Part Two · Weight Cohorts, Oral Delivery & Head-to-Head Trials
Weight Loss Clinical Trials in Adults and Comparison Data
Reviewing the 68-week STEP 1 cohort, the 104-week STEP 5 durability study, adolescent outcomes in STEP TEENS, oral SNAC pharmacokinetics, and the 2025 SURMOUNT-5 comparison against tirzepatide.
What STEP 1, STEP 5, and STEP TEENS Measured at 2.4 mg Weekly
Once-weekly 2.4 mg subcutaneous semaglutide was evaluated across 68-week adult, 104-week adult, and 68-week adolescent weight-management cohorts, beginning with the 2021 once-weekly STEP 1 obesity study led by Wilding and colleagues. That trial randomized 1,961 adults with overweight or obesity without diabetes to 2.4 mg weekly or placebo. After 68 weeks, participants in the active arm achieved a mean body-weight change of -14.9% compared with -2.4% in the placebo group, representing an estimated treatment difference of about 12.4 percentage points.
Garvey and colleagues reported two-year outcomes in the 2022 two-year STEP 5 trial. Across 104 weeks of continuous once-weekly 2.4 mg subcutaneous dosing in adults with overweight or obesity, the trial confirmed sustained, clinically meaningful weight loss compared with placebo.
That same year, Weghuber and the STEP TEENS investigators published their 68-week adolescent obesity trial in the New England Journal of Medicine. Adolescents with obesity assigned to once-weekly 2.4 mg subcutaneous dosing achieved a significantly greater reduction in body mass index than peers receiving placebo. Reading these three trials together shows how the 2.4 mg weekly regimen performed across 68-week adult, 104-week adult, and 68-week adolescent cohorts.
Oral SNAC Bioavailability and the 2025 SURMOUNT-5 Trial Against Tirzepatide
As detailed in the 2024 StatPearls clinical pharmacology summary, oral bioavailability of semaglutide with SNAC is approximately 0.4-1%. Both oral and subcutaneous semaglutide have an elimination half-life of approximately 1 week and remain in circulation for approximately 5 weeks after the last dose.
In 2025, Aronne and the SURMOUNT-5 investigators published their 72-week head-to-head trial against tirzepatide comparing once-weekly semaglutide 2.4 mg with tirzepatide in 751 adults with obesity. At week 72, mean body-weight change was -20.2% with tirzepatide versus -13.7% with semaglutide 2.4 mg, an approximate 6.5 percentage-point advantage for tirzepatide (P<0.001). When I place SURMOUNT-5 beside the STEP cohorts, I see how a head-to-head trial in 751 participants answers comparative efficacy questions far more directly than cross-trial estimates.
| Trial & Year | Cohort & Duration | Regimen Tested | Key Reported Finding |
|---|---|---|---|
| STEP 1 (2021) | 1,961 adults without diabetes · 68 weeks | Semaglutide 2.4 mg weekly vs placebo | -14.9% vs -2.4% mean weight change (~12.4 percentage-point difference) |
| STEP 5 (2022) | Adults with overweight or obesity · 104 weeks | Semaglutide 2.4 mg weekly vs placebo | Sustained, clinically meaningful two-year weight loss vs placebo |
| STEP TEENS (2022) | Adolescents with obesity · 68 weeks | Semaglutide 2.4 mg weekly vs placebo | Significantly greater BMI reduction than placebo |
| SURMOUNT-5 (2025) | 751 adults with obesity · 72 weeks | Tirzepatide vs semaglutide 2.4 mg weekly | -20.2% vs -13.7% mean weight change (~6.5 percentage-point tirzepatide advantage, P < 0.001) |
How prescription access relates to the weight trials
After comparing the weight trials, I turn to how the medicines reach patients. FDA-approved semaglutide products require a prescription. Individually compounded medicines also depend on a prescription, though FDA approval does not cover the compounded preparation. Research-labelled material is intended for laboratory work. Semaglutide care at Promise Peptides (mypromise.com) is prescription-only, with a clinician assessing the patient and making the prescribing decision.