Pharmacology and mechanism

GLP-1 RA class MARKETED

Pharmacology and mechanism No change

Very low evidence

In rodents, liraglutide shifts gut-microbiota composition in a broadly consistent direction (enriching Akkermansia, Bifidobacterium, Lactobacillus), and semaglutide...

Zhao L, Qiu Y, Zhang P, Wu X, Zhao Z, Deng X, Yang L, Wang D, Yuan G. Gut microbiota medi... Source

Full findingIn rodents, liraglutide shifts gut-microbiota composition in a broadly consistent direction (enriching Akkermansia, Bifidobacterium, Lactobacillus), and semaglutide does similarly, but the specific taxa are heterogeneous and the evidence is 16S-only, small, and confounded by reduced food intake.

PopulationHigh-fat-diet C57BL/6 mice, liraglutide (Zhao 2022 Front Nutr; 16S); semaglutide corroboration encoded separately (Feng 2024 PeerJ mice).

Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)

Scope limitsanimal data; human relevance uncertain; 16S compositional only

Comparatorshigh-fat-diet control; normal-chow control

GLP-1 RA class MARKETED

Pharmacology and mechanism Not directional

Very low evidence

Across the whole compositional literature, no study demonstrates that the gut-microbiome change CAUSES the weight loss from GLP-1 receptor agonists: the designs are...

Zhao L, Chen Y, Xia F, Abudukerimu B, Zhang W, Guo Y, Wang N, Lu Y. A Glucagon-Like Pepti... Source

Full findingAcross the whole compositional literature, no study demonstrates that the gut-microbiome change CAUSES the weight loss from GLP-1 receptor agonists: the designs are associational (16S only), confounded by reduced food intake, and despite some 'mediates' titles, causal weight-loss mediation is unestablished for every agent.

PopulationCompositional GLP-1-RA microbiome studies reviewed as a body (rodent: Wang 2016, Zhao 2018, Zhao 2022, Feng 2024; human: Chen 2025 n=15) for any weight-loss causal/mediation design - none present.

Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)

Scope limitsanimal data; human relevance uncertain; 16S compositional only

Comparatorsn/a (structural across the compositional corpus)

GLP-1 RA class MARKETED

Pharmacology and mechanism No change

Low evidence

In a single small human pilot, patients' baseline gut microbiome differed between those who did and did not respond glycaemically to GLP-1 receptor agonists, and an...

Tsai CY, Lu HC, Chou YH, Liu PY, Chen HY, Huang MC, Lin CH, Tsai CN. Gut Microbial Signat... Source

Full findingIn a single small human pilot, patients' baseline gut microbiome differed between those who did and did not respond glycaemically to GLP-1 receptor agonists, and an in-sample model predicted response well - but this is correlational, single-centre, not externally validated, and says nothing about GI tolerability.

Population52 type-2-diabetes patients on liraglutide (n=22) or dulaglutide (n=30); single-centre Taiwanese pilot; baseline 16S microbiome vs glycaemic response (n=52).

Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)

Scope limitssmall sample (n=52); single-centre pilot; correlational (baseline-predicts-response); in-sample AUROC (not externally validated)

Comparatorsresponders vs non-responders (within-cohort)

GLP-1 RA class MARKETED

Pharmacology and mechanism Increase

Very low evidence

Gut microbes make short-chain fatty acids that causally stimulate the body's OWN GLP-1 and PYY (proven with FFAR2/FFAR3-knockout rodents) - but this...

Psichas A, Sleeth ML, Murphy KG, et al. (Frost G, senior). The short chain fatty acid pro... Source

Full findingGut microbes make short-chain fatty acids that causally stimulate the body's OWN GLP-1 and PYY (proven with FFAR2/FFAR3-knockout rodents) - but this endogenous-incretin pathway is a DISTINCT question from how injected GLP-1 receptor agonists work; it does not show the microbiome mediates the drugs' weight loss.

PopulationFFA2/FFAR2 (and FFAR3) knockout mice + Wistar rats; primary murine colonic crypt cultures and in-vivo intra-colonic propionate infusion (Psichas 2015 Int J Obes; Tolhurst 2012 Diabetes, Gribble/Reimann).

Fundingacademic/independent (Imperial College London; MRC/Wellcome; Frost/Bloom lab)

Scope limitsanimal data; human relevance uncertain; mechanistic (endogenous-incretin axis, not injected-drug mechanism)

Comparatorswild-type; FFA2(-/-) / FFAR3(-/-) knockout

GLP-1 RA class MARKETED

Pharmacology and mechanism Increase

Very low evidence

A second knockout study confirms that gut-microbial short-chain fatty acids stimulate the body's own GLP-1 through the FFAR2 receptor - reinforcing the...

Tolhurst G, Heffron H, Lam YS, et al. (Gribble FM, Reimann F, senior). Short-chain fatty ... Source

Full findingA second knockout study confirms that gut-microbial short-chain fatty acids stimulate the body's own GLP-1 through the FFAR2 receptor - reinforcing the endogenous-incretin pathway, which is distinct from the mechanism of injected GLP-1 receptor agonists.

Populationffar2(-/-) and ffar3(-/-) knockout mice + mixed primary murine colonic cultures; in-vitro and in-vivo SCFA-triggered GLP-1 secretion (Tolhurst 2012 Diabetes; Gribble/Reimann, Cambridge).

Fundingacademic/independent (Cambridge; Wellcome Trust/MRC; Gribble & Reimann lab)

Scope limitsanimal data; human relevance uncertain; mechanistic (endogenous-incretin axis, not injected-drug mechanism)

Comparatorswild-type; ffar2(-/-) / ffar3(-/-) knockout

Cotadutide MARKETED

Pharmacology and mechanism Decrease

Moderate evidence

Cotadutide (MEDI0382) is a balanced GLP-1/glucagon receptor dual agonist (oxyntomodulin-like) reported to activate GLP-1 and glucagon receptors at approximately 5:1,...

Nahra et al., Diabetes Care 2021;44(6):1433-1442 (phase 2b); Ambery et al., Lancet 2018 (... Source

Full findingCotadutide (MEDI0382) is a balanced GLP-1/glucagon receptor dual agonist (oxyntomodulin-like) reported to activate GLP-1 and glucagon receptors at approximately 5:1, GLP-1 activity counterbalancing glucagon-driven hepatic glucose output while glucagon adds energy expenditure and hepatic-fat-lowering. In a 54-week phase 2b study in overweight/obesity + T2D it reduced body weight, HbA1c and liver fat vs placebo and vs liraglutide; AstraZeneca reportedly deprioritised it.

