Glycaemic control

Albiglutide MARKETED

Glycaemic control Decrease

Moderate evidence

Once-weekly albiglutide (30/50 mg) monotherapy reduced HbA1c by approx 0.8% vs placebo (HARMONY 2); in HARMONY Outcomes it reduced MACE by ~22% vs placebo. Weight loss...

Hernandez AF et al., Lancet 2018 (HARMONY Outcomes); Reusch J et al., Diabetes Obes Metab... Source

Full findingOnce-weekly albiglutide (30/50 mg) monotherapy reduced HbA1c by approx 0.8% vs placebo (HARMONY 2); in HARMONY Outcomes it reduced MACE by ~22% vs placebo. Weight loss was modest and lower than competing GLP-1 RAs.

PopulationHARMONY 2: T2D inadequately controlled with diet/exercise, 52 weeks, placebo-controlled. HARMONY Outcomes: 9463 T2D with CV disease, median 1.6 years, vs placebo

Fundingindustry - GlaxoSmithKline

Scope limitsMechanism: two tandem GLP-1(7-36) copies fused to recombinant human albumin (once-weekly). Marketed Tanzeum (US)/Eperzan (EU); GSK withdrew worldwide July 2018 for commercial reasons (lower efficacy/weight effect) despite positive CV outcomes. Historical/withdrawn landscape row.

Comparatorsplacebo

Dulaglutide MARKETED

Glycaemic control Decrease

Moderate evidence

In AWARD-1, once-weekly dulaglutide on background metformin plus pioglitazone gave superior HbA1c reduction versus both placebo and twice-daily exenatide at 26 weeks...

Wysham C, Blevins T, Arakaki R, et al. Efficacy and safety of dulaglutide added onto piog... Source

Full findingIn AWARD-1, once-weekly dulaglutide on background metformin plus pioglitazone gave superior HbA1c reduction versus both placebo and twice-daily exenatide at 26 weeks in type 2 diabetes.

PopulationAWARD-1: phase-3, multicentre, parallel-arm randomised trial (2:2:2:1), N=976; type 2 diabetes on metformin (1500-3000 mg) + pioglitazone (30-45 mg); 52 weeks (primary endpoint 26 weeks); comparators placebo (double-blind via double-dummy) and exenatide 10 ug twice daily (OPEN-LABEL active comparator). MIXED blinding: the dulaglutide-vs-placebo comparison is double-blind, the dulaglutide-vs-exenatide superiority comparison is open-label.

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

Scope limitsopen-label (unblinded)

Comparatorsplacebo; exenatide

Dulaglutide MARKETED

Glycaemic control Decrease

High evidence

In AWARD-10, adding once-weekly dulaglutide to an SGLT2 inhibitor (with or without metformin) gave superior HbA1c reduction versus placebo at 24 weeks in inadequately...

Ludvik B, Frias JP, Tinahones FJ, et al. Dulaglutide as add-on therapy to SGLT2 inhibitor... Source

Full findingIn AWARD-10, adding once-weekly dulaglutide to an SGLT2 inhibitor (with or without metformin) gave superior HbA1c reduction versus placebo at 24 weeks in inadequately controlled type 2 diabetes.

PopulationAWARD-10: phase-3b, double-blind, placebo-controlled randomised trial, N=424; type 2 diabetes inadequately controlled on an SGLT2 inhibitor with or without metformin; dulaglutide 1.5/0.75 mg vs placebo; 24 weeks; NCT02597049.

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

Scope limitsNET-NEW gather (WI-5). Dulaglutide on top of SGLT2i - the modern combination position. Observation only. Industry (Eli Lilly). Council interpretive review not yet run.

Comparatorsplacebo

Dulaglutide MARKETED

Glycaemic control Decrease

High evidence

In AWARD-3, dulaglutide monotherapy gave superior HbA1c reduction versus metformin monotherapy at 26 weeks in early type 2 diabetes.

Umpierrez G, Tofe Povedano S, Perez Manghi F, et al. Efficacy and safety of dulaglutide m... Source

PopulationAWARD-3: 52-week double-blind randomised trial, N=807; treatment-naive or low-dose-OAM type 2 diabetes (HbA1c 6.5-9.5%); subcutaneous dulaglutide 1.5/0.75 mg weekly vs metformin; primary endpoint 26 weeks.

