Goal
Weight Loss
Also known as: Fat loss, Obesity treatment
A research reference for the incretin compounds mapped to weight loss, covering what the registrational trials measured, what happens when treatment stops, what the body-composition data show, and which parts of the picture come from a label rather than from a trial.
Last reviewed August 3, 2026
What "weight loss" actually means in the research
This is the one goal page on this site where the literature and the reader are mostly asking the same question. The trials behind these three compounds measured percentage change in body weight in people with obesity, over 40 to 72 weeks, against placebo. That is close enough to what a reader means that the usual translation problem barely arises.[1][3]
Three gaps between the trial and the reader are worth naming anyway, because they are where most of the disappointment lives.
Everything was measured on treatment. The headline numbers describe people still receiving the drug at the moment of measurement. What happens afterwards was studied separately, and it is a different result.[2]
Weight is not composition. A percentage change in body weight says nothing about what tissue left, and the trials that measured that used imaging substudies with far fewer participants than the trials themselves.[9]
The trial populations were specific. The semaglutide and tirzepatide obesity trials excluded people with diabetes; the largest cardiovascular trial enrolled only people who already had cardiovascular disease; the phase 3 retatrutide result published so far is in type 2 diabetes with glycaemic control as its primary endpoint. None of these is "adults in general".[1][5][11]
What the evidence supports
Large, replicated, placebo-controlled weight reduction. Once-weekly semaglutide 2.4 mg over 68 weeks produced a mean weight change of −14.9% against −2.4% with placebo in 1,961 adults, with half the treated group losing 15% or more of body weight.[1] Tirzepatide over 72 weeks in 2,539 adults produced −15.0%, −19.5%, and −20.9% at its three doses against −3.1% with placebo, with 57% of the highest-dose group losing at least a fifth of their body weight.[3] Retatrutide's 48-week phase 2 trial in 338 adults reported −8.7% to −24.2% across its four ascending dose levels against −2.1% with placebo.[4] These are among the best-powered obesity trials ever run, and the effect sizes are not in serious dispute.
A hard clinical outcome, for one compound. In 17,604 patients with established cardiovascular disease, overweight or obesity, and no diabetes, semaglutide reduced the composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke from 8.0% to 6.5% over a mean 39.8 months of follow-up, a hazard ratio of 0.80.[5] That is a different and much stronger class of evidence than a weight endpoint, and only one compound on this page has it.
Maintenance works, and has been tested as its own question. In a randomized withdrawal design, participants who reached a mean 20.9% reduction over a 36-week open-label tirzepatide lead-in and then continued lost a further 5.5% over the next 52 weeks, while those switched to placebo regained 14.0%; 89.5% of continuing participants held at least 80% of their lead-in loss, against 16.6% on placebo.[6]
Retatrutide has real randomized data. Beyond the phase 2 obesity trial, a completed 40-week phase 3 trial randomized 537 adults with type 2 diabetes to three doses or placebo and reported HbA1c reductions of 1.69 to 1.94 percentage points and weight changes of −11.5% to −15.3% against −2.6% with placebo, with mostly mild-to-moderate gastrointestinal adverse events and 2–5% discontinuing for adverse events.[11]
Where the evidence is weak
Stopping undoes most of it. In the off-treatment extension, 327 participants who had lost a mean 17.3% regained 11.6 percentage points over the following year, finishing 5.6% below baseline, and most cardiometabolic improvements reverted toward where they started.[2] The tirzepatide withdrawal trial found the same pattern by a different route.[6] The honest framing is that these treat a chronic condition rather than fix it.
A substantial share of the loss is not fat. Across 35 randomized trials, the median proportion of total weight loss attributable to muscle-related measures was 28.3%, with two-thirds of studies above the reviewers' expected benchmark, and the variation between studies was wide. Not one of the 35 reported an objective physical function outcome.[9] A retatrutide substudy funded by its sponsor, in which 103 participants completed paired scans, reported that the proportion of lean mass lost looked similar to other obesity treatments.[8] That is reassurance from a small, sponsor-run analysis, not a settled answer.
