New England Journal of Medicine July 21, 2022

Tirzepatide Once Weekly for the Treatment of Obesity (SURMOUNT-1)

Ania M. Jastreboff, Louis J. Aronne, Nadia N. Ahmad, Sean Wharton, Lisa Connery, Breno Alves, Arihiro Kiyosue, Shuyu Zhang, Bing Liu, Mathijs C. Bunck, Adam Stefanski

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Bottom Line

In a phase 3 randomized controlled trial of adults with obesity or overweight without diabetes, once-weekly tirzepatide demonstrated unprecedented, dose-dependent mean body weight reductions of up to 20.9% over 72 weeks.

Key Findings

1. At baseline, the 2,539 participants had a mean body weight of 104.8 kg and a mean BMI of 38.0, with 94.5% having a BMI of 30 or higher [4.1.6].

2. At week 72, the mean percentage change in body weight was -15.0% for the 5-mg dose, -19.5% for the 10-mg dose, and -20.9% for the 15-mg dose, compared with -3.1% for placebo (P<0.001 for all comparisons).

3. A weight reduction of 5% or more was achieved by 85%, 89%, and 91% of participants receiving 5 mg, 10 mg, and 15 mg of tirzepatide, respectively, versus 35% in the placebo group.

4. Notably, 50% and 57% of participants in the 10-mg and 15-mg groups, respectively, achieved a massive weight reduction of 20% or more, compared to only 3% in the placebo group (P<0.001).

5. The most common adverse events were gastrointestinal, primarily mild to moderate in severity, and occurred predominantly during the 20-week dose-escalation phase.

6. Adverse events led to treatment discontinuation in 4.3% (5 mg), 7.1% (10 mg), and 6.2% (15 mg) of participants in the tirzepatide arms, compared to 2.6% in the placebo arm.

Study Design

Design

Phase 3 RCT

Double-Blind

Sample

2,539

Patients

Duration

72 wk

Median

Setting

Multicenter, global

Population Adults with a body-mass index (BMI) of at least 30, or a BMI of at least 27 with one or more weight-related complications, excluding diabetes.

Intervention Once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) along with a lifestyle intervention.

Comparator Once-weekly subcutaneous placebo along with a lifestyle intervention.

Outcome Percentage change in body weight from baseline and the proportion of participants achieving a weight reduction of 5% or more at week 72.

Study Limitations

• The study excluded patients with type 2 diabetes, a population that often experiences different metabolic and weight-loss trajectories, which was subsequently evaluated in the SURMOUNT-2 trial [4.1.6].

• The 72-week follow-up period is insufficient to assess long-term weight maintenance, real-world adherence, or the impact of tirzepatide on hard cardiovascular outcomes such as myocardial infarction or stroke.

• High rates of gastrointestinal side effects, such as nausea, diarrhea, and vomiting, may limit tolerability for some patients and require careful dose titration.

• The requirement for once-weekly subcutaneous injections alongside the high cost of the medication poses accessibility and long-term adherence challenges.

Clinical Significance

The SURMOUNT-1 trial represents a major breakthrough in obesity medicine, demonstrating that a pharmacological therapy can achieve weight loss magnitudes previously reserved for bariatric surgery. By surpassing the 20% weight-loss threshold, tirzepatide significantly improves obesity-related cardiometabolic risk factors and fundamentally shifts the clinical treatment paradigm toward highly effective incretin-based medical management.

Historical Context

Prior to the introduction of tirzepatide, the standard of care in anti-obesity medications was semaglutide 2.4 mg, which produced a mean weight loss of approximately 15% in the STEP trials. Bariatric surgery remained the only reliable method for achieving greater than 20% body weight reduction. Tirzepatide, a first-in-class dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist, was hypothesized to provide synergistic appetite suppression and energy regulation. SURMOUNT-1 definitively proved this concept, establishing tirzepatide as the most potent weight-loss medication to date.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

Tirzepatide is described as a novel 'twincretin' targeting both GIP and GLP-1 receptors. How does the addition of GIP agonism theoretically enhance weight loss compared to selective GLP-1 receptor agonists like semaglutide, considering the historical understanding of GIP's role in lipid metabolism?

Key Response

Tests foundational endocrine physiology. Historically, GIP was thought to be obesogenic, but in combination with GLP-1, it acts synergistically to decrease appetite, improve insulin sensitivity, reduce nausea, and possibly increase energy expenditure, highlighting a major paradigm shift in incretin physiology.