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

Scope limitsNET-NEW gather (WI-5). Defines dulaglutide-vs-metformin monotherapy glycaemic position. Observation only. Industry (Eli Lilly). Council interpretive review not yet run. funding_basis inferred-wrapper at gather; resolve to disclosed locator if load-bearing.

Comparatorsmetformin

Dulaglutide MARKETED

Glycaemic control Decrease

High evidence

In AWARD-5, dulaglutide 1.5 mg added to metformin gave greater HbA1c reduction than sitagliptin over 52 weeks; the Bayesian dose-finding portion selected 1.5 mg and...

Skrivanek Z, Gaydos BL, Chien JY, et al. Dose-finding results in an adaptive, seamless, r... Source

Full findingIn AWARD-5, dulaglutide 1.5 mg added to metformin gave greater HbA1c reduction than sitagliptin over 52 weeks; the Bayesian dose-finding portion selected 1.5 mg and 0.75 mg as the doses to carry forward.

PopulationAWARD-5: adaptive, seamless, double-blind randomised dose-finding plus confirmatory trial; type 2 diabetes on metformin; randomised 3:1:1 to seven dulaglutide doses, sitagliptin 100 mg, or placebo (placebo to 26 weeks, sitagliptin to 104 weeks); Bayesian adaptive randomisation.

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

Scope limitsNET-NEW gather (WI-5). Dulaglutide-vs-sitagliptin (DPP-4i) glycaemic position plus the dose-selection rationale for the marketed 1.5/0.75 mg doses. This paper reports the dose-finding portion; the 104-week confirmatory AWARD-5 vs sitagliptin (Weinstock 2015) is a separate paper, not duplicated here. Observation only. Industry (Eli Lilly). Council interpretive review not yet run.

Comparatorssitagliptin; placebo

Dulaglutide MARKETED

Glycaemic control Decrease

Moderate evidence

In AWARD-6, once-weekly dulaglutide 1.5 mg was non-inferior to once-daily liraglutide 1.8 mg for HbA1c reduction at 26 weeks in metformin-treated type 2 diabetes.

Dungan KM, Povedano ST, Forst T, et al. Once-weekly dulaglutide versus once-daily liraglu... Source

PopulationAWARD-6: phase-3, randomised, open-label, parallel-group non-inferiority trial, N=599 (299 dulaglutide, 300 liraglutide); metformin-treated type 2 diabetes (HbA1c 7.0-10.0%); 26 weeks; NCT01624259.

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

Scope limitsopen-label (unblinded)

Comparatorsliraglutide

Dulaglutide MARKETED

Glycaemic control Decrease

High evidence

In AWARD-9, adding once-weekly dulaglutide 1.5 mg to titrated insulin glargine gave superior HbA1c reduction versus placebo plus glargine at 28 weeks, with concurrent...

Pozzilli P, Norwood P, Jodar E, et al. Placebo-controlled, randomized trial of the additi... Source

Full findingIn AWARD-9, adding once-weekly dulaglutide 1.5 mg to titrated insulin glargine gave superior HbA1c reduction versus placebo plus glargine at 28 weeks, with concurrent weight loss and a smaller required glargine dose increase.

PopulationAWARD-9: phase-3, double-blind, placebo-controlled randomised trial, N=300; type 2 diabetes inadequately controlled on titrated insulin glargine with or without metformin; dulaglutide 1.5 mg vs placebo added to glargine; 28 weeks; NCT02152371.

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

Scope limitsNET-NEW gather (WI-5). Dulaglutide as add-on to basal insulin - a distinct clinical position. Carries both HbA1c and weight plus an insulin-sparing observation. Observation only. Industry (Eli Lilly). Council interpretive review not yet run.

Comparatorsplacebo

Dulaglutide MARKETED

Glycaemic control Decrease

High evidence

Once-weekly dulaglutide at 4.5 mg gave superior HbA1c reduction (approx -1.9%) and weight change (-4.7 kg) vs 1.5 mg (-1.5%, -3.1 kg) at 36 weeks in metformin-treated...