Direct comparisons barely exist. A 2026 living systematic review and network meta-analysis for the American College of Physicians pooled 69 trials and 112,511 participants and concluded that semaglutide and tirzepatide showed the most favourable results across outcomes, while stating plainly that direct head-to-head comparisons between treatments were limited and that evidence for mortality, major adverse cardiovascular events, and serious adverse events was itself limited.[10] Most of what circulates as "X beats Y" is cross-trial comparison, which is not the same thing.
Tolerability is not a footnote. Gastrointestinal adverse events were reported by up to 72.8% of tirzepatide-treated participants across four phase 3 trials, and between 1.0% and 10.5% stopped because of them.[7] In the cardiovascular trial, permanent discontinuation for adverse events was 16.6% on semaglutide against 8.2% on placebo.[5]
Retatrutide's obesity programme has not reported. The widely circulated figures come from a 48-week trial in 338 people, and the compound has no marketing approval anywhere. Published trial results and completed regulatory review are not interchangeable: review is where the full safety dataset is examined, the contraindications are set, and a manufacturing standard is attached to what is actually in the vial.[4]
How to decide between these
The comparison that matters is rarely "which one loses the most weight". Three questions do more work.
First, what outcome are you actually buying? If it is cardiovascular risk, exactly one compound here has been tested against it.[5] If it is weight alone, the pooled network analysis puts semaglutide and tirzepatide ahead across outcomes while cautioning that the head-to-head evidence underneath that ranking is thin.[10]
Second, what is the plan for month eighteen? Both withdrawal studies point the same way.[2][6]
Third, what are you protecting on the way down? The muscle-loss share is consistent enough across trials to plan around, and no trial has yet measured whether it costs anything functionally.[9]
The stack assessment on this site is built to structure that conversation with a clinician rather than to answer it, and its output is a starting point for a visit, not a protocol.
Questions to bring to a provider
- What am I treating: weight, a cardiometabolic risk, sleep apnoea, joint pain? And which of those has trial evidence behind it for me?[5]
- What is the plan if I need to stop, given that most of the loss returns within a year?[2]
- How will muscle mass be protected and monitored, given that roughly a quarter to a third of the loss is muscle-related in the published trials?[9]
- Does anything in my personal or family history change whether this class is appropriate at all: thyroid cancer, endocrine neoplasia syndromes, pancreatitis, gallbladder disease?
- If I am of reproductive age, what does this mean for contraception and for pregnancy planning?
- If an investigational compound is being discussed, what specifically is known about what is in the vial, and what is the argument for it over an agent that has completed review?[4]
What the labels say, and why it belongs in the first conversation
The following are statements from the approved prescribing information for the weight-management products in this class, not findings from the trials above. They are reproduced here as provider-discussion flags. The label itself is the authority, not this page.
Both approved products carry a boxed warning about thyroid C-cell tumours observed in rodents, note that human relevance has not been determined, and are contraindicated in people with a personal or family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia syndrome type 2. The semaglutide labeling directs that treatment be stopped when pregnancy is recognized and, for weight reduction, at least two months before a planned pregnancy, because of the drug's long half-life. The tirzepatide labeling carries an interaction the semaglutide labeling does not: because tirzepatide delays gastric emptying, oral hormonal contraception may be less effective, and the label advises switching to a non-oral method or adding a barrier method for four weeks after starting and for four weeks after each dose increase. Contraception that is not taken orally is not affected.
None of that is a verdict about any individual, and none of it can be settled from a web page. It is listed because these three items are the ones most often missing from the version of this discussion that happens online, and because the same delayed gastric emptying that underlies the contraceptive advisory also underlies the nausea, vomiting, and diarrhoea that were the most common adverse events in every trial on this page.[7][1]
Retatrutide has no approved prescribing information anywhere, which means it has no boxed warning, no contraindication list, no interaction section, and no pregnancy statement. Those risks have not been ruled out. Nobody has completed the review that would write them down.[11]
Anti-doping status
Read from the World Anti-Doping Agency Prohibited List in force for 2026, not from the research literature or from a summary of it:
- No GLP-1, GIP, or glucagon receptor agonist appears anywhere on the 2026 list. Not by name in the peptide-hormone class, not among the metabolic modulators, and not in the index. Semaglutide and tirzepatide are approved medicines and therefore fall outside section S0 by its own definition, which reaches only substances with no current approval by any governmental regulatory health authority for human therapeutic use.
