New England Journal of Medicine FEBRUARY 10, 2021

Once-Weekly Semaglutide in Adults with Overweight or Obesity (STEP 1)

John P.H. Wilding, Rachel L. Batterham, Salvatore Calanna, et al. (STEP 1 Study Group)

Bottom Line

In this phase 3 randomized, double-blind, placebo-controlled trial, once-weekly subcutaneous semaglutide 2.4 mg combined with lifestyle intervention resulted in a significant and clinically meaningful reduction in body weight compared with placebo at 68 weeks in adults without type 2 diabetes.

Key Findings

1. Participants receiving semaglutide achieved a mean change in body weight of -14.9% from baseline at week 68, compared to -2.4% in the placebo group, representing an estimated treatment difference of -12.4 percentage points (95% CI, -13.4 to -11.5; P<0.001).

2. A significantly higher proportion of participants in the semaglutide group achieved weight reductions of at least 5% (86.4% vs 31.5%), 10% (69.1% vs 12.0%), and 15% (50.5% vs 4.9%) compared to placebo (P<0.001 for all).

3. Semaglutide was associated with greater improvements in cardiometabolic risk factors—including waist circumference, systolic and diastolic blood pressure, and HbA1c levels—as well as self-reported physical functioning compared to placebo.

4. Gastrointestinal disorders were the most common adverse events, occurring more frequently in the semaglutide group (74.2%) than in the placebo group (47.9%), though these were generally transient and mild-to-moderate.

Study Design

Design

RCT

Double-Blind

Sample

1,961

Patients

Duration

68 wk

Median

Setting

Multicenter, international

Population Adults with a body-mass index (BMI) of 30 or greater, or 27 or greater with at least one weight-related co-morbidity, without type 2 diabetes.

Intervention Once-weekly subcutaneous semaglutide 2.4 mg plus lifestyle intervention.

Comparator Once-weekly subcutaneous placebo plus lifestyle intervention.

Outcome Percentage change in body weight from baseline to week 68.

Study Limitations

• The trial excluded patients with type 2 diabetes, limiting the generalizability of these specific weight-loss findings to that population.

• The study population was predominantly white and female, which may not fully represent the demographic diversity of the global population with obesity.

• Participants received relatively intensive, standardized counseling; real-world effectiveness might vary depending on the availability and intensity of lifestyle support.

• The 68-week follow-up period, while sufficient for assessing weight-loss efficacy, does not provide evidence on the long-term maintenance of weight loss after cessation of treatment or potential very-long-term safety profiles.

Clinical Significance

The magnitude of weight loss observed with once-weekly semaglutide 2.4 mg (nearly 15% mean reduction) approaches results historically achieved only through bariatric surgery, providing a highly effective, non-invasive pharmacological option for the management of obesity and its associated cardiometabolic complications in patients without diabetes.

Historical Context

Prior to the STEP 1 trial, pharmacological treatments for obesity typically yielded modest weight loss (often 4-10%). Semaglutide, previously established as a potent GLP-1 receptor agonist for glycemic control in type 2 diabetes, was repurposed at a higher dose (2.4 mg) for chronic weight management, representing a paradigm shift in the medical treatment of obesity.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

How does the molecular mechanism of semaglutide, specifically as a GLP-1 receptor agonist, facilitate weight loss in non-diabetic patients compared to its role in glucose regulation?

Key Response

While GLP-1 agonists stimulate insulin secretion (the incretin effect), weight loss is primarily driven by their action on the hypothalamus to increase satiety and decrease hunger, as well as a delay in gastric emptying. Understanding this neuroendocrine pathway is foundational for clinical reasoning in obesity management.

Resident

In a patient following the STEP 1 protocol, what is the clinical significance of the 16-week dose-escalation phase, and how should a clinician manage a patient who cannot tolerate the 2.4 mg target dose due to persistent gastrointestinal side effects?

Key Response

The 16-week titration (0.25 mg to 2.4 mg) is designed to minimize the most common adverse events—nausea, diarrhea, and vomiting. If the target dose is not reached, clinical guidelines and trial data suggest that the highest tolerated dose still provides significant benefit, though potentially less than the 14.9% mean weight loss seen in the full-dose cohort.

