Best Peptides for Weight Loss: What the Research Shows

The weight loss peptide space has changed more in the last five years than it did in the previous twenty. What started with early GLP-1 receptor agonists like exenatide has now evolved into triple-agonist compounds that are producing weight loss numbers we genuinely didn't think were possible with pharmacotherapy alone.

If you've been searching for the best peptides for weight loss, you're probably already aware that names like semaglutide, tirzepatide, and retatrutide keep coming up. But the differences between them matter quite a lot, and most articles out there don't actually break down the clinical data properly. Thats what we're going to do here.

This guide covers every major weight loss peptide backed by published trial data, compares them side by side, and briefly touches on other peptides studied for body composition. Everything is framed through the lens of published research - not anecdote, not marketing.

Why Peptides for Weight Loss?

Traditional approaches to weight management - calorie restriction, exercise programmes, even older pharmaceutical options - have always struggled with one fundamental problem. They fight against the body's own regulatory systems. Your brain actively resists sustained weight loss through hormonal signalling, increased hunger drive and reduced metabolic rate. It's an evolutionary feature, not a bug.

Peptide-based approaches work differently because they target the hormonal machinery itself.

The GLP-1 revolution really began with exenatide back in 2005, which was originally developed for type 2 diabetes. Researchers noticed patients were losing significant weight as a side effect, which sparked an entirely new direction in obesity research. From there, liraglutide came along, then semaglutide, and each generation brought better efficacy and more convenient dosing.

The key mechanism is appetite regulation through the incretin system. GLP-1 (glucagon-like peptide-1) is a hormone your gut naturally releases after eating. It signals satiety to the brain, slows gastric emptying, and influences insulin secretion. Synthetic GLP-1 agonists mimic this hormone but last much longer in the body than natural GLP-1, which breaks down within minutes.

What makes the newer peptide approaches so interesting is how they've expanded beyond just GLP-1. Tirzepatide added GIP (glucose-dependent insulinotropic polypeptide) receptor activation. Retatrutide went further still, adding glucagon receptor agonism on top of both. Each additional mechanism seems to produce meaningfully better results, which the trial data confirms.

The best peptides for fat loss aren't just suppressing appetite. They're changing how the body processes energy at multiple levels simultaneously. That's fundamentally different from anything we had before.

Semaglutide

Semaglutide is where most people's understanding of weight loss peptides begins, and for good reason. It was the first GLP-1 agonist to really break into mainstream awareness, largely thanks to the brand names Ozempic (for diabetes) and Wegovy (for weight management).

How It Works

Semaglutide is a selective GLP-1 receptor agonist. It mimics the natural incretin hormone GLP-1, binding to receptors in the brain's appetite centres, the pancreas, and the gut. The practical effects are reduced hunger, earlier satiety when eating, and slower gastric emptying so meals keep you feeling full longer.

It has a half-life of approximately one week, which allows for once-weekly subcutaneous injection. That was a genuine breakthrough when it launched - previous GLP-1 agonists needed daily or even twice-daily dosing.

The STEP Trial Programme

The evidence base for semaglutide in weight management comes primarily from the STEP (Semaglutide Treatment Effect in People with Obesity) trial programme. These are large, well-designed, placebo-controlled studies.

STEP 1 enrolled over 1,900 adults with obesity or overweight with at least one weight-related comorbidity. At 68 weeks, participants receiving semaglutide 2.4 mg achieved a mean weight loss of 14.9% compared to 2.4% with placebo. That's substantial. Roughly 69-79% of participants across the STEP trials achieved at least 10% weight loss.

STEP 5 looked at longer-term outcomes over two years, which is important because sustained weight loss is where most interventions fall apart. The results held up well.

More recently, the STEP UP trial tested a higher 7.2 mg dose and reported even better outcomes. At 72 weeks, mean weight loss was 18.7% with the 7.2 mg dose versus 15.6% with the standard 2.4 mg dose. Over 90% of participants on the higher dose achieved at least 5% weight loss, with roughly a third losing 25% or more of their body weight.