- Retatrutide is different, and the difference is the approval, not the molecule. S0 is written as a criterion rather than a roster, and it explicitly reaches drugs under pre-clinical or clinical development. Retatrutide is described in its own phase 3 report as under clinical development for type 2 diabetes, obesity, and related complications.[11] An investigational compound in that position, with no marketing approval anywhere and no home in any later section of the list, sits inside S0's criterion whether or not it is named as an example. This is a reading of the definition rather than a naming, which is exactly the kind of question a national anti-doping organization exists to answer. A therapeutic use exemption is a separate process again.
The list is reissued every year and its sections renumber between editions. A competing athlete should confirm the current year's list, and their own organization's guidance, rather than this page.
What the evidence supports for this goal
Grades describe how strong the evidence is; the line under each grade describes what kind of studies it is. How we grade evidence.
- Body-weight reduction with semaglutide
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Human RCT evidence
human RCT
In 1,961 adults with obesity, or overweight plus a weight-related condition, and without diabetes, 68 weeks of once-weekly semaglutide 2.4 mg alongside lifestyle intervention produced a mean weight change of −14.9% versus −2.4% with placebo, an estimated treatment difference of −12.4 percentage points. Half the semaglutide group lost 15% or more. Nausea and diarrhoea were the most common adverse events and 4.5% of the semaglutide group discontinued for gastrointestinal reasons versus 0.8% on placebo.
- Body-weight reduction with tirzepatide
-
Human RCT evidence
human RCT
In 2,539 adults with obesity, or overweight plus a complication, and without diabetes, 72 weeks of once-weekly tirzepatide produced mean weight changes of −15.0%, −19.5%, and −20.9% at 5 mg, 10 mg, and 15 mg against −3.1% with placebo. Fifty-seven percent of the 15 mg group lost at least 20% of body weight, compared with 3% on placebo. Adverse events were predominantly gastrointestinal and concentrated in the 20-week dose escalation.
- Body-weight reduction with retatrutide
-
Human RCT evidence
human RCT
A 48-week phase 2 trial in 338 adults randomized participants to placebo or one of four ascending dose levels, and reported mean weight changes of −8.7% at the lowest level and −17.1%, −22.8%, and −24.2% at the three higher ones, against −2.1% with placebo. Doses are described here by arm rank rather than in milligrams, because retatrutide has no approved prescribing information anywhere and therefore no labelled dose that a number could refer to. A completed 40-week phase 3 trial in 537 adults with type 2 diabetes reported weight changes of −11.5% to −15.3% against −2.6% with placebo, with glycaemic control as its primary endpoint. Adverse events were dose-related and mostly gastrointestinal, and dose-dependent heart-rate increases peaked at 24 weeks in the phase 2 trial before declining. The registrational obesity programme has not reported.
- What happens after stopping
-
Human RCT evidence
human RCT
In an off-treatment extension of the semaglutide trial, 327 participants who had lost a mean 17.3% of body weight regained 11.6 percentage points of it over the following year, ending 5.6% below where they started, with most cardiometabolic gains reverting toward baseline. In a randomized withdrawal trial of tirzepatide, participants switched to placebo after a 36-week lead-in regained weight while those who continued lost a further 5.5%; 89.5% of continuing participants held at least 80% of the lead-in loss versus 16.6% on placebo.
- Cardiovascular outcomes
-
Human RCT evidence
human RCT
In 17,604 patients aged 45 or older with pre-existing cardiovascular disease, a body-mass index of 27 or greater, and no history of diabetes, once-weekly semaglutide 2.4 mg reduced the composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke from 8.0% to 6.5% over a mean 39.8 months, a hazard ratio of 0.80. Permanent discontinuation for adverse events was roughly twice as common on semaglutide as on placebo. This is the only hard-outcome trial behind any compound on this page.
- Body composition and muscle loss
-
Human RCT evidence
review · human RCT
Across 35 randomized trials of incretin therapies, weight loss was consistently accompanied by reductions in total fat mass and visceral adiposity, and the median share of total weight loss attributable to muscle-related indices was 28.3%, with two-thirds of studies exceeding the reviewers' expected benchmark. No study reported an objective measure of physical function. A sponsor-funded substudy of retatrutide in type 2 diabetes, with 103 participants completing paired scans, reported large fat-mass reductions and concluded that the proportion of lean mass lost was similar to that seen with other obesity treatments.
