Semaglutide and GLP‑1 receptor agonism: what the STEP trials established

Semaglutide is one of the most thoroughly studied peptides in modern medicine. Originally developed for type 2 diabetes, it was then tested for weight management in the STEP programme, a series of large phase 3 trials. This article explains how the molecule was designed, summarises what the principal STEP trials measured, and sets out the questions the evidence leaves open.

Semaglutide is a licensed prescription medicine. This article describes published trial results for scientific understanding and is not a guide to treatment.

From a gut hormone to a weekly peptide

Glucagon-like peptide-1 (GLP-1) is a hormone released from the gut after eating. Acting through a single receptor, the GLP-1 receptor, it increases glucose-dependent insulin release, reduces glucagon secretion and slows gastric emptying. It also reduces food intake, through receptors in the brain and in the nerves connecting gut and brain^[1].

Native GLP-1 is short-lived in the circulation, which limits its usefulness as a medicine. Semaglutide was designed to be stable against metabolic degradation and to bind strongly to serum albumin^[2]. Compared with human GLP-1, it carries two amino-acid substitutions (Aib at position 8 and arginine at position 34) and a fatty-acid side chain attached at lysine 26 through a linker^[2]. The fatty-acid moiety and its linker were the key features giving high albumin affinity and prolonged exposure. In mini-pigs the plasma half-life after intravenous dosing was 46.1 hours^[2]. In people, semaglutide has a half-life of about seven days, which allows once-weekly administration^[3].

How it reduces body weight

The weight effect appears to come mainly from reduced food intake. In a 20-week randomised study of 72 adults with obesity, ad libitum energy intake at a test lunch was 35% lower with semaglutide than with placebo. Participants reported less hunger, greater fullness, better control of eating and fewer food cravings. A small increase in a measure of gastric emptying was no longer significant after adjusting for body weight^[4]. These findings support a central effect on appetite rather than a primarily gastric mechanism.

The STEP trials at a glance

The table summarises the headline result of each trial discussed here. All tested once-weekly subcutaneous semaglutide 2.4 mg against placebo alongside lifestyle intervention, unless noted.

STEP 1: the reference trial

STEP 1 enrolled 1,961 adults with a body mass index of 30 or more, or 27 or more with a weight-related condition, and no diabetes. Over 68 weeks, mean body weight fell by 14.9% with semaglutide and 2.4% with placebo, a treatment difference of 12.4 percentage points. Half of participants on semaglutide (50.5%) lost at least 15% of their body weight, compared with 4.9% on placebo^[5].

The trial used a "treatment policy" estimand, analysing all randomised participants regardless of whether they stopped treatment. This gives a more conservative and realistic estimate than analysing only those who completed treatment.

STEP 2: people with type 2 diabetes

Weight loss was smaller in people with type 2 diabetes: 9.6% with semaglutide 2.4 mg against 3.4% with placebo^[6]. Smaller weight loss in diabetes is a recurring finding with weight-management medicines. The trial also included a semaglutide 1.0 mg arm, the dose then used for diabetes treatment, allowing a comparison between doses.

STEP 3 and STEP 5: intensity and duration

STEP 3 combined semaglutide with an intensive behavioural programme of 30 counselling sessions and an initial eight-week low-calorie diet. The placebo group lost 5.7% of body weight, showing what intensive lifestyle support can achieve alone, while the semaglutide group lost 16.0%^[7]. STEP 5 extended follow-up to two years and found that weight loss was maintained over that period, at 15.2% compared with 2.6%^[9].

What happens when treatment stops

Two studies addressed this question directly. In STEP 4, all participants received semaglutide for 20 weeks, losing an average of 10.6%. They were then randomised either to continue or to switch to placebo. Over the next 48 weeks, those who continued lost a further 7.9%, while those switched to placebo regained 6.9%^[8].

The STEP 1 extension followed 327 participants for a year after all treatment, including lifestyle support, had ended. By week 120, those who had taken semaglutide had regained 11.6 percentage points of their earlier 17.3% loss, leaving a net loss of 5.6%. Most improvements in cardiometabolic risk factors also returned towards baseline^[11].

Beyond body weight: cardiovascular outcomes

Weight loss is a surrogate outcome. The SELECT trial asked whether semaglutide reduced cardiovascular events. It enrolled 17,604 people aged 45 or over with established cardiovascular disease and overweight or obesity, but without diabetes. Over a mean follow-up of about 40 months, the combined outcome of cardiovascular death, non-fatal heart attack or non-fatal stroke occurred in 6.5% of the semaglutide group and 8.0% of the placebo group, a hazard ratio of 0.80^[12].

Tolerability

Gastrointestinal effects, chiefly nausea and diarrhoea, were the most common adverse events across the programme. In STEP 1 they were typically transient and mild to moderate, but 4.5% of participants on semaglutide stopped treatment because of them, compared with 0.8% on placebo^[5]. Gastrointestinal events were reported by 63.5% on semaglutide 2.4 mg in STEP 2, against 34.3% on placebo^[6], and by 82.2% against 53.9% over two years in STEP 5^[9]. In SELECT, adverse events led to permanent discontinuation in 16.6% of the semaglutide group and 8.2% of the placebo group^[12].

Reading the evidence critically

• Sponsorship. The STEP 1 and STEP 2 papers report funding by the manufacturer, Novo Nordisk. The trials were large, double-blind and registered, which limits the scope for bias, but independent replication remains valuable.
• Populations. Participants were mostly women (around four in five in STEP 3, STEP 4 and STEP 5), and 93% of STEP 5 participants were white. Results may not apply equally to every group.
• Co-interventions. Every STEP trial combined the drug with lifestyle support, so the results describe semaglutide plus lifestyle intervention, not the drug alone.
• Surrogate versus hard outcomes. Weight change is well established. Evidence on cardiovascular events comes from SELECT, in a population with existing cardiovascular disease.

Summary

The STEP programme established that once-weekly semaglutide, alongside lifestyle intervention, produces substantial and sustained weight loss in controlled trials, with smaller effects in people with type 2 diabetes. It also showed that much of the weight is regained when treatment stops. SELECT extended the evidence to cardiovascular outcomes in people with established heart disease. Together, these trials make semaglutide one of the best-documented examples of how a naturally occurring peptide can be engineered into a long-acting research and therapeutic molecule.