Contents
- The numbers
- What the two established options actually showed
- The part most benefit articles leave out
- The weight comes back
- Some of it is muscle
- Tesamorelin: a real fat benefit with a narrow label
- The fat-loss peptides with no fat-loss data
- Weight-loss claims, graded
- One thing that decides whether any of this applies to you
- Where to go next
Key findings
- 1Tirzepatide produced about 20% mean weight loss at 72 weeks and semaglutide about 14–15% at 68–72 weeks; a head-to-head trial (SURMOUNT-5) found tirzepatide superior.
- 2The weight loss is not permanent — STEP 1 participants regained roughly two-thirds within a year of stopping, and SURMOUNT-4 showed about 14% regain over a year on placebo.
- 3A meaningful share of the weight lost is lean tissue, which is why resistance training and adequate protein are being studied alongside these drugs.
- 4Tesamorelin reduces visceral fat by 15–18% but only has approval and phase 3 evidence in HIV-associated lipodystrophy, and the effect reverses on discontinuation.
- 5Growth-hormone secretagogues such as CJC-1295 and ipamorelin are widely marketed for fat loss with zero controlled trials measuring body composition.
Evidence level
Semaglutide and tirzepatide have large randomised placebo-controlled trials and FDA approvals for chronic weight management, with a head-to-head trial comparing them. Growth-hormone secretagogues marketed for fat loss have no body-composition outcome trials.
Regulatory status
Semaglutide (Wegovy) and tirzepatide (Zepbound) are FDA-approved for chronic weight management. Tesamorelin is approved only for visceral fat in HIV-associated lipodystrophy. CJC-1295 and ipamorelin are not approved for any use.
This is the benefit people search for most, and it is the one where the evidence is clearest — in both directions. Two peptides have produced weight loss at a scale no previous drug class matched, in trials with thousands of participants. Several others are sold for fat loss on the strength of a hormone measurement and nothing else.
The numbers
| Peptide | Trial | Mean weight change | Duration |
|---|---|---|---|
| Tirzepatide 15 mg | SURMOUNT-1 | −20.9% vs −3.1% placebo | 72 weeks |
| Tirzepatide 15 mg | SURMOUNT-5 (head-to-head) | −20.2% | 72 weeks |
| Semaglutide 2.4 mg | STEP 1 | −14.9% vs −2.4% placebo | 68 weeks |
| Semaglutide 2.4 mg | SURMOUNT-5 (head-to-head) | −13.7% | 72 weeks |
| Tesamorelin | Phase 3 pooled (HIV lipodystrophy) | −15 to −18% visceral fat | 26 weeks |
| CJC-1295 / ipamorelin | None | Never measured | — |
What the two established options actually showed
Semaglutide. STEP 1 randomised 1,961 adults with overweight or obesity and no diabetes. Mean weight change was −14.9% at 68 weeks against −2.4% on placebo[1].
Study details: Once-Weekly Semaglutide in Adults with Overweight or Obesity (STEP 1)
- Study type
- Randomised, double-blind, placebo-controlled phase 3
- Population
- Adults with BMI ≥30, or ≥27 with a weight-related condition, without diabetes
- Sample size
- 1961
- Primary result
- Mean weight change −14.9% versus −2.4% with placebo at 68 weeks.
- Limitations
- 68 weeks; regain documented after discontinuation.
- Year
- 2021
- Source
- New England Journal of Medicine(link not yet independently re-verified)
Tirzepatide. SURMOUNT-1 randomised 2,539 adults with obesity, and produced dose-dependent losses up to −20.9% at 72 weeks against −3.1%[2].
Study details: Tirzepatide Once Weekly for the Treatment of Obesity (SURMOUNT-1)
- Study type
- Randomised, double-blind, placebo-controlled phase 3
- Population
- Adults with obesity without diabetes
- Sample size
- 2539
- Primary result
- Mean weight change −15.0% (5 mg), −19.5% (10 mg), −20.9% (15 mg) versus −3.1% placebo at 72 weeks.
- Year
- 2022
- Source
- New England Journal of Medicine(link not yet independently re-verified)
Directly compared. SURMOUNT-5 put them head to head in 751 adults: −20.2% for tirzepatide versus −13.7% for semaglutide at 72 weeks[3]. It was open-label and sponsor-run, which is worth knowing, but it is still the only randomised direct comparison.
Study details: Tirzepatide as Compared with Semaglutide for the Treatment of Obesity (SURMOUNT-5)
- Study type
- Randomised, open-label, head-to-head phase 3b
- Population
- Adults with obesity without diabetes
- Sample size
- 751
- Primary result
- Mean weight change −20.2% with tirzepatide versus −13.7% with semaglutide 2.4 mg at 72 weeks.
- Limitations
- Open-label; sponsor-run.
- Year
- 2025
- Source
- New England Journal of Medicine(link not yet independently re-verified)
The part most benefit articles leave out
The weight comes back
The same trial programmes that produced those numbers also measured what happens on stopping. STEP 1's off-treatment extension followed 327 participants for a year after discontinuation: they regained about two-thirds of the weight they had lost[4].
