURMOUNT-2 key efficacy results, source: reference [2]

Tirzepatide also met all key secondary endpoints, including reductions in A1C and other cardiometabolic parameters. The A1C reduction compared to placebo was similar to that of the SURPASS trial in adults with type 2 diabetes.

Lilly has now submitted a rolling submission of a new drug application (NDA) for tirzepatide in adults with obesity or overweight. which is based primarily on data from the SURMOUNT-1 and SURMOUNT-2 studies.


The SURMOUNT-1 study in obese patients without diabetes showed that tirzepatide met two co-primary endpoints. The mean percentage change in weight at week 72 was −15.0% with 5-mg weekly doses of tirzepatide, −19.5% with 10-mg doses, and −20.9%  with 15-mg doses and −3.1% with placebo. The percentage of participants who had weight reduction of 5% or more was 85%, 89%, and 91% with 5 mg, 10 mg, and 15 mg of tirzepatide, respectively, and 35%  with placebo.


Figure 4. SURMOUNT-1 key efficacy results, source: reference [3]

Lilly also has other Phase 3 clinical trials of tirzepatide underway.

SURMOUNT-5, the most anticipated trial, will compare tirzepatide to a GLP-1 agonist approved for the treatment of obesity in obese or overweight patients ( without type 2 diabetes) with weight-related co-morbidities. Patient enrollment for this trial has begun and results are expected in early 2025.


Figure 4. Phase 3 clinical trials of tirzepatide, source: reference [2]

Semaglutide -  OASIS 1

Since the introduction of Lilly's Tirzepatide, Novo Nordisk has been under pressure to move forward. Previously, 2.4mg Semaglutide injection lost 15.8% of weight at 68 weeks (STEP-8 trial); 15mg Tirzepatide injection lost 20.9% of weight at 72 weeks (SURMOUNT-1 trial). Under such pressure, Novo Nordisk needs to achieve a new breakthrough in oral Semaglutide tablets to break this deadlock.

OASIS 1 is a 68-week, efficacy and safety trial comparing once-daily oral semaglutide 50 mg for weight management to placebo in 667 adults with obesity or overweight with one or more comorbidities. Both treatment arms were in conjunction with lifestyle intervention. OASIS 1 met its primary endpoint of a statistically significant weight loss at week 68 in the oral semaglutide (50 mg) versus placebo group, whihch marks a milestone step toward the goal of an oral weight loss drug.

In the OASIS 1 trial, subjects receiving oral semaglutide (50 mg) lost 17.4% of their body weight at 68 weeks, while the placebo group achieved only 1.8% weight loss. In addition, 89.2% of subjects receiving oral semaglutide (50 mg) lost 5% or more of their body weight at 68 weeks, compared to 24.5% with placebo. In addition to the OASIS 1 trial, which has already achieved its primary clinical endpoint, Novo Nordisk plans to conduct a series of related clinical studies for oral semaglutide.

OASIS 2: A 68-week efficacy and safety phase 3a trial comparing once-daily oral semaglutide (50 mg) to placebo for weight loss in 198 East Asian (including Japanese) adults with obesity or overweight with one or more comorbidities.

OASIS 3: A 44-week efficacy and safety phase 3a trial comparing once-daily oral semaglutide (50 mg) to placebo for weight loss in 200 Chinese adults with obesity or overweight with one or more comorbidities.

OASIS 4: A 64-week efficacy and safety phase 3b trial comparing once-daily oral semaglutide (25 mg) to placebo for weight loss in 300 obese or overweight adults with one or more comorbidities.

Novo Nordisk expects to apply for regulatory approval in the US and EU in 2023.


In the field of obesity, tirzepatide, although not yet approved by the FDA for weight loss, has superior clinical data to Wegovy® (Figure 2). The tirzepatide (15mg) resulted in a 20.9% weight loss, making it by far the titan of the weight loss world. Other pharmaceutical companies are pouring in, with Amgen, AstraZeneca and Boehringer Ingelheim all working on more potent incretin drugs, including some tablets rather than injectables.

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​[1] Tirzepatide demonstrated significant and superior weight loss compared to placebo in two pivotal studies,
[2] Lilly's tirzepatide achieved up to 15.7% weight loss in adults with obesity or overweight and type 2 diabetes in SURMOUNT-2. Retrieved April 27, 2023 from
[3] Q1 2023 Lilly Presentation. Retrieved April 27, 2023 from
[4] Tirzepatide Once Weekly for the Treatment of Obesity
[5] Novo Nordisk A/S: Oral semaglutide 50 mg achieved 15.1% weight loss (17.4% if all people adhered to treatment) in adults with obesity or overweight in the OASIS 1 trial,

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