Semaglutide and tirzepatide are the two medicines most patients have heard about in the current wave of injectable weight-management treatments. They are closely related in what they do but distinct in how they do it, in their trial evidence, and in how they are used in UK practice. This article walks through both — what makes each molecule different, what the trials showed, and how a clinician thinks about choosing between them.
How GLP-1 receptor agonists work — quick recap
GLP-1 (glucagon-like peptide-1) is a hormone released by the small intestine after a meal. It signals to the brain to reduce appetite, slows gastric emptying so the stomach empties more gradually, and helps regulate the release of insulin and glucagon from the pancreas. A GLP-1 receptor agonist is a medicine engineered to mimic that natural hormone but resist rapid breakdown, so it can be dosed once weekly or once daily instead of every few minutes. If you want the fuller mechanism, our explainer on GLP-1 receptor agonists covers it in more depth.
What makes tirzepatide a dual agonist (GLP-1 + GIP)
Semaglutide — the active ingredient in Wegovy, Ozempic and the oral tablet Rybelsus — acts on the GLP-1 receptor only. Tirzepatide, the active ingredient in Mounjaro, is different. It is what pharmacologists call a dual agonist: a single molecule that binds and activates two receptors — the GLP-1 receptor and the GIP (glucose-dependent insulinotropic polypeptide) receptor.
GIP is another incretin hormone, released from the upper small intestine after eating. Like GLP-1, it contributes to insulin release when blood glucose rises. Its role in appetite and body-weight regulation is more complicated and still being characterised, but adding GIP activity to GLP-1 activity in the same molecule appears to produce a stronger overall effect on weight and glucose than GLP-1 activity alone. That is the pharmacological premise of tirzepatide as a class of its own — sometimes called "twincretin" therapy.
Semaglutide and tirzepatide also differ in structure. Semaglutide is a modified peptide closely related to native GLP-1; tirzepatide is a more heavily engineered peptide designed to fit both receptors. That difference in molecular design contributes to their different pharmacokinetic profiles and their side-effect distributions.
UK licensing and what a clinician can prescribe
Both molecules have UK marketing authorisations, but their licensed indications differ by brand. Semaglutide is licensed under the Wegovy brand for weight management in adults meeting specific BMI criteria — usually a BMI at or above 30, or at or above 27 with a weight-related comorbidity. It is also licensed for type 2 diabetes under other brands and as an oral tablet. Tirzepatide is licensed under the Mounjaro brand for type 2 diabetes and, more recently, for weight management with broadly similar BMI thresholds. Exact eligibility, dose and duration are set out by the MHRA and reflected in the BNF and NICE guidance. A UK-registered clinician prescribes within the licence and the local access pathway.
Both use a slow titration schedule — starting at a low dose, stepping up every four weeks, and reaching a maintenance dose after several months. That schedule is not optional decoration; it is the reason side effects stay tolerable for most patients. Skipping steps or self-adjusting doses is not appropriate. Our related article covers when a Mounjaro dose is stepped up in more detail.
Trial-level signals — STEP and SURMOUNT
The most cited comparison of the two comes from their flagship weight-management trials. Semaglutide was studied in the STEP programme; the STEP-1 trial reported mean weight loss of approximately 15 percent from baseline over 68 weeks with semaglutide 2.4 mg once weekly plus lifestyle support. Tirzepatide was studied in the SURMOUNT programme; SURMOUNT-1 reported mean weight loss of approximately 22 percent at the highest tirzepatide dose of 15 mg once weekly over 72 weeks, again with lifestyle support.
Two important caveats on those numbers. First, they come from separate trials with different populations, so they are indicative rather than a direct head-to-head. There have been more recent trials with head-to-head designs that broadly support the direction of that signal, but the point stands that trial-level averages are population estimates. Second, individual response is highly variable. Some patients on semaglutide lose more than the average tirzepatide response; some patients on tirzepatide plateau earlier than the average semaglutide response. A number is not a promise.
Side-effect profiles — what the BNF and NICE describe
The two share most of their common side effects because both act on GLP-1 signalling and both slow gastric emptying. Nausea, constipation, diarrhoea, reflux and occasional vomiting are the most commonly reported. They are usually worst in the days after a dose increase and settle over the following weeks. Advice on hydration, meal size and pacing often helps as much as anti-emetic medication.
Less common but recognised concerns for both include acute pancreatitis, gallbladder events (particularly with larger amounts of weight loss), and significant dehydration if vomiting or diarrhoea persist. Both classes carry precautions around medullary thyroid cancer and multiple endocrine neoplasia type 2 based on animal data. All of this is set out in the summary of product characteristics and summarised in the BNF, and warrants clinical review if it applies to you.
How a clinician chooses between them
Choosing between semaglutide and tirzepatide is a clinical decision, not a preference vote. A clinician will weigh the licensed indication that fits your case, your medical history, prior weight-management treatments and how you tolerated them, comorbidities (particularly cardiovascular, gastrointestinal and renal), other medicines you take, monitoring needs, and your goals and expectations. Practical factors also matter — pen device familiarity, injection frequency, dose availability, supply, and your own preference between injection and oral options where relevant.
Neither molecule is right for everyone, and neither is universally superior. Higher average trial weight loss is one data point among several. If you have already tried one, that history is relevant to the choice of the next step. Your clinician will advise based on your individual circumstances. If you want to explore how these decisions play out in practice, our article on staying on a low dose of Wegovy gives a sense of the trade-offs at the maintenance stage.
Beyond weight — cardiometabolic effects
Both medicines have shown broader cardiometabolic effects beyond weight itself — improvements in glucose control, blood pressure, lipid profile and inflammatory markers in the relevant patient groups. For patients with type 2 diabetes, both are also licensed for glucose control, and prescribing decisions in that context are different again. A weight-management consultation is not a diabetes consultation, and one is not a substitute for the other, but the overlap is part of why these medicines have become as clinically prominent as they have.