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. (STEP 5 Study Group)

Bottom Line

The STEP 5 trial demonstrated that once-weekly subcutaneous semaglutide 2.4 mg, combined with lifestyle intervention, induced substantial and sustained weight loss over 104 weeks in adults with overweight or obesity without type 2 diabetes.

Key Findings

1. Participants receiving semaglutide achieved a mean weight loss of 15.2% from baseline to week 104, compared to a 2.6% reduction in the placebo group, for an estimated treatment difference of 12.6 percentage points (95% CI: -15.3 to -9.8; P < 0.0001).

2. A significantly higher proportion of participants in the semaglutide group achieved weight loss of ≥5% at week 104 (77.1%) compared to those in the placebo group (34.4%; P < 0.0001).

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

Study Design

Design

RCT

Double-Blind

Sample

304

Patients

Duration

104 wk

Median

Setting

Multicenter, international

Population Adults with obesity (BMI ≥30 kg/m2) or overweight (BMI ≥27 kg/m2) with at least one weight-related comorbidity, excluding type 2 diabetes.

Intervention Once-weekly subcutaneous semaglutide 2.4 mg plus lifestyle intervention

Comparator Placebo once-weekly subcutaneous injection plus lifestyle intervention

Outcome Percentage change in body weight from baseline to week 104 and the proportion of participants achieving weight loss of ≥5% at week 104.

Study Limitations

• The study population was relatively homogeneous, consisting predominantly of white, female participants, which may limit the generalizability of the findings to broader, more diverse populations.

• The 104-week duration, while the longest in the STEP program, remains limited in the context of chronic, lifelong management required for obesity.

• The high rate of reported gastrointestinal adverse events, while consistent with the known safety profile of GLP-1 receptor agonists, highlights potential barriers to long-term adherence in clinical practice.

Clinical Significance

This trial reinforces the efficacy of long-term semaglutide therapy for sustained weight management in individuals with obesity or overweight and comorbidities, supporting its role as a pharmacological adjunct to behavioral interventions for chronic weight control.

Historical Context

Following earlier 68-week trials in the STEP program that established the short-term efficacy of semaglutide 2.4 mg, the STEP 5 trial served as the critical investigation into the sustainability of this weight loss over a 2-year period, providing essential evidence for the durability of the treatment effect.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What is the physiological mechanism by which long-acting GLP-1 receptor agonists like semaglutide 2.4 mg facilitate weight loss, and how does this mechanism address the 'set point' theory of obesity?

Key Response

Semaglutide acts as a GLP-1 mimetic that crosses the blood-brain barrier to target the hypothalamus and hindbrain, increasing satiety and reducing hunger signals. By pharmacologically modulating these homeostatic pathways, it helps overcome the biological adaptations (like increased ghrelin) that typically occur during calorie restriction, effectively lowering the body's 'defended' fat mass or set point.

Resident

Given the 104-week data from STEP 5, how should a clinician respond to a patient who asks to stop semaglutide after reaching their goal weight at 68 weeks?

Key Response

The STEP 5 trial demonstrates that weight loss plateaus around week 60 and is maintained through week 104 with continued treatment. Residents should counsel patients that obesity is a chronic disease; trial data (including the STEP 4 withdrawal study) suggest that discontinuation leads to a reversal of the physiological satiety benefits and significant weight regain, meaning therapy is likely required long-term for weight maintenance.

Fellow

The STEP 5 trial noted improvements in multiple cardiometabolic risk factors over 2 years. How do these findings integrate with the SELECT trial results to refine the management of patients with 'metabolic obesity' but without type 2 diabetes?

Key Response

STEP 5 provides the long-term durability data for weight loss and improvements in blood pressure and lipids. When integrated with the SELECT trial—which showed a 20% reduction in MACE—the fellow must recognize semaglutide 2.4 mg as not just a weight-loss drug, but a cardiovascular risk-modifying therapy for patients with a BMI over 27 and established CVD, regardless of their glycemic status.

Attending

How does the 15.2% mean weight loss observed at 104 weeks in STEP 5 change the clinical conversation regarding the 'bariatric surgery gap,' and what are the implications for institutional resource allocation?

Key Response

STEP 5 confirms that medical management can now achieve sustained weight loss previously only seen with surgery (which typically yields 25-30%). This 'narrows the gap,' allowing attendings to offer a potent alternative for patients who are high surgical risks or prefer non-invasive routes. This necessitates a shift in resource allocation from purely surgical weight-loss centers to comprehensive metabolic programs incorporating high-acuity pharmacotherapy.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

Critique the use of the 'treatment-policy estimand' in the STEP 5 trial's primary analysis regarding the handling of missing data and treatment discontinuation over a 2-year period.

Key Response

The treatment-policy estimand measures the effect of the drug regardless of whether the patient stayed on it, which is the most conservative and 'real-world' approach. However, over 104 weeks, high attrition or non-adherence can dilute the perceived pharmacological efficacy. A PhD researcher would evaluate whether the multiple imputation methods used for missing data sufficiently accounted for the 'not at random' nature of dropouts in obesity trials.

Journal Editor

Despite the impressive 15.2% weight loss, the STEP 5 trial reported that 82% of the semaglutide group experienced gastrointestinal adverse events. As an editor, how would you evaluate the trade-off between efficacy and tolerability for a long-term (2-year) maintenance claim?

Key Response

An editor would scrutinize whether the GI side effects (nausea, diarrhea) were transient or persistent. While 82% is high, the low discontinuation rate (roughly 6%) suggests that for most, the symptoms were manageable. A reviewer would look for a sub-analysis on whether those with the greatest weight loss also had the most side effects, ensuring the drug's benefit isn't simply due to chronic malaise or malabsorption.

Guideline Committee

Based on the STEP 5 findings, should clinical guidelines move away from BMI-based targets and toward 'percentage weight loss' or 'comorbidity-based' endpoints for assessing GLP-1 RA success?

Key Response

The 104-week durability evidence supports the 2022 AGA and 2023 AACE guidelines which recommend GLP-1 RAs for long-term obesity management. STEP 5 suggests that the 10-15% weight loss threshold is achievable and sustainable; therefore, guidelines should emphasize these targets because they correlate with significant reductions in sleep apnea, NASH, and cardiovascular risk, moving the needle from 'cosmetic' weight loss to 'metabolic' health.

Clinical Landscape

Noteworthy Related Trials

2021

STEP 1 Trial

n = 1,961 · NEJM

Tested

Semaglutide 2.4 mg weekly

Population

Adults with overweight or obesity without diabetes

Comparator

Placebo

Endpoint

Percentage change in body weight from baseline to week 68

Key result: Once-weekly semaglutide resulted in a mean weight loss of 14.9% compared to 2.4% in the placebo group.

2021

STEP 3 Trial

n = 611 · JAMA

Tested

Semaglutide 2.4 mg weekly plus intensive behavioral therapy

Population

Adults with overweight or obesity

Comparator

Placebo plus intensive behavioral therapy

Endpoint

Percentage change in body weight from baseline to week 68

Key result: Participants receiving semaglutide plus behavioral intervention achieved a 16.0% weight loss versus 5.7% in the placebo group.

2021

STEP 4 Trial

n = 902 · JAMA

Tested

Continued semaglutide vs. switch to placebo

Population

Adults with overweight or obesity

Comparator

Placebo

Endpoint

Difference in mean percentage change in body weight from week 20 to week 68

Key result: Participants who continued semaglutide lost additional weight, while those switched to placebo regained weight.

Tailored to your role

Want this tailored to you?

Add your specialty or training stage to get role-specific takeaways and more questions.

Personalize this analysis