Semaglutide vs Tirzepatide: Mechanism, Dosing, Side Effects and Cost

At its receptor semaglutide does what native GLP-1 does, continuously: glucose-dependent insulin release, glucagon suppression, slowed gastric emptying and reduced hunger and food reward. The slowed stomach is also the source of most side effects, which is why they cluster around dose increases.

The STEP trials are the evidence base for the branded product Wegovy. STEP 1, in the New England Journal of Medicine in 2021, randomized 1,961 adults with overweight or obesity and no diabetes to semaglutide 2.4 mg weekly or placebo with lifestyle intervention; at 68 weeks body weight changed by −14.9% versus −2.4%, and half of the semaglutide group lost 15% or more. STEP 2, in The Lancet the same year, ran the design in type 2 diabetes and reported −9.6% versus −3.4%, the smaller effect every agent in this class shows when diabetes is present. STEP 3 (JAMA, 2021) paired it with intensive behavioral therapy, STEP 5 (Nature Medicine, 2022) found the reduction held at two years, and STEP 8 (JAMA, 2022) found −15.8% against −6.4% with daily liraglutide. A 2025 phase 3b trial in The Lancet Diabetes & Endocrinology (STEP UP) tested a 7.2 mg weekly dose in adults with obesity, and that dose has since been added to the Wegovy label.

SELECT, in the New England Journal of Medicine in 2023, enrolled 17,604 adults with established cardiovascular disease and overweight or obesity but no diabetes and followed them for a mean of about 40 months. The primary composite of major adverse cardiovascular events occurred in 6.5% on semaglutide and 8.0% on placebo, a hazard ratio of 0.80, which is the basis for the cardiovascular indication on the Wegovy label. In type 2 diabetes, SUSTAIN-6 in the same journal in 2016 had already reported fewer major adverse cardiovascular events with semaglutide than placebo.

ESSENCE, in the New England Journal of Medicine in 2025, studied semaglutide 2.4 mg in adults with metabolic dysfunction-associated steatohepatitis and moderate-to-advanced fibrosis: resolution of steatohepatitis without worsening fibrosis in 62.9% versus 34.3%, and fibrosis improvement in 36.8% versus 22.4%. That is now a Wegovy indication under accelerated approval, and a disease endpoint tirzepatide does not yet carry on its label.

One subcutaneous injection a week, same day each week, in the abdomen, thigh or upper arm. The approved product starts at 0.25 mg weekly for four weeks and steps up every four weeks to a usual adult maintenance of 2.4 mg; the June 2026 label adds a 7.2 mg maximum for people who tolerate 2.4 mg and need further reduction, and allows delaying any step by four weeks if a dose is not tolerated. Compounded semaglutide at Pepti is supplied as dose-specific vials; the strengths and directions printed on each are on the semaglutide product page, and your physician sets the strength you are on.

A pooled analysis of the STEP trials in Diabetes, Obesity and Metabolism in 2022 gives the clearest numbers for 2.4 mg: nausea in 43.9% of participants versus 16.1% on placebo, diarrhea 29.7% versus 15.9%, vomiting 24.5% versus 6.3%, constipation 24.2% versus 11.1%. Almost all were mild to moderate and transient, concentrated around dose increases, and only 4.3% stopped because of them. Weight reduction was largely independent of whether a person had gastrointestinal symptoms, so nausea is not how the drug works. Reflux, burping, fatigue and headache are also common. Managing all of this is covered in GLP-1 nausea.

Tirzepatide does everything semaglutide does at the GLP-1 receptor and additionally activates the GIP receptor. In a phase 1 mechanistic trial in The Lancet Diabetes & Endocrinology in 2022, it improved measures of islet function and insulin sensitivity in people with type 2 diabetes more than semaglutide 1 mg did. The working explanation in the 2025 Diabetes review is that GIP signaling in fat tissue and the brain contributes independently to energy handling and appetite, and may blunt the nausea that GLP-1 agonism alone produces, allowing higher effective GLP-1 exposure. That is a hypothesis with supporting data, not a settled fact.

SURMOUNT-1, in the New England Journal of Medicine in 2022, randomized 2,539 adults with obesity and no diabetes to tirzepatide 5, 10 or 15 mg weekly or placebo. At 72 weeks weight changed by −15.0%, −19.5% and −20.9% respectively against −3.1%; more than half of the 15 mg group lost 20% or more. SURMOUNT-2, in The Lancet in 2023, was the diabetes trial: −12.8% and −14.7% with 10 and 15 mg versus −3.2%. SURMOUNT-3, in Nature Medicine in 2023, added tirzepatide after an intensive lifestyle program and reported further reduction on top of it.

SURPASS-2, in the New England Journal of Medicine in 2021, compared tirzepatide 5, 10 and 15 mg with semaglutide 1 mg, the diabetes dose rather than the 2.4 mg obesity dose, in 1,879 people with type 2 diabetes. All three tirzepatide doses lowered HbA1c more, and body weight fell by an additional 1.9, 3.6 and 5.5 kg. Because the comparator was the lower semaglutide dose, this trial is often misquoted as a fair weight comparison. It is not; SURMOUNT-5 is.

SURPASS-CVOT, in the New England Journal of Medicine in 2025, compared tirzepatide with dulaglutide, an older GLP-1 agonist with its own established cardiovascular benefit, in 13,299 people with type 2 diabetes and atherosclerotic cardiovascular disease. Tirzepatide was non-inferior on the composite of major adverse cardiovascular events (hazard ratio 0.92); the superiority test did not reach significance. A pre-specified meta-analysis in Nature Medicine in 2022 had found no increase in cardiovascular event risk versus controls. So tirzepatide is cardiovascularly safe and at least as protective as an active comparator in diabetes; it does not yet have a placebo-controlled outcomes trial in people without diabetes equivalent to SELECT.