PopulationAdults with overweight/obesity and T2D; phase 2a (n~65) and phase 2b 54-week study (n~834), double-blind, placebo- and liraglutide-controlled

Fundingindustry-AstraZeneca

Scope limitsMechanism: balanced GLP-1/GCGR co-agonist, OXM-analogue. Glucagon arm framed as driving hepatic glycogenolysis/fat reduction and energy expenditure. Receptor ratio (~5:1) from review/company sources, not regulatory. Development status as reported (deprioritised), not a verdict.

Comparatorsplacebo; liraglutide

Danuglipron INVESTIGATIONAL

Pharmacology and mechanism Decrease

Very low evidence

Oral non-peptide GLP-1RA (PF-06882961, Pfizer). Phase 2b twice-daily data showed clinically meaningful weight loss in obesity; once-daily formulation met PK...

Pfizer press release, 14 April 2025; STAT/CNBC/BioPharma Dive coverage Source

Full findingOral non-peptide GLP-1RA (PF-06882961, Pfizer). Phase 2b twice-daily data showed clinically meaningful weight loss in obesity; once-daily formulation met PK objectives. Development DISCONTINUED for weight management on 14 April 2025 after a single asymptomatic participant experienced potential drug-induced liver injury that resolved on discontinuation; Pfizer stated overall liver-enzyme elevation frequency across the >1,400 participant database was in line with approved class agents.

PopulationPhase 2b: adults with obesity (with/without T2D); >1,400 participant total safety database

Fundingindustry - Pfizer (trial sponsor; inferred from registration trial)

Scope limitsMECHANISM: oral non-peptide small-molecule GLP-1R agonist. DISCONTINUED Apr 2025 - single case of potential DILI (asymptomatic, resolved) plus regulator input. Pfizer's SECOND oral GLP-1 dropped for hepatic concerns (see lotiglipron). Phase-2b magnitudes are press-reported.

Comparatorsplacebo

Ecnoglutide INVESTIGATIONAL

Pharmacology and mechanism Decrease

Moderate evidence

CLARIFICATION RECORD: ecnoglutide (XW003, Sciwind Biosciences) is NOT an oral small-molecule GLP-1RA. It is an injectable long-acting modified GLP-1(7-37) PEPTIDE...

Zhang et al., Nat Commun 2024;15:8408 (phase 2 T2D); Lancet Diabetes Endocrinol 2025 (pha... Source

Full findingCLARIFICATION RECORD: ecnoglutide (XW003, Sciwind Biosciences) is NOT an oral small-molecule GLP-1RA. It is an injectable long-acting modified GLP-1(7-37) PEPTIDE (Ala8->Val8 plus C18 fatty-acid conjugation at Lys30), once-weekly s.c., and a cAMP signalling-BIASED GLP-1R agonist. Phase 2 (T2D, N=145, China, 20 wk): HbA1c -1.81/-1.90/-2.39% (0.4/0.8/1.2 mg) vs -0.55% placebo; 33.3% of 1.2 mg achieved >=5% weight loss vs 3.0% placebo. Phase 3 obesity and T2D (EECOH/EECOH-1) reported.

PopulationPhase 2 T2D: 145 adults, China, once-weekly s.c., 20 wk, placebo-controlled; phase 3 obesity and T2D (EECOH/EECOH-1)

Fundingindustry - Hangzhou Sciwind Biosciences (sponsor of record; disclosed)

Scope limitsMECHANISM CLARIFICATION: peptide, injectable (once-weekly s.c.), cAMP-biased GLP-1R agonist - NOT an oral small molecule. Roster listed it under oral small-molecule GLP-1 but identity does not match; recorded here with corrected classification. cAMP bias hypothesised to reduce receptor internalisation and enhance insulin secretion.

Comparatorsplacebo

Tirzepatide MARKETED

Pharmacology and mechanism Mixed

High evidence

RECORDED OBSERVATION (why explicitly open): Two clinically active obesity agents act in OPPOSITE directions on the GIP receptor yet both produce substantial weight...

Juxtaposition of SURMOUNT-1 (NEJM 2022) and MariTide phase 2 (ADA 2025); see also LY35370... Source

Full findingRECORDED OBSERVATION (why explicitly open): Two clinically active obesity agents act in OPPOSITE directions on the GIP receptor yet both produce substantial weight loss atop GLP-1 activity. Tirzepatide AGONISES GIP (plus GLP-1) and delivers ~22.5% weight loss (SURMOUNT-1); MariTide ANTAGONISES GIP (plus GLP-1 agonism) and delivers ~20% weight loss (phase 2). Separately, the selective GIP agonist LY3537021 reduces weight with GIP agonism alone. These findings stand side by side; the mechanism is not adjudicated.

PopulationCross-trial juxtaposition: SURMOUNT-1 (tirzepatide, N=2539, 72 wk) vs MariTide phase 2 (N=592, 52 wk); not head-to-head

Fundingindustry - Eli Lilly (SURMOUNT-1; disclosed)

Scope limitsconference/abstract-level

Comparatorsplacebo

Liraglutide MARKETED

Pharmacology and mechanism No change

Very low evidence

In high-fat-diet rodents, liraglutide reproducibly changes gut-microbiota composition, and in one study the drug's effect on the microbiota was statistically separable...

Wang L, Li P, Tang Z, Yan X, Feng B. Structural modulation of the gut microbiota and the ... Source

Full findingIn high-fat-diet rodents, liraglutide reproducibly changes gut-microbiota composition, and in one study the drug's effect on the microbiota was statistically separable (by ridge regression) from the effect of reduced food intake - but this is a compositional shift only, with no test of whether the shift causes any metabolic benefit.

PopulationHigh-fat-diet C57BL/6 mice (Wang 2016 Sci Rep, liraglutide vs saxagliptin/control; 16S rRNA), corroborated by Wistar and Goto-Kakizaki rats (Zhao 2018 Front Endocrinol; 16S).

Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)

Scope limitsanimal data; human relevance uncertain; 16S compositional only

Comparatorssaxagliptin; saline/control

Liraglutide MARKETED

Pharmacology and mechanism No change

Very low evidence

The one study that does show causation (a germ-free/antibiotic faecal-transplant experiment in mice) transferred an improvement in INSULIN SECRETION and gut immunity -...

Charpentier J, Briand F, Lelouvier B, et al. (Burcelin R, senior). Liraglutide targets th... Source

Full findingThe one study that does show causation (a germ-free/antibiotic faecal-transplant experiment in mice) transferred an improvement in INSULIN SECRETION and gut immunity - not weight loss - was specific to liraglutide (exendin-4 did not reproduce it), and has no human equivalent; it does not show the microbiome mediates GLP-1-RA weight loss.