- Gastrointestinal tolerability
-
Human RCT evidence
human RCT
Gastrointestinal adverse events were reported by 27.8% to 72.8% of tirzepatide-treated participants across four phase 3 trials versus 12.2% to 32.5% on placebo, were mostly non-serious, and clustered during dose escalation; between 1.0% and 10.5% discontinued because of them. A post hoc mediation analysis found nausea, vomiting, diarrhoea, and dyspepsia accounted for at most about 3% of the weight reduction, so the effect is not simply people feeling too unwell to eat.
Compounds people map to this goal
Each card carries the compound's FDA status and its overall evidence grade, plus why it shows up on this goal in particular. Follow the card to the full library page for the claim-by-claim evidence review and what published research reported. Dosing and protocol ranges are never on this page.
Semaglutide
Also known as: GLP-1 receptor agonist, Ozempic, Wegovy, Rybelsus
A research reference for semaglutide, an FDA-approved GLP-1 receptor agonist with one of the largest randomized trial programmes in metabolic medicine, and real limits that the headlines skip.
Why it's on this page
The compound that made this an entire category, and the only one on this page with a published cardiovascular outcome trial rather than a weight endpoint alone. It is also the compound with the best-characterized answer to the question most readers are really asking, which is what happens when you stop. The trial that established its effect ran a formal off-treatment extension.
Last reviewed August 2, 2026
Tirzepatide
Also known as: Dual GIP/GLP-1 receptor agonist, Mounjaro, Zepbound
A research reference for tirzepatide, an FDA-approved dual GIP/GLP-1 receptor agonist with the largest weight reductions yet reported in randomized obesity trials, and a shorter safety record than the numbers suggest.
Why it's on this page
A dual GIP and GLP-1 receptor agonist, on this page because its registrational obesity trial produced the largest placebo-adjusted weight reduction of any agent here and because a dedicated randomized withdrawal trial tested maintenance directly. It also carries a labeled interaction that semaglutide does not: oral hormonal contraception may be less effective after starting it and after each dose increase. That makes the choice between the two more than a comparison of percentages.
Last reviewed August 2, 2026
FOR RESEARCH PURPOSES ONLY
Retatrutide
Also known as: LY3437943, Triple hormone receptor agonist
A research reference for retatrutide, an investigational GIP/GLP-1/glucagon triple receptor agonist with striking phase 2 weight data, no approval anywhere, and an unfinished registrational programme.
Why it's on this page
A triple GIP, GLP-1, and glucagon receptor agonist still moving through its development programme, mapped here because it is the compound people encounter as "the next one" and because published phase 2 and phase 3 results now exist for it. Nothing about it is settled: the obesity trial behind the widely quoted numbers ran 48 weeks in 338 people, and the registrational obesity programme has not reported. An investigational compound with no marketing approval also sits inside the criterion that defines WADA section S0, whether or not it is named there.
Last reviewed August 2, 2026
How to decide between them
These are the questions that actually change the answer. Work through them with a licensed provider. None of them can be answered by a page that does not know your labs, your history, or your medications.
-
Are you after weight loss, or after a health outcome that weight loss is standing in for?
This is the first fork, and it narrows the field immediately. Only one compound on this page has been tested against hard cardiovascular endpoints: in 17,604 adults with established cardiovascular disease, overweight or obesity, and no diabetes, semaglutide reduced the composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke over a mean 40 months of follow-up. If the reason for considering any of this is heart risk rather than a number on a scale, that trial is the relevant evidence, not the weight percentages.
Human RCT evidence [5] -
Are you prepared for this to be a long-term treatment?
The withdrawal data are unusually clear and are the part most often left out. A year after semaglutide and lifestyle intervention were stopped, participants had regained about two-thirds of the weight they had lost, and most of the cardiometabolic improvements had drifted back toward baseline. In a randomized withdrawal trial of tirzepatide, people switched to placebo regained weight while those who continued kept and extended their loss. Neither result is a criticism of the drugs; both say the same thing about the condition. If continuing indefinitely is not realistic, that belongs in the decision now rather than later.
