Semaglutide vs Tirzepatide: Which GLP-1 Works Better for Weight Loss?

In the only head-to-head trial, tirzepatide produced more weight loss than semaglutide: an average of 20.2% of body weight against 13.7% after 72 weeks, in 751 adults with obesity. That trial, SURMOUNT-5, was published in the New England Journal of Medicine in 2025. The side effects were similar in kind, mostly nausea, constipation and diarrhea, and fewer people stopped tirzepatide because of them.

There is one thing every comparison page should say and most do not. Those numbers were measured on the FDA-approved brand-name products, Zepbound (tirzepatide) and Wegovy (semaglutide). They do not automatically describe a compounded version of either drug. This page explains both halves: what the trials show, and what they do not cover.

The comparison at a glance

Approved versus compounded: read this before the numbers

The semaglutide and tirzepatide offered at Revive are compounded medications. Compounded medications are not FDA-approved. The FDA does not review them for safety, effectiveness, or quality before they are marketed. That is the agency's own wording on its page about unapproved GLP-1 drugs, which it last updated on 1 October 2026.

Every trial figure on this page, from SURMOUNT-5, STEP 1 and SURMOUNT-1, comes from studies of Wegovy and Zepbound made by Novo Nordisk and Eli Lilly. No randomized trial has tested a compounded semaglutide or tirzepatide against the brand-name product or against each other. So the honest framing is this: the trials tell you how the two molecules compare when manufactured to an FDA-approved standard. They are the best evidence available, and they are evidence about the approved drugs.

The regulatory picture also changed. Compounding of these two drugs expanded while both were on the FDA's shortage list. The FDA declared the tirzepatide shortage resolved on 19 December 2024 and the semaglutide shortage resolved on 21 February 2025. The grace periods for state-licensed compounding pharmacies (503A) and outsourcing facilities (503B) have since ended. FDA policy now treats a compounded product that is "essentially a copy" of an approved drug as restricted, unless the prescriber documents a change that makes "a significant difference" for an identified individual patient. On 6 February 2026, the FDA announced it intends to take action against non-approved GLP-1 drugs being mass-marketed, and stated that companies "cannot claim that non-FDA-approved compounded products are generic versions."

The FDA also flags specific risks: dosing errors when patients measure doses themselves from multi-dose vials, and salt forms such as semaglutide sodium and semaglutide acetate, which it says "are different active ingredients than are used in the approved drugs." As of 31 May 2026, the agency had received 990 adverse event reports linked to compounded semaglutide and more than 730 linked to compounded tirzepatide, and it notes these are likely underreported. Its advice to patients is to get a prescription and fill it at a state-licensed pharmacy.

A compounded medication may be appropriate when a patient's medical needs cannot be met by an FDA-approved drug. That decision belongs to a licensed prescribing clinician after an evaluation.

How the two drugs work

Both drugs copy gut hormones called incretins, which the body releases after eating.

Semaglutide is a GLP-1 analogue with 94% sequence homology to human GLP-1, according to the Wegovy label. It activates the GLP-1 receptor, which slows stomach emptying, lowers appetite and helps regulate blood sugar.

Tirzepatide is a single molecule that activates two receptors: GLP-1 and GIP (glucose-dependent insulinotropic polypeptide). The Zepbound label describes it as a "GIP receptor and GLP-1 receptor agonist." Strictly speaking, that makes it a dual agonist rather than a pure GLP-1 drug, although it is usually grouped with them.

Whether the GIP half explains the extra weight loss is still being studied. The trials show the outcome. They do not prove the mechanism.

Both have long half-lives, about one week for semaglutide and about five days for tirzepatide, which is why both are dosed once a week.

The head-to-head trial: SURMOUNT-5

SURMOUNT-5 is the only randomized trial that put the two drugs directly against each other for weight loss.

• Who: 751 adults with obesity, or overweight with at least one weight-related condition, and without type 2 diabetes, recruited in the US and Puerto Rico.
• What: each person received the highest dose they could tolerate. That meant tirzepatide 10 mg or 15 mg, or semaglutide 1.7 mg or 2.4 mg, injected once weekly, with diet and activity counseling for both groups. At least one dose of the top strength was received by 89.3% of the tirzepatide group and 92.8% of the semaglutide group.
• How long: 72 weeks.

The 20.2% and 13.7% figures and the waist results are from the NEJM abstract (Aronne et al., 2025). The threshold percentages are from Eli Lilly's announcement of the published results.

Three caveats that belong next to those numbers

1. It was open-label. Participants and investigators knew which drug was being given. The placebo-controlled trials for each drug were blinded, and they point the same way, but open-label designs can introduce bias.
2. It was funded by Eli Lilly, which makes tirzepatide. That does not make the result wrong. It is a fact worth knowing.
3. It excluded people with type 2 diabetes. The result does not tell you how the drugs compare in that group.

Averages also hide wide individual variation. In the semaglutide arm, 16.1% of people lost a quarter of their body weight. In the tirzepatide arm, 18.4% did not reach a 10% loss. A trial can answer which drug does more on average. It cannot answer which one a particular person will respond to better.

The original placebo trials

Before the head-to-head trial, each drug was approved on its own placebo-controlled studies. These are the figures in the FDA labels.

