Semaglutide:
what the research shows

Weight: STEP 1, STEP 5 and STEP 8

STEP 1 enrolled 1,961 adults with obesity or overweight and no diabetes. Over 68 weeks, with lifestyle support, the mean change was -14.9% on 2.4 mg weekly and -2.4% on placebo. 86.4% of the semaglutide group reached a 5% loss, against 31.5% on placebo (STEP 1, NEJM 2021).

STEP 5 followed 304 adults for 104 weeks. The mean change was -15.2% on semaglutide and -2.6% on placebo (STEP 5, Nature Medicine 2022).

STEP 8 compared it head to head with liraglutide 3.0 mg daily in 338 adults for 68 weeks. Weight fell 15.8% on semaglutide and 6.4% on liraglutide, with pooled placebo at -1.9% (STEP 8, JAMA 2022).

How the dose is built up

The labeled schedule starts at 0.25 mg once weekly for four weeks, then 0.5 mg for four weeks, 1 mg for four weeks and 1.7 mg for four weeks. The maintenance dose for weight is 2.4 mg weekly, or 1.7 mg if 2.4 mg is not tolerated. If a step is not tolerated, the label allows delaying the next increase by four weeks (Wegovy prescribing information, FDA).

Side effects

• Nausea, diarrhea and vomiting were the most common side effects in the weight trials.
• In SELECT, adverse events led 16.6% of people on semaglutide to stop the trial drug permanently, against 8.2% on placebo (SELECT, NEJM 2023).
• The label warns of acute pancreatitis and acute gallbladder disease. Gallbladder disease was more frequent than on placebo even after accounting for the weight lost (Wegovy prescribing information).
• In SUSTAIN-6, adults with type 2 diabetes had more diabetic retinopathy complications on semaglutide, with a hazard ratio of 1.76 (SUSTAIN-6, NEJM 2016).

The oral tablet is not the injection

Oral semaglutide 25 mg once daily is a tablet that is swallowed. In OASIS 4, 307 adults without diabetes took it for 64 weeks; the mean change was -13.6% on the tablet and -2.2% on placebo (treatment policy estimand; OASIS 4, NEJM 2025).

Rybelsus is a different tablet, approved for type 2 diabetes. In PIONEER 1, 703 adults with type 2 diabetes took it for 26 weeks. At the 14 mg dose it lowered HbA1c by 1.1% more than placebo and body weight by 2.3 kg (PIONEER 1, Diabetes Care 2019).

What this does not say

• The weight figures are for brand-name semaglutide at the doses studied, with diet and activity, in trials of 68 to 104 weeks. They are averages, not predictions.
• Compounded semaglutide and the sublingual form (dissolved under the tongue) were not studied in these trials. The oral trials used a swallowed tablet.
• These trials do not measure what happens over the long term after stopping treatment.

Sources

1. 1.Wilding JPH et al. Once-weekly semaglutide in adults with overweight or obesity (STEP 1). N Engl J Med 2021. NEJM
2. 2.Garvey WT et al. Two-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial. Nature Medicine 2022. Nature Medicine
3. 3.Rubino DM et al. Effect of weekly subcutaneous semaglutide vs daily liraglutide on body weight in adults with overweight or obesity without diabetes (STEP 8). JAMA 2022. JAMA
4. 4.Lincoff AM et al. Semaglutide and cardiovascular outcomes in obesity without diabetes (SELECT). N Engl J Med 2023. NEJM
5. 5.Wharton S et al. Oral semaglutide at a dose of 25 mg in adults with overweight or obesity (OASIS 4). N Engl J Med 2025. NEJM
6. 6.PIONEER 1: randomized trial of oral semaglutide monotherapy vs placebo in type 2 diabetes. Diabetes Care 2019. Diabetes Care
7. 7.Marso SP et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes (SUSTAIN-6). N Engl J Med 2016. NEJM
8. 8.Wegovy (semaglutide) injection, prescribing information, section 2.2 and Table 1 (dose escalation). FDA