The Incretin Pipeline Scorecard

The incretin business works roughly like this. The gut already makes hormones that tell the brain you have eaten. Drugmakers take those hormones, make them last longer, bolt on a second or third receptor, and then publish a percentage. The percentage is the product, and the percentage keeps going up. This scorecard puts every serious next generation molecule in one place: what it hits, how it gets into the body, how far along it is, the best weight result anyone has published, the trial that produced that number, and the question that number does not answer.

How to read it: each row is a molecule. Best published weight loss is the highest mean figure in the published record, with dose, duration and estimand attached, because the same drug in the same trial can lose 28.3% or 25% depending on whether you count the people who stopped taking it. Read the duration before the percentage. A 24 week number and an 80 week number are not the same kind of fact. Where the half-life column says not public, the published sources behind this scorecard do not report it. That is most rows, which tells you what makes headlines and what does not.

What is not settled is a fairly long list. Nobody has explained why turning the GIP receptor on and turning it off both seem to add weight loss when paired with GLP-1. Weight comes back when treatment stops, some of what is lost is lean mass, and long term safety is still open. Those questions, more than the next percentage point, are expected to decide which molecules win.

The headline three

Molecule	Receptors	How it is taken	Half-life	Phase	Best published weight loss	Trial behind the number	Open question
Tirzepatide	GIP and GLP-1, a 39 amino acid dual agonist peptide	Once weekly peptide	not public	Phase 3 complete; SURMOUNT-MMO outcomes trial designed	20.9% at 15 mg in SURMOUNT-1; 25.5% at 84 weeks in a phase 3 comparison with CagriSema	SURMOUNT-1 (19.5% at 10 mg); a systematic review puts the 15 mg placebo adjusted figure at 17.8% after 72 weeks	Why GIP agonism adds weight loss when GIP antagonism in maridebart cafraglutide appears to as well
Retatrutide	GIP, GLP-1 and glucagon	Once weekly peptide	not public	Phase 3 (TRIUMPH and TRANSCEND programs)	28.3% at 80 weeks at 12 mg; 30.3% at 104 weeks in a BMI 35 or higher extension cohort	TRIUMPH-1, topline May 21, 2026, n=2,339, efficacy estimand	Where the curve flattens: no plateau was seen through 40 weeks in TRANSCEND-T2D-1
Orforglipron	GLP-1, oral non-peptide small molecule from Eli Lilly	Oral pill	not public	Phase 3 complete, the first oral small molecule GLP-1 agonist to get there	11.2% at 72 weeks at 36 mg versus 2.1% on placebo	ATTAIN-1, 3,127 patients	Whether a pill near 11% competes with injected peptides above 20%

Single receptor benchmarks

Molecule	Receptors	How it is taken	Half-life	Phase	Best published weight loss	Trial behind the number	Open question
Semaglutide	GLP-1	2.4 mg once weekly in trials	not public	Phase 3 complete	14.9% at 68 weeks versus 2.4% on placebo	STEP-1; the semaglutide arm of REDEFINE 1 also reached 14.9% at 68 weeks	Real world persisters in SHAPE lost 14.1%, close to the per protocol trial figure
Liraglutide	GLP-1	3.0 mg once daily in trials	not public	not settled	5.8% placebo adjusted at 26 weeks	Systematic review of trials in adults without diabetes	Mouse work proposes brown fat activation via type 2 deiodinase, beyond appetite

Glucagon multi-agonists and the GIP antagonist

Molecule	Receptors	How it is taken	Half-life	Phase	Best published weight loss	Trial behind the number	Open question
UBT251	GLP-1, GIP and glucagon (peptide)	Once weekly subcutaneous	not public	Phase 2	19.7% at 24 weeks (about 17.5 kg) versus 2.0% on placebo	Phase 2 in China, 205 adults, range 13.6% to 19.7%	Whether a 24 week result holds over 68 to 80 week trials
Survodutide	GLP-1 and glucagon	not settled	not public	Phase 3	16.6% at 76 weeks, efficacy estimand	SYNCHRONIZE-1; 10.74 kg versus placebo in a network meta-analysis	Whether glucagon driven energy expenditure shows up beyond the scale
Mazdutide	GLP-1 and glucagon	not settled	not public	Phase 3	6.47 kg versus placebo; percentage not public	Network meta-analysis of 14 glucagon agonist trials	How it ranks once its phase 3 percentages are published
Cotadutide	Glucagon receptor based; full profile not settled	not settled	not public	not settled	3.41 kg versus placebo, not statistically significant	Same network meta-analysis	Whether it stays in the race
Maridebart cafraglutide	GLP-1 agonism with GIP receptor antagonism	not settled	not public	not settled	not public	not public	The GIP paradox itself

Amylin combinations

Molecule	Receptors	How it is taken	Half-life	Phase	Best published weight loss	Trial behind the number	Open question
CagriSema	GLP-1 (semaglutide) plus amylin and calcitonin (cagrilintide)	Two peptide combination, 2.4 mg and 2.4 mg in trials	not public	Phase 3	22.7% at 68 weeks; 23% at 84 weeks	REDEFINE 1, published in NEJM; 97.6% of adherent patients lost at least 5%	It trailed tirzepatide, 23% to 25.5%, in the 84 week trial
Cagrilintide alone	Amylin and calcitonin	2.4 mg in trials	not public	Phase 3 monotherapy arm	11.5% at 68 weeks	REDEFINE 1	Rats on cagrilintide plus tirzepatide lost 11.0% versus 7.22% and 2.53% alone; human data not public
Amycretin (zenagamtide)	GLP-1 and amylin in one molecule; one source adds calcitonin	Oral daily and once weekly subcutaneous	not public	Phase 3, recruiting	24.3% at 36 weeks subcutaneous; 13.1% at 12 weeks oral	Early phase trials, published in The Lancet; oral figure versus 1.2% placebo at 100 mg per day	Whether the subcutaneous figure survives phase 3
ACCG-2671 (Structure Therapeutics)	Amylin (AMY3R) and calcitonin (CTR)	Oral small molecule	not public	Preclinical	not public in humans	Obese rats, dose dependent, additive with semaglutide	Whether oral amylin agonism works in people