Dosing and Titration

Semaglutide for weight management follows a gradual titration schedule, starting at 0.25 mg weekly and increasing every four weeks through 0.5 mg, 1.0 mg, and 1.7 mg before reaching the maintenance dose of 2.4 mg. This slow escalation is specifically designed to minimise gastrointestinal side effects.

Side Effects

The most common adverse effects are gastrointestinal. Nausea is the big one, affecting a significant proportion of users particularly during dose escalation. Diarrhoea, constipation and vomiting are also reported. Most of these effects are mild to moderate and tend to ease over time as the body adjusts.

There's also been attention on the potential for muscle mass loss alongside fat loss, which is a concern with any significant weight reduction. Some lean mass loss appears to occur, though the ratio of fat-to-lean mass lost generally favours fat.

Pros and Cons

• Pros: Extensive clinical data across multiple large trials. Once-weekly dosing. Well-characterised safety profile with years of real-world use. Available in both injectable and oral formulations.
• Cons: GI side effects can be bothersome during titration. Weight regain after discontinuation has been documented (STEP 1 extension showed significant regain after stopping). Less effective than newer dual and triple agonists based on head-to-head data.

Tirzepatide

Tirzepatide changed the conversation. When the SURMOUNT trial data came out, the numbers were genuinely striking - even to researchers who'd been following the GLP-1 field closely. Here was a compound consistently outperforming semaglutide, and the mechanism explained why.

How It Works

Unlike semaglutide which only targets GLP-1 receptors, tirzepatide is a dual GIP/GLP-1 receptor agonist. GIP (glucose-dependent insulinotropic polypeptide) is another incretin hormone, and while its role in weight management was historically unclear, tirzepatide demonstrated that activating both pathways produces meaningfully better results then GLP-1 alone.

The GIP component appears to enhance the fat-burning effects through mechanisms that are still being fully characterised. There's evidence it improves insulin sensitivity independently of weight loss and may influence fat metabolism directly in adipose tissue.

SURMOUNT-1 Trial Data

SURMOUNT-1 was a Phase 3, 72-week study in adults with obesity or overweight. The results across three dose levels were impressive:

• 5 mg dose: 16.0% mean weight reduction
• 10 mg dose: 21.4% mean weight reduction
• 15 mg dose: 22.5% mean weight reduction
• Placebo: 2.4% mean weight reduction

At the highest dose, 39.7% of participants achieved at least 25% body weight reduction. Compare that to just 0.3% in the placebo group. Half of participants on the 10 mg and 15 mg doses lost 20% or more of their body weight.

These numbers represent a genuine step forward. The average person in the highest dose group lost roughly 52 pounds.

Head-to-Head Against Semaglutide

The SURMOUNT-5 trial provided what everyone had been waiting for: a direct comparison. At 72 weeks, tirzepatide achieved a mean weight reduction of 20.2% compared to 13.7% for semaglutide. In absolute terms, tirzepatide participants lost about 50 pounds versus 33 pounds for semaglutide.

Participants on tirzepatide were significantly more likely to hit every weight loss threshold measured - 10%, 15%, 20% and 25% reductions.

Dosing and Titration

Tirzepatide also uses a gradual titration approach, starting at 2.5 mg weekly and increasing in 2.5 mg increments every four weeks. The target maintenance doses are 5 mg, 10 mg, or 15 mg, depending on individual response and tolerability. Its administered as a once-weekly subcutaneous injection.

Side Effects Compared to Semaglutide

The side effect profile is broadly similar - gastrointestinal effects dominate, including nausea, diarrhoea, vomiting, and constipation. These were mostly mild to moderate and occurred primarily during the dose escalation period.

In the head-to-head SURMOUNT-5 trial, the safety profiles of both compounds were comparable. Neither showed a clear advantage in tolerability. However some analyses suggest that tirzepatide may produce slightly less nausea at equivalent efficacy levels, possibly because the dual mechanism allows lower relative GLP-1 receptor activation for the same overall effect.