PopulationGerm-free + antibiotic-treated diet-induced-dysmetabolic mice; faecal microbiota transfer from liraglutide-treated vs control mice; Exendin-4 as a non-reproducing comparator (Charpentier/Burcelin 2021 Acta Diabetol).

Fundingacademic/independent (INSERM/I2MC Toulouse; Burcelin lab)

Scope limitsanimal data; human relevance uncertain; 16S compositional only

Comparatorsvehicle; Exendin-4; germ-free recipients of control microbiota

Lotiglipron INVESTIGATIONAL

Pharmacology and mechanism Not directional

Low evidence

Oral non-peptide GLP-1RA (PF-07081532, Pfizer/Sosei Heptares). Two phase 1 MAD studies in T2D and obesity reported PK/PD signals. Development DISCONTINUED June 2023 on...

Buckeridge et al., Diabetes Obes Metab 2024 (phase 1); Pfizer update June 2023 Source

Full findingOral non-peptide GLP-1RA (PF-07081532, Pfizer/Sosei Heptares). Two phase 1 MAD studies in T2D and obesity reported PK/PD signals. Development DISCONTINUED June 2023 on elevated transaminases in phase 1 DDI studies and ongoing phase 2 (transaminase elevation 6.0-6.6% on lotiglipron vs 1.6% placebo, obesity cohort); no liver symptoms/failure. Pfizer noted such elevations had not been seen with danuglipron at that time.

PopulationTwo phase 1 randomised placebo-controlled MAD studies in T2D and obesity; plus ongoing phase 2

Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)

Scope limitsno outcome data yet (ongoing)

Comparatorsplacebo

LY3463251 MARKETED

Pharmacology and mechanism Decrease

Low evidence

Proof-of-mechanism: in overweight/obese participants, 12-week multiple-ascending-dose LY3463251 significantly reduced food intake and appetite scores independent of...

Benichou et al., Cell Metab 2023 (LY3463251 discovery and clinical proof of mechanism) Source

Full findingProof-of-mechanism: in overweight/obese participants, 12-week multiple-ascending-dose LY3463251 significantly reduced food intake and appetite scores independent of nausea/emesis, but produced only modest body-weight reduction. The GDF15 axis suppresses appetite without the expected weight magnitude, a challenge for clinical weight-loss use.

PopulationPhase 1 multiple-ascending-dose, 12 weeks, healthy and overweight/obese participants, placebo-controlled

Fundingindustry - Eli Lilly (trial sponsor; inferred from registration trial)

Scope limitsMechanism: agonist at GFRAL/RET (the GDF15 receptor complex restricted to area postrema/NTS), suppressing appetite via a non-incretin brainstem pathway. Eli Lilly. Co-occurs in incretin comparisons as the canonical GDF15/GFRAL mechanism and a contrast case (appetite suppression without proportional weight loss).

Comparatorsplacebo

Retatrutide INVESTIGATIONAL

Pharmacology and mechanism Not directional

Moderate evidence

EXPLICIT ABSENCE: there is no retatrutide gut-microbiome data of any kind - human or animal. Unlike liraglutide and semaglutide (rodent + small human compositional...

Jastreboff AM et al. (retatrutide phase 2), NEJM, 2023;389:514-526 Source

Full findingEXPLICIT ABSENCE: there is no retatrutide gut-microbiome data of any kind - human or animal. Unlike liraglutide and semaglutide (rodent + small human compositional studies), retatrutide's microbiome effects are a complete void, not a measured-null, and cannot be inferred from its weight-loss data.

PopulationRetatrutide evidence base reviewed for any gut-microbiome indication (pinned to the phase-2 obesity trial, Jastreboff et al., NCT04881760, as the reviewed-for-indication anchor) - none present.

Fundingindustry-Eli Lilly

Scope limitsconference/abstract-level; magnitude web/secondary-sourced; surrogate/exploratory endpoint

Comparatorsplacebo

Semaglutide MARKETED

Pharmacology and mechanism Not directional

High evidence

For Ozempic, a missed dose should be administered as soon as possible within 5 days after the missed dose; if more than 5 days have elapsed, skip the missed dose and...

Ozempic (semaglutide) US Prescribing Information, Novo Nordisk Source

Full findingFor Ozempic, a missed dose should be administered as soon as possible within 5 days after the missed dose; if more than 5 days have elapsed, skip the missed dose and resume at the next regularly scheduled dose.

PopulationRegulatory label / SmPC (primary document)

Fundingregulatory agency (FDA/EMA/MHRA/WHO)

Scope limitsregulatory label; reflects approved labelling, not an independent effect estimate

Semaglutide MARKETED

Pharmacology and mechanism Not directional

High evidence

For Wegovy, if a dose is missed and the next scheduled dose is more than 2 days (48 hours) away, administer it as soon as possible; if the next scheduled dose is less...

Wegovy (semaglutide) US Prescribing Information, Novo Nordisk Source

Full findingFor Wegovy, if a dose is missed and the next scheduled dose is more than 2 days (48 hours) away, administer it as soon as possible; if the next scheduled dose is less than 2 days away, skip the missed dose and resume on the regularly scheduled day.

PopulationRegulatory label / SmPC (primary document)

Fundingregulatory agency (FDA/EMA/MHRA/WHO)

Scope limitsregulatory label; reflects approved labelling, not an independent effect estimate

Semaglutide MARKETED

Pharmacology and mechanism Not directional

High evidence

Oral semaglutide must be taken fasting in the morning with a small sip of water and a 30-minute wait before food, other drinks or other oral medicines.

Rybelsus (oral semaglutide) US Prescribing Information, Novo Nordisk Source

PopulationRegulatory label / SmPC (primary document)

Fundingregulatory agency (FDA/EMA/MHRA/WHO)

Scope limitsregulatory label; reflects approved labelling, not an independent effect estimate

Semaglutide MARKETED

Pharmacology and mechanism Not directional

High evidence

Subcutaneous semaglutide is injected once weekly into the abdomen, thigh or upper arm with site rotation, on any day, with or without food.

Ozempic (semaglutide) US Prescribing Information, Novo Nordisk Source

PopulationRegulatory label / SmPC (primary document)

Fundingregulatory agency (FDA/EMA/MHRA/WHO)

Scope limitsregulatory label; reflects approved labelling, not an independent effect estimate

Semaglutide MARKETED

Pharmacology and mechanism Not directional

High evidence

Semaglutide delays gastric emptying and can theoretically affect oral-drug absorption, but did not alter the absorption of orally administered medications to a...

