Orforglipron vs Wegovy vs Mounjaro: How These Weight-Loss Medicines Compare

The UK weight-management landscape has evolved rapidly in recent years, driven by the approval of injectable incretin-based medicines such as Wegovy (semaglutide) and Mounjaro (tirzepatide). Alongside these established treatments, a newer medicine - Orforglipron - is currently progressing through late-stage clinical development.

Although all three medicines influence appetite and satiety via incretin pathways, they differ in how they work, how they are taken, and the degree of weight loss observed in clinical trials. This article provides a direct comparison of Orforglipron, Wegovy, and Mounjaro, focusing on clinical evidence and UK regulatory status.

Mechanism of action: key differences

All three medicines act on hormonal pathways involved in appetite regulation, but they do so using distinct biological approaches.

Wegovy is a glucagon-like peptide-1 (GLP-1) receptor agonist. It mimics the naturally occurring GLP-1 hormone, increasing feelings of fullness and slowing gastric emptying. Semaglutide is a peptide-based medicine with a structure similar to the human hormone, which is why it must be administered by injection.

Mounjaro acts on two incretin pathways. It is a dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist. The GLP-1 component suppresses appetite, while GIP receptor activation is thought to enhance metabolic regulation. Like Wegovy, tirzepatide is a peptide-based injectable treatment.

Orforglipron differs at a molecular level. It is a non-peptide, small-molecule GLP-1 receptor agonist. Its chemical structure allows it to survive digestion and be absorbed orally, while still activating the same GLP-1 receptor targeted by injectable medicines.

In practical terms, the primary distinction lies not in the biological target, but in molecular design and route of administration.

Weight-loss outcomes: evidence from trials

The weight-loss efficacy of Wegovy and Mounjaro is supported by large Phase 3 clinical trials, while evidence for Orforglipron currently comes from late-stage investigational studies.

In the STEP 1 trial, adults without diabetes taking Wegovy achieved an average weight reduction of around 15% over 68 weeks. This trial established semaglutide as a high-efficacy GLP-1-based treatment for obesity.

Mounjaro demonstrated greater average weight loss in the SURMOUNT-1 trial. Participants receiving the highest dose achieved mean weight reductions of approximately 22.5% over 72 weeks. This difference is widely attributed to tirzepatide’s dual GIP and GLP-1 mechanism.

For Orforglipron, Phase 3 data from the ATTAIN programme suggests mean weight loss of around 12–13% at higher doses over a similar time frame. While clinically meaningful, these results are lower than those reported for injectable semaglutide and tirzepatide.

It is important to note that Orforglipron data remains trial-based and has not yet translated into real-world UK prescribing.

Side effects and tolerability

Across all three medicines, gastrointestinal side effects are the most commonly reported adverse events.

Nausea, vomiting, diarrhoea, and constipation occur frequently during dose escalation with Wegovy and Mounjaro, and similar patterns have been observed in Orforglipron trials. These effects are generally dose-dependent and often lessen over time.

Discontinuation rates due to side effects appear broadly comparable across the three medicines in clinical trials, typically in the region of 10–15%. Current evidence does not suggest that Orforglipron offers a markedly different tolerability profile compared with injectable GLP-1-based treatments, despite its oral formulation.

Dosing and administration

Administration is one of the clearest practical differences between these medicines.

Wegovy and Mounjaro are administered as once-weekly subcutaneous injections, usually delivered via pre-filled pen devices.

Orforglipron is taken as a once-daily oral tablet. In clinical trials, it was taken with or without food, distinguishing it from oral semaglutide formulations that require strict fasting conditions.

While oral dosing may improve convenience for some patients, current trial data does not suggest superior weight-loss outcomes compared with injectable options.

UK regulatory status

From a UK regulatory perspective, the three medicines are at very different stages.

Wegovy and Mounjaro both hold marketing authorisation from the Medicines and Healthcare products Regulatory Agency (MHRA) for weight management in eligible adults. NICE has issued technology appraisal guidance recommending their use within the NHS for defined patient groups, typically those with higher BMI thresholds and obesity-related comorbidities.

Orforglipron does not currently have MHRA approval and cannot be prescribed in the UK. NICE appraisal has not yet been completed and would only proceed following regulatory authorisation.

As such, Orforglipron remains an investigational medicine rather than an available treatment option.

What Orforglipron could change - if approved

If approved, Orforglipron could represent the first high-efficacy oral GLP-1 receptor agonist for weight management in the UK. Its primary distinction would be oral administration rather than superior weight-loss outcomes.

Based on current evidence, injectable therapies - particularly tirzepatide - continue to demonstrate greater average reductions in body weight. Orforglipron may therefore occupy a complementary role, offering an alternative for those unable or unwilling to use injections.

FeatureWegovy (Semaglutide)Mounjaro (Tirzepatide)Orforglipron (Investigational)
Drug classGLP-1 receptor agonistDual GIP / GLP-1 receptor agonistGLP-1 receptor agonist (non-peptide)
Molecular typePeptidePeptideSmall-molecule (non-peptide)
Route of administrationSubcutaneous injectionSubcutaneous injectionOral tablet
Dosing frequencyOnce weeklyOnce weeklyOnce daily
Food restrictionsNoneNoneNone reported in trials
Mean weight loss (trials)~15% at 68 weeks (STEP 1)~22.5% at 72 weeks (SURMOUNT-1)~12–13% at ~72 weeks (ATTAIN)
Primary mechanismAppetite suppression via GLP-1Appetite suppression + metabolic effects via GIP and GLP-1Appetite suppression via GLP-1
Common side effectsNausea, vomiting, diarrhoea, constipationNausea, vomiting, diarrhoea, constipationNausea, vomiting, diarrhoea, constipation
Discontinuation due to side effects~10–15% (trial data)~10–15% (trial data)~10–15% (dose-dependent, trials)
MHRA approval (UK)YesYesNo
NICE guidanceYesYesNo (not yet appraised)
Current UK availabilityPrescription onlyPrescription onlyNot available

Pharmacist comment

Alessandro Grenci, Superintendent Pharmacist at medino comments on the developments of weight loss medications:

"Wegovy and Mounjaro are currently the most effective prescription weight-loss medicines available in the UK, with strong evidence supporting their use under appropriate medical supervision. Orforglipron is an interesting development because it uses a different molecular approach to deliver GLP-1 activity in tablet form. However, until it receives regulatory approval, it remains an investigational option. Any future role it plays will depend on how its real-world effectiveness and tolerability compare with established injectable treatments."

Final thoughts

Wegovy and Mounjaro remain the established, evidence-based options for medical weight management in the UK, with tirzepatide demonstrating the greatest average weight loss in clinical trials. Orforglipron represents a promising future alternative that prioritises oral administration, but current data suggest this convenience may come with lower peak efficacy compared with injectable therapies.

Sources

Written by Christian Jakobsson
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