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How much of what you lose do you want to be fat?
A 2026 systematic review of body-composition outcomes across 35 randomized trials of incretin therapies found that the median share of total weight loss attributable to muscle-related measures was about 28%, above the benchmark the reviewers set for expected loss, with wide variation between studies. Not one of those studies reported an objective physical function outcome. That is the gap worth planning around with a clinician before starting, through resistance training and protein intake, rather than discovering it afterwards.
Human RCT evidence [9] -
Does it matter to you whether a compound has been through a regulator, or only whether it has been through a trial?
Those are different questions and this page is where they separate. Retatrutide has published randomized evidence, a 48-week phase 2 obesity trial and a completed 40-week phase 3 trial in type 2 diabetes. It has no marketing approval anywhere. Published trial data and regulatory review are not substitutes for each other: review is what examines the full safety dataset, sets the contraindications, and puts a manufacturing standard behind what is in the vial. A reader comfortable with the first and indifferent to the second is accepting a specific and nameable risk.
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Is there something in your history that settles this before efficacy matters at all?
Several things can. The approved products in this class carry a boxed warning about thyroid C-cell tumours seen in rodents and are contraindicated in people with a personal or family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia syndrome type 2; the semaglutide labeling instructs stopping at least two months before a planned pregnancy; and tirzepatide labeling advises that oral hormonal contraception may be less effective for four weeks after starting and after each dose increase. Those are label statements to raise with a clinician, not verdicts from this page. Separately, gastrointestinal adverse events were the most common in every registrational trial and the leading reason people stopped.
Questions for your provider
Bring this goal page to a licensed provider. A provider can order labs, review your medications and history, and tell you whether anything here applies to your situation. This goal page cannot. Peptide Health Lab does not prescribe and does not sell peptides.
A goal is not a diagnosis. The most useful version of this conversation usually starts with what is actually driving the symptom, not with which compound to try.
Citations
11 sources · every identifier checked against PubMed
- [1] Once-weekly semaglutide in adults with overweight or obesity · The New England Journal of Medicine, 2021. Human RCT
- [2] Weight regain and cardiometabolic effects after withdrawal of semaglutide: the STEP 1 trial extension · Diabetes, Obesity and Metabolism, 2022. Human RCT
- [3] Tirzepatide once weekly for the treatment of obesity · The New England Journal of Medicine, 2022. Human RCT
- [4] Triple-hormone-receptor agonist retatrutide for obesity — a phase 2 trial · The New England Journal of Medicine, 2023. Human RCT
- [5] Semaglutide and cardiovascular outcomes in obesity without diabetes · The New England Journal of Medicine, 2023. Human RCT
- [6] Continued treatment with tirzepatide for maintenance of weight reduction in adults with obesity: the SURMOUNT-4 randomized clinical trial · JAMA, 2024. Human RCT
- [7] Gastrointestinal tolerability and weight reduction associated with tirzepatide in adults with obesity or overweight with and without type 2 diabetes in the SURMOUNT-1 to -4 trials · Diabetes, Obesity and Metabolism, 2025. Human RCT
- [8] Effects of retatrutide on body composition in people with type 2 diabetes: a substudy of a phase 2, double-blind, parallel-group, placebo-controlled, randomised trial · The Lancet Diabetes & Endocrinology, 2025. Human RCT
- [9] Effect of incretin-based and nonpharmacologic weight loss on body composition: a systematic review · Annals of Internal Medicine, 2026. Review
- [10] Benefits and harms of pharmacologic treatments in adults with overweight or obesity: a living systematic review and network meta-analysis for the American College of Physicians · Annals of Internal Medicine, 2026. Review
- [11] Efficacy and safety of retatrutide, a GIP, GLP-1, and glucagon receptor agonist, in people with type 2 diabetes and inadequate glycaemic control with diet and exercise (TRANSCEND-T2D-1): a double-blind, randomised, phase 3 trial · The Lancet, 2026. Human RCT
Before you act on any of this
This page is educational only and is not medical advice. It does not diagnose, treat, or prescribe. Review it with a licensed provider before making any health decision. Peptide Health Lab does not sell peptides.
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