What percentage of patients in the STEP-1 trial failed to achieve clinically meaningful weight loss, defined as a loss of 5% or more of initial body weight?

STEP-1 Trial Weight Loss Failure Rate

In the STEP-1 trial, approximately 13.6% of patients treated with semaglutide 2.4 mg failed to achieve clinically meaningful weight loss of ≥5% body weight, while 68.5% of placebo-treated patients failed to reach this threshold. 1

Detailed Breakdown of STEP-1 Results

The STEP-1 trial demonstrated robust efficacy for once-weekly semaglutide 2.4 mg as an adjunct to lifestyle intervention in adults with obesity or overweight without diabetes:

Primary Weight Loss Outcomes

• 86.4% of semaglutide-treated participants achieved ≥5% weight loss at 68 weeks, meaning 13.6% failed to reach this clinically meaningful threshold 1
• In contrast, only 31.5% of placebo participants achieved ≥5% weight loss, indicating a 68.5% failure rate 1
• The mean weight reduction was -14.9% with semaglutide versus -2.4% with placebo 1

Greater Weight Loss Thresholds

Beyond the 5% threshold, the trial revealed dose-response patterns:

• 69.1% achieved ≥10% weight loss with semaglutide (30.9% failure rate) versus 12.0% with placebo 1
• 50.5% achieved ≥15% weight loss with semaglutide (49.5% failure rate) versus 4.9% with placebo 1

Clinical Context: Defining Treatment Success

The 5% weight loss threshold used in STEP-1 aligns with FDA criteria for anti-obesity medication approval and represents the minimum for clinically meaningful health benefits 2. Multiple guidelines confirm that ≥5% weight loss produces significant improvements in cardiometabolic risk factors 3.

However, certain obesity-related complications require greater weight loss:

• Type 2 diabetes remission typically requires >10% weight loss 3
• Non-alcoholic steatohepatitis, obstructive sleep apnea, and GERD often need >10-15% weight loss for meaningful improvement 2

Comparison to Other Interventions

The STEP-1 success rate (86.4% achieving ≥5% loss) substantially exceeds historical benchmarks:

• Intensive behavioral therapy alone: Approximately 50% achieve ≥5% weight loss at 8 years in Look AHEAD trial 3
• Minimal assistance programs: About 60% achieve 5% loss, but 40% fail even with stepped-care intensification 4
• Early behavioral therapy non-responders: Only 35-50% achieve ≥5% loss without medication augmentation 5

Important Clinical Caveats

Treatment discontinuation due to adverse events occurred in 4.5% of semaglutide participants versus 0.8% with placebo, primarily from gastrointestinal symptoms (nausea, diarrhea) 1. These events were typically transient and mild-to-moderate 1.

Weight regain after discontinuation is expected with all anti-obesity medications, emphasizing the need for long-term treatment strategies 6. The principle that discontinuation leads to rapid weight regain applies across all pharmacologic weight loss interventions 6.

Individual response variability exists even with highly effective medications—the 13.6% who failed to achieve 5% loss with semaglutide in STEP-1 may benefit from alternative approaches including higher-intensity behavioral therapy, different medications (such as tirzepatide, which achieves 15-20.9% mean weight reduction), or consideration for bariatric procedures 6, 1.