What Is Semaglutide?
Semaglutide is a GLP-1 receptor agonist — a synthetic version of a naturally occurring gut hormone called glucagon-like peptide-1. It is the active molecule in two licensed medicines that have dominated the weight loss conversation in Ireland and globally over the past few years: Ozempic (licensed for type 2 diabetes) and Wegovy (licensed for obesity and weight management). Both are manufactured by Novo Nordisk.
The compound itself is not new. Semaglutide was first approved by the US FDA for type 2 diabetes in 2017. What changed the public conversation was the publication of the STEP clinical trial programme from 2021 onwards, which produced weight loss figures that were significantly higher than anything previously seen from a pharmacological agent. The STEP-1 trial result — nearly 15% mean body weight loss at 68 weeks — set a new benchmark for the entire field.
There is also an oral formulation of semaglutide (Rybelsus, 7mg and 14mg tablets) licensed for type 2 diabetes, though the injectable 2.4mg dose used in the STEP obesity trials is not available in oral form.
How Semaglutide Works
Semaglutide mimics GLP-1, a hormone released naturally by the gut after eating. It works through three primary pathways simultaneously:
The key structural advantage of semaglutide over earlier GLP-1 drugs like liraglutide is its half-life. A modification to the molecule allows it to bind to albumin (a blood protein), which means it is cleared from the body more slowly. The result is a weekly injection rather than a daily one, which matters substantially for adherence in long-term use.
Worth noting: GLP-1 receptors are also found in the brain's reward circuits. Research suggests semaglutide may reduce the hedonic drive to eat — the desire to eat for pleasure or habit rather than hunger. This may partly explain why many users report the medication "changing their relationship with food," not just reducing hunger signals.
The STEP Clinical Trial Programme
The STEP (Semaglutide Treatment Effect in People with Obesity) trials were a four-study Phase 3 programme designed to establish semaglutide 2.4mg as an obesity treatment, separate from its diabetes indication. All trials ran to 68 weeks and used once-weekly subcutaneous injection of semaglutide 2.4mg versus placebo, alongside lifestyle counselling.
| Trial | Population | N | Mean Weight Loss (Semaglutide) | Mean Weight Loss (Placebo) | Key Finding |
|---|---|---|---|---|---|
| STEP-1 | Adults with obesity/overweight, no T2D | 1,961 | −14.9% | −2.4% | Primary obesity trial; established the benchmark result |
| STEP-2 | Adults with obesity + type 2 diabetes | 1,210 | −9.6% | −3.4% | Lower effect in T2D population; still significant vs placebo |
| STEP-3 | Adults with obesity/overweight, no T2D + intensive behavioural therapy | 611 | −16.0% | −5.7% | Higher placebo response due to IBT; semaglutide still superior |
| STEP-4 | Adults who completed 20-week run-in on semaglutide | 803 | −7.9% (additional, from week 20) | +6.9% regain (placebo arm) | Weight regain on discontinuation; maintenance requires continuation |
Sources: Wilding et al. (STEP-1), Davies et al. (STEP-2), Wadden et al. (STEP-3), Rubino et al. (STEP-4). All published in New England Journal of Medicine, 2021. All trials 68 weeks; semaglutide dose 2.4mg s.c. once weekly.
STEP-1: The Primary Result
STEP-1 (Wilding et al., NEJM 2021) is the most cited of the four. It enrolled 1,961 adults with a BMI of 30 or above, or 27 or above with at least one weight-related comorbidity, who did not have type 2 diabetes. After 68 weeks, the semaglutide group achieved a mean body weight reduction of 14.9% compared to 2.4% for placebo. Over 69% of participants on semaglutide achieved at least 10% weight loss; 50% achieved at least 15%.
STEP-2: The Diabetes Population
STEP-2 (Davies et al., NEJM 2021) focused specifically on adults who had both obesity and type 2 diabetes — the population already being treated with Ozempic for glycaemic control. Weight loss was lower at 9.6% for semaglutide 2.4mg versus 3.4% for placebo. The attenuated response in people with T2D is consistent across the GLP-1 class and is thought to be related to underlying insulin resistance and the metabolic context of diabetes.
