Semaglutide vs tirzepatide: what is the difference?

Semaglutide activates one hormone receptor, GLP-1, while tirzepatide activates two, GIP and GLP-1.[1][2] The two medicines have been compared directly in a randomized trial in adults with obesity without type 2 diabetes, SURMOUNT-5, and their heart-outcome evidence comes from trials in different groups of people.

Wegovy injection (under the skin) and Wegovy tablets (by mouth) are FDA-approved for weight management in certain people; Ozempic injection, Ozempic tablets and Rybelsus tablets are approved only for adults with type 2 diabetes (checked September 27, 2026). Among tirzepatide products, Zepbound injection, given under the skin, is FDA-approved for weight management in certain adults, while Mounjaro injection is approved only for uses in people with type 2 diabetes (checked October 14, 2026).

Quick comparison

Semaglutide and tirzepatide compared on the evidence we reviewed as of October 1, 2026; rows that name SURMOUNT-5, a head-to-head trial, take their figures from it, and every other row comes from separate trials or labels for each medicine. SURMOUNT-5 was a 72-week, open-label trial of 751 adults with obesity without type 2 diabetes, funded by Eli Lilly, the maker of tirzepatide, that compared semaglutide 1.7 or 2.4 mg with tirzepatide 10 or 15 mg, each given once weekly at the highest dose the person tolerated.[3] STEP 1 and SURMOUNT-1 were separate trials with different lengths, doses and participants, so their results cannot be compared directly, and one trial's figure should not be subtracted from the other's. Trial figures on this page are group averages, and in each drug's own placebo-controlled trial some people taking the drug did not lose at least 5% of their body weight. Evidence levels on this page follow our grading key: Established means consistent results from randomized trials or a systematic review of them, and Emerging means some controlled human evidence that falls short of that, for example a single trial or trials funded mostly by the drug's maker. In these tables, Not yet checked by us means a source exists that we have not yet reviewed.

Sources: Wegovy injection prescribing information, Revised 06/2026; Zepbound injection prescribing information, Revised 08/2026.

How each medicine acts

According to the Wegovy label, semaglutide acts like the natural hormone GLP-1, which helps regulate appetite and calorie intake.[1] The Wegovy label says semaglutide lowers calorie intake, likely by affecting appetite, and slows stomach emptying.[1]

According to the Zepbound label, GLP-1 is a natural regulator of appetite and calorie intake, and nonclinical (laboratory and animal) studies suggest that GIP may add to that effect.[2] The Zepbound label says tirzepatide lowers calorie intake, likely by affecting appetite, and slows stomach emptying, an effect that is largest after the first dose and lessens over time.[2]

How semaglutide and tirzepatide act in the body does not by itself show a health benefit; the evidence for weight loss comes from the clinical trials described on this page.

Weight loss in head-to-head studies

SURMOUNT-5 was a 72-week, open-label trial of 751 adults with obesity without type 2 diabetes, funded by Eli Lilly, the maker of tirzepatide, that compared semaglutide 1.7 or 2.4 mg with tirzepatide 10 or 15 mg, each given once weekly at the highest dose the person tolerated.[3] In SURMOUNT-5, average weight loss at 72 weeks was 13.7% with semaglutide and 20.2% with tirzepatide.[3] In SURMOUNT-5, the 95% confidence intervals for average weight loss were 12.6% to 14.9% with semaglutide and 19.1% to 21.4% with tirzepatide.[3] In SURMOUNT-5, average waist size fell by 13.0 cm with semaglutide and 18.4 cm with tirzepatide at 72 weeks.[3] The SURMOUNT-5 result is rated Emerging because it comes from SURMOUNT-5, an open-label trial funded by the maker of tirzepatide. In searches of PubMed, Europe PMC and ClinicalTrials.gov on October 1, 2026, SURMOUNT-5 was the largest randomized head-to-head trial with reported results that we found in adults with obesity and without type 2 diabetes. In the same searches, a 2026 pilot study at one Italian university (La Vignera 2026, no external funding) assigned 90 adults with a body-mass index above 40 and no known diabetes at random to semaglutide or tirzepatide for six months. Across all participants it reported average weight loss of 10.2% with semaglutide and 11.8% with tirzepatide; its authors state that no formal inferential statistics were performed for its primary outcome, and they describe the study as observational and its findings as hypothesis-generating.[4] As of October 1, 2026, ClinicalTrials.gov lists each of the following randomized trials of semaglutide, tirzepatide and dulaglutide as completed, with no results posted: NCT07834398, in 150 adults without diabetes, and NCT07820111, in 159 adults with overweight or obesity, with and without diabetes. Zagazig University is the lead sponsor of both records.[5][6] Because SURMOUNT-5 compared the highest dose each person tolerated, its result does not show how the two medicines compare at lower doses. SURMOUNT-5 was open-label, meaning participants and researchers knew which medicine each person was taking. We read only the published summary of the SURMOUNT-5 report, not the full paper, so details such as how missing data were handled are not on this page.

