Which compound produces the largest reduction?

Retatrutide, on the figures reported so far — 28.3% at 80 weeks in TRIUMPH-1. It is also still investigational, so that number comes from trials rather than clinical use.

Why does the tablet lose less weight?

Because orforglipron engages only the GLP-1 receptor. The larger figures come from molecules adding GIP, glucagon or amylin, and no small molecule has yet achieved that. Route matters less than receptor count — aleniglipron is also an oral single-receptor agonist and reported 15.3% in Phase 2.

Are any of these available in the UK?

Orforglipron is authorised as Foundayo. The rest are investigational or, in mazdutide's case, approved only in China.

GLP-1 & Incretin Science

The Obesity Drug Pipeline in 2026

JMWritten & reviewed by Jack Muncaster · Founder, UK PeptidesLast reviewed 2026-08-235 cited sources

The 2026 obesity pipeline splits along two axes: how many receptors a molecule engages, and how it is administered. Retatrutide leads on magnitude as a triple agonist, CagriSema and amycretin add amylin to GLP-1, survodutide and mazdutide add glucagon, and orforglipron is the first non-peptide taken as a tablet.

Key facts

Largest reported reduction: Retatrutide — 28.3% at 80 weeks
First non-peptide approved: Orforglipron — MHRA, 10 Aug 2026
Amylin + GLP-1: CagriSema, amycretin
Glucagon-containing: Retatrutide, survodutide, mazdutide
Approved in China: Mazdutide
Highest oral Phase 2: Aleniglipron — 15.3% at 44 weeks
Common limitation: Gastrointestinal tolerability across all

The two axes that organise the field

Almost every compound in development can be placed by answering two questions. How many receptors does it engage — one, two or three? And is it a peptide, which generally means injection, or a small molecule, which can be a tablet? Adding receptors has consistently increased effect size and consistently increased gastrointestinal burden. The oral trade-off looked equally consistent until 2026: orforglipron reported 11.2% where injectable multi-agonists report twice that. Aleniglipron has complicated it, reporting 15.3% absolute at 44 weeks in Phase 2 — still short of retatrutide, but no longer in a different league. The gap between routes now looks narrower than the gap between one receptor and three.

Triple agonists: retatrutide

Retatrutide engages GIP, GLP-1 and glucagon receptors from a single 39-residue peptide. TRIUMPH-1 reported mean reduction of 28.3% at 80 weeks on 12 mg, the largest figure yet reported for a single molecule, with a 104-week extension reaching 30.3% in participants with baseline BMI of 35 or above. It remains investigational everywhere; an FDA filing was signalled for Q1 2027.

Research material referenced

Retatrutide 10mg — third-party HPLC tested

View — £59.99

Amylin combinations: CagriSema and amycretin

Amylin is a separate satiety hormone co-secreted with insulin, and combining amylin agonism with GLP-1 agonism is the other main strategy for increasing effect size. CagriSema is a fixed-dose combination of cagrilintide and semaglutide, both at 2.4 mg once weekly. Amycretin takes the harder route, engaging both GLP-1 and amylin receptors from one molecule, and exists in both weekly subcutaneous and daily oral forms.

Glucagon-containing dual agonists: survodutide and mazdutide

Adding glucagon-receptor activity raises energy expenditure and has a particular effect on hepatic fat, which is why survodutide has been pursued in metabolic liver disease alongside obesity. Mazdutide, a GLP-1/glucagon dual agonist developed by Innovent with Eli Lilly, is approved in China but not in the United States or European Union, and reported roughly 20% reduction on 9 mg in Chinese Phase 3 work.

The oral route: orforglipron

Orforglipron is the outlier because it is not a peptide at all. It reached 11.2% mean reduction at 72 weeks on its highest dose — well below the injectable multi-agonists — but it is an ordinary tablet with no absorption enhancer, no fasting window and conventional manufacturing economics. The MHRA authorised it on 10 August 2026, the first such approval in Europe. Aleniglipron, a second oral non-peptide from Structure Therapeutics, has since reported substantially higher Phase 2 figures — 15.3% absolute at 44 weeks on 180 mg, with no plateau reached — which suggests orforglipron's effect size reflects that molecule rather than a ceiling on the oral route.

What everything in the pipeline still shares

Gastrointestinal adverse events dominate across every compound and every mechanism, and discontinuation rates rise with dose in all of them. Weight regain after cessation is unresolved across the entire class. Adding receptors has not solved either problem, and neither has changing route.

