20 findings across 13 drug records. Domain pages are descriptive indexes, not advice.
Most represented records
Retatrutide (4)
Tirzepatide|semaglutide (head-to-head) (3)
GLP-1 RA class (2)
Exenatide (2)
Cotadutide (1)
Evidence spread
High evidence 0Moderate evidence 11Low evidence 9Very low evidence 0
GLP-1 RA classMARKETED
Insulin and beta-cell functionIncrease
Moderate evidence
NEGATIVE HEADLINE FIRST: no incretin, INCLUDING retatrutide, has demonstrated increased beta-cell MASS or disease modification in humans; all positive human data are...
SourceBunck MC, Diamant M, Corner A et al., Diabetes Care, 2009Source
Full findingNEGATIVE HEADLINE FIRST: no incretin, INCLUDING retatrutide, has demonstrated increased beta-cell MASS or disease modification in humans; all positive human data are on-treatment FUNCTION surrogates (HOMA-B, C-peptide, proinsulin:insulin, disposition index, clamp ISR - none measures MASS), and the only off-drug test reverted at 1 year. POLE A (well-supported but confounded): every direct human beta-cell-function measure improves while ON drug (semaglutide, tirzepatide, exenatide). POLE B (the LEADING caution): the on-treatment gain is substantially confounded by large weight loss and relief of gluco-/lipotoxicity - the only direct human test (exenatide washout) reverted WITH weight regain, supporting mediation; the cited tirzepatide clamp with no weight correlation (Yamaguchi) measures insulin SENSITIVITY (glucose-infusion-rate), NOT beta-cell secretion, so a weight-INDEPENDENT beta-cell effect remains UNPROVEN. The positive on-treatment pole is also near-uniformly manufacturer-sponsored (a further confidence discount).
PopulationClass-level synthesis across human clamp / IVGTT / HOMA / off-drug studies (semaglutide, tirzepatide, exenatide).
Fundingindustry-Amylin Pharmaceuticals/Eli Lilly
Scope limitsopen-label (unblinded); small sample (N~69)
Comparatorsplacebo; insulin glargine; semaglutide
CotadutideMARKETED
Insulin and beta-cell functionMixed
Moderate evidence
The GLP-1/glucagon dual cotadutide reduced fasting hepatic glycogen ~38% vs placebo and ~41% vs liraglutide (13C-MRS), confirming GCGR engagement promoting...
SourceParker VER et al., Nat Metab 2023;5(12):2086-2093Source
Full findingThe GLP-1/glucagon dual cotadutide reduced fasting hepatic glycogen ~38% vs placebo and ~41% vs liraglutide (13C-MRS), confirming GCGR engagement promoting glycogenolysis (glycogen not fully depleted); mouse receptor dissection shows cotadutide's glucose control and weight loss are predominantly GLP-1-mediated while liver lipid/glycogen-flux effects are glucagon-mediated.
Scope limitsReused from corpus T3-008/L2-028 (+ Boland 2020 mouse PMID:32478287). cotadutide-minus-liraglutide isolates GCGR on the liver. Glycogen readout, NOT a formal EGP tracer.
Comparatorsplacebo; liraglutide
SurvodutideINVESTIGATIONAL
Insulin and beta-cell functionDecrease
Low evidence
GLP-1/glucagon dual agonists lower HbA1c in T2D phase 2 trials (survodutide -1.46% to -1.71% over 16 wk; mazdutide -1.41% to -1.67% over 20 wk vs placebo +0.03%), but...
Sourcesurvodutide: Blüher M et al., Lancet Diabetes Endocrinol 2024 (PMID:38095657); mazdutide:...Source
Full findingGLP-1/glucagon dual agonists lower HbA1c in T2D phase 2 trials (survodutide -1.46% to -1.71% over 16 wk; mazdutide -1.41% to -1.67% over 20 wk vs placebo +0.03%), but historically show modest or no glycaemic improvement (or even impaired glucose tolerance) when the glucagon weighting is too high — net glycaemia depends on maintained incretin dominance over the glucagon arm.
PopulationT2D phase 2 (survodutide BI 456906; mazdutide, Chinese cohort)
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Scope limitsReused from corpus L2-030/L2-031/L2-032. Net glycaemia (not isolated insulin-sensitivity/beta-cell endpoint). Illustrates the glucagon-weighting balance relevant to retatrutide's offset.