Study details: Weight regain and cardiometabolic effects after withdrawal of semaglutide — the STEP 1 trial extension
- Study type
- Off-treatment extension of a randomised trial
- Population
- STEP 1 participants followed one year after stopping
- Sample size
- 327
- Primary result
- Participants regained about two-thirds of prior weight loss within a year.
- Year
- 2022
- Source
- Diabetes, Obesity and Metabolism(link not yet independently re-verified)
SURMOUNT-4 tested it as a randomised withdrawal: after a 36-week lead-in, people switched to placebo regained about 14% of body weight over the following year, while those who continued kept losing[5].
Study details: Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity (SURMOUNT-4)
- Study type
- Randomised withdrawal trial
- Population
- Adults with obesity after a 36-week tirzepatide lead-in
- Sample size
- 670
- Primary result
- Switching to placebo led to about 14% weight regain over 52 weeks versus further loss on continued treatment.
- Limitations
- Only responders entered the randomised withdrawal phase.
- Year
- 2024
- Source
- JAMA(link not yet independently re-verified)
The correct way to read this is not "the drugs fail". It is that obesity behaves like a chronic condition and these are chronic treatments. That has real consequences for cost, planning and expectations.
Some of it is muscle
DEXA substudies across both programmes show that a meaningful fraction of the weight lost is lean tissue — which is true of substantial weight loss by any method, but matters more when the loss is this large and this fast. It is the reason resistance training, protein intake and muscle-preserving co-therapies are among the most active research questions in the field right now.
Tesamorelin: a real fat benefit with a narrow label
Tesamorelin reduced visceral adipose tissue by 15–18% over 26 weeks across two phase 3 trials[6].
Study details: Effects of tesamorelin in HIV-infected patients with excess abdominal fat — pooled analysis of two phase 3 trials
- Study type
- rct
- Population
- HIV-infected adults with abdominal fat accumulation
- Sample size
- 806
- Primary result
- Visceral adipose tissue reduced 15.4–17.5% at 26 weeks; regained on switching to placebo.
- Year
- 2010
- Source
- Journal of Clinical Endocrinology & Metabolism(link not yet independently re-verified)
Two things must travel with that number. The trials were in HIV-infected adults with lipodystrophy, which is the only approved indication. And the reduction reverses when treatment stops. Off-label use for general abdominal fat is extrapolation from a different population, not a demonstrated benefit.
The fat-loss peptides with no fat-loss data
CJC-1295 and ipamorelin are marketed almost entirely on body composition. What the human studies show is that they raise growth hormone and IGF-1 for a period of time. No controlled trial has measured fat mass, lean mass, waist circumference or weight with either compound, alone or in the popular combination.
The nearest available benchmark is not encouraging. A systematic review of growth hormone given to healthy older adults found small changes — a couple of kilograms less fat, a couple more lean mass — with no improvement in strength or function, and significantly more swelling, joint pain and glucose intolerance[7].
Study details: Systematic review: the safety and efficacy of growth hormone in the healthy elderly
- Study type
- systematic-review
- Population
- Healthy older adults across 31 studies
- Sample size
- 220
- Primary result
- Growth hormone modestly reduced fat mass and increased lean mass but did not improve strength or function, with significantly more oedema, arthralgia and glucose intolerance.
- Year
- 2007
- Source
- Annals of Internal Medicine(link not yet independently re-verified)
Secretagogues might behave better, since they preserve pulsatile release and are self-limiting. Or they might not. Nobody has checked.
Weight-loss claims, graded
| Claim | Peptide | Best evidence | Grade |
|---|---|---|---|
| ~20% mean weight loss at 72 weeks | Tirzepatide | SURMOUNT-1, SURMOUNT-5 | Established evidenceLarge phase 3 RCTs |
| ~15% mean weight loss at 68 weeks | Semaglutide | STEP 1 | Established evidenceLarge phase 3 RCT |
| Visceral fat reduction (HIV lipodystrophy) | Tesamorelin | Two phase 3 RCTs | Established evidenceApproved indication only |
| Visceral fat reduction (general population) | Tesamorelin | Mechanism; small studies | Preliminary evidenceExtrapolation |
| Fat loss | CJC-1295, ipamorelin | None | Preclinical evidenceHormone levels only |
| Weight stays off after stopping | Semaglutide, tirzepatide | STEP 1 ext., SURMOUNT-4 | Unsupported evidenceContradicted by trials |
| Fat loss without lean-mass loss | Any | DEXA substudies show lean loss | Unsupported evidenceNot demonstrated |
One thing that decides whether any of this applies to you
These are prescription drugs with labelled risks — gastrointestinal effects that cause a minority to discontinue, a boxed warning for thyroid C-cell tumours based on rodent studies, and pancreatitis and gallbladder disease among listed risks. Whether the benefit is worth those risks for you is a clinical decision, not one this publication makes.
