Semaglutide vs tirzepatide: how Ozempic, Wegovy and Mounjaro differ (and what the "clicks" on each pen mean)

Few families of medicines have transformed the pharmacy counter as much as incretin analogues. Semaglutide (marketed as Ozempic, Wegovy and Rybelsus) and tirzepatide (Mounjaro) are currently two of the most sought-after, most discussed and, also, most misunderstood active ingredients. Both share a biological origin and many effects, but they are not the same: they differ in their molecular target, their potency, the trial data and the device used to administer them.

This article is a scientific and calm comparison between the two. It is not a weight-loss guide nor a brand recommendation: it is a rigorous explanation of how they work, what head-to-head trials say, what risks they share and why the issue of the "clicks" on the pens generates so many questions in the pharmacy. If you want to delve specifically into the Mounjaro KwikPen phenomenon, we have a dedicated article linked below.

Incretins: the system that both drugs mimic

To understand the difference between semaglutide and tirzepatide, one must start with physiology. After a meal, the intestine releases hormones called incretins that alert the pancreas that glucose is coming. The two main incretins are:

• GLP-1 (glucagon-like peptide-1): secreted by L-cells in the distal intestine. It stimulates insulin secretion in a glucose-dependent manner (only when there is sugar, which avoids hypoglycaemia), inhibits glucagon secretion, slows gastric emptying and acts on brain appetite centres to generate satiety.
• GIP (glucose-dependent insulinotropic polypeptide): secreted by K-cells in the proximal intestine. It also enhances insulin secretion and participates in fat metabolism in adipose tissue. Its role is complementary to that of GLP-1.

The starting difference is simple to state: semaglutide activates a single receptor (the GLP-1 receptor), while tirzepatide activates two at once (GLP-1 and GIP). Hence, tirzepatide is called a "dual agonist" or "twincretin". That second target is the main hypothesis explaining why, on average, tirzepatide achieves slightly higher results in trials.

Semaglutide: three brands, three different uses

One of the great sources of confusion at the counter is that "semaglutide" does not equate to a single product. The same active ingredient is sold under three brands that are not interchangeable, because the route, dose and authorised indication change:

This is a critical point for public health: Ozempic is authorised for type 2 diabetes, not for weight loss. When it is prescribed or used off-label for weight loss in people without diabetes, it contributes to shortages that harm those who need it to control their blood glucose. For weight management, there is a specific brand with its own dose escalation (Wegovy).

Tirzepatide: the dual agonist

Tirzepatide is marketed in Europe under a single brand name, Mounjaro, authorised for both type 2 diabetes and weight management. Its dose escalation schedule is broader than that of semaglutide: it starts at 2.5 mg weekly (starting dose, non-therapeutic) and can be progressively increased to 5, 7.5, 10, 12.5 and 15 mg, always with steps every four weeks to allow the body time to adapt.

This addition of the GIP component is what distinguishes the molecule. In phase III trials, the mean magnitude of the effect on weight and on HbA1c (glycated haemoglobin, a marker of diabetes control) has been greater than that observed with semaglutide, although — and this is essential — individual response varies greatly: some patients reach their target with low doses while others need the maximum.

Head-to-head: what the clinical trials say

The great advantage of these two medicines is that they have not only been compared against placebo, but directly against each other in randomised trials. These head-to-head studies are what allow us to speak properly about differences.

In type 2 diabetes: SURPASS-2

The SURPASS-2 trial (published in the New England Journal of Medicine in 2021) compared tirzepatide (5, 10 and 15 mg) versus semaglutide 1 mg in people with type 2 diabetes. Tirzepatide reduced HbA1c and weight to a greater extent across all its doses:

It is worth noting: the comparator was semaglutide 1 mg, which was the maximum dose of Ozempic at the time of the trial. Today the 2 mg dose exists, which was not included in SURPASS-2, so the comparison does not exhaust the question. Even so, the signal of greater potency for tirzepatide is consistent.

In obesity: STEP, SURMOUNT and the decisive SURMOUNT-5

Each medicine has its own trial programme in obesity. Semaglutide 2.4 mg was evaluated in the STEP programme: in STEP-1 (NEJM, 2021), participants with obesity without diabetes lost on average −14.9% of their body weight at 68 weeks versus −2.4% with placebo. Tirzepatide was evaluated in the SURMOUNT programme: in SURMOUNT-1 (NEJM, 2022) the reductions at 72 weeks were −15% (5 mg), −19.5% (10 mg) and −20.9% (15 mg) versus −3.1% with placebo.