Comparatorsplacebo
ExenatideMARKETED
Insulin and beta-cell functionIncrease
Moderate evidence
The canonical washout test of DURABILITY (reversible pole): one year of exenatide improved clamp-measured beta-cell function markedly versus titrated glargine at...
SourceBunck MC, Diamant M, Corner A et al., Diabetes Care, 2009Source
Full findingThe canonical washout test of DURABILITY (reversible pole): one year of exenatide improved clamp-measured beta-cell function markedly versus titrated glargine at matched glycaemia, but after a 4-week off-drug washout the beta-cell-function measures returned to pretreatment in both arms - the authors concluded ongoing treatment is necessary, i.e. the 1-year on-treatment gain is NOT a durable, disease-modifying change.
Scope limitsopen-label (unblinded); small sample (N~69)
Comparatorsinsulin glargine
ExenatideMARKETED
Insulin and beta-cell functionIncrease
Moderate evidence
The contested PRESERVATION pole, recorded beside its own contradiction: in the 3-year extension, the off-drug disposition index was sustained ABOVE pretreatment with...
SourceBunck MC, Corner A, Eliasson B et al., Diabetes Care, 2011Source
Full findingThe contested PRESERVATION pole, recorded beside its own contradiction: in the 3-year extension, the off-drug disposition index was sustained ABOVE pretreatment with exenatide (and fell with glargine), which the authors read as a beneficial effect on beta-cell health - standing AGAINST the same group's 1-year result where the off-drug measures reverted. Duration of exposure and the disposition-index (vs raw secretion) endpoint may drive the divergence.
GCGR antagonists lowered glucose in T2D but caused dose-dependent rises in hepatic fat, liver enzymes, LDL/serum lipids and body weight, and human GCGR...
SourceGuzman CB et al. (GCGR antagonist trials review); Larger S et al. (Mahvash, PMID:30032256)Source
Full findingGCGR antagonists lowered glucose in T2D but caused dose-dependent rises in hepatic fat, liver enzymes, LDL/serum lipids and body weight, and human GCGR loss-of-function causes alpha-cell hyperplasia/hyperglucagonaemia (Mahvash disease) — establishing that blocking the glucagon axis has adverse hepatic/lipid consequences, the inverse-direction evidence framing why retatrutide AGONISES (not blocks) GCGR.
PopulationT2D trials (antagonists) + human GCGR-inactivating genetics
Fundingindustry - Eli Lilly and Company
Scope limitsReused from corpus L2-035 / T8-024. Inverse-direction (antagonist) evidence; bears on the glucagon-arm safety/metabolic logic. PMID not independently re-confirmed for this DOI by this collector — identifier carried as DOI per corpus.
GIP is insulinotropic only at elevated glucose; the GIPR antagonist GIP(3-30)NH2 cut GIP-induced insulin secretion by 82%, confirming receptor specificity.
SourceGasbjerg LS et al., Diabetologia 2017 (GIP(3-30)NH2 antagonist)Source
PopulationHealthy humans and T2D (clamp/infusion studies)
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Scope limitsReused from corpus L2-008 (antagonist), L2-010/L2-011 (PMID:21984584, glucose-dependence + glucagonotropic), L2-013 (PMID:21386059, T2D glucagon hypersecretion). Mixed direction: insulinotropic (beta) but glucagonotropic (alpha) — the GIPR islet paradox underlying the agonism-vs-antagonism debate. Individual sub-claim PMIDs carried in cross_ref notes. [CORRECTED 2026-06-20] The glucagonotropic / blunted-in-T2D claims rest on the cross-ref corpus records (L2-010/011/013), not this source.
Comparatorssaline; glucose-matched controls
GLP-1 (native; Physiology)MARKETED
Insulin and beta-cell functionMixed
Low evidence
GLP-1 augments glucose-stimulated insulin secretion in a glucose-dependent manner (acting already at fasting glucose, more strongly as glucose rises) and suppresses...
SourceHare KJ et al. (GLP-1 physiology); per corpus L2-006Source
Full findingGLP-1 augments glucose-stimulated insulin secretion in a glucose-dependent manner (acting already at fasting glucose, more strongly as glucose rises) and suppresses alpha-cell glucagon secretion in hyperglycaemic and euglycaemic states, lowering hepatic glucose output; GLP-1R blockade with exendin(9-39) raises glucagon and produces fasting hyperglycaemia.