Where to go next
- GLP-1 benefits beyond weight loss — heart, kidney, liver, sleep.
- Semaglutide vs tirzepatide — the full comparison.
- CJC-1295 and ipamorelin: growth hormone research and unanswered risks
- Body composition research hub
Frequently asked questions
- Which peptide causes the most weight loss?
- Tirzepatide, on current evidence. In the SURMOUNT-5 head-to-head trial it produced about 20% mean weight loss at 72 weeks versus about 14% for semaglutide 2.4 mg.
- How fast does the weight come off?
- In the pivotal trials, weight declined steadily over roughly the first 60 weeks before plateauing. These were 68- and 72-week trials, so the plateau is measured, not extrapolated.
- Will I regain the weight if I stop?
- Most likely a large share of it. STEP 1 participants regained about two-thirds within a year of stopping, and SURMOUNT-4 showed about 14% of body weight regained over a year after switching to placebo.
- Do fat-loss peptides like CJC-1295 work?
- No controlled trial has measured body composition with them. They raise growth hormone and IGF-1, which is a hormone measurement, not a fat-loss result.
- Is some of the weight lost muscle?
- Yes. DEXA substudies show a meaningful proportion of the loss is lean tissue, as with any large weight loss. That is why resistance training, protein intake and muscle-preserving co-therapies are active research areas.
References
Numbered in order of first use. Study type is shown for every source; see our methodology for how we rank evidence.
- 1.
Wilding JPH, Batterham RL, Calanna S, et al.. Once-Weekly Semaglutide in Adults with Overweight or Obesity (STEP 1) New England Journal of Medicine, 2021.
Randomized controlled trialAdults with BMI ≥30, or ≥27 with a weight-related condition, without diabetesn = 1961
Result: Mean weight change −14.9% versus −2.4% with placebo at 68 weeks.
Limitations: 68 weeks; regain documented after discontinuation.
↑ back to text - 2.
Jastreboff AM, Aronne LJ, Ahmad NN, et al.. Tirzepatide Once Weekly for the Treatment of Obesity (SURMOUNT-1) New England Journal of Medicine, 2022.
Randomized controlled trialAdults with obesity without diabetesn = 2539
Result: Mean weight change −15.0% (5 mg), −19.5% (10 mg), −20.9% (15 mg) versus −3.1% placebo at 72 weeks.
↑ back to text - 3.
Aronne LJ, Horn DB, le Roux CW, et al.. Tirzepatide as Compared with Semaglutide for the Treatment of Obesity (SURMOUNT-5) New England Journal of Medicine, 2025.
Randomized controlled trialAdults with obesity without diabetesn = 751
Result: Mean weight change −20.2% with tirzepatide versus −13.7% with semaglutide 2.4 mg at 72 weeks.
Limitations: Open-label; sponsor-run.
↑ back to text - 4.
Wilding JPH, Batterham RL, Davies M, et al.. Weight regain and cardiometabolic effects after withdrawal of semaglutide — the STEP 1 trial extension Diabetes, Obesity and Metabolism, 2022.
Randomized controlled trialSTEP 1 participants followed one year after stoppingn = 327
Result: Participants regained about two-thirds of prior weight loss within a year.
↑ back to text - 5.
Aronne LJ, Sattar N, Horn DB, et al.. Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity (SURMOUNT-4) JAMA, 2024.
Randomized controlled trialAdults with obesity after a 36-week tirzepatide lead-inn = 670
Result: Switching to placebo led to about 14% weight regain over 52 weeks versus further loss on continued treatment.
Limitations: Only responders entered the randomised withdrawal phase.
↑ back to text - 6.
Falutz J, Mamputu JC, Potvin D, et al.. Effects of tesamorelin in HIV-infected patients with excess abdominal fat — pooled analysis of two phase 3 trials Journal of Clinical Endocrinology & Metabolism, 2010.
Randomized controlled trialHIV-infected adults with abdominal fat accumulationn = 806
Result: Visceral adipose tissue reduced 15.4–17.5% at 26 weeks; regained on switching to placebo.
↑ back to text - 7.
Liu H, Bravata DM, Olkin I, et al.. Systematic review: the safety and efficacy of growth hormone in the healthy elderly Annals of Internal Medicine, 2007.
Systematic reviewHealthy older adults across 31 studiesn = 220
Result: Growth hormone modestly reduced fat mass and increased lean mass but did not improve strength or function, with significantly more oedema, arthralgia and glucose intolerance.
↑ back to text - 8.
FDA's concerns with unapproved GLP-1 drugs used for weight loss U.S. Food and Drug Administration, 2025.
Regulatory source
Result: Shortage resolutions, adverse events reported with compounded products including dosing errors, and counterfeit products.
↑ back to text
Review status: Editorially reviewed against primary sources. This article was fact-checked against the primary sources listed in the references by our editorial team, and it has not been reviewed by a licensed clinician. It is educational content, not medical advice. Read our editorial policy and methodology. Spotted an error? Tell us.
