GLP-1 receptor agonists, better known under the brand names used for diabetes and obesity treatment, have changed how medicine approaches weight reduction in recent years. We look at what the clinical trials actually show.
TL;DR — key takeaways
Semaglutide belongs to a class of drugs called GLP-1 (glucagon-like peptide-1) receptor agonists — it mimics the action of a natural gut hormone released after a meal, which slows gastric emptying, increases the feeling of fullness, and supports blood glucose regulation. The drug was originally developed to treat type 2 diabetes, and its pronounced effect on body weight, observed as a side effect in diabetes trials, led to separate studies and approval for obesity treatment.
This isn't a new, experimental drug
GLP-1 agonists have been used to treat diabetes for more than fifteen years — what's relatively new is their approval and widespread use specifically for treating obesity in people without diabetes.
The randomized STEP 1 trial, published in the New England Journal of Medicine, was one of the first large studies to evaluate semaglutide specifically for obesity treatment in people without diabetes — and its results, showing substantially greater weight loss than previously available drugs, were one of the drivers of the current surge of interest in this drug class.
Once-Weekly Semaglutide in Adults with Overweight or Obesity
Strong evidenceWilding JPH, Batterham RL, Calanna S, et al. · New England Journal of Medicine · 2021
Participants taking semaglutide combined with lifestyle changes lost an average of about 15% of body weight over 68 weeks, significantly more than the placebo group — a result substantially exceeding the effects of previously available obesity drugs.
View studyUnlike many earlier obesity drugs, which acted mainly by stimulating the central nervous system, semaglutide works largely at the level of appetite and satiety regulation via GLP-1 receptors present both in the digestive tract and in the hypothalamus. Slowing gastric emptying and strengthening satiety signals means patients subjectively feel less hungry and full up faster, which makes it easier to maintain a caloric deficit without experiencing it as a constant fight against hunger.
Gastrointestinal complaints are the most common side effect
Nausea, vomiting and diarrhea, especially in the first weeks or with too-rapid dose increases, are the most commonly reported side effects. Rarer but more serious risks include pancreatitis and, in rare cases, gallbladder problems — the drug should be used only under a doctor's supervision.
An important, still-open question is how durable the effect is after stopping the drug — available data suggests a significant portion of lost weight returns after ending therapy, which leads some clinicians to treat obesity treatment with GLP-1 agonists as a long-term therapy, similar to treatment of other chronic diseases, rather than a one-off course.
GLP-1 drugs are a 'shortcut' that removes the need to change diet and physical activity.
In all major clinical trials, including STEP 1, the drug was used together with lifestyle change, not on its own — and behavioral changes themselves remain key to maintaining the effect, especially after the drug is potentially discontinued.
Semaglutide isn't the only drug in this class to have changed obesity treatment. Tirzepatide acts on two receptors simultaneously — GLP-1 and GIP (glucose-dependent insulinotropic polypeptide) — which in clinical trials translated into even greater weight loss than semaglutide alone, though direct head-to-head comparisons between the drugs are still scarce.
Tirzepatide Once Weekly for the Treatment of Obesity
Strong evidenceJastreboff AM, Aronne LJ, Ahmad NN, et al. · New England Journal of Medicine · 2022
In the SURMOUNT-1 trial, participants taking the highest dose of tirzepatide lost an average of about 21% of body weight over 72 weeks — a result significantly higher than in the STEP 1 trial for semaglutide, though the trials did not compare the drugs directly against each other in a single study.
View studyThe choice between the available drugs in this class — like the choice of whether to start such therapy at all — shouldn't rest solely on comparing weight-loss percentages from different studies, since differences in participant populations and protocols make direct comparison difficult. The decision belongs to the treating physician, weighing side-effect profile, availability and the patient's individual situation.
GLP-1 agonists represent a real, well-documented breakthrough in pharmacological obesity treatment, but they aren't a universal solution free of trade-offs — the decision to start therapy should be made together with a doctor, with full awareness of potential side effects and the likely need for long-term use.
What we're seeing in clinics today isn't a fad, but a real shift in the available tools for treating obesity — the question that remains open is how long patients should stay on them and what happens after they stop.
dr Piotr Zieliński, VitMode editorial team
No — it's a prescription-only drug, requiring qualification and a doctor's supervision because of potential side effects and the need for individual dose adjustment.
Available data suggests a significant portion of lost weight can return after stopping therapy, which is why many clinicians treat obesity treatment with this drug class as a long-term therapy.
No — people with a history of pancreatitis, certain thyroid cancers in their family history, or other contraindications should avoid this drug; qualification is always carried out by a doctor.
dr Piotr Zieliński
Specialist physician in endocrinology, scientific consultant
Piotr reviews content on hormones, metabolic health and supplement pharmacology.
4.6Two opposing hormones that regulate hunger and satiety — understanding how they work explains why losing weight is physiologically harder than a simple calorie-balance model suggests.
4.6A cluster of five risk factors — from abdominal obesity to elevated triglycerides — that multiplies the risk of type 2 diabetes and cardiovascular disease, but is largely modifiable through lifestyle change.
4.6Fat tissue that accumulates around the internal organs of the abdominal cavity is metabolically far more active and harmful than subcutaneous fat — even though the two can look similar from the outside.
4.6A chronic disease linked to excess body fat — and its relationship with mortality, mapped in the largest available meta-analysis covering over 10 million participants, has the shape of a curve, not a straight line.
Kasia W. 2 weeks ago
Very clearly explained, especially the interactions section — I hadn't seen it laid out this well anywhere else.
Marek T. a month ago
Are you planning to update this with the newest study from this year? I saw an interesting meta-analysis.