Why Dual Agonism Appears Superior

The question of why targeting both GIP and GLP-1 works better then GLP-1 alone doesn't have a single clean answer yet. Several factors likely contribute: enhanced insulin sensitivity, improved lipid metabolism in adipose tissue, better glucose disposal, and potentially complementary effects on appetite centres in the brain. The clinical outcomes speak clearly even if the mechanistic picture is still being refined.

Retatrutide

If semaglutide started the revolution and tirzepatide accelerated it, retatrutide might represent where it's ultimately heading. This is the first triple agonist to reach advanced clinical trials, and the early data is remarkable.

How It Works

Retatrutide activates three receptors simultaneously: GLP-1, GIP, and glucagon. The addition of glucagon receptor agonism is the key innovation here. While that might seem counterintuitive - glucagon raises blood sugar, after all - the metabolic effects at the doses used appear to favour increased energy expenditure and enhanced fat oxidation.

Glucagon increases thermogenesis and energy expenditure in the liver and potentially in brown adipose tissue. Combined with the appetite-suppressing effects of GLP-1 and the metabolic benefits of GIP, you get a compound that's reducing caloric intake while simultaneously increasing caloric output. That's a combination no previous peptide has achieved.

Phase 2 Trial Results

The Phase 2 results, published in the New England Journal of Medicine, generated enormous excitement. At 48 weeks with the 12 mg dose, participants achieved a mean weight reduction of 24.2% - roughly 58 pounds on average. Even at 24 weeks the results were striking, with the same dose group showing 17.5% weight loss.

The dose-response data was clear:

• 1 mg dose: 8.7% at 48 weeks
• 4 mg dose: 17.1% at 48 weeks
• 8 mg dose: 22.8% at 48 weeks
• 12 mg dose: 24.2% at 48 weeks
• Placebo: 2.1% at 48 weeks

Importantly, the weight loss curves hadn't fully plateaued at 48 weeks, suggesting that longer treatment periods could yield even greater reductions.

Phase 3 Updates

The TRIUMPH-4 trial - the first completed Phase 3 study for retatrutide - reported that participants with obesity and knee osteoarthritis lost an average of 28.7% of body weight at 68 weeks on the 12 mg dose. That's nearly a third of their body weight. The trial also showed significant reductions in knee pain, suggesting the weight loss itself produced meaningful clinical improvements beyond just the number on the scale.

Seven additional Phase 3 trials are ongoing, with most expected to complete in 2026. These cover obesity, type 2 diabetes, osteoarthritis, obstructive sleep apnoea, chronic lower back pain, cardiovascular outcomes, and liver disease.

Why Glucagon Receptor Agonism Matters

Adding glucagon to the mix addresses something the GLP-1-only and dual GIP/GLP-1 approaches don't - energy expenditure. Semaglutide and tirzepatide primarily work by reducing food intake. They're very effective at that, but metabolic adaptation (where the body reduces its energy output in response to lower intake) still occurs to some degree.

Glucagon receptor activation appears to partially counteract this by maintaining or increasing energy expenditure. Think of it this way: GLP-1 and GIP turn down the "calories in" side. Glucagon turns up the "calories out" side. Together, the effect is greater than either approach alone.

Safety Considerations

GI side effects remain common with retatrutide, consistent with the class. The TRIUMPH-4 trial reported nausea in 43% of participants, diarrhoea in 33%, and vomiting in 21%.

A new safety signal worth noting is dysesthesia - an abnormal tingling or burning sensation - which was reported in 8.8% of the 9 mg group and 20.9% of the 12 mg group, compared to just 0.7% with placebo. This will need careful monitoring in ongoing trials as its something that wasn't seen with the earlier compounds.

Retatrutide has not yet received regulatory approval. Based on current trial timelines, the earliest potential approval window would be late 2026 or early 2027, assuming Phase 3 results remain positive.

Head-to-Head Comparison: Semaglutide vs Tirzepatide vs Retatrutide

This is the comparison most people searching "semaglutide vs tirzepatide" or "tirzepatide vs retatrutide" are actually looking for. Here's how the three compounds stack up based on published trial data.