Wegovy injection and Zepbound injection each carry a boxed warning about thyroid C-cell tumors seen in rodents.

In a separate 68-week trial (STEP 1), funded by semaglutide's maker, adults with obesity, or overweight with a weight-related condition, without diabetes, lost about 15% of their body weight on average with semaglutide 2.4 mg once weekly, compared with about 2% on placebo.[7] In a separate 72-week trial (SURMOUNT-1), funded by tirzepatide's maker, adults with obesity, or overweight with a weight-related condition, without diabetes, lost about 15% to 21% of their body weight on average with tirzepatide, depending on the dose, compared with about 3% on placebo.[8] STEP 1 and SURMOUNT-1 were separate trials with different lengths, doses and participants, so their results cannot be compared directly, and one trial's figure should not be subtracted from the other's. Weight loss compared with placebo in adults without diabetes is rated Established for both semaglutide and tirzepatide, because independent reviews of placebo-controlled trials, not funded by the drug makers, found consistent results for each drug.[9][10][11][12][13] Trial figures on this page are group averages, and in each drug's own placebo-controlled trial some people taking the drug did not lose at least 5% of their body weight.[1][2]

A 2026 network meta-analysis of 262 randomized trials (Nong 2026), which compared drugs indirectly across trials, estimated that at one year, weight loss was 14.9 percentage points greater with tirzepatide and 9.8 points greater with semaglutide injections than with lifestyle changes alone.[14] Comparing the two drugs through a network of separate trials is an indirect comparison, so the difference between them in that review is rated Emerging.

Weight loss in people with type 2 diabetes

Wegovy injection (under the skin) and Wegovy tablets (by mouth) are FDA-approved for weight management in certain people; Ozempic injection, Ozempic tablets and Rybelsus tablets are approved only for adults with type 2 diabetes (checked September 27, 2026). Among tirzepatide products, Zepbound injection, given under the skin, is FDA-approved for weight management in certain adults, while Mounjaro injection is approved only for uses in people with type 2 diabetes (checked October 14, 2026).

In SURPASS-2, a 40-week open-label trial of 1,879 adults with type 2 diabetes funded by tirzepatide's maker, tirzepatide 5, 10 and 15 mg lowered HbA1c, a measure of average blood sugar, and body weight more than semaglutide 1 mg once weekly.[15] In SURPASS-2, average weight loss was 1.9 kg, 3.6 kg and 5.5 kg greater with tirzepatide 5, 10 and 15 mg than with semaglutide 1 mg.[15] SURPASS-2 enrolled only adults with type 2 diabetes and used 1 mg of semaglutide, less than the 2.4 mg dose studied in STEP 1 and SELECT, so it does not show how the two drugs compare in people without diabetes.

Side effects reported for each product

The Wegovy and Zepbound side-effect tables come from different trials with different participants, and each label says its rates cannot be directly compared with rates from trials of another drug.