PopulationHealthy humans and T2D (physiology)
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Scope limitsReused from corpus L2-001/L2-003 (PMID:15985560)/L2-006 (PMID:22855730). Direction mixed: insulinotropic (beta, +) and glucagonostatic (alpha, glucagon decrease). Foundational pure-GLP-1R islet physiology underpinning the offset.
Comparatorssaline; exendin(9-39)
Glucagon (native; Physiology)MARKETED
Insulin and beta-cell functionIncrease
Moderate evidence
Glucagon acting on GCGR drives hepatic glycogenolysis and gluconeogenesis, raising plasma glucose; protein-induced hyperglucagonaemia (~8x basal) raised endogenous...
SourceAng T et al., Diabetes 2019;68(5):939-946; per corpus L2-016/L2-017Source
Full findingGlucagon acting on GCGR drives hepatic glycogenolysis and gluconeogenesis, raising plasma glucose; protein-induced hyperglucagonaemia (~8x basal) raised endogenous glucose production ~25% and rendered the liver unresponsive to insulin-mediated EGP suppression (stable-isotope tracer). The liver-alpha-cell axis: GCGR agonism increases hepatic amino-acid uptake/ureagenesis, while GCGR blockade/loss-of-function causes alpha-cell hyperplasia and hyperglucagonaemia.
Fundingacademic-Diabetes Australia Research Program
Scope limitsReused from corpus T3-011/L2-016/L2-017. Glucose-RAISING side of the offset: insulin counterbalances glucagon-on-EGP. +25% is a NET of protein bolus + gluconeogenic substrate + ~6x insulin rise (acute/supraphysiological), not a clean signal-only isolation.
Comparatorsbasal/euglycaemic control
LiraglutideMARKETED
Insulin and beta-cell functionIncrease
Low evidence
GLP-1R agonism improves hepatic insulin sensitivity at the clamp and tracer level: liraglutide (12 wk, biopsy-proven NASH) increased suppression of endogenous glucose...
SourceArmstrong MJ et al., J Hepatol 2016;64(2):399-408Source
Full findingGLP-1R agonism improves hepatic insulin sensitivity at the clamp and tracer level: liraglutide (12 wk, biopsy-proven NASH) increased suppression of endogenous glucose production under low-dose insulin and improved adipose insulin sensitivity, using paired hyperinsulinaemic-euglycaemic clamps with stable-isotope tracers.
PopulationBiopsy-proven NASH, n=14, 12 weeks
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Scope limitssmall sample (N~14)
Comparatorsplacebo
OrforglipronINVESTIGATIONAL
Insulin and beta-cell functionDecrease
Low evidence
In a 26-week phase 2 T2D trial, oral orforglipron (>=12 mg) produced significant HbA1c reductions vs placebo and dulaglutide alongside dose-dependent weight loss,...
SourceFrías JP et al. Efficacy and safety of oral orforglipron in patients with type 2 diabetes...Source
Full findingIn a 26-week phase 2 T2D trial, oral orforglipron (>=12 mg) produced significant HbA1c reductions vs placebo and dulaglutide alongside dose-dependent weight loss, consistent with class GLP-1R glucose-lowering (incretin-driven insulin secretion + glucagon suppression). Discrete clamp/HOMA insulin-sensitivity endpoints were not the primary readouts of this trial.
PopulationAdults with T2D, n=383, 26 weeks (NCT05048719)
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Scope limitsCOI-flag (Lilly-funded, Lilly authors). Newly added. HbA1c/weight surrogate for the insulin-beta-cell axis; per-mechanism insulin-sensitivity/secretion endpoints not isolated here. Direction = glucose-lowering.
Comparatorsplacebo; dulaglutide 1.5 mg
RetatrutideINVESTIGATIONAL
Insulin and beta-cell functionDecrease
Moderate evidence
Higher retatrutide doses reduced biomarkers of insulin resistance (fasting insulin, fasting C-peptide and HOMA2-IR) by up to 50% or more from baseline — a combination...