STEP-3: Adding Intensive Behavioural Therapy
STEP-3 (Wadden et al., NEJM 2021) combined semaglutide with intensive behavioural therapy (IBT) — regular counselling sessions on diet, physical activity, and behaviour change. Semaglutide plus IBT produced 16.0% weight loss. The placebo group, which also received IBT, achieved 5.7% — notably higher than the STEP-1 placebo arm, illustrating the real but modest standalone effect of structured behavioural support.
STEP-4: What Happens When You Stop
STEP-4 (Rubino et al., NEJM 2021) is the most instructive trial for anyone thinking about long-term use. All participants completed a 20-week run-in on semaglutide first, then were randomised to either continue semaglutide or switch to placebo for a further 48 weeks.
- Those who continued semaglutide lost an additional 7.9% of body weight over weeks 20–68.
- Those who switched to placebo regained approximately 6.9% — recovering roughly two-thirds of what they had lost.
The clinical implication of STEP-4: Weight loss with semaglutide is not a one-time reset. The underlying biology that drives weight regain — reduced satiety hormone signalling, metabolic adaptation — reasserts itself when the medication is discontinued. This is not specific to semaglutide; it reflects the chronic nature of obesity as a condition. It is relevant to conversations about long-term prescribing versus short-course use.
Semaglutide vs Tirzepatide vs Retatrutide
These three compounds are frequently discussed together as a generation of progressively more effective GLP-1-class agents. No head-to-head trials have been completed. The data below draws on each compound's own pivotal trial results. Population differences, trial durations, and dosing schedules mean direct comparison is approximate.
| Compound | Brand Name(s) | Mechanism | Pivotal Trial | Max Weight Loss | Duration | Status in Ireland |
|---|---|---|---|---|---|---|
| Semaglutide 2.4mg | Ozempic (T2D) Wegovy (obesity) |
GLP-1 agonist | STEP-1 | 14.9% | 68 weeks | Ozempic: HSE-listed for T2D. Wegovy: EU approved 2022, access in Ireland limited. |
| Tirzepatide 15mg | Mounjaro (T2D) Zepbound (obesity) |
GLP-1 + GIP dual agonist | SURMOUNT-1 | 22.5% | 72 weeks | Mounjaro: EMA approved for T2D. Zepbound: EU approval granted 2024. Access in Ireland via private prescription. |
| Retatrutide 12mg LY3437943 |
Not yet named (not approved) | GLP-1 + GIP + Glucagon triple agonist | Phase 2 NCT05019444 | 22.8% at 48 wk (curve not plateaued) | 48 weeks | Phase 3 trials ongoing. Not approved anywhere. |
These are not head-to-head results. Each trial enrolled different populations under different conditions. Comparisons are illustrative only.
Side Effects: What the STEP Trials Showed
The adverse event data from the STEP programme is well-documented. The side effect profile is consistent with the broader GLP-1 class and is primarily gastrointestinal:
- Nausea — the most commonly reported side effect, affecting 44% of participants in STEP-1 on semaglutide versus 16% on placebo. Usually most pronounced during dose escalation and tends to reduce over time.
- Vomiting — reported in approximately 24% of the semaglutide group in STEP-1, versus 6% placebo. Dose-dependent.
- Diarrhoea — around 30% in the semaglutide group versus 16% placebo in STEP-1. Generally mild to moderate.
- Constipation — reported in approximately 24% semaglutide versus 11% placebo. Related to slowed gastric motility.
- Injection site reactions — mild and consistent with other subcutaneous injectables.
- Headache and fatigue — reported at modestly higher rates in the semaglutide group.
- Gallbladder events — a small but noted increase in cholelithiasis (gallstones) in the semaglutide group. Relevant for anyone with a prior gallbladder history.
Serious adverse events were uncommon. Pancreatitis was numerically low in both arms. The trials included standard exclusions for people with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2 (MEN2), consistent with the product label. Overall discontinuation due to adverse events was around 7% in the semaglutide group across the STEP trials.
On muscle mass: All GLP-1 class agents produce some loss of lean mass alongside fat loss. In STEP-1, approximately 40% of weight lost was lean mass. Adequate protein intake and resistance training are commonly recommended in clinical guidelines alongside GLP-1 therapy to preserve muscle. This is an active area of research.