A few things stand out from this comparison.

First, each generation shows a clear improvement in efficacy. Semaglutide set the bar, tirzepatide raised it considerably, and retatrutide appears to raise it further still. The 28.7% weight loss figure from TRIUMPH-4 is the highest reported in any obesity trial of this class.

Second, the side effect profiles are broadly similar across all three. GI effects are the price of entry with incretin-based therapies. Retatrutide adds the dysesthesia concern, which is unique to that compound and needs further investigation.

Third, there's a maturity gap. Semaglutide has years of real-world data and regulatory approval in multiple countries. Tirzepatide has approval and growing real-world experience. Retatrutide is still in Phase 3 trials. More data always means more certainty about both efficacy and safety.

When people search "semaglutide vs tirzepatide" specifically, the head-to-head SURMOUNT-5 data is the most relevant. Tirzepatide produced 20.2% weight loss versus 13.7% for semaglutide over 72 weeks. That's a meaningful difference - about 17 additional pounds lost on average. Both had comparable safety profiles.

For "tirzepatide vs retatrutide", direct comparison is harder because we don't yet have a head-to-head trial. Comparing across studies (which always requires caution due to differences in trial populations and designs), retatrutide's Phase 3 numbers appear superior, but we'll need more Phase 3 data and ideally a direct comparison trial before drawing firm conclusions.

Other Peptides Studied for Body Composition

Beyond the GLP-1 family, several other peptides have been researched for there effects on fat loss and body composition. None have produced results anywhere near the compounds above, but they deserve a mention for completeness.

AOD-9604

AOD-9604 is a modified fragment of human growth hormone (specifically amino acids 177-191). The theory behind it is sound enough - it targets the lipolytic (fat-burning) region of the growth hormone molecule without affecting blood sugar or growth.

Early animal studies in obese mice showed promise. However, human clinical trials told a different story. A 12-week trial showed modest results (2.6 kg lost vs 0.8 kg on placebo), but a larger 24-week Phase IIb trial with 536 participants failed to show statistically significant weight loss. Development was terminated in 2007.

Despite the disappointing clinical outcomes, AOD-9604 remains popular in the research peptide space. It has not received regulatory approval from any major health authority for weight management.

Tesamorelin

Tesamorelin is a growth hormone-releasing hormone (GHRH) analogue thats actually FDA-approved - but specifically for reducing visceral adipose tissue in HIV-associated lipodystrophy, not for general weight loss.

In clinical trials for that indication, tesamorelin reduced visceral fat by approximately 15-18% over 26 weeks. Interestingly, it was selective - subcutaneous fat levels remained largely unchanged. It also appeared to preserve or slightly increase skeletal muscle area and density, which is a meaningful advantage over approaches that reduce both fat and lean mass.

The research on tesamorelin outside of HIV-associated lipodystrophy is limited. Its mechanism - stimulating your own growth hormone release rather than directly agonising incretin receptors - is fundamentally different from the GLP-1 class, and the magnitude of fat reduction is much smaller.

CJC-1295 and Ipamorelin

These two peptides are often discussed together because they're frequently combined in research settings. CJC-1295 is a long-acting GHRH analogue that can sustain elevated growth hormone levels for days after a single injection. Ipamorelin is a selective growth hormone secretagogue that stimulates GH release through a different mechanism (ghrelin mimicry).

The hormonal effects are real and well documented. A single injection of CJC-1295 produces 2- to 10-fold increases in growth hormone levels lasting up to 6 days, with IGF-1 elevations persisting for 9-11 days.

However - and this is important - hormone elevation doesn't automatically translate to meaningful fat loss. Hard outcome data on body composition changes in healthy individuals is limited. The theoretical pathway (more GH leads to more lipolysis leads to fat loss) makes mechanistic sense, but the actual clinical evidence for significant weight reduction is thin compared to the incretin-based peptides.

Neither CJC-1295 nor ipamorelin is approved by any major regulatory body for weight loss or body composition improvement.