Ozempic (semaglutide) US Prescribing Information, Novo Nordisk Source

Full findingSemaglutide delays gastric emptying and can theoretically affect oral-drug absorption, but did not alter the absorption of orally administered medications to a clinically relevant degree.

PopulationRegulatory label / SmPC (primary document)

Fundingregulatory agency (FDA/EMA/MHRA/WHO)

Scope limitsregulatory label; reflects approved labelling, not an independent effect estimate

Semaglutide MARKETED

Pharmacology and mechanism Increase

High evidence

Oral semaglutide increased levothyroxine exposure by about 33% in a drug-interaction study; this is an oral-semaglutide (SNAC co-formulation) interaction, not stated...

Rybelsus (oral semaglutide) US Prescribing Information, Novo Nordisk Source

Full findingOral semaglutide increased levothyroxine exposure by about 33% in a drug-interaction study; this is an oral-semaglutide (SNAC co-formulation) interaction, not stated for the injectable products.

PopulationRegulatory label / SmPC (primary document)

Fundingregulatory agency (FDA/EMA/MHRA/WHO)

Scope limitsregulatory label; reflects approved labelling, not an independent effect estimate

Semaglutide MARKETED

Pharmacology and mechanism Not directional

High evidence

Semaglutide does not reduce the effectiveness of combined oral contraceptives to a clinically relevant degree; no additional contraceptive method is required.

Ozempic (semaglutide) EU Summary of Product Characteristics (EMA) Source

PopulationRegulatory label / SmPC (primary document)

Fundingregulatory agency (FDA/EMA/MHRA/WHO)

Scope limitsregulatory label; reflects approved labelling, not an independent effect estimate

Semaglutide MARKETED

Pharmacology and mechanism Not directional

High evidence

Ozempic is titrated from a 0.25 mg starter to a maximum of 2 mg once weekly.

Ozempic (semaglutide) US Prescribing Information, Novo Nordisk Source

PopulationRegulatory label / SmPC (primary document)

Fundingregulatory agency (FDA/EMA/MHRA/WHO)

Scope limitsregulatory label; reflects approved labelling, not an independent effect estimate

Semaglutide MARKETED

Pharmacology and mechanism Not directional

High evidence

Rybelsus is titrated 3 -> 7 -> 14 mg once daily; the 3 mg dose is a non-therapeutic starter and 14 mg the maximum.

Rybelsus (oral semaglutide) US Prescribing Information, Novo Nordisk Source

PopulationRegulatory label / SmPC (primary document)

Fundingregulatory agency (FDA/EMA/MHRA/WHO)

Scope limitsregulatory label; reflects approved labelling, not an independent effect estimate

Semaglutide MARKETED

Pharmacology and mechanism Not directional

High evidence

Wegovy is titrated over 16+ weeks to a maintenance dose of 2.4 mg once weekly (1.7 mg an allowed fallback).

Wegovy (semaglutide) US Prescribing Information, Novo Nordisk Source

PopulationRegulatory label / SmPC (primary document)

Fundingregulatory agency (FDA/EMA/MHRA/WHO)

Scope limitsregulatory label; reflects approved labelling, not an independent effect estimate

Semaglutide MARKETED

Pharmacology and mechanism No change

Low evidence

A small 12-week single-arm study in 15 type-2-diabetes patients found semaglutide changed gut-microbiota composition (e.g. more Bifidobacterium, less Firmicutes), but...

Chen Y, Shan Y, Wang T, Liu Z, Zhao Z, He Y. The Effect of Semaglutide on Gut Microbiota ... Source

Full findingA small 12-week single-arm study in 15 type-2-diabetes patients found semaglutide changed gut-microbiota composition (e.g. more Bifidobacterium, less Firmicutes), but with no control group and an appetite/diet confound the authors themselves say causation cannot be established.

Population15 Chinese type-2-diabetes patients poorly controlled on metformin; 12-week single-arm semaglutide; 16S rRNA, n=15 (no control arm).

Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)

Scope limitssmall sample (n=15); single-arm (no control); short duration (12wk); appetite/diet confound

Comparatorsbaseline (pre-treatment)

Semaglutide MARKETED

Pharmacology and mechanism No change

Very low evidence

In obese mice, semaglutide reversed diet-induced gut-microbiota changes (16S), with the shifted taxa correlating with lower inflammation - but this is a...

Feng J, Teng Z, Yang Y, Liu J, Chen S. Effects of semaglutide on gut microbiota, cognitiv... Source

Full findingIn obese mice, semaglutide reversed diet-induced gut-microbiota changes (16S), with the shifted taxa correlating with lower inflammation - but this is a compositional/correlational rodent finding, not evidence that the microbiome mediates semaglutide's effects.

PopulationHigh-fat-diet C57BL/6J obese mice; 12-week semaglutide vs HFD/normal-chow controls; 16S rRNA (Feng 2024 PeerJ).

Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)

Scope limitsanimal data; human relevance uncertain; 16S compositional only

Comparatorshigh-fat-diet control; normal-chow control

Semaglutide MARKETED

Pharmacology and mechanism Not directional

High evidence

Oral semaglutide (Rybelsus) has a very low absolute bioavailability (~0.4-1%) and requires the SNAC absorption enhancer; absorption is highly sensitive to...

Rybelsus (oral semaglutide) US Prescribing Information, Novo Nordisk Source

Full findingOral semaglutide (Rybelsus) has a very low absolute bioavailability (~0.4-1%) and requires the SNAC absorption enhancer; absorption is highly sensitive to fasting/water conditions.

PopulationRegulatory label / SmPC (primary document)

Fundingregulatory agency (FDA/EMA/MHRA/WHO)

Scope limitsregulatory label; reflects approved labelling, not an independent effect estimate

Semaglutide MARKETED

Pharmacology and mechanism Not directional

High evidence

Subcutaneous semaglutide has an absolute bioavailability of 89%.

Ozempic (semaglutide) US Prescribing Information, Novo Nordisk Source

PopulationRegulatory label / SmPC (primary document)

Fundingregulatory agency (FDA/EMA/MHRA/WHO)

Scope limitsregulatory label; reflects approved labelling, not an independent effect estimate

Semaglutide MARKETED

Pharmacology and mechanism Not directional

High evidence

Semaglutide-related material is excreted via urine and faeces, with ~3% of the dose excreted as intact semaglutide in urine.