But the definitive comparison arrived with SURMOUNT-5 (NEJM, 2025), the first trial to directly pit the two medicines against each other at their maximum doses for obesity:

The difference was statistically significant and clinically relevant. This does not make semaglutide a bad medicine — a sustained 13-15% weight reduction is an excellent result from a clinical standpoint — but it does place tirzepatide, on average, a step higher in magnitude of effect.

Comparative summary at a glance

The "cardiovascular benefit" column deserves a note: semaglutide currently accumulates more evidence of hard cardiovascular event reduction, simply because it has been on the market for more years and its outcome trials were completed earlier. Tirzepatide has cardiovascular studies underway; the absence of published results does not mean an absence of benefit, but rather that it is not yet confirmed.

Safety: shared adverse effects and contraindications

The safety profile of both drugs is very similar, precisely because they share the GLP-1 mechanism. The most frequent adverse effects are gastrointestinal and usually appear or intensify when increasing the dose:

• Nausea, vomiting, diarrhoea and constipation. These are the main cause of treatment discontinuation. The slow dose escalation exists precisely to minimise them.
• Early satiety and dyspepsia, resulting from the slowing of gastric emptying.
• Increased risk of gallbladder problems (cholelithiasis), partly associated with rapid weight loss.
• Pancreatitis: infrequent, but requires caution and discontinuation in the event of severe and persistent abdominal pain.
• With semaglutide, the summaries of product characteristics (SmPCs) warn of the need to monitor diabetic retinopathy in patients with diabetes, especially if blood glucose levels drop very rapidly (a signal observed in SUSTAIN-6).

There is an additional nuance that is very relevant for the pharmacy: these medicines delay gastric emptying, which can alter the absorption of other orally administered drugs and, in the case of oral contraceptives, it is advisable to review the recommendations in the summary of product characteristics. It is a good example of why professional monitoring is not optional.

The pens and the question of "clicks"

This is where the technical debate becomes more confusing—and riskier. Not all devices work the same way, and the word "clicks" means different things depending on the pen. Let us review the three formats that coexist today in the Spanish pharmacy (note: please check your own national regulator for local availability and guidance):

In multi-dose pens, each click of the dial corresponds to a small volume increment. Some users count clicks with two objectives: to administer a dose different from the one marked by the device or to "stretch" a high-concentration pen so that it yields more injections. Neither practice is authorised, and the reasons are solid:

• There is no safety or efficacy data for doses calculated manually with clicks in a presentation other than the one prescribed. The trials used fixed doses and specific devices.
• The margin of error is real: one click too many or too few changes the dose, and in higher-concentration pens, that error is proportionally greater.
• Stability has a time limit: once opened, the pen has a maximum number of days of use indicated in the summary of product characteristics. Stretching it beyond this compromises potency and sterility.
• Clinical traceability is lost: if the medical record states one dose and the patient administers another, the management of any adverse effect becomes complicated.

Read: "Mounjaro and the clicks: the KwikPen phenomenon in Spanish pharmacies"

Access, price and supply shortages in Spain

The economic and supply context is inseparable from this topic. In Spain, neither Wegovy nor Mounjaro are funded by the National Health System for weight management, meaning the patient bears the full cost, which amounts to hundreds of euros per month. That expenditure is precisely what drives some people to look for ways to "make the most" of each pen.

On the other hand, the enormous demand—driven in part by its use for weight loss—has caused supply problems, especially for Ozempic. The AEMPS (the Spanish Agency for Medicines and Medical Devices) has published notices reminding that Ozempic is authorised for type 2 diabetes and asking prescribers to reserve its use for that indication, with the aim of protecting supply for diabetic patients. It is a reminder that individual decisions regarding these drugs have a collective dimension.

The role of the pharmacist at the counter

When a patient arrives with questions about semaglutide or tirzepatide—and more are arriving all the time—the pharmacist has a huge opportunity to add value without stepping outside their scope of practice. A useful script:

1. Confirm the brand and the indication. Remind them that Ozempic, Wegovy and Rybelsus are not interchangeable and that only the doctor decides the regimen.
2. Reinforce the injection technique and storage: rotation of sites, first use, and maximum days of use for the pen once opened.
3. Anticipate gastrointestinal effects and explain that a slow escalation reduces them; advise lighter meals when increasing the dose.
4. Insist that the drug is a support, not a substitute for a balanced diet and physical activity, which are the foundation of treatment.
5. Refer to the doctor in the event of severe abdominal pain, suspected adverse effects or any intention to modify the dose. Document the information provided.
6. Do not recommend or facilitate off-label practices such as click counting to split doses.

The community pharmacy is, often, the first point of contact and the most accessible. Providing rigorous education about these medicines—without alarmism and without promotion—is one of the best contributions the pharmacist can make to patient safety and the sustainability of the system.