The STEP-1 Extension Data Should Change How We Open Every Semaglutide Conversation

What the STEP 1 extension measured

STEP 1 randomized 1,961 adults with a body mass index of 30 or higher, or 27 or higher with at least one weight-related condition, and without diabetes, to 68 weeks of once-weekly semaglutide 2.4 mg or placebo, both alongside a lifestyle intervention. Mean weight change at week 68 was -14.9% with semaglutide versus -2.4% with placebo [2].

At week 68, treatment and the lifestyle intervention stopped. A subset of 327 participants who completed the main phase was then followed off treatment for another year [1]. In that subset, mean weight loss from week 0 to week 68 was 17.3% with semaglutide and 2.0% with placebo. By week 120, semaglutide participants had regained 11.6 percentage points of that prior loss (SD 7.7) and placebo participants 1.9 points (SD 4.8), leaving net losses of 5.6% and 0.1% from baseline [1]. Cardiometabolic improvements seen with semaglutide by week 68 reverted toward baseline at week 120 for most variables [1].

The authors concluded that one year after withdrawal participants regained two-thirds of their prior weight loss, with similar changes in cardiometabolic variables, and that the findings confirm the chronicity of obesity and suggest ongoing treatment is required to maintain improvements in weight and health [1]. All analyses in the extension were exploratory, and the figures come from a 327-person subset [1].

What continuing treatment looked like

STEP 5 followed 304 adults for 104 weeks: mean weight change was -15.2% with semaglutide 2.4 mg versus -2.6% with placebo, a difference of 12.6 percentage points, and 77.1% of the semaglutide group lost at least 5% of body weight versus 34.4% on placebo [4].

STEP 4 took 803 adults who had reached the 2.4 mg dose during a 20-week run-in and randomized them to continue semaglutide or switch to placebo for 48 weeks. Those who continued lost a further 7.9% of body weight; those switched to placebo gained 6.9%, a difference of 14.8 percentage points [3].

STEP 5 shows the loss sustained over two years on treatment, and STEP 4 compares continuing with switching to placebo directly [3][4]. In the extension, both semaglutide and the lifestyle intervention were discontinued at week 68, so it does not show whether a lifestyle program continued after withdrawal would preserve the loss [1].

What the Wegovy label says about duration

The Wegovy label describes the injection as an adjunct to a reduced-calorie diet and increased physical activity, indicated to 'reduce excess body weight and maintain weight reduction long term' in adults and children aged 12 and older with obesity, in adults with overweight plus at least one weight-related condition, and to reduce the risk of major adverse cardiovascular events in adults with established cardiovascular disease and either obesity or overweight [5].

The label gives the maintenance dose for adults as 1.7 mg or 2.4 mg once weekly, with 2.4 mg recommended, and says the dose may be increased to a maximum of 7.2 mg weekly for patients who tolerate 2.4 mg for at least 4 weeks and need additional weight reduction [5].

The cardiovascular dimension

SELECT randomized 17,604 adults aged 45 or older with established cardiovascular disease and a body mass index of 27 or higher, without diabetes, to semaglutide 2.4 mg or placebo. The primary composite of cardiovascular death, nonfatal heart attack or nonfatal stroke occurred in 6.5% of the semaglutide group and 8.0% of the placebo group, hazard ratio 0.80, over a mean follow-up of 39.8 months [6]. The Wegovy label carries that cardiovascular risk reduction indication [5]. The STEP 1 extension reported weight and cardiometabolic risk factors after withdrawal, not cardiovascular events [1].