SourceSanyal AJ et al. Triple hormone receptor agonist retatrutide for metabolic dysfunction-as...Source
Full findingHigher retatrutide doses reduced biomarkers of insulin resistance (fasting insulin, fasting C-peptide and HOMA2-IR) by up to 50% or more from baseline — a combination and weight-mediated effect not isolable per receptor.
PopulationMASLD substudy of phase 2 obesity trial (NCT04881760)
Fundingindustry-Eli Lilly
Scope limitssmall sample (N~98); prespecified/exploratory secondary of RCT (substudy)
Comparatorsplacebo
RetatrutideINVESTIGATIONAL
Insulin and beta-cell functionDecrease
Low evidence
In phase 1, fasting glucagon decreased under retatrutide from 24 h to day 15 at 4.5/6 mg, while fasting-glucose changes were similar to placebo — net neutrality on...
SourceCoskun T et al. phase 1 SAD, as restated in Biomolecules 2025 review (PMC12190491)Source
Full findingIn phase 1, fasting glucagon decreased under retatrutide from 24 h to day 15 at 4.5/6 mg, while fasting-glucose changes were similar to placebo — net neutrality on fasting glucose despite an engaged glucagon arm (the glucagon-offset in action at the drug level). Whether the glucagon fall reflects GLP-1R glucagonostasis, weight loss, improved glycaemia, or direct islet effects is unresolved.
PopulationPhase 1 SAD, humans
Fundingindustry - Eli Lilly (trial sponsor; inferred from registration trial)
Scope limitsDOWN-WEIGHT: review restatement (PMC12190491) of the Coskun phase 1 primary, not the primary itself — maturity=review; the underlying phase-1 primary numbers not independently fetched by this collector (FLAG). Reused from corpus L2-021/L2-026. Combination-only.
Comparatorsplacebo
RetatrutideINVESTIGATIONAL
Insulin and beta-cell functionDecrease
Moderate evidence
No study indexed under these search terms as of 2026 has performed a hyperinsulinaemic-euglycaemic clamp or stable-isotope endogenous-glucose-production tracer study...
SourcePearson SM et al., J Clin Endocrinol Metab 2026 (metabolomics); PubMed null result 2026 (...Source
Full findingNo study indexed under these search terms as of 2026 has performed a hyperinsulinaemic-euglycaemic clamp or stable-isotope endogenous-glucose-production tracer study under retatrutide; the drug-level decomposition of net glycaemic benefit into insulin secretion, glucagon suppression and hepatic-clearance-driven insulin sensitivity remains unmeasured directly. A post-hoc metabolomic analysis of both phase 2 trials found retatrutide shifted an insulin-resistance metabolite signature (BCAAs, 2-aminoadipic acid, 2-hydroxybutyrate, urate, short-chain/saturated triglycerides) toward improved metabolic health.
Scope limitspost-hoc (not prespecified); small sample (N~282)
Comparatorsplacebo
RetatrutideINVESTIGATIONAL
Insulin and beta-cell functionNot directional
Moderate evidence
RETATRUTIDE BETA-CELL GAP (the absence is the finding): the reta phase-2 T2D trial reported HbA1c, fasting glucose, weight and tolerability but NO beta-cell-FUNCTION...
SourceRosenstock J, Frias J, Jastreboff AM, et al. Lancet 2023Source
Full findingRETATRUTIDE BETA-CELL GAP (the absence is the finding): the reta phase-2 T2D trial reported HbA1c, fasting glucose, weight and tolerability but NO beta-cell-FUNCTION readout, and no other indexed study reports one. Retatrutide's only insulin-axis numbers are insulin-RESISTANCE biomarkers (HOMA2-IR, fasting insulin/C-peptide as IR surrogates) from the obesity/MASLD substudies, NOT secretion/function. Whether retatrutide improves beta-cell function is therefore UNKNOWN, not negative - a notable gap given tirzepatide and semaglutide both have direct human beta-cell-FUNCTION (secretion/clamp/HOMA) data. TRIPLE JEOPARDY (Council Red-team): reta's beta-cell story is the LEAST-evidenced (zero function data) AND the MOST weight-confounded (largest weight loss in class) of any agent here, plus it uniquely adds a glucagon arm - so even a future positive reta beta-cell signal could not be read as a direct beta-cell effect.
PopulationReta phase-2 T2D (Rosenstock, Lancet 2023, NCT04867785), N=281; plus a null PubMed search for reta beta-cell secretion/function as of 2026.