Ozempic (semaglutide) US Prescribing Information, Novo Nordisk Source

PopulationRegulatory label / SmPC (primary document)

Fundingregulatory agency (FDA/EMA/MHRA/WHO)

Scope limitsregulatory label; reflects approved labelling, not an independent effect estimate

Semaglutide MARKETED

Pharmacology and mechanism Not directional

High evidence

Subcutaneous semaglutide has an elimination half-life of approximately one week, the basis for once-weekly dosing and the prolonged washout.

Ozempic (semaglutide) US Prescribing Information, Novo Nordisk Source

PopulationRegulatory label / SmPC (primary document)

Fundingregulatory agency (FDA/EMA/MHRA/WHO)

Scope limitsregulatory label; reflects approved labelling, not an independent effect estimate

Semaglutide MARKETED

Pharmacology and mechanism Not directional

High evidence

Semaglutide is cleared mainly by metabolism via proteolytic cleavage of the peptide backbone and beta-oxidation of the fatty-acid side chain, not by CYP enzymes.

Ozempic (semaglutide) US Prescribing Information, Novo Nordisk Source

PopulationRegulatory label / SmPC (primary document)

Fundingregulatory agency (FDA/EMA/MHRA/WHO)

Scope limitsregulatory label; reflects approved labelling, not an independent effect estimate

Semaglutide MARKETED

Pharmacology and mechanism Not directional

High evidence

Steady-state semaglutide exposure is reached after 4-5 weeks of once-weekly administration.

Ozempic (semaglutide) US Prescribing Information, Novo Nordisk Source

PopulationRegulatory label / SmPC (primary document)

Fundingregulatory agency (FDA/EMA/MHRA/WHO)

Scope limitsregulatory label; reflects approved labelling, not an independent effect estimate

Semaglutide MARKETED

Pharmacology and mechanism Not directional

High evidence

Semaglutide has a small volume of distribution consistent with high (>99%) albumin binding.

Ozempic (semaglutide) US Prescribing Information, Novo Nordisk Source

PopulationRegulatory label / SmPC (primary document)

Fundingregulatory agency (FDA/EMA/MHRA/WHO)

Scope limitsregulatory label; reflects approved labelling, not an independent effect estimate

Semaglutide MARKETED

Pharmacology and mechanism No change

Low evidence

FDA Ozempic Pharm/Tox review confirms semaglutide does not bind the human glucagon receptor, and a broad receptor-profile assay showed no greater-than-50% activity at...

FDA Ozempic NDA 209637 Pharmacology/Toxicology Review, Reference ID 4134195 (reviewer Basso) Source

Full findingFDA Ozempic Pharm/Tox review confirms semaglutide does not bind the human glucagon receptor, and a broad receptor-profile assay showed no greater-than-50% activity at any other receptor. The GLP-1 monoagonist comparator is GCGR-negative, completing (with the tirzepatide GCGR-silence datum) the receptor-level elimination: the glucagon arm is the sole added pharmacology in retatrutide versus both characterised duals.

PopulationIn-vitro human receptor binding/selectivity assays (FDA NDA 209637 Pharm/Tox, Sec 4.2 Secondary Pharmacology, p.31)

Fundingindustry - Novo Nordisk (applicant/manufacturer; FDA Pharm/Tox review of Novo's NDA 209637 submission)

Scope limitsin-vitro receptor assay; human relevance via pharmacology only

Comparatorsbroad receptor panel

Tirzepatide MARKETED

Pharmacology and mechanism Not directional

High evidence

Tirzepatide is injected subcutaneously once weekly into the abdomen, thigh or upper arm with site rotation, at any time of day with or without meals, and into a...

Mounjaro (tirzepatide) US Prescribing Information, Eli Lilly; FDA/MHRA/TGA advisories Source

Full findingTirzepatide is injected subcutaneously once weekly into the abdomen, thigh or upper arm with site rotation, at any time of day with or without meals, and into a different site from any insulin.

PopulationRegulatory label / SmPC (primary document)

Fundingregulatory agency (FDA/EMA/MHRA/WHO)

Scope limitsanimal data; human relevance uncertain

Tirzepatide MARKETED

Pharmacology and mechanism Not directional

High evidence

A missed tirzepatide dose may be taken within 4 days (96 h); otherwise skip it. The dosing day may be changed if at least 3 days separate doses.

Mounjaro (tirzepatide) US Prescribing Information, Eli Lilly; FDA/MHRA/TGA advisories Source

PopulationRegulatory label / SmPC (primary document)

Fundingregulatory agency (FDA/EMA/MHRA/WHO)

Scope limitsanimal data; human relevance uncertain

Tirzepatide MARKETED

Pharmacology and mechanism Not directional

High evidence

Tirzepatide delays gastric emptying and may alter absorption of co-administered oral drugs; the EU SmPC advises monitoring narrow-therapeutic-index drugs (e.g....

Mounjaro (tirzepatide) US Prescribing Information, Eli Lilly; FDA/MHRA/TGA advisories Source

Full findingTirzepatide delays gastric emptying and may alter absorption of co-administered oral drugs; the EU SmPC advises monitoring narrow-therapeutic-index drugs (e.g. warfarin, digoxin), and in vitro it shows low potential to inhibit/induce CYP enzymes.

PopulationRegulatory label / SmPC (primary document)

Fundingregulatory agency (FDA/EMA/MHRA/WHO)

Scope limitsanimal data; human relevance uncertain

Tirzepatide MARKETED

Pharmacology and mechanism Not directional

High evidence

Co-administration of tirzepatide with another tirzepatide-containing product or any GLP-1 receptor agonist is not recommended.

Zepbound (tirzepatide) US Prescribing Information, Eli Lilly Source

PopulationRegulatory label / SmPC (primary document)

Fundingregulatory agency (FDA/EMA/MHRA/WHO)

Scope limitsregulatory label; reflects approved labelling, not an independent effect estimate

Tirzepatide MARKETED

Pharmacology and mechanism Not directional

High evidence

When tirzepatide is combined with insulin or a sulfonylurea, reducing the secretagogue/insulin dose (stepwise for insulin) lowers hypoglycaemia risk.

Mounjaro (tirzepatide) US Prescribing Information, Eli Lilly; FDA/MHRA/TGA advisories Source

PopulationRegulatory label / SmPC (primary document)

Fundingregulatory agency (FDA/EMA/MHRA/WHO)

Scope limitsanimal data; human relevance uncertain

Tirzepatide MARKETED

Pharmacology and mechanism Not directional

High evidence

A first tirzepatide (Zepbound) dose transiently reduced paracetamol/acetaminophen peak concentration by ~55% and delayed tmax, resolving by week 6 on continued dosing;...

