Nature Medicine October 10, 2022

Two-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial

W Timothy Garvey, Rachel L Batterham, Meena Bhatta, et al.

Bottom Line

In adults with overweight or obesity without diabetes, once-weekly subcutaneous semaglutide 2.4 mg combined with behavioral intervention led to significant and sustained weight loss over a two-year period compared to placebo.

Key Findings

1. At week 104, the mean change in body weight from baseline was -15.2% in the semaglutide group compared to -2.6% in the placebo group, demonstrating an estimated treatment difference of -12.6 percentage points (95% CI, -15.3 to -9.8; P < 0.0001) [2.1.1].

2. A significantly higher proportion of participants receiving semaglutide achieved a weight loss of 5% or more at week 104 compared to those receiving placebo (77.1% vs. 34.4%; P < 0.0001).

3. Gastrointestinal adverse events, primarily characterized as mild-to-moderate in severity, were reported more frequently in the semaglutide group (82.2%) than in the placebo group (53.9%).

Study Design

Design

Phase 3 RCT

Double-Blind

Sample

304

Patients

Duration

104 wk

Median

Setting

Multicenter

Population Adults with obesity (BMI ≥ 30 kg/m²) or overweight (BMI ≥ 27 kg/m²) with at least one weight-related comorbidity, without type 2 diabetes.

Intervention Semaglutide 2.4 mg subcutaneously once weekly plus behavioral intervention.

Comparator Placebo subcutaneously once weekly plus behavioral intervention.

Outcome Percentage change in body weight and achievement of weight loss of ≥5% from baseline at week 104.

Study Limitations

• The study cohort was predominantly female (77.6%) and White (93.1%), potentially limiting the generalizability of the findings across more diverse demographic groups [2.1.1].

• Individuals diagnosed with type 2 diabetes were excluded from the trial, meaning these specific weight-loss trajectory results cannot be directly extrapolated to the diabetic population.

• The high frequency of gastrointestinal adverse events, although generally mild to moderate, highlights potential tolerability challenges for long-term, real-world adherence.

• The sustained effects require continuous administration; prior semaglutide data (e.g., the STEP 4 trial) show that significant weight regain occurs upon treatment discontinuation.

Clinical Significance

The STEP 5 trial successfully established the long-term durability of semaglutide 2.4 mg, proving that the profound weight reduction (approximately 15% of body weight) seen in short-term studies does not wane but is sustained for at least two years with continuous therapy. This solidifies the medical paradigm shift of treating obesity as a chronic, relapsing disease that requires uninterrupted, long-term pharmacological management rather than short-term intervention.

Historical Context

Historically, anti-obesity pharmacotherapies produced modest results (typically 5-10% body weight reduction) and were plagued by poor long-term adherence, safety withdrawals, and inevitable weight regain. The Semaglutide Treatment Effect in People with obesity (STEP) clinical trial program revolutionized this landscape, showing that GLP-1 receptor agonists could safely bridge the gap between lifestyle modifications and bariatric surgery. While STEP 1 proved dramatic short-term efficacy at 68 weeks, skeptics questioned whether weight loss would eventually plateau and regress. STEP 5 provided the pivotal 2-year (104-week) follow-up data demonstrating that the clinical benefits of semaglutide are durable over prolonged periods.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What is the primary mechanism of action by which semaglutide induces significant weight loss in patients without diabetes, and how does this differ from its role in glycemic control?

Key Response

Semaglutide is a GLP-1 receptor agonist. While it enhances glucose-dependent insulin secretion in diabetes, its primary mechanism for weight loss involves crossing the blood-brain barrier to target the hypothalamus and hindbrain, promoting satiety and reducing appetite, alongside delaying gastric emptying.

Resident

When prescribing semaglutide 2.4 mg weekly as demonstrated in the STEP 5 trial, what are the most common adverse events, and what practical strategies should be employed to maximize long-term adherence over a 2-year period?

Key Response

Gastrointestinal issues (nausea, diarrhea, vomiting, constipation) are the most common adverse events, typically peaking during the dose-escalation phase. Strategies include adhering to the gradual 16-week dose-escalation schedule, dietary modifications like eating smaller meals, and symptomatic management to prevent early discontinuation.