SURMOUNT-OSA, in the same journal in 2024, ran two trials in people with moderate-to-severe obstructive sleep apnea and obesity. At 52 weeks the apnea-hypopnea index fell by about 25 and 29 events per hour with tirzepatide versus about 5 with placebo, the basis for the sleep apnea indication on the Zepbound label, which semaglutide does not carry.

One subcutaneous injection a week. The approved product starts at 2.5 mg weekly for four weeks, which the label calls an initiation dose only, then 5 mg, with further 2.5 mg steps after at least four weeks on each; maintenance is 5, 10 or 15 mg, and the label allows dropping to a lower maintenance dose if a higher one does not suit. Compounded tirzepatide at Pepti is supplied as dose-specific vials with cyanocobalamin; the strengths and directions are on the tirzepatide product page, and the strength you are on is your physician's decision.

The same family as semaglutide. In SURMOUNT-1 the commonest events were nausea, diarrhea and constipation, mostly mild to moderate and concentrated in escalation; discontinuation for any adverse event was 4.3%, 7.1% and 6.2% at 5, 10 and 15 mg versus 2.6% on placebo. In SURPASS-2, nausea ran 17 to 22% with tirzepatide versus 18% with semaglutide 1 mg, diarrhea 13 to 16% versus 12%, vomiting 6 to 10% versus 8%: similar at matched stages. Whether one feels heavier in practice depends far more on how fast the dose climbs than on which molecule is in the vial.

Cost at the strength you will need is the deciding factor. You have taken it before and responded. You have established cardiovascular disease, where semaglutide holds the only placebo-controlled outcomes trial in people without diabetes. You have a liver-fat diagnosis, where the ESSENCE data belong to semaglutide. Your physician prefers the agent with the longer post-marketing history.

You reached the top of semaglutide's ladder and stalled, or could not tolerate it. Moderate-to-severe obstructive sleep apnea is part of the picture. You and your physician decided the larger average reduction in SURMOUNT-5 is worth the higher monthly cost. You have type 2 diabetes with HbA1c well above target. Starting on tirzepatide without trying semaglutide first is entirely reasonable; nothing in either label or in compounding law requires a sequence.

A personal or family history of medullary thyroid carcinoma or MEN 2 rules out both, as does pregnancy, planning one, or breastfeeding. A pancreatitis history needs a specific conversation. If appetite is not the problem, an incretin is not the tool: weight driven by untreated hypothyroidism, a medication that causes weight gain, or years of poor sleep needs that found first. Where body composition rather than scale weight is the goal, a physician may steer toward a growth-hormone-axis product such as tesamorelin instead of, or after, an incretin.

Semaglutide is the active ingredient in Wegovy (weight reduction; cardiovascular risk reduction in adults with established cardiovascular disease and overweight or obesity; and, under accelerated approval, non-cirrhotic MASH with moderate-to-advanced fibrosis; the June 2026 label also covers a once-daily tablet) and Ozempic (type 2 diabetes, with cardiovascular and kidney indications in that population). Tirzepatide is the active ingredient in Zepbound (weight reduction, and moderate-to-severe obstructive sleep apnea in adults with obesity; label revised August 2026) and Mounjaro (type 2 diabetes in adults and children from age 10, and cardiovascular risk reduction in adults with type 2 diabetes at high risk).

Both carry the same boxed warning: in rodents the drug causes thyroid C-cell tumors at clinically relevant exposures, it is unknown whether this applies to humans, and the products are contraindicated in anyone with a personal or family history of medullary thyroid carcinoma or MEN 2. That warning is about the molecule, not the manufacturer, and a physician applies it to compounded semaglutide and compounded tirzepatide exactly as to the branded products.

While a drug is on the FDA shortage list, 503A pharmacies and 503B outsourcing facilities may compound it even though an approved product exists. The FDA determined the tirzepatide shortage resolved on 19 December 2024, with enforcement discretion for 503A pharmacies ending 18 February 2025 and for 503B facilities 19 March 2025; it determined the semaglutide shortage resolved on 21 February 2025, with the corresponding dates 22 April and 22 May 2025.

So the shortage exemption is gone and ordinary compounding law applies. Under section 503A a state-licensed pharmacy may compound for an identified patient on a prescription, but may not regularly compound what is "essentially a copy" of a commercially available approved product; a preparation is not a copy where the prescriber determines that a change, such as a different strength, dosage form or added ingredient, produces a significant difference for that patient and documents it. That is the footing on which compounded semaglutide and compounded tirzepatide are prescribed now: patient by patient, on a physician's documented judgment.

The FDA's consumer page on unapproved GLP-1 drugs, updated 1 September 2026, says a compounded drug may be appropriate if a patient's medical need cannot be met by an FDA-approved drug or the approved drug is not commercially available, and that compounded drugs are not FDA approved and have not been reviewed for safety, effectiveness or quality. It notes an import alert on foreign-sourced GLP-1 active ingredient that does not meet FDA standards, which is a good reason to ask any provider where its pharmacy sources the peptide and to read the testing on /quality and /quality/lab-results. It also states that retatrutide and cagrilintide, next-generation incretin molecules still in trials, cannot be used in compounding under federal law. Semaglutide and tirzepatide are different: each is a component of an approved product, which is what makes lawful compounding of them possible.