Weight Loss Peptides in the UK

For those specifically researching weight loss peptides UK availability, the regulatory picture is worth understanding. Semaglutide and tirzepatide are both available on NHS prescription and through private clinics, though supply has been inconsistent due to global demand. Retatrutide is not yet approved anywhere.

Research peptides like AOD-9604, tesamorelin, CJC-1295, and ipamorelin occupy a different category entirely. They are available from specialist research suppliers for laboratory and research use but are not licensed medicines in the UK for weight management.

All products sold through our store are for research purposes only. They are not intended for human consumption, and nothing on this page should be taken as medical advice. If you are considering any form of weight management treatment, consult a qualified healthcare professional.

Frequently Asked Questions

What is the most effective peptide for weight loss based on current research?

Based on published clinical trial data, retatrutide has produced the highest average weight loss figures - 28.7% at 68 weeks in the TRIUMPH-4 Phase 3 trial. However, it hasn't received regulatory approval yet. Among approved treatments, tirzepatide currently shows superior efficacy to semaglutide, with 22.5% mean weight loss at the highest dose in SURMOUNT-1 compared to semaglutide's 14.9% in STEP 1.

How do semaglutide and tirzepatide compare in head-to-head trials?

The SURMOUNT-5 trial directly compared them over 72 weeks. Tirzepatide achieved 20.2% mean weight reduction versus 13.7% for semaglutide. In practical terms, thats about 50 pounds lost with tirzepatide compared to 33 pounds with semaglutide. Side effect profiles were similar between the two.

What makes retatrutide different from tirzepatide?

Retatrutide adds glucagon receptor activation on top of the GLP-1 and GIP agonism that tirzepatide provides. This third mechanism appears to increase energy expenditure - meaning your body burns more calories even at rest. Tirzepatide and semaglutide primarily reduce weight through appetite suppression and reduced caloric intake. Retatrutide does both: reduces intake and increases expenditure.

Are there serious side effects with weight loss peptides?

Gastrointestinal effects (nausea, vomiting, diarrhoea, constipation) are the most commonly reported side effects across all three major weight loss peptides. These are typically mild to moderate and most pronounced during the dose escalation period. Retatrutide has shown a unique signal for dysesthesia (tingling/burning sensations) that wasn't seen with the other compounds. Pancreatitis and thyroid concerns have been monitored across the GLP-1 class, though rates remain low in clinical trials.

Does weight come back after stopping these peptides?

Research from the STEP 1 trial extension showed significant weight regain after discontinuing semaglutide. This isn't unique to peptides - it reflects the body's hormonal drive to return to its previous set point. Current evidence suggests these compounds need continued use to maintain results, which is an important consideration for long term planning.

What about AOD-9604? Does it work for fat loss?

The clinical evidence for AOD-9604 is disappointing compared to incretin-based peptides. Its largest trial (536 participants, 24 weeks) failed to achieve statistically significant weight loss, and development was terminated in 2007. It remains available as a research peptide but lacks the robust efficacy data that supports semaglutide, tirzepatide, and retatrutide.

When will retatrutide be available?

Retatrutide is currently in Phase 3 clinical trials, with seven studies expected to complete during 2026. Assuming positive results and no major safety concerns, the earliest potential regulatory approval window is estimated at late 2026 to early 2027. This timeline could shift depending on trial outcomes and regulatory review processes.

Can you combine different weight loss peptides?

There is very limited published research on combining weight loss peptides. The major clinical trials have all studied individual compounds against placebo or against each other - not in combination. Without clinical data on safety and interactions, any discussion of combining these compounds would be speculative.

Which peptide has the best evidence for preserving muscle during weight loss?

Tesamorelin has shown the most favourable data specifically for muscle preservation, actually increasing skeletal muscle area in some studies. However, its overall fat reduction is modest compared to the incretin class. Among the major weight loss peptides, body composition analyses from the SURMOUNT trials suggest that tirzepatide produces a favourable fat-to-lean mass loss ratio, though some lean mass loss still occurs with any significant weight reduction.