Resident

A 35-year-old female with a BMI of 32 presents for weight management and requests tirzepatide based on the SURMOUNT-1 trial. If prescribed, how would you counsel her on the expected trajectory of weight loss, the most common adverse effects, and the necessity of the specific dose titration schedule?

Key Response

Focuses on practical clinical application. Emphasizes counseling on gastrointestinal side effects (nausea, diarrhea), the necessity of a slow 4-week dose escalation scheme to mitigate these effects, and setting realistic expectations about the timeline of weight loss plateaus.

Fellow

While SURMOUNT-1 excluded patients with type 2 diabetes, tirzepatide demonstrated profound weight loss approaching bariatric surgery levels (up to 20.9 percent). How might this magnitude of weight loss alter the treatment algorithms for patients with obesity-related complications like MASH (metabolic dysfunction-associated steatohepatitis) or HFpEF (heart failure with preserved ejection fraction)?

Key Response

Pushes the fellow to integrate obesity medicine with hepatology and cardiology. Discusses the pleiotropic benefits of massive weight loss and dual incretin agonism on systemic inflammation, hepatic steatosis, and myocardial mechanics beyond simple glycemic control.

Attending

The dramatic weight reduction seen in SURMOUNT-1 challenges the traditional role of bariatric surgery. As an attending, how do you navigate the long-term management of patients who achieve massive weight loss on tirzepatide, particularly regarding the potential for sarcopenia (loss of lean muscle mass) and the near certainty of weight regain upon discontinuation?

Key Response

Addresses real-world, long-term implications. The loss of fat-free mass and the chronic nature of obesity requiring indefinite therapy are major clinical dilemmas needing attending-level wisdom to balance long-term risks, benefits, and patient expectations.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

In SURMOUNT-1, the primary endpoint was evaluated using both an efficacy estimand and a treatment-policy estimand. How does the choice of the treatment-policy estimand impact the power and generalizability of the trial, and what are the statistical challenges in handling missing data for patients who discontinued the study drug due to adverse events?

Key Response

Focuses on advanced trial design and ICH E9(R1) guidelines. Evaluates how intention-to-treat (treatment-policy) reflects real-world effectiveness but can dilute the pharmacological effect, interrogating imputation methods for missing data in obesity trials.

Journal Editor

From an editorial perspective, the blinding in weight-loss pharmacotherapy trials like SURMOUNT-1 is often compromised by the high incidence of distinctive gastrointestinal adverse events and rapid, visible weight loss in the active arms. How severely does this functional unblinding threaten the internal validity of the patient-reported outcomes, and what methodological safeguards should be demanded in future trials?

Key Response

Highlights structural flaws in clinical trials. Functional unblinding is a massive issue in GLP-1/GIP trials, forcing consideration of placebo effects, expectation bias, and how behavioral interventions might be skewed if patients know their assignment.

Guideline Committee

Current obesity guidelines (e.g., AHA/ACC/TOS) recommend pharmacotherapy as an adjunct for BMI over 30, but historical drugs offered only modest weight loss. With SURMOUNT-1 demonstrating over 20 percent weight loss, should guidelines reclassify incretin co-agonists from adjunctive therapy to primary disease-modifying therapy, and how should they address cost-effectiveness and prioritization criteria?

Key Response

Connects trial data to policy updates. Forces consideration of redefining obesity as a chronic medically treatable disease rather than a lifestyle issue, and tackles the health economics of recommending costly, life-long biologics as first-line therapy.

Clinical Landscape

Noteworthy Related Trials

2015

SCALE Obesity and Prediabetes Trial

n = 3,731 · NEJM

Tested

Liraglutide 3.0 mg daily

Population

Adults with obesity or overweight with comorbidities (without diabetes)

Comparator

Placebo

Endpoint

Change in body weight at week 56

Key result: Liraglutide resulted in an 8.0 percent reduction in body weight compared to 2.6 percent with placebo.

2021

STEP 1 Trial

n = 1,961 · NEJM

Tested

Semaglutide 2.4 mg once weekly

Population

Adults with obesity or overweight and weight-related conditions (without diabetes)

Comparator

Placebo

Endpoint

Percentage change in body weight at week 68

Key result: Participants taking semaglutide achieved an average weight loss of 14.9 percent compared to 2.4 percent in the placebo group.

2023

SELECT Trial

n = 17,604 · NEJM

Tested

Semaglutide 2.4 mg once weekly

Population

Adults with overweight or obesity and established cardiovascular disease (without diabetes)

Comparator

Placebo

Endpoint

3-point MACE

Key result: Semaglutide reduced the risk of major adverse cardiovascular events by 20 percent compared to placebo.

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