Comparing these two columns directly is tempting. It is also the reason SURMOUNT-5 was needed. The trials enrolled different people at different times, ran for different lengths, and gave different amounts of lifestyle support. A head-to-head trial removes those differences, and its 6.5-point gap is the number to rely on.

Side effects compared

Both labels list the same most common side effects: nausea, diarrhea, vomiting and constipation. Both say most stomach symptoms happen while the dose is being increased.

In the head-to-head trial

The adverse event rates are from Lilly's Zepbound healthcare-professional site, which summarises the trial. The stomach-related discontinuation figures are those reported in the NEJM paper. Lilly itself notes that the trial "was not powered to compare the safety and tolerability" of the two drugs. So the honest reading is that the side-effect profiles look similar, with somewhat more vomiting and more GI-related stopping on semaglutide and more injection-site reactions on tirzepatide. This is not proof that one drug is gentler.

In the FDA labels (placebo-controlled trials)

The Zepbound groups had 630, 948 and 941 people. Because the two labels draw on different trial pools, these columns are not a head-to-head comparison either.

The serious warnings both drugs share

• Boxed warning, thyroid C-cell tumors. In rodents, both drugs caused thyroid C-cell tumors. Both labels say it is unknown whether they cause these tumors, including medullary thyroid carcinoma, in humans. Both are contraindicated for anyone with a personal or family history of medullary thyroid carcinoma or with Multiple Endocrine Neoplasia syndrome type 2.
• Pancreatitis. Both labels list acute pancreatitis as a warning. In Wegovy's weight trials, it was confirmed in 4 treated patients, which the label gives as 0.2 cases per 100 patient-years.
• Gallbladder disease. In the Zepbound pooled trials, cholelithiasis was reported in 1.1% of treated patients against 1% on placebo, and cholecystitis in 0.7% against 0.2%. In the Wegovy adult trials, cholelithiasis was reported in 1.6% against 0.7%. Both labels link gallbladder events to weight reduction.
• Severe stomach reactions, and dehydration leading to kidney injury. Both labels carry these warnings, along with a warning about aspiration during anesthesia or deep sedation.

How the labels schedule the doses

This section describes the FDA labels. It is not dosing guidance, and compounded products may be prescribed differently. Dosing is set by the prescribing clinician.

• Wegovy injection starts at 0.25 mg weekly and steps up every four weeks, through 0.5 mg, 1 mg and 1.7 mg, reaching the maintenance dose at week 17. That maintenance dose is 2.4 mg (recommended) or 1.7 mg.
• Zepbound starts at 2.5 mg weekly for four weeks. The label states that "the 2.5 mg dosage is for treatment initiation and is not approved as a maintenance dosage." Increases come in 2.5 mg steps after at least four weeks on each dose, and maintenance is 5 mg, 10 mg or 15 mg.

The practical point is that both drugs take months to reach full strength. For more on that timeline, see how long a GLP-1 takes to work.

What changed in 2025 and 2026

• Oral Wegovy. A once-daily semaglutide tablet was approved for weight reduction in December 2025. The label's maintenance dose is 25 mg daily, reached after 90 days of step-ups. This is different from Rybelsus, the oral semaglutide approved for type 2 diabetes.
• Wegovy HD (7.2 mg). The FDA approved a higher weekly semaglutide dose on 19 March 2026. It is for patients who have tolerated 2.4 mg for at least four weeks and need further weight reduction. In the label's 72-week trial of 1,407 adults, average weight change was −18.8% on 7.2 mg, −15.5% on 2.4 mg and −3.9% on placebo. Dysesthesia, an altered skin sensation such as tingling, was reported by 22% of people on 7.2 mg, against 6% on 2.4 mg.
• Foundayo (orforglipron). On 1 April 2026, the FDA approved Lilly's once-daily non-peptide GLP-1 tablet for chronic weight management. It also carries the thyroid C-cell boxed warning.
• Label updates. In February 2026, the Wegovy label removed its warning section on suicidal behavior and ideation.

None of these change the SURMOUNT-5 comparison. They do mean the choice is no longer only between two weekly injections.

So which one is better?

On average weight loss, the best available evidence favours tirzepatide, by a clear margin, in adults without type 2 diabetes. That is what SURMOUNT-5 was designed to answer, and it answered it.

"Better for a particular person" is a different question, and the trials cannot answer it. A prescribing clinician typically weighs:

• Medical history, including thyroid cancer history in the family, pancreatitis, gallbladder disease, gastroparesis, kidney function and pregnancy plans.
• Other conditions. Wegovy carries an approved cardiovascular risk-reduction indication. Zepbound carries an approved sleep apnea indication.
• Tolerability, if someone has used one before.
• Form and access. The choice now includes a weekly injection, a daily tablet, or a compounded product, along with cost and insurance.

For a broader look at the options beyond these two drugs, see which GLP-1 injection is best for weight loss.

For what the start of treatment usually looks like, read what to expect in the first 90 days. GLP-1 side effects covers symptoms in more depth, and how long to stay on GLP-1 injections covers duration. If you have seen GLP-1 patches advertised, this explainer covers why none is approved. Revive's medical weight loss page explains the program and its compounded options.

Angelica Alcaraz, BSN, RN, will assess your specific needs during your consultation.

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