What are the results of the STEP (Semaglutide Treatment Effect in People with obesity) studies with semaglutide (glucagon-like peptide-1 receptor agonist) for weight loss in adults with obesity?

Summary of STEP Studies with Semaglutide

Overview of the STEP Program

The STEP (Semaglutide Treatment Effect in People with obesity) clinical trial program demonstrated that once-weekly subcutaneous semaglutide 2.4 mg produces substantial and sustained weight loss of 14.9-17.4% in adults with overweight or obesity without diabetes, significantly outperforming placebo (2.4-5.7% weight loss). 1, 2

The STEP program consists of multiple phase 3 randomized controlled trials evaluating semaglutide 2.4 mg subcutaneous weekly injection for chronic weight management in adults with obesity (BMI ≥30) or overweight (BMI ≥27) with at least one weight-related comorbidity. 1, 3

STEP 1: Standard Lifestyle Intervention

• Primary trial in adults without diabetes (mean BMI 38, n=1961) comparing semaglutide 2.4 mg weekly versus placebo over 68 weeks 1, 4
• Mean weight loss: 14.9% with semaglutide versus 2.4% with placebo (difference 12.4 percentage points, 95% CI 11.5-13.4%) 1, 4
• Absolute weight reduction: 15.3 kg with semaglutide versus 2.6 kg with placebo 4
• Achievement of weight loss thresholds: 1, 4
  • ≥5% weight loss: 86.4% versus 31.5% with placebo
  • ≥10% weight loss: 69.1% versus 12.0% with placebo
  • ≥15% weight loss: 50.5% versus 4.9% with placebo
• Participants followed a reduced-calorie diet (500 kcal deficit) and 150 minutes weekly of physical activity 1

STEP 2: Population with Type 2 Diabetes

• Adults with overweight/obesity AND type 2 diabetes showed attenuated but still significant weight loss 1, 2
• Mean weight loss: 9.6% with semaglutide 2.4 mg versus 3.4% with placebo at 68 weeks 2
• Weight loss appears lower in individuals with diabetes (4-6.2%) compared to those without diabetes (6.1-17.4%) 5

STEP 3: Intensive Behavioral Therapy

• Intensive lifestyle intervention including low-calorie meal replacements for 8 weeks, reduced-calorie diet, 200 minutes weekly physical activity, and 30 individual dietitian visits 1
• Mean weight loss: 16.0% with semaglutide versus 5.7% with placebo (difference 10.3%, 95% CI 8.6-12.0%) 1
• Despite more intensive behavioral intervention compared to STEP 1, weight loss outcomes were remarkably similar, suggesting semaglutide's effect may not be substantially enhanced by behavioral program intensity 6

STEP 4: Weight Maintenance After Initial Treatment

• Withdrawal design: participants completed 20 weeks of semaglutide treatment, then randomized to continue semaglutide or switch to placebo for additional 48 weeks 1
• Mean weight regain: 6.9% of lost weight during placebo administration 1
• This demonstrates the necessity of long-term continuous treatment to maintain weight loss 1

STEP 5: Extended Duration (2-Year Study)

• Longest duration trial (104 weeks) in adults with overweight/obesity without diabetes (n=304, mean BMI 38.5) 7, 2
• Mean weight loss: -15.2% with semaglutide versus -2.6% with placebo at week 104 7, 2
• 77.1% achieved ≥5% weight loss versus 34.4% with placebo 7
• Demonstrated sustained weight loss over 2 years, confirming durability of effect 7, 2

STEP 8: Head-to-Head Comparison

• Direct comparison of semaglutide 2.4 mg versus liraglutide 3.0 mg (another GLP-1 receptor agonist) 2
• Semaglutide demonstrated superior weight loss and lower rates of gastrointestinal adverse events compared to liraglutide 1

Weight Regain After Discontinuation

A critical finding across STEP trials: significant weight regain occurs after semaglutide cessation, highlighting the need for lifelong treatment. 1, 5

• Among participants followed 52 weeks after completing 68 weeks of treatment, mean weight regain was 11.6% of lost weight 1
• This pattern mirrors other chronic disease treatments requiring continuous therapy 1, 5

Cardiometabolic Benefits Beyond Weight Loss

• Improvements in blood pressure, atherogenic lipids, and glycemic control across all STEP trials 2, 3
• Enhanced physical function and quality of life reported by participants 4, 2
• The SELECT study (not part of STEP but relevant) demonstrated 20% reduction in major adverse cardiovascular events (HR 0.80,95% CI 0.72-0.90) in patients with established CVD and BMI ≥27 1, 5

Safety Profile Across STEP Trials

Gastrointestinal adverse events were the most common side effects, typically transient and mild-to-moderate in severity. 4, 3

• Most frequent adverse events: nausea, diarrhea, vomiting, and constipation 4, 3, 6
• These events were dose-dependent and typically subsided with time 3, 6
• Treatment discontinuation due to gastrointestinal events: 4.5% with semaglutide versus 0.8% with placebo in STEP 1 4
• Serious adverse events occurred in 38% higher rate with semaglutide versus placebo (95% CI 1.10-1.73), including pancreatitis, cholelithiasis, and cholecystitis 1
• Contraindicated in patients with personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2 based on animal studies 1, 5

Dosing and Titration Protocol

Gradual dose escalation is essential to minimize gastrointestinal side effects: 1, 5

• Start 0.25 mg weekly for 4 weeks
• Increase to 0.5 mg weekly for 4 weeks
• Increase to 1.0 mg weekly for 4 weeks
• Increase to 1.7 mg weekly for 4 weeks
• Reach maintenance dose of 2.4 mg weekly after 16 weeks 5

Clinical Implications and Positioning

Given the magnitude of weight loss, the AGA recommends semaglutide 2.4 mg may be prioritized over other approved anti-obesity medications for most patients. 1

• Semaglutide offers dual benefits in patients with type 2 diabetes: improved glycemic control and weight loss 1, 5
• Must be used in conjunction with lifestyle modifications (reduced-calorie diet and increased physical activity) 1, 3
• Likely requires lifelong use to maintain weight loss benefits 1, 5
• Cost considerations remain significant, with average wholesale price around $1,600 for 30-day supply 5