Frias JP et al. (AWARD-11), Diabetes Care 2021;44:765 Source

Full findingOnce-weekly dulaglutide at 4.5 mg gave superior HbA1c reduction (approx -1.9%) and weight change (-4.7 kg) vs 1.5 mg (-1.5%, -3.1 kg) at 36 weeks in metformin-treated T2D.

PopulationAWARD-11: T2D on metformin, randomised to dulaglutide 1.5/3.0/4.5 mg, 52 weeks (primary at 36 weeks)

Fundingindustry-Eli Lilly

Scope limitsMechanism: GLP-1(7-37) analogue linked to modified human IgG4 Fc (~5 day half-life, once-weekly). Marketed as Trulicity (T2D); approved US/EU. CV benefit in REWIND. No dedicated obesity (non-T2D) indication; weight is secondary. AWARD-11 identifiers are the established ones, reconfirm flag noted.

Comparatorsdulaglutide 1.5 mg; dulaglutide 3.0 mg

Ecnoglutide INVESTIGATIONAL

Glycaemic control Decrease

Moderate evidence

The cAMP-biased GLP-1 agonist ecnoglutide lowered HbA1c by up to ~2.4% in phase-2 type-2 diabetes.

Ecnoglutide in type 2 diabetes, phase-2, Nat Commun 2024 Source

PopulationPeer-reviewed RCT / meta-analysis

FundingSciwind Biosciences

Scope limitsPhase-2; China-only; injectable. The ecnoglutide phase-3 OBESITY result (PMID 40555243) is already in the corpus (C2-ECNO-WL-01).

Exenatide MARKETED

Glycaemic control Decrease

Moderate evidence

Exenatide ER 2 mg once weekly reduced HbA1c by approx -1.9% vs -1.5% for exenatide IR 10 mcg twice daily at 30 weeks; weight loss approx -3.6 kg with either...

Drucker DJ et al., Lancet 2008 (DURATION-1) Source

Full findingExenatide ER 2 mg once weekly reduced HbA1c by approx -1.9% vs -1.5% for exenatide IR 10 mcg twice daily at 30 weeks; weight loss approx -3.6 kg with either formulation.

PopulationDURATION-1: 295 patients with T2D on background therapy, exenatide ER 2 mg weekly vs IR 10 mcg twice daily, 30-week controlled phase, open-label non-inferiority

Fundingindustry - Amylin Pharmaceuticals / Eli Lilly (disclosed)

Scope limitsopen-label (unblinded)

Comparatorsexenatide IR (twice daily)

Liraglutide MARKETED

Glycaemic control No change

Moderate evidence

FDA Victoza Clinical Pharmacology review: in a stepwise hypoglycaemic clamp, a single liraglutide dose did NOT impair the glucagon counter-regulatory response...

FDA Victoza NDA 022341 Clinical Pharmacology (OCP) Review (scanned/OCR) Source

Full findingFDA Victoza Clinical Pharmacology review: in a stepwise hypoglycaemic clamp, a single liraglutide dose did NOT impair the glucagon counter-regulatory response (glucagon rose ~1.5-fold with falling glucose in both arms). This is the GLP-1-monoagonist baseline for the retatrutide GCGR-arm hypoglycaemia-counter-regulation question: pure GLP-1 does not impair counter-regulation; whether chronic GCGR agonism plus incretin insulin secretion does is retatrutide-specific and open.

PopulationStepwise hypoglycaemic clamp, single-dose liraglutide vs comparator (FDA Victoza NDA 022341 ClinPharm/OCP review, counter-regulation section, Fig 10)

Fundingindustry - Novo Nordisk (applicant/manufacturer; FDA Clinical Pharmacology/OCP review of Novo's NDA 022341 submission)

Scope limitsscanned/OCR source; single-dose hypoglycaemic-clamp substudy

Comparatorsplacebo/comparator arm

Lixisenatide MARKETED

Glycaemic control Decrease

High evidence

In the GetGoal phase 3 programme lixisenatide reduced HbA1c by approx 0.5-0.9%; in the ELIXA cardiovascular outcomes trial it was MACE-neutral vs placebo in T2D after...