The Wegovy label's boxed warning says that in rodents, semaglutide causes thyroid C-cell tumors, and that it is unknown whether Wegovy causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, because the human relevance of the rodent tumors has not been determined.[1] The Wegovy label says people should not use Wegovy if they or a family member have had medullary thyroid carcinoma (MTC), if they have Multiple Endocrine Neoplasia syndrome type 2 (MEN 2), or if they have had a serious allergic reaction to semaglutide or any ingredient in Wegovy.[1] The Wegovy label also warns about acute pancreatitis, acute gallbladder disease, low blood sugar, kidney injury from dehydration, severe stomach and bowel reactions, serious allergic reactions, diabetic eye complications in people with type 2 diabetes, heart rate increase, and inhaling stomach contents during anesthesia or deep sedation.[1] The Wegovy label reports average resting heart-rate increases of 1 to 4 beats per minute with Wegovy compared with placebo in its weight-loss trials.[1] The Wegovy label advises stopping Wegovy at least 2 months before a planned pregnancy because of semaglutide's long half-life.[1]

According to the Wegovy prescribing information, "Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice."[1] The Wegovy label's side-effect table for the 2.4 mg injection pools 3 placebo-controlled trials of up to 68 weeks in 2,116 adults with obesity or overweight, 19% of whom had type 2 diabetes.[1] In Table 3 of the Wegovy label, the side effects reported most often with the 2.4 mg injection were nausea (44% vs 16% on placebo), diarrhea (30% vs 16%), vomiting (24% vs 6%) and constipation (24% vs 11%).[1] In the Wegovy label's pooled weight-loss trials, 6.8% of people on the 2.4 mg injection and 3.2% on placebo stopped treatment because of side effects.[1]

The Zepbound label's boxed warning says that in rats, tirzepatide causes thyroid C-cell tumors, and that it is unknown whether Zepbound causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, because the human relevance of the rat tumors has not been determined.[2] The Zepbound label says people should not use Zepbound if they or a family member have had medullary thyroid carcinoma (MTC), if they have Multiple Endocrine Neoplasia syndrome type 2 (MEN 2), or if they have had a serious allergic reaction to tirzepatide or any ingredient in Zepbound.[2] The Zepbound label also warns about severe stomach and bowel reactions, kidney injury from dehydration, gallbladder problems, pancreatitis, serious allergic reactions, low blood sugar, worsening diabetic eye disease in people with type 2 diabetes, and inhaling stomach contents during anesthesia or deep sedation.[2] The Zepbound label reports an average heart-rate increase of 1 to 3 beats per minute with Zepbound, compared with no increase on placebo.[2] The Zepbound label says weight loss offers no benefit during pregnancy and may harm the fetus, and advises stopping Zepbound when a pregnancy is recognized.[2] The Zepbound label does not give a time to stop Zepbound before a planned pregnancy.[2]

According to the Zepbound prescribing information, "Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice."[2] The Zepbound label's Table 1 pools two trials of up to 72 weeks, one of which enrolled only people with type 2 diabetes; 25% of the pooled patients had type 2 diabetes.[2] Nausea and diarrhea were the most common side effects in Table 1 of the Zepbound label: nausea was reported by 25% to 29% of people on Zepbound vs 8% on placebo, and diarrhea by 19% to 23% vs 8%.[2] In the Zepbound label's pooled weight-loss trials, 4.8%, 6.3% and 6.7% of people on Zepbound 5 mg, 10 mg and 15 mg stopped treatment because of side effects, compared with 3.4% on placebo, most often during the first few months and because of stomach and bowel side effects.[2]

Sources: Wegovy injection prescribing information, Revised 06/2026; Zepbound injection prescribing information, Revised 08/2026.

If you have severe symptoms, call 911 or seek emergency care. Report side effects to FDA MedWatch.

Heart-outcome evidence

The heart-outcome evidence for semaglutide and tirzepatide is uneven: the two medicines were tested in different groups of people and against different comparisons, so their heart results cannot be compared with each other.

In the SELECT trial, which was funded by semaglutide's maker, adults aged 45 or older with existing cardiovascular disease and overweight or obesity, but without diabetes, who took semaglutide 2.4 mg once weekly had about a 20% lower risk of a first heart attack, stroke or cardiovascular death, counted together, than those on placebo: 6.5% vs 8% of people had one of these events.[16] The SELECT result is rated Emerging because it comes from one trial funded by semaglutide's maker, and the rating covers only adults aged 45 or older with existing cardiovascular disease and overweight or obesity, without diabetes. SELECT enrolled only people who already had cardiovascular disease, so its results do not show a heart or survival benefit for people without it.