Zepbound (tirzepatide) US Prescribing Information, Eli Lilly Source

Full findingA first tirzepatide (Zepbound) dose transiently reduced paracetamol/acetaminophen peak concentration by ~55% and delayed tmax, resolving by week 6 on continued dosing; overall exposure (AUC) unchanged - a rate-of-absorption effect.

PopulationRegulatory label / SmPC (primary document)

Fundingregulatory agency (FDA/EMA/MHRA/WHO)

Scope limitsregulatory label; reflects approved labelling, not an independent effect estimate

Tirzepatide MARKETED

Pharmacology and mechanism Not directional

High evidence

Zepbound maintenance dosing differs by indication, with obstructive sleep apnoea requiring 10 mg or 15 mg once weekly.

Zepbound (tirzepatide) US Prescribing Information, Eli Lilly Source

PopulationRegulatory label / SmPC (primary document)

Fundingregulatory agency (FDA/EMA/MHRA/WHO)

Scope limitsregulatory label; reflects approved labelling, not an independent effect estimate

Tirzepatide MARKETED

Pharmacology and mechanism Not directional

High evidence

Tirzepatide starts at 2.5 mg once weekly, increases to 5 mg after 4 weeks, then in 2.5 mg steps at no less than 4-week intervals up to a 15 mg maximum (10 mg max in...

Mounjaro (tirzepatide) US Prescribing Information, Eli Lilly; FDA/MHRA/TGA advisories Source

Full findingTirzepatide starts at 2.5 mg once weekly, increases to 5 mg after 4 weeks, then in 2.5 mg steps at no less than 4-week intervals up to a 15 mg maximum (10 mg max in paediatric patients).

PopulationRegulatory label / SmPC (primary document)

Fundingregulatory agency (FDA/EMA/MHRA/WHO)

Scope limitsanimal data; human relevance uncertain

Tirzepatide MARKETED

Pharmacology and mechanism Not directional

Moderate evidence

Dose-headroom confound (competing hypothesis): the FDA Mounjaro Clinical Pharmacology FG/HbA1c Emax model shows tirzepatide's marketed doses reach only 74-89% of the...

FDA Mounjaro NDA 215866 Clinical Pharmacology Review, Reference ID 4954959 (FG/HbA1c Emax... Source

Full findingDose-headroom confound (competing hypothesis): the FDA Mounjaro Clinical Pharmacology FG/HbA1c Emax model shows tirzepatide's marketed doses reach only 74-89% of the maximal effect on FASTING GLUCOSE, with EMA reporting effect still increasing at the highest doses tested. CRITICAL: this is a FASTING-GLUCOSE Emax, NOT weight-loss headroom - it must not be read as the dual being undertitrated for weight loss. Part of any dual-to-triple efficacy gap could be exposure-response position rather than the glucagon mechanism, so it must be controlled before assigning a retatrutide-over-tirzepatide gap to the glucagon arm.

PopulationType-2-diabetes exposure-response popPK/PD model (FDA Mounjaro NDA 215866 ClinPharm FG-HbA1c PK/PD model, p.65-66; EMA Mounjaro EPAR)

Fundingindustry - Eli Lilly (applicant/manufacturer; FDA Clinical Pharmacology review of Lilly's NDA 215866 submission)

Scope limitssponsor-derived popPK/PD model output; fasting-glucose Emax, not a weight-loss exposure-response

Comparatorsmarketed-dose vs modelled Emax

Tirzepatide MARKETED

Pharmacology and mechanism Not directional

High evidence

The absolute bioavailability of subcutaneous tirzepatide is 80%.

Mounjaro (tirzepatide) US Prescribing Information, Eli Lilly; FDA/MHRA/TGA advisories Source

PopulationRegulatory label / SmPC (primary document)

Fundingregulatory agency (FDA/EMA/MHRA/WHO)

Scope limitsanimal data; human relevance uncertain

Tirzepatide MARKETED

Pharmacology and mechanism Not directional

High evidence

Tirzepatide metabolites are excreted via urine and faeces, with no intact tirzepatide observed in urine or faeces.

Mounjaro (tirzepatide) US Prescribing Information, Eli Lilly; FDA/MHRA/TGA advisories Source

PopulationRegulatory label / SmPC (primary document)

Fundingregulatory agency (FDA/EMA/MHRA/WHO)

Scope limitsanimal data; human relevance uncertain

Tirzepatide MARKETED

Pharmacology and mechanism Not directional

High evidence

Tirzepatide has an elimination half-life of about 5 days (5-6 days for Zepbound populations), the basis for once-weekly dosing.

Mounjaro (tirzepatide) US Prescribing Information, Eli Lilly; FDA/MHRA/TGA advisories Source

PopulationRegulatory label / SmPC (primary document)

Fundingregulatory agency (FDA/EMA/MHRA/WHO)

Scope limitsanimal data; human relevance uncertain

Tirzepatide MARKETED

Pharmacology and mechanism Not directional

High evidence

Tirzepatide is cleared by metabolism via proteolytic cleavage of the peptide backbone, beta-oxidation of its C20 fatty diacid and amide hydrolysis.

Mounjaro (tirzepatide) US Prescribing Information, Eli Lilly; FDA/MHRA/TGA advisories Source

PopulationRegulatory label / SmPC (primary document)

Fundingregulatory agency (FDA/EMA/MHRA/WHO)

Scope limitsanimal data; human relevance uncertain

Tirzepatide MARKETED

Pharmacology and mechanism Not directional

High evidence

Steady-state tirzepatide concentrations are reached after about 4 weeks of once-weekly dosing.

Mounjaro (tirzepatide) US Prescribing Information, Eli Lilly; FDA/MHRA/TGA advisories Source

PopulationRegulatory label / SmPC (primary document)

Fundingregulatory agency (FDA/EMA/MHRA/WHO)

Scope limitsanimal data; human relevance uncertain

Tirzepatide MARKETED

Pharmacology and mechanism Not directional

High evidence

Tirzepatide has a small apparent steady-state volume of distribution (~10 L) and is ~99% albumin-bound.

Mounjaro (tirzepatide) US Prescribing Information, Eli Lilly; FDA/MHRA/TGA advisories Source

PopulationRegulatory label / SmPC (primary document)

Fundingregulatory agency (FDA/EMA/MHRA/WHO)

Scope limitsanimal data; human relevance uncertain

Tirzepatide MARKETED

Pharmacology and mechanism No change

Very low evidence

The EMA Mounjaro EPAR quantifies tirzepatide's potency at the human glucagon receptor (GCGR) as a cAMP functional EC50 of ~2350 nM - some three orders of magnitude...