Availability in Ireland
Ozempic (Type 2 Diabetes)
Ozempic (semaglutide 0.5mg, 1mg, 2mg) is listed on the HSE Medicines Management Programme formulary for the management of type 2 diabetes in adults. It is available via GP prescription where clinically indicated. Ozempic has been subject to supply shortages globally since 2022–2023, partly driven by off-label weight loss demand, which affected availability through the HSE and pharmacy channels in Ireland.
Wegovy (Obesity)
Wegovy (semaglutide 2.4mg) received European Medicines Agency (EMA) approval in January 2022 for chronic weight management in adults with obesity (BMI ≥30) or overweight (BMI ≥27) with at least one weight-related comorbidity. However, EMA approval does not automatically mean immediate availability in all EU member states.
As of mid-2026, Wegovy is available in Ireland via private prescription. It is not currently reimbursed by the HSE under the General Medical Scheme (GMS) or Drug Payment Scheme (DPS) for the obesity indication. Private costs vary by pharmacy but are typically in the range of €250–€350 per month at the maintenance dose, before any private health insurance considerations.
The Prescribing Reality
In practice, Irish access to semaglutide for weight management has taken two routes:
- GP prescription (private): Some GPs prescribe Wegovy privately where patients meet the clinical criteria. Assessment varies by practice.
- Obesity medicine clinics: HSE-funded and private weight management clinics can prescribe. Waiting lists for HSE services can be lengthy.
There has been public and political discussion in Ireland about HSE reimbursement for Wegovy, similar to the debate that has played out in the NHS in the UK. As of mid-2026, a formal HSE reimbursement decision had not been made. The National Obesity Policy and Action Plan acknowledges the emerging evidence for pharmacotherapy, but cost and capacity constraints continue to shape access.
Frequently Asked Questions
What is semaglutide and how is it different from Ozempic and Wegovy?
Semaglutide is the active molecule. Ozempic and Wegovy are the brand names for different licensed uses at different doses. Ozempic (0.5mg–2mg) is licensed for type 2 diabetes. Wegovy (up to 2.4mg) is licensed for obesity and weight management. Same molecule, different indications, different dose ceilings.
Is Ozempic available on the HSE in Ireland?
Yes, Ozempic is HSE-listed for type 2 diabetes management. Wegovy for the obesity indication is not currently HSE-reimbursed and is available privately. This situation may change; the reimbursement question has been raised politically and is under ongoing review.
What weight loss did STEP-1 show?
STEP-1 showed a mean body weight reduction of 14.9% at 68 weeks for semaglutide 2.4mg versus 2.4% for placebo. More than half of participants on semaglutide achieved 15% or more body weight reduction.
What happens if you stop taking semaglutide?
STEP-4 showed that participants who discontinued semaglutide after initial weight loss regained approximately two-thirds of what they had lost within 48 weeks, while those who continued lost additional weight. This is consistent with current understanding of obesity as a chronic condition requiring ongoing management.
How does semaglutide compare to tirzepatide and retatrutide?
Based on each compound's own trial data (not head-to-head): semaglutide 2.4mg produced 14.9% weight loss in STEP-1 at 68 weeks. Tirzepatide 15mg produced 22.5% in SURMOUNT-1 at 72 weeks. Retatrutide 12mg produced 22.8% in its Phase 2 trial at 48 weeks with the curve still declining. These figures are not directly comparable due to different trial designs and populations.
Research Updates
This section is updated as significant new publications emerge. Last review: July 2026.
- 2024 — SELECT cardiovascular trial: The SELECT trial (NEJM 2023) enrolled over 17,600 adults with overweight or obesity and established cardiovascular disease, without T2D. Semaglutide 2.4mg reduced major adverse cardiovascular events (MACE) by 20% versus placebo over approximately 3.3 years. This was a landmark finding: it established cardiovascular benefit independent of the diabetes indication and is expected to inform future prescribing guidelines.
- 2025 — Semaglutide and kidney outcomes: The FLOW trial (NEJM 2024) demonstrated that semaglutide 1mg reduced the progression of kidney disease in people with T2D and chronic kidney disease, with a 24% reduction in the primary kidney endpoint. Further expanding the evidence base beyond weight and glycaemia.
- July 2026: No major new STEP programme publications. SELECT and FLOW findings are the most recent additions to the evidence base. Access and reimbursement debates in Ireland ongoing.