Quick reference

Compound	Receptors	Route	Reported reduction	Status
Retatrutide	GIP/GLP-1/glucagon	Weekly injection	28.3% @ 80 wks	Investigational
CagriSema	Amylin + GLP-1	Weekly injection	22.7% @ 68 wks	Filed / under review
Amycretin	GLP-1 + amylin	Weekly SC or daily oral	Up to 14.5% @ 36 wks	Entering Phase 3
Mazdutide	GLP-1/glucagon	Weekly injection	~20% (9 mg, Ph3)	Approved in China
Survodutide	GLP-1/glucagon	Weekly injection	Phase 3 reported	Investigational
Orforglipron	GLP-1 only	Daily tablet	11.2% @ 72 wks	Authorised (UK)
Aleniglipron	GLP-1 only	Daily tablet	15.3% @ 44 wks (Ph2)	Investigational

Extended research context

The GLP-1 & Incretin Science deep dive

Deep dive: the two routes to a bigger effect

Every compound trying to beat GLP-1 alone has taken one of two routes. The first adds more receptors from the same hormone family — GIP in tirzepatide, GIP and glucagon in retatrutide. The second adds a non-incretin satiety hormone, which in practice means amylin: CagriSema combines cagrilintide with semaglutide, and amycretin engages both receptors from one molecule. Both routes work, because they recruit signalling pathways that do not fully overlap. Neither has escaped the constraint that binds all of them, which is that gastrointestinal tolerability worsens as effect size grows.

Deep dive: why a percentage is not a result

The most-quoted numbers in this field are the least comparable. REDEFINE 1 reported 22.7% and 20.4% for the same compound in the same trial — the first among participants who adhered to treatment, the second across everyone randomised. TRIUMPH-1 reported 28.3% in an uncomplicated obesity population while TRIUMPH-3 reported up to 22.6% in adults with established cardiovascular disease, using the same compound. Before any two figures can be compared they have to match on estimand, population, duration, comparator and whether the number is placebo-adjusted. Most published comparisons match on none of them.

Deep dive: what happens after the trial stops

Every headline figure describes weight while treatment continues. The STEP-1 extension found that a year after semaglutide was stopped, participants had given back roughly two-thirds of what they lost, moving from 17.3% mean reduction to a net 5.6% — though average weight remained below baseline and nearly half stayed at least 5% down. Meta-analysis puts regain at around 0.8 kg per month. This is why maintenance studies such as TRIUMPH-6 matter more to the field's future than another two points of peak reduction.

Research applications

▸Comparing incretin and amylin compounds on a like-for-like basis
▸Interpreting estimands, thresholds and placebo-adjusted figures in trial reports
▸Tracking the obesity pipeline across sponsors and jurisdictions
▸Understanding receptor pharmacology behind GLP-1, GIP, glucagon and amylin
▸Distinguishing licensed medicines from investigational compounds

Handling checklist

✓Identify which estimand a quoted percentage comes from before citing it
✓Check the trial population and baseline BMI against the comparison you are making
✓Confirm the duration and whether the reduction curve had plateaued
✓Read discontinuation rates alongside efficacy figures
✓Verify every NCT identifier against ClinicalTrials.gov rather than secondary reporting

Common research-handling mistakes

Learnt from thousands of researcher orders across our UK labs.

✗ Comparing headline percentages across different trials

Fix: Population, duration, estimand and comparator all differ; the numbers are not interchangeable.

✗ Quoting the larger of two figures from the same trial

Fix: Name the estimand. Efficacy and treatment-policy answer different questions.

✗ Treating peak reduction as a durable outcome

Fix: Substantial regain follows cessation across the class; peak figures describe a maintained state.

✗ Assuming an oral route means a weaker mechanism

Fix: Route and receptor count are independent. Orforglipron is weaker because it hits one receptor, not because it is a tablet.

✗ Reading investigational compounds as available treatments

Fix: Most of this pipeline holds no authorisation anywhere; mazdutide is approved only in China.

Continue researching

Peer-reviewed guides, comparators and matched reference materials.

Frequently asked questions

Which compound produces the largest reduction?: Retatrutide, on the figures reported so far — 28.3% at 80 weeks in TRIUMPH-1. It is also still investigational, so that number comes from trials rather than clinical use.
Why does the tablet lose less weight?: Because orforglipron engages only the GLP-1 receptor. The larger figures come from molecules adding GIP, glucagon or amylin, and no small molecule has yet achieved that. Route matters less than receptor count — aleniglipron is also an oral single-receptor agonist and reported 15.3% in Phase 2.
Are any of these available in the UK?: Orforglipron is authorised as Foundayo. The rest are investigational or, in mazdutide's case, approved only in China.

Primary sources & clinical trials

Peer-reviewed research and registered trials from PubMed, ClinicalTrials.gov, PubChem, FDA and NIH. All links open in a new tab and point to the primary source, so every claim can be verified at origin.

Written and reviewed by

Jack Muncaster · Founder, UK Peptides

Jack founded UK Peptides in Manchester after repeatedly receiving research compounds with missing or recycled paperwork. He is responsible for supplier selection, batch release decisions and the content published in this research library. Every article here is sourced to primary literature and every product page to a signed third-party certificate.

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