In the SELECT trial, which was funded by semaglutide's maker, 17,604 adults aged 45 or older with overweight or obesity and existing cardiovascular disease, but without diabetes, were randomly assigned to once-weekly semaglutide 2.4 mg or placebo, and death from any cause was the third of three secondary outcomes that the trial planned to test in a fixed order.[16] According to the SELECT paper, the first of the three, death from cardiovascular causes, did not reach the statistical threshold the trial required, so the other two, including death from any cause, were not formally tested.[16] The SELECT paper reports deaths from any cause in 375 of 8,803 people assigned to semaglutide (4.3%) and 458 of 8,801 assigned to placebo (5.2%), a hazard ratio of 0.81 (95% confidence interval 0.71 to 0.93), and says this interval, which was not adjusted for testing several outcomes, should not be used to infer a definite treatment effect.[16] The Wegovy prescribing information gives the same figures and says the result for death from any cause was not statistically significant under the trial's planned testing order.[1]

In the Wegovy prescribing information's SELECT results, the hazard ratio for cardiovascular death alone was 0.85 (95% confidence interval 0.71 to 1.01), and the stroke result alone was not part of the trial's formal testing and its range included no difference (hazard ratio 0.89, 0.72 to 1.11).[1]

In SURPASS-CVOT, a trial of 13,299 adults with type 2 diabetes and established cardiovascular disease, funded by tirzepatide's maker, tirzepatide was compared with dulaglutide, another diabetes drug, not with placebo: its rate of heart attack, stroke or cardiovascular death, counted together, met the trial's test for being no worse than dulaglutide's, but a lower rate than dulaglutide's was not shown.[17] In SURPASS-CVOT, heart attack, stroke or cardiovascular death occurred in 12.2% of people on tirzepatide and 13.1% on dulaglutide (hazard ratio 0.92; 95.3% CI 0.83 to 1.01).[17] The SURPASS-CVOT result is rated Emerging because it comes from a single trial that compared tirzepatide with another active drug, not placebo, and was funded by tirzepatide's maker. SURPASS-CVOT enrolled only adults with type 2 diabetes and established cardiovascular disease, and it did not test people using tirzepatide for weight loss without diabetes. In a search of PubMed, Europe PMC and ClinicalTrials.gov on October 1, 2026, we found no reported results from a randomized trial designed to test whether tirzepatide prevents heart attacks or strokes in people without diabetes. SURMOUNT-MMO, a randomized trial of tirzepatide against placebo in adults without diabetes, is registered on ClinicalTrials.gov and had posted no results in the record we read on October 1, 2026; funded by Eli Lilly, it enrolled 15,374 adults aged 40 or older with a body-mass index of 27 or higher and cardiovascular disease or cardiovascular risk factors, and its main outcome counts deaths from any cause, heart attacks, strokes, coronary revascularization and heart-failure events together.[18]

SELECT tested semaglutide, not tirzepatide, so its result cannot be applied to tirzepatide.

Lean mass and stopping treatment

The Wegovy label says semaglutide lowers body weight with greater fat mass loss than lean mass loss.[1] The Zepbound label says tirzepatide lowers body weight with greater fat mass loss than lean mass loss.[2] Reviews of trials in adults with overweight or obesity, with or without type 2 diabetes, report that part of the weight lost with semaglutide or tirzepatide is lean mass rather than fat, a finding rated Emerging because the reviews' independence from the drug makers could not be confirmed.[19][20]

In one trial funded by semaglutide's maker (STEP 4), adults who had reached semaglutide 2.4 mg during a 20-week run-in and were then switched to placebo saw their body weight rise by 6.9% on average by week 68, while those who stayed on semaglutide lost a further 7.9%.[21] In one trial funded by the drug's maker (SURMOUNT-4), adults without diabetes who had lost weight during 36 weeks on tirzepatide and were then switched to placebo saw their body weight rise by 14.0% on average over the next 52 weeks, while those who stayed on tirzepatide lost a further 5.5%.[22] STEP 4 and SURMOUNT-4 were separate trials with different lengths of treatment before the switch to placebo, so their results cannot be compared directly.

