Semaglutide: Science, Results and Clinical Trials

What is semaglutide?

Semaglutide is a GLP-1 receptor agonist – a modified peptide that stimulates glucose-dependent insulin secretion, suppresses glucagon, delays gastric emptying and reduces appetite.

Because of its long half-life (~175 hours), it is administered once a week under the skin.

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The largest and longest-running semaglutide (2.4 mg) trial: the SELECT trial

Overview

• The most extensive, long-term study on the safety and efficacy of semaglutide 2.4 mg administered weekly.

• Participants: 17,604 overweight adults with established cardiovascular disease, without diabetes.

• Duration: follow-up of up to 4 years (≈208 weeks).

Main results

Reduction in cardiovascular events (MACE)

• Semaglutide reduced the risk of major adverse cardiovascular events (cardiovascular death, non-fatal myocardial infarction or stroke) by 20% (6.5% versus 8.0%; HR 0.80; 95% CI 0.72–0.90; P<0.001) compared with placebo.

Continued weight loss

• Mean weight loss was tracked for up to 4 years, remaining consistently above the difference from placebo. All demographic groups showed significant results.

Safety and tolerability

• Gastrointestinal adverse events: more common with semaglutide (RR ~1.47); low rates of discontinuation due to side effects.

• Serious adverse events: low rate (~9%) in both the semaglutide group and the placebo group.

• After treatment discontinuation, weight regain is significant.

In all subgroups

• The result is consistent regardless of sex, race, BMI or glycaemic status.

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Summary of this Phase III/IV programme

Category	Result
Number of participants	17.604
Follow-up	Up to 4 years
Weight loss	Stable means above 4 g at 2.4 mg
Reduction in MACE risk	–20% (HR 0.80)
Adverse events	Gastrointestinal symptoms common, but a small % of serious events
Discontinuation	Regain on discontinuation

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Why this programme matters:

• It surpasses all other randomised controlled trial programmes (STEP trials) in size and duration and, as such, provides the strongest basis for assessing long-term safety and sustained effect.

• The SELECT study reflects real patients with chronic heart disease but without diabetes, demonstrating the benefits of semaglutide even in the absence of diabetic disease.
  
  

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Clinical data: STEP programmes

STEP 1 (68 weeks)

Includes 1,961 adults with BMI ≥ 30 or ≥ 27 with comorbidity, without diabetes. Dose 2.4 mg once a week + behavioural therapy.

Mean weight loss: −14.9% with semaglutide versus −2.4% with placebo (difference −12.4%).

Loss ≥ 5%: 86.6% of the active group versus 47.6% of the placebo group.

STEP 5 (104 weeks)

Continuation of the STEP trials – mean weight loss 15.2% up to week 104. 44.2% achieved weight loss ≥10%, 11% ≥15%, 4.9% ≥25% from baseline.

The study recorded minimal weight regain between weeks 52 and 104.

STEP UP (7.2 mg dose)

New study (72 weeks) with 1,407 participants:

Mean weight loss: 20.7% (7.2 mg) versus 17.5% (2.4 mg) and 2.4% (placebo). 33.2% achieved weight loss ≥25%.

Real-world practice: Cohort analysis

The cohort study includes 175 patients:

Weight loss: 5.9% after 3 months, 10.9% after 6 months, according to data from randomised controlled trials.

Systematic review (science)

One study summarises data from multiple randomised controlled trials: in the studies semaglutide reduced weight, improved HbA1c, blood pressure and lipids and was associated with a reduction in MACE risk, with the effect not depending solely on the amount of weight loss.

Safety and side effects

• The most common adverse events – nausea, vomiting, diarrhoea, constipation.

• Serious warnings: possible risk of pancreatitis, gallstones and a rare risk in patients with medullary thyroid carcinoma or MEN2 syndrome.

• After treatment discontinuation – risk of weight regain: participants lost 17.3% on average over 68 weeks, but regained about 11.6% by week 120 after stopping treatment.

• Real-world conditions – in cohort studies with mass use, only ~50% of patients remain on the full dose for 1 year, the mean weight loss is around 6.9% due to early discontinuation or low doses, but with a stable dose and maintenance, the results resemble data from randomised controlled trials (~15–18%).

• Muscle mass risk – the studies also recorded loss of lean muscle mass.

Other research data

• Semaglutide demonstrates anti-inflammatory action, independent of weight: it affects MASLD, metabolic inflammation and cellular regulation in animal models and patients .

• New studies show possible benefits in patients with type 1 diabetes and obesity: improved glycaemic control and weight loss among those using semaglutide plus insulin without an increased risk of hypoglycaemia. , although additional large randomised controlled trials are needed.