Fellow

The STEP 5 trial showed sustained weight loss over 104 weeks. How does this extended duration challenge the traditional episodic treatment model of obesity, and what does it imply about the physiological defense of body weight?

Key Response

The trial reinforces obesity as a chronic, relapsing disease. The plateau in weight loss and the known rebound weight gain upon cessation highlight metabolic adaptation and the body's physiological defense of a higher set-point, necessitating continuous pharmacological intervention rather than short-term, episodic use.

Attending

Given the clinical reality that weight is typically regained if semaglutide is stopped, how should you counsel a patient starting this medication regarding lifelong therapy, financial cost, and the risk-benefit ratio based on the sustained efficacy data from STEP 5?

Key Response

Counseling must emphasize that anti-obesity medications are chronic treatments akin to antihypertensives. Shared decision-making should explicitly address the long-term financial burden, the necessity of concurrent and permanent lifestyle modifications, and the sustained cardiometabolic benefits observed at two years to ensure realistic patient expectations.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The STEP 5 trial utilized both a treatment policy estimand and a trial product estimand. Why is this dual-estimand approach essential for evaluating the efficacy of a 2-year anti-obesity intervention, and what specific methodological biases does each address?

Key Response

The treatment policy estimand assesses the effect regardless of treatment adherence or use of rescue interventions, reflecting real-world effectiveness (intention-to-treat). The trial product estimand assumes all patients remained on the drug, reflecting pure biological efficacy. Using both provides a comprehensive view of drug performance while addressing confounding from missing data and treatment attrition.

Journal Editor

In evaluating the STEP 5 manuscript, how does the 104-week duration expose the trial to significant missing data and attrition biases, and what statistical methods for imputation would be critical to scrutinize to ensure the treatment effect is not overstated?

Key Response

Long-term obesity trials often suffer from differential dropout rates, where patients experiencing side effects or lack of efficacy leave the study. A reviewer must scrutinize whether the missing-at-random assumption holds and verify that multiple imputation models or mixed models for repeated measures adequately adjust for potential survivorship bias.

Guideline Committee

How does the 2-year durability data from the STEP 5 trial influence current obesity guidelines regarding the duration of pharmacotherapy, and what level of evidence does it provide to shift recommendations toward long-term complication-centric management?

Key Response

Current guidelines (e.g., AACE, AHA/ACC/TOS) increasingly recognize obesity as a chronic disease. The STEP 5 data provides high-quality, Level 1 evidence demonstrating the safety and efficacy of continuous, long-term GLP-1 RA use, strengthening Class I recommendations for chronic pharmacotherapy over short-term interventions and supporting sustained cardiometabolic risk reduction.

Clinical Landscape

Noteworthy Related Trials

2021

STEP 1 Trial

n = 1,961 · NEJM

Tested

Semaglutide 2.4 mg once weekly

Population

Adults with BMI >= 30 or >= 27 with >= 1 weight-related condition (without diabetes)

Comparator

Placebo

Endpoint

Percentage change in body weight at week 68

Key result: Participants receiving semaglutide achieved a mean weight loss of 14.9% compared to 2.4% with placebo.

2022

SURMOUNT-1 Trial

n = 2,539 · NEJM

Tested

Tirzepatide 5 mg, 10 mg, or 15 mg once weekly

Population

Adults with BMI >= 30 or >= 27 with >= 1 weight-related condition (without diabetes)

Comparator

Placebo

Endpoint

Percentage change in body weight at week 72

Key result: Participants taking the 15 mg dose of tirzepatide achieved a mean weight reduction of 22.5% compared to 2.4% for placebo.

2023

SELECT Trial

n = 17,604 · NEJM

Tested

Semaglutide 2.4 mg once weekly

Population

Adults >= 45 years with preexisting cardiovascular disease and BMI >= 27 (without diabetes)

Comparator

Placebo

Endpoint

Time to first occurrence of a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (3-point MACE)

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

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