Which might make sense for a given goal

A 2026 American College of Physicians living guideline suggests semaglutide or tirzepatide as first-line medicines, together with lifestyle changes, for nonpregnant adults with obesity, as a conditional recommendation based on moderate-certainty evidence for each.[23] A 2026 guidance statement from three U.S. obesity organizations (TOS, OMA and OAC) makes strong recommendations for semaglutide and tirzepatide, among other medicines, based on moderate-certainty evidence.[24] The American College of Physicians guideline says clinicians and patients should discuss benefits, harms, other health conditions, weight-loss goals, values and preferences, and contraindications and warnings, among other factors.[23]

Whether a product is appropriate for a specific person is decided by a licensed clinician using that product's prescribing information. This page compares published evidence and FDA status; it does not recommend one medicine over the other.

Novo Nordisk, which makes semaglutide, funded STEP 1, STEP 4 and SELECT, and Eli Lilly, which makes tirzepatide, funded SURMOUNT-1, SURMOUNT-4, SURMOUNT-5, SURPASS-2, SURPASS-CVOT and SURMOUNT-MMO; the 2026 pilot study by La Vignera reported no external funding, and ClinicalTrials.gov lists Zagazig University as the lead sponsor of NCT07834398 and NCT07820111.

Are semaglutide and tirzepatide approved for the same uses?

Approved uses differ by semaglutide product. Approved uses differ by tirzepatide product.

The FDA status table lists each semaglutide and tirzepatide product with its route and the uses in its prescribing information.

Ozempic injection, Ozempic tablets and Rybelsus tablets are not FDA-approved for weight management. Their approved uses are listed in the FDA status table. Prescribing them for weight management is off-label. For weight management in certain people, together with a reduced-calorie diet and more physical activity, FDA has approved Wegovy injection, given under the skin, and Wegovy tablets, taken by mouth.

Mounjaro injection is not FDA-approved for weight management. Its approved uses are listed in the FDA status table. Prescribing it for weight management is off-label. For weight management in certain adults, together with a reduced-calorie diet and more physical activity, FDA has approved Zepbound injection, given under the skin.

Each semaglutide product in the FDA status table is available only with a prescription (checked September 27, 2026).

Each tirzepatide product in the FDA status table is available only with a prescription (checked October 14, 2026).

Completing an intake form or making a payment does not guarantee a prescription.

Regulatory status checked September 27, 2026. Sources: www.accessdata.fda.gov/…/209637s038lbl.pdf; www.accessdata.fda.gov/…/213051Orig1s030lbl.pdf; www.accessdata.fda.gov/…/215256s025lbl.pdf; www.fda.gov/…/fda-clarifies-policies-compounders-national-glp-1-supply-begins-stabilize; public-inspection.federalregister.gov/…/2026-12937.pdf; www.fda.gov/…/fda-proposes-exclude-semaglutide-tirzepatide-and-liraglutide-503b-bulks-list; www.fda.gov/…/fdas-concerns-unapproved-glp-1-drugs-used-weight-loss; www.fda.gov/…/compounding-and-fda-questions-and-answers; www.accessdata.fda.gov/…/218316Orig1s000ltr.pdf; www.accessdata.fda.gov/…/218316s007lbl.pdf

Regulatory status checked October 14, 2026. Sources: www.accessdata.fda.gov/…/215866s044s045lbl.pdf; www.accessdata.fda.gov/…/215866Orig1s044,215866Orig1s045ltr.pdf; www.accessdata.fda.gov/…/217806Orig1s041correctedlbl.pdf; www.fda.gov/…/fda-clarifies-policies-compounders-national-glp-1-supply-begins-stabilize; public-inspection.federalregister.gov/…/2026-08552.pdf; www.fda.gov/…/compounding-and-fda-questions-and-answers; www.fda.gov/…/fdas-concerns-unapproved-glp-1-drugs-used-weight-loss

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