STEP 5: what two years of semaglutide did to body weight

Most semaglutide obesity trials stopped at 68 weeks. STEP 5 ran for 104. At two years, average body weight was down 15.2% on semaglutide 2.4 mg and 2.6% on placebo, and the loss had stopped falling long before the end [1].

Why this study matters

A short trial leaves open whether a large early loss lasts. STEP 5 was designed to answer that for continued treatment, and it was the longest semaglutide weight-management trial at the time of publication. Our breakdowns of STEP 1 and the STEP 3 intensive programme trial cover the 68-week results. The wider picture is in the semaglutide evidence guide.

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 such as high blood pressure, abnormal blood fats, sleep apnoea or cardiovascular disease. They also needed at least one self-reported unsuccessful diet attempt. People with diabetes were excluded. The sites were in Canada, Italy, Hungary, Spain and the United States [1].

In total, 304 people were randomised, 152 to each arm. Of these, 282 (92.8%) completed the trial and 243 (79.9%) were still on treatment at the end [1].

Both groups also received a behavioural intervention. A dietitian or similarly qualified professional counselled each person every 4 weeks, in person or by phone, on a reduced-calorie diet (a 500 kcal daily deficit relative to estimated needs) and on raising activity, with 150 minutes a week encouraged. Both were recorded daily [1].

What they found

The headline gap was 12.6 percentage points (95% CI −15.3 to −9.8). That figure counts everyone randomised, whether or not they stayed on treatment. A second analysis assuming everyone took treatment as intended gave −16.7% against −0.6% [1].

The percentages for 5%, 10%, 15% and 20% loss are among people with a weight measurement at week 104: 144 on semaglutide and 128 on placebo. The 20% threshold was not part of the formal statistical testing [1].

Did the weight stay off?

On semaglutide, average loss was 15.6% at week 52 and 15.2% at week 104. The authors describe a plateau after about week 60, held for the rest of the study [1]. For comparison, STEP 1 reported 14.9% at 68 weeks [2].

This is a statement about people who kept taking the drug. STEP 5 did not stop treatment. The authors point to the STEP 4 withdrawal trial and the STEP 1 follow-up, both of which showed weight regain after treatment ended [1].

Other measures

Compared with placebo, semaglutide was also linked to lower HbA1c, fasting glucose, triglycerides and C-reactive protein. These were supportive secondary endpoints, not adjusted for multiple comparisons [1].

In an exploratory look at people with prediabetes at the start who had a week 104 assessment, 59 of 74 (79.7%) on semaglutide were back in the normal glucose range, against 20 of 54 (37.0%) on placebo. The authors say whether this delays or prevents type 2 diabetes needs confirming [1].

Safety reported

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

Gastrointestinal events led to stopping treatment in 6 people (3.9%) on semaglutide and 1 (0.7%) on placebo. Hypoglycaemia was reported by 4 people on semaglutide and none on placebo. There was no acute pancreatitis in either group. One person on semaglutide died of a heart attack. An independent committee judged the death unrelated to the trial product [1].

Caveats

• Sponsor. Novo Nordisk funded the trial. The funder designed it, oversaw its conduct and analysed the data, and some authors work for the company [1].
• Size. 304 people is far smaller than the 68-week STEP trials, so subgroup and safety signals are less precise [1].
• Who was in it. Most participants were female and 93.1% were white, which the authors list as a limitation [1].
• Structured support. Everyone had regular dietitian counselling, which is not typical of routine care, so real-world results may differ [1].
• Different trials. Comparing STEP 5 with STEP 1 is a rough guide only, because they were separate trials [1][2].

What it means in practice

For a reader weighing this evidence, the result is about duration. Two years of continued treatment kept the average loss near its 52-week level in a group with high completion. The trial 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 long the plateau lasts beyond two years.
• Whether the weight-related health benefits in the supportive measures translate into fewer clinical events. STEP 5 was not designed to show that.
• How results look in people with diabetes or in more diverse groups.

What this means

We read STEP 5 as showing that, among people who stayed in a two-year trial with regular counselling, semaglutide 2.4 mg produced a large average loss that did not slip back between one year and two [1]. Side effects were common, mostly gastrointestinal, and the manufacturer designed and funded the trial. To disagree with this reading you would need long-term data showing average weight returning while treatment continues, and this trial gives no sign of that.

Educational content only — not medical advice. Many peptides discussed on HPR are not approved for human use. Talk to a qualified clinician before making any decision about your health.