Fundingindustry - Eli Lilly and Company
Scope limitsDeepens C2-RETATRUTIDE-INS-03 (which bounded the absence of a reta clamp/EGP tracer) by extending the absence specifically to beta-cell SECRETION/FUNCTION markers in the dedicated T2D trial. The robustness grade rates the trial, not the gap. Contrast tirzepatide (C2-TIRZEPATIDE-INS-01..04) and semaglutide (C2-SEMAGLUTIDE-INS-01), which DO have human beta-cell-function data.
Comparatorsplacebo; dulaglutide 1.5 mg
SemaglutideMARKETED
Insulin and beta-cell functionIncrease
Low evidence
Twelve weeks of once-weekly semaglutide 1.0 mg significantly improved beta-cell function and glycaemic control in T2D: both first- and second-phase insulin secretion...
Full findingTwelve weeks of once-weekly semaglutide 1.0 mg significantly improved beta-cell function and glycaemic control in T2D: both first- and second-phase insulin secretion (IVGTT) increased markedly; the arginine stimulation test showed increased maximal insulin capacity; a graded glucose infusion test restored insulin secretion rate to levels similar to healthy participants; and a 24-h meal test showed reduced fasting/postprandial/overall glucose AND glucagon responses.
In a 28-week randomised phase 1 clamp trial, tirzepatide improved the clamp disposition index more than placebo and more than semaglutide, reflecting greater total...
SourceHeise T et al., Lancet Diabetes Endocrinol 2022;10(6):418-429Source
Full findingIn a 28-week randomised phase 1 clamp trial, tirzepatide improved the clamp disposition index more than placebo and more than semaglutide, reflecting greater total insulin secretion rate and greater clamp insulin sensitivity (M-value), with greater glucagon lowering. The tirzepatide-minus-semaglutide differential isolates a human GIP increment on insulin secretion and sensitivity.
Scope limitsReused from corpus T3-003/T3-004. Drug-level decomposition is combination-only; the human tirz-minus-sema differential is the permitted GIP isolation (caveat C1 not triggered — human, not mouse). No glucagon-agonist arm, so does not model retatrutide's GCGR offset.
Comparatorsplacebo; semaglutide
TirzepatideMARKETED
Insulin and beta-cell functionIncrease
Low evidence
In a single-arm 12-week clamp study (obese T2D, tirzepatide up to 5 mg) the glucose infusion rate rose and glucagon fell, with no significant correlation between GIR...
SourceYamaguchi S et al., Diabetologia 2025; Mather KJ et al., Diabetes Obes Metab 2025Source
Full findingIn a single-arm 12-week clamp study (obese T2D, tirzepatide up to 5 mg) the glucose infusion rate rose and glucagon fell, with no significant correlation between GIR change and weight change, indicating early insulin sensitisation not solely attributable to weight loss. A separate post-hoc analysis found a greater M-value improvement per unit weight loss for tirzepatide than semaglutide.
Scope limitsReused from corpus T11-S2-08/09/10/03. CONFOUNDS (flagged, not resolved): (a) GIP-or-different-GLP-1 (sema dosed 1 mg not 2.4 mg); (b) the larger HOMA2-IR/insulin improvement is substantially WEIGHT-confounded (tirzepatide lost more weight); (c) greater glucagon suppression is mechanistically counter-intuitive for GIP (GIP is glucagonotropic at fasting), so likely GLP-1-led or downstream of greater glycaemia/weight. HOMA2-B is the axis where GIP attribution is most coherent. COI (sponsor framing).
Comparatorssemaglutide 1 mg
Tirzepatide|semaglutide (head-to-head)MARKETED
Insulin and beta-cell functionIncrease
Moderate evidence
SURMOUNT-5 prediabetes subgroup (post-hoc, n=425): tirzepatide produced greater HbA1c reduction, higher reversion to normoglycaemia, and greater improvements in...
SourceGalindo RJ, Aronne LJ, Horn DB et al., J Endocrinol Invest 2026Source
Full findingSURMOUNT-5 prediabetes subgroup (post-hoc, n=425): tirzepatide produced greater HbA1c reduction, higher reversion to normoglycaemia, and greater improvements in fasting insulin and HOMA2-IR than semaglutide, alongside greater weight loss.
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