Oral small molecules

Molecule	Receptors	How it is taken	Half-life	Phase	Best published weight loss	Trial behind the number	Open question
Elecoglipron (AZD5004, AstraZeneca)	GLP-1	Oral small molecule	not public	Phase 2	10.5% at 26 weeks versus 0.6% on placebo	VISTA, 75 mg arm with weekly titration	Whether the trend continues past 26 weeks
Aleniglipron	GLP-1	Oral small molecule	not public	not settled	not public	Rosenstock et al., Nature Medicine, 2026	Where it lands against orforglipron
HRS-7535	GLP-1	Oral small molecule	not public	Phase 2 in type 2 diabetes	not public	Multicenter phase 2 in patients inadequately controlled on metformin and SGLT2 inhibitors	Whether an obesity trial follows

Trial ledger

Trial	Molecule	Population and length	Result	Note
TRIUMPH-1	Retatrutide	Obesity, 80 weeks, baseline 248.5 lb, BMI 40.0	19.0% at 4 mg, 25.9% at 9 mg, 28.3% (70.3 lb) at 12 mg	Efficacy estimand; up to 25% by treatment regimen estimand
TRIUMPH-1 extension	Retatrutide	BMI 35 or higher, 104 weeks	Up to 30.3%	Extension cohort
TRIUMPH-2	Retatrutide	Obesity and type 2 diabetes	Up to 20.8%	Duration not public
TRIUMPH-3	Retatrutide	Severe obesity and cardiovascular disease	Up to 22.6%	Duration not public
TRANSCEND-T2D-1	Retatrutide	Type 2 diabetes, 40 weeks	11.5% at 4 mg, 15.5% at 9 mg, 16.8% at 12 mg	Efficacy estimand; the paper reports 13.9% and 15.3% at 9 and 12 mg versus 2.6% placebo
Phase 3, name not public	Retatrutide	68 weeks	Up to 28.7%	Reported in trade coverage
Annals of Internal Medicine review	Retatrutide 12 mg	26 trials, 15,491 adults without diabetes	24.2% in one summary; 22.1% (19.3% to 24.9%) placebo adjusted at 48 weeks in another	Sources disagree on the headline figure
SURMOUNT-1	Tirzepatide	Obesity	19.5% at 10 mg, 20.9% at 15 mg	Per protocol figure 20.9%; SHAPE real world persisters 16.5%
ATTAIN-1	Orforglipron	Obesity, 72 weeks, 3,127 patients	7.5%, 8.4%, 11.2% at 6, 12, 36 mg	Placebo 2.1%
ACHIEVE-1	Orforglipron	Early type 2 diabetes, 40 weeks	HbA1c down 1.24% to 1.48%; weight down 4.5% to 7.6%	Placebo HbA1c down 0.41%
REDEFINE 2	CagriSema	Type 2 diabetes, 68 weeks	13.7% versus 3.4% placebo; 15.7% by adherence estimand	Treatment policy estimand for 13.7%
REIMAGINE 2	CagriSema	68 weeks	14.2% versus 10.2% on semaglutide 2.4 mg	Efficacy estimand
NCT06542874	Amycretin	Type 2 diabetes, phase 2, 36 weeks	Up to 14.6% at 40 mg weekly versus 2.1%	Subcutaneous
UBT251 phase 1b	UBT251	12 weeks, 1 to 6 mg weekly	8.96 to 13.48 kg lost versus a 1.57 kg gain on placebo	Subcutaneous
ZUPREME-2	not public	Type 2 diabetes, 28 weeks	Up to 9.2% versus 2.0% placebo	Released October 7, 2026

Phase 3 work still running

Trial	Molecule	What it tests	Planned enrollment	Status
AMAZE 1 (NCT07339423)	Amycretin	Weight loss in obesity	1,150	Recruiting
AMAZE 3 (NCT07571005)	Amycretin	Weight and sleep apnea, no positive airway pressure	300	Recruiting
AMAZE 4 (NCT07571109)	Amycretin	Weight and sleep apnea, with positive airway pressure	300	Recruiting
NCT07481630	Amycretin	Weight and knee osteoarthritis pain	400	Recruiting
Phase 3 programs	Ecnoglutide, TG103	GLP-1 agonists in obesity	not public	Ongoing as of a 2024 review; results not public

How to read this

Compare like with like. Efficacy estimands count people who stayed on drug; treatment regimen and treatment policy estimands count everyone, and run a few points lower. Diabetes trials run lower again, so TRANSCEND-T2D-1 and REDEFINE 2 are not weak results, just different populations. Kilogram figures from network meta-analyses are placebo adjusted and cannot be set beside raw percentages. As of 2024, completed phase 2 incretin trials ranged from 7.4% to 24.2% mean weight loss, which is the range the field is trying to escape upward. Mechanism matters to the rows: glucagon is added for energy expenditure, with GLP-1 and GIP there to offset its effect on blood sugar.

What would change it

A head to head between retatrutide and tirzepatide would settle the top row. An explanation of the GIP paradox would tell everyone whether to agonize or antagonize. Phase 3 results for amycretin, survodutide and mazdutide percentages would fill blank cells. Durable data on regain after stopping, on lean mass, and on long term safety would matter more than any of these, because they decide which molecules people stay on.