Pfeffer MA et al., NEJM 2015 (ELIXA) Source

Full findingIn the GetGoal phase 3 programme lixisenatide reduced HbA1c by approx 0.5-0.9%; in the ELIXA cardiovascular outcomes trial it was MACE-neutral vs placebo in T2D after acute coronary syndrome.

PopulationGetGoal: ~5000 T2D across settings. ELIXA: 6068 T2D within 70 days of ACS, lixisenatide vs placebo, median ~2.1 years

Fundingindustry - Sanofi

Scope limitsMechanism: exendin-4-derived short-acting GLP-1 receptor agonist with pronounced gastric-emptying delay (strong postprandial lowering). Marketed Adlyxin (US)/Lyxumia (EU); also fixed-ratio with insulin glargine (Soliqua/Suliqua). First GLP-1 RA CV outcomes trial; CV-safe, no benefit. Later largely withdrawn commercially in some markets.

Comparatorsplacebo

Retatrutide INVESTIGATIONAL

Glycaemic control Decrease

Moderate evidence

In a phase 2 trial in adults with type 2 diabetes, retatrutide reduced HbA1c and body weight versus both placebo and active comparator dulaglutide 1.5 mg.

Rosenstock J, Frias J, Jastreboff AM, et al. Lancet 2023 (retatrutide phase 2 in T2D) Source

PopulationPhase 2 NCT04867785: adults with T2D, USA, randomised double-blind, placebo- and dulaglutide-1.5mg-controlled, 36 wk (24-wk primary).

Fundingindustry - Eli Lilly (disclosed in publication)

Scope limitsNotable as a rare obesity-class agent showing strong glycaemic efficacy despite a glucagon-receptor arm (glucagon agonism would naively raise glucose); net effect is HbA1c lowering, attributed to dominant GLP-1/GIP action plus weight loss. Active dulaglutide comparator = within-class head-to-head.

Comparatorsplacebo; dulaglutide

Retatrutide INVESTIGATIONAL

Glycaemic control No change

Moderate evidence

In the phase-2 T2D dose-ranging trial, retatrutide's lowest (0.5 mg) dose produced a measured null - no significant HbA1c or weight separation from placebo - defining...

Rosenstock J, Frias J, Jastreboff AM, et al. Lancet 2023 Source

Full findingIn the phase-2 T2D dose-ranging trial, retatrutide's lowest (0.5 mg) dose produced a measured null - no significant HbA1c or weight separation from placebo - defining the bottom of the dose-response.

PopulationPeer-reviewed RCT (measured null)

Fundingindustry - Eli Lilly and Company

Scope limitsThe ONLY true retatrutide measured null in the corpus: a sub-therapeutic dose-floor effect, NOT 'retatrutide does not work'.

Comparatorsplacebo

Amycretin MARKETED

Glycaemic control Decrease

Moderate evidence

Fasting plasma glucose change assessed as exploratory PD endpoint (oral)

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

PopulationPhase 1 oral first-in-human (n=144)

Fundingindustry - Novo Nordisk

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

Comparatorsplacebo

Cagrilintide MARKETED

Glycaemic control Decrease

Moderate evidence

As monotherapy in T2D, HbA1c reduction smaller than semaglutide or CagriSema

Frias JP et al. Lancet 2023;402:720-730 Source

PopulationT2D BMI ≥27 on metformin±SGLT2i (n=30 cagrilintide arm), phase 2, 32 wk, RCT (NCT04982575)

Fundingindustry-Novo Nordisk

Scope limitssmall sample (N~30)

Comparatorssemaglutide 2.4 mg; CagriSema

CagriSema INVESTIGATIONAL

Glycaemic control Decrease

High evidence

In REDEFINE 2 (phase 3a, T2D + overweight/obesity), CagriSema markedly increased the proportion of patients reaching HbA1c ≤6.5% vs placebo at 68 weeks (glycaemic...

Davies MJ, Bajaj HS, et al. N Engl J Med 2025 (REDEFINE 2) Source

Full findingIn REDEFINE 2 (phase 3a, T2D + overweight/obesity), CagriSema markedly increased the proportion of patients reaching HbA