Fellow

Considering the 14.9% mean weight loss achieved in STEP 1, how does this efficacy compare to metabolic surgery benchmarks, and what are the specific implications for the management of Obesity-Related Heart Failure with Preserved Ejection Fraction (HFpEF)?

Key Response

Semaglutide 2.4 mg bridges the gap between traditional pharmacotherapy (5-10% weight loss) and bariatric surgery (25-30%). Fellows should recognize that the magnitude of weight loss in STEP 1 is sufficient to significantly improve hemodynamics and functional capacity in HFpEF patients, a population frequently encountered in subspecialty clinics.

Attending

STEP 1 demonstrated a paradigm shift in obesity treatment; however, given the 'STEP 1 Extension' data showing weight regain after cessation, how should we modify our long-term treatment algorithms and patient counseling regarding the chronicity of obesity pharmacotherapy?

Key Response

Clinicians must transition from viewing obesity as a condition to be 'cured' with a short course of medication to a chronic disease requiring long-term maintenance. High-yield teaching points should focus on the 'relapsing' nature of weight when the biological stimulus (semaglutide) is removed, necessitating indefinite treatment for sustained results.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

Evaluate the statistical implications of the 'Treatment-Policy Estimand' used in STEP 1. How does this approach handle missing data and treatment discontinuation compared to the 'Trial-Product Estimand', and why is this distinction critical for assessing 'effectiveness' versus 'efficacy'?

Key Response

The Treatment-Policy estimand (intent-to-treat) accounts for all participants regardless of adherence, providing a conservative and realistic 'effectiveness' measure (12.4% vs. placebo). The Trial-Product estimand represents 'efficacy' (14.9% vs. placebo) under ideal conditions. PhDs must critique these choices to understand the potential for bias in industry-sponsored trials.

Journal Editor

While the STEP 1 trial was double-blinded, the significant gastrointestinal side effect profile in the treatment arm (74.2% vs. 47.9% in placebo) creates a risk of 'unblinding' for both participants and investigators. How does this threat to internal validity impact the interpretation of the subjective 'quality of life' secondary endpoints?

Key Response

A tough reviewer would flag that if patients suspect they are on the active drug because of side effects, their responses to patient-reported outcome measures (like the SF-36) may be biased by expectation. This necessitates a critical appraisal of whether the perceived benefit is purely physiological or partially influenced by the trial's open-label 'feel'.

Guideline Committee

Does the evidence from STEP 1 warrant an upgrade of semaglutide to a 'First-Line' recommendation in obesity guidelines (e.g., AACE or AHA/ACC/TOS), and how should the committee weigh the cost-effectiveness against the 12.4% placebo-subtracted weight loss?

Key Response

STEP 1 provides 'High Quality' evidence for significant weight loss. Most current guidelines (like the 2024 updated Endocrine Society guidelines) now prioritize high-potency GLP-1s. However, the committee must balance the 'Strong Recommendation' for efficacy with 'Conditional' warnings regarding health equity and the high cost of long-term therapy, which was not addressed in the trial.

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

Comparator

Placebo

Endpoint

Weight loss percentage and proportion of subjects losing at least 5% and 10% of body weight

Key result: Treatment with liraglutide 3.0 mg in combination with diet and exercise resulted in significantly greater weight loss than placebo at 56 weeks.

2022

SURMOUNT-1 Trial

n = 2,539 · NEJM

Tested

Tirzepatide 5, 10, or 15 mg weekly

Population

Adults with obesity or overweight with weight-related complications

Comparator

Placebo

Endpoint

Percentage change in body weight and proportion of participants with at least 5% reduction

Key result: Tirzepatide, a dual GIP and GLP-1 receptor agonist, led to substantial and sustained weight reduction compared to placebo across all doses.

2023

SELECT Trial

n = 17,604 · NEJM

Tested

Semaglutide 2.4 mg weekly

Population

Adults aged 45 or older with overweight or obesity and established cardiovascular disease without diabetes

Comparator

Placebo

Endpoint

Composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke

Key result: Semaglutide 2.4 mg significantly reduced the incidence of major adverse cardiovascular events in people with overweight or obesity without diabetes.

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