FDA Mounjaro NDA 215866 Pharmacology/Toxicology Review, Reference ID 4953686 (reviewer Br... Source

Full findingThe EMA Mounjaro EPAR quantifies tirzepatide's potency at the human glucagon receptor (GCGR) as a cAMP functional EC50 of ~2350 nM - some three orders of magnitude weaker than its GIP/GLP-1 receptor potency - i.e. minimal-to-no glucagon-receptor agonism at therapeutic exposure. The FDA NDA 215866 Pharm/Tox review states the same qualitatively. This is the tirzepatide GCGR-silence half of the receptor-level glucagon-by-elimination argument (the semaglutide GCGR-negative half is C-SEMA-REG-GCGR-NEGATIVE-01): both characterised dual/mono comparators carry no meaningful glucagon-receptor activity, so the glucagon arm is the sole added pharmacology in retatrutide. Arm-elimination only - this establishes which receptor differs, NOT how much of any weight-loss difference is apportionable to glucagon agonism.

Populationin-vitro human glucagon-receptor (GCGR) cAMP functional assay (EMA Mounjaro EPAR EMEA/H/C/005620; FDA NDA 215866 Pharm/Tox cross-confirm)

Fundingindustry - Eli Lilly (applicant/manufacturer; FDA Pharm/Tox review of Lilly's NDA 215866 submission)

Scope limitsanimal data; human relevance uncertain

Comparatorshuman GIP receptor; human GLP-1 receptor

Tirzepatide MARKETED

Pharmacology and mechanism Not directional

Low evidence

FDA Zepbound Clinical Pharmacology review characterises tirzepatide as having GIPR activity similar to native GIP but GLP-1R activity lower than native GLP-1, and as a...

FDA Zepbound NDA 217806 Clinical Pharmacology Review, Reference ID 5258712 Source

Full findingFDA Zepbound Clinical Pharmacology review characterises tirzepatide as having GIPR activity similar to native GIP but GLP-1R activity lower than native GLP-1, and as a biased GLP-1R agonist favouring cAMP over beta-arrestin (in-vitro human Ki GIPR 4.02 nM vs GLP-1R 378 nM). This establishes WHICH arms are engaged; it must NOT be read as a quantitative weight-loss apportionment (the sign of the GIPR contribution is itself unsettled).

PopulationIn-vitro human receptor binding/signalling assays (FDA Zepbound NDA 217806 ClinPharm, Sec 3.2 General Pharmacology, Table 3)

Fundingindustry - Eli Lilly (applicant/manufacturer; FDA Clinical Pharmacology review of Lilly's NDA 217806 submission)

Scope limitsin-vitro receptor assay; human relevance via pharmacology only

Comparatorsnative GIP; native GLP-1

Tirzepatide MARKETED

Pharmacology and mechanism Decrease

High evidence

Tirzepatide is a once-weekly subcutaneous dual agonist of the GIP and GLP-1 receptors (39-amino-acid acylated peptide). Marketed (Mounjaro for T2D; Zepbound for...

Juxtaposition of SURMOUNT-1 (NEJM 2022) and MariTide phase 2 (ADA 2025); see also LY35370... Source

Full findingTirzepatide is a once-weekly subcutaneous dual agonist of the GIP and GLP-1 receptors (39-amino-acid acylated peptide). Marketed (Mounjaro for T2D; Zepbound for obesity). In SURMOUNT-1 (obesity, no diabetes) mean weight reduction at 72 weeks was 16.0/21.4/22.5% at 5/10/15 mg vs 2.4% placebo. In SURPASS-2 (T2D, head-to-head vs semaglutide 1 mg) HbA1c fell 2.01/2.24/2.30% vs 1.86% semaglutide at 40 weeks, with superior weight loss.

PopulationSURMOUNT-1: N=2539 adults obesity/overweight + comorbidity, no T2D, 72 wk, vs placebo. SURPASS-2: T2D, BMI >=25, HbA1c 7-10.5%, 40 wk, vs semaglutide 1 mg s.c.

Fundingindustry - Eli Lilly (SURMOUNT-1; disclosed)

Scope limitsconference/abstract-level

Comparatorsplacebo; semaglutide

Amycretin MARKETED

Pharmacology and mechanism Not directional

Moderate evidence

First-in-class single-molecule GLP-1R + amylin receptor agonist; both oral and s.c. formulations; dose-proportional exposure

Gasiorek A et al. Lancet 2025;406:135-148 Source

PopulationPhase 1 oral and phase 1b/2a s.c.

Fundingindustry - Novo Nordisk

Scope limitsconference/abstract-level; identifier not fully verified; small sample (N~144); surrogate/exploratory endpoint

Comparatorsplacebo

BI 3034701 MARKETED

Pharmacology and mechanism Not directional

Very low evidence

Mechanism verified: investigational, potential first-in-class triple agonist at GLP-1, GIP and NPY2 (Y2) receptors, designed to engage multiple satiety pathways.

Gubra / Boehringer Ingelheim announcement: Boehringer Ingelheim advances Gubra-originated... Source

PopulationPreclinical/early development (mechanism per company/partner disclosures)

Fundingindustry - Boehringer Ingelheim (trial sponsor; inferred from registration trial)

Scope limitsMechanism confirmed as GLP-1/GIP/NPY2 triple AGONIST (note: GIP arm is agonist, unlike MariTide's GIPR antagonism). NPY2 (Y2) agonism = additional anorexigenic axis (PYY-like). No human efficacy data yet; Phase 2 planned ~mid-2026. Press-sourced; no PMID/NCT verified for this asset yet.

Cagrilintide MARKETED

Pharmacology and mechanism Not directional

Low evidence

Long-acting amylin analogue, once-weekly; half-life 159-195 h; PK dose-proportional and independent of co-dosed semaglutide

Enebo LB et al. Lancet 2021;397:1736-1748 Source

PopulationHealthy overweight (n=96), phase 1b co-administration with semaglutide 2.4 mg (NCT03600480)

Fundingindustry - Novo Nordisk (trial sponsor; inferred from registration trial)

Scope limitssmall sample (N~96)

Comparatorsplacebo

Cotadutide MARKETED

Pharmacology and mechanism Not directional

Low evidence

GLP-1R/GcgR dual agonist with GcgR-biased lipid engagement; lipid C18 moiety gives stronger GcgR engagement vs SAR425899; once-daily s.c.

Li Y et al. PNAS 2023;120:e2303696120 Source

PopulationIn-vitro/structural (cryo-EM) and PK

Fundingindustry - AstraZeneca (trial sponsor; inferred from registration trial)

ComparatorsSAR425899; peptide 15

CT-388/enicepatide INVESTIGATIONAL

Pharmacology and mechanism Not directional

Low evidence

Unimolecular peptide dual GLP-1R/GIPR agonist that is cAMP signal-biased at both receptors (minimal receptor internalisation vs native ligands); PK supports...

Chakravarthy MV et al. Effects of CT-388, a once-weekly signaling-biased dual GLP-1/GIP r... Source

Full findingUnimolecular peptide dual GLP-1R/GIPR agonist that is cAMP signal-biased at both receptors (minimal receptor internalisation vs native ligands); PK supports once-weekly dosing.

PopulationCell assays, mice, monkeys, phase 1 humans

Fundingindustry - Roche

Scope limitsanimal data; human relevance uncertain; conference/abstract-level; identifier not fully verified

Comparatorsnative GLP-1/GIP ligands

Danuglipron INVESTIGATIONAL

Pharmacology and mechanism Not directional

Very low evidence

Moderate hepatic metabolism / low intrinsic clearance in vitro; multiple phase I/II metabolites identified.

Jaiswal A et al. Comprehensive identification and characterization of in vitro and in viv... Source

PopulationIn vitro (human/rat liver microsomes, S9) and in vivo rat

Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)

Scope limitsanimal data; human relevance uncertain

Ecnoglutide INVESTIGATIONAL

Pharmacology and mechanism Not directional

Very low evidence

cAMP-biased GLP-1 analog (Ala8Val + C18 diacid fatty-acid acylation): potent cAMP induction with minimal receptor internalisation; long half-life supporting...

Guo W et al. Discovery of ecnoglutide - a novel, long-acting, cAMP-biased GLP-1 analog. M... Source

Full findingcAMP-biased GLP-1 analog (Ala8Val + C18 diacid fatty-acid acylation): potent cAMP induction with minimal receptor internalisation; long half-life supporting once-weekly dosing.

PopulationIn vitro, db/db mice, DIO rats, phase 1 humans (NCT04389775)

Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)

Scope limitsanimal data; human relevance uncertain

Comparatorssemaglutide (preclinical)

Efinopegdutide MARKETED

Pharmacology and mechanism Not directional

Moderate evidence

GLP-1/glucagon receptor co-agonist; glucagon arm posited to drive direct hepatic fatty-acid oxidation/reduced lipogenesis

Romero-Gómez M et al. A phase IIa active-comparator-controlled study to evaluate the effi... Source

PopulationMechanistic framing in NAFLD trial

Fundingindustry-Merck (Merck Sharp & Dohme LLC; efinopegdutide licensed from Hanmi)

Scope limitsopen-label (unblinded)

Comparatorssemaglutide

LY3537021 MARKETED

Pharmacology and mechanism Not directional

Low evidence

In-vitro potency greater than native GIP, GIPR-selective; half-life ~12 days supporting once-weekly dosing; no delay in gastric emptying after single SC dose.

Long-acting GIPR agonist LY3537021 reduces body weight and fasting glucose in T2D: precli... Source

PopulationIn vitro, rats, phase 1 humans

Fundingindustry - Eli Lilly (trial sponsor; inferred from registration trial)

Scope limitsLack of gastric-emptying delay distinguishes GIPR agonism mechanistically from GLP-1R agonism.

Comparatorsnative GIP; placebo

MariTide MARKETED

Pharmacology and mechanism Not directional

Moderate evidence

Long-acting peptide-antibody (anti-GIPR monoclonal antibody) conjugate combining GLP-1R agonism with GIPR antagonism; supports once-monthly (q4w) and tested q8w dosing.

Jastreboff AM et al. Once-Monthly Maridebart Cafraglutide for the Treatment of Obesity - ... Source

PopulationMechanistic/PK description; phase 2

Fundingindustry - Amgen

Scope limitsanimal data; human relevance uncertain; conference/abstract-level; identifier not fully verified; small sample (N~127)

MariTide MARKETED

Pharmacology and mechanism Mixed

Very low evidence

Rodent mechanistic comparison: GIPR agonism vs antagonism produce distinct metabolic profiles despite both lowering weight in obese mice.

Davies I et al. A metabolic comparison of GIPR agonism versus GIPR antagonism in male mic... Source

PopulationLean and high-fat-diet obese male mice; preclinical

Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)

Scope limitsanimal data; human relevance uncertain

ComparatorsGIPR agonist GIP108; GIPR antagonist NN-GIPR-Ant; pair-fed controls

Orforglipron INVESTIGATIONAL

Pharmacology and mechanism Not directional

High evidence

Oral, non-peptide, once-daily GLP-1R agonist with no food or fluid intake restrictions (unlike peptide oral semaglutide).

Horn DB et al. Orforglipron... for obesity in people with type 2 diabetes (ATTAIN-2): a p... Source

PopulationMechanistic/formulation description across phase 3 program

Fundingindustry-Eli Lilly

Scope limitsLack of food/fluid restriction is a key differentiator from peptide oral GLP-1 (oral semaglutide). Manufacturing scalability is a stated commercial advantage (press).

Comparatorsoral semaglutide (peptide)

Petrelintide MARKETED

Pharmacology and mechanism Not directional

Low evidence

Long-acting amylin analogue / dual amylin-calcitonin receptor agonist (DACRA); used as reference scaffold for next-gen DACRA optimisation

Zong L et al. J Med Chem 2025;68:14907-14918 Source

PopulationMedicinal-chemistry / SAR (in-vitro + in-vivo)

Fundingindustry - Zealand / Roche (trial sponsor; inferred from registration trial)

Scope limitsPaper characterises petrelintide's agonism as 'insufficient vs natural agonists' (third-party framing)

ComparatorsBGM1812; natural amylin/calcitonin

Pramlintide MARKETED

Pharmacology and mechanism Not directional

High evidence

Synthetic human amylin analogue; slows gastric emptying, suppresses glucagon, promotes satiety; t.i.d. mealtime dosing

SYMLIN FDA label 2015 Source

PopulationPharmacology / label

Fundingregulatory agency (FDA/EMA/MHRA/WHO)

Scope limitsFirst marketed amylin analogue — mechanistic precedent for cagrilintide/amycretin/petrelintide

Survodutide INVESTIGATIONAL

Pharmacology and mechanism Not directional

Very low evidence

Acylated (C18) GCGR/GLP-1R dual agonist, once-weekly; engages both receptors in vivo

Zimmermann T et al. Mol Metab 2022;66:101633 Source

PopulationIn-vitro + in-vivo preclinical

Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)

Comparatorssemaglutide

Most represented records

Evidence spread