STEP 3: what semaglutide added to an intensive lifestyle programme

STEP 3 asked whether semaglutide still adds much when everyone already gets an intensive lifestyle programme. It did. At 68 weeks, average weight fell 16.0% on semaglutide 2.4 mg and 5.7% on placebo, and both groups had the same diet, activity targets and 30 counselling visits [1].

Why this study matters

Most semaglutide trials give people the drug alongside basic lifestyle advice. STEP 3 raised the lifestyle side as far as a trial reasonably can. That makes it the cleanest test of the objection that the drug is doing little that a serious programme would not.

Our breakdown of the original obesity trial is in STEP 1, and the drug as a whole is in the semaglutide evidence guide. This page covers the intensive-programme trial on its own.

What they did

Adults were eligible with a body mass index of 30 or more, or 27 or more with at least one weight-related condition. People with diabetes were excluded. Of the 611 randomised, 407 received semaglutide and 204 received placebo [1].

Everyone followed the same programme. For the first 8 weeks they ate 1,000 to 1,200 kcal a day, provided as meal replacements such as shakes and bars. After that they moved to 1,200 to 1,800 kcal a day of ordinary food. Activity started at 100 minutes a week and rose by 25 minutes every 4 weeks to 200 minutes. Across the 68 weeks each person had 30 individual behavioural therapy visits [1].

What they found

The headline gap was 10.3 percentage points (95% CI −12.0 to −8.6). That figure counts everyone randomised, whether or not they stayed on treatment. A second analysis assuming everyone stayed on the assigned treatment gave −17.6% against −5.0% [1].

The completion numbers were high: 567 people (92.8%) finished the trial and 505 (82.7%) were still on treatment at the end [1].

How it sits next to STEP 1

In STEP 1, semaglutide 2.4 mg produced a 14.9% average loss against 2.4% on placebo with lifestyle counselling alone [2]. STEP 3 put the semaglutide result at 16.0% and the placebo result at 5.7% [1]. Both arms lost more here: the placebo group by more than 3 percentage points and the semaglutide group by about 1. The trials ran in different populations, so the comparison is a rough guide, not a controlled test.

Safety reported

Gastrointestinal events were the most common and were more frequent on semaglutide. Most were mild to moderate [1].

Serious events on semaglutide were most often hepatobiliary (2.5%, mainly gallstones), against none on placebo. In total, 3.4% of the semaglutide group stopped treatment because of gastrointestinal events, against none on placebo. Malignant neoplasms were reported in 3 people on semaglutide and 1 on placebo. There were no cases of acute pancreatitis and no deaths [1].

Caveats

• Sponsor. Novo Nordisk funded the trial, and its representatives were involved in design, conduct, analysis and manuscript approval. The sponsor also supplied the meal replacements [1].
• Mixed intervention. The trial cannot separate what the low-calorie diet start and the counselling each contributed in the placebo group, or how much each added alongside semaglutide [1].
• Length. At 68 weeks it did not show whether the 16% loss holds if treatment continues longer. The authors point to a longer trial then underway [1].
• Who was in it. About 76% of participants were White, all sites were in the US, and 77.4% of the semaglutide group and 88.2% of the placebo group were women [1].

What it means in practice

For a reader weighing this evidence, the result is about size and combination. With a structured programme and the drug together, roughly one in three people on semaglutide lost 20% or more of their weight in this trial, against about one in twenty-seven on placebo [1]. The study says nothing about starting, stopping or adjusting any medicine. Those decisions belong with a prescriber who knows the person's history.

What is still open

• How much of the 16.0% depends on the 30-visit programme, since the trial did not test the drug without it.
• How long the loss lasts once treatment or the programme ends. STEP 1's follow-up is the closest human evidence we cover [2].
• How the result looks in people outside the US or with diabetes, who were excluded here.

What this means

We read STEP 3 as showing that semaglutide's effect holds up against the strongest comparison a placebo arm can offer: a group that was also on an intensive diet and counselling programme lost 5.7%, and the drug group lost 16.0% [1]. The loss is large, the side effects are real and mostly gastrointestinal, and the manufacturer funded and helped run the trial. To disagree with this reading you would need a randomised trial showing that an equally intensive programme alone matches the drug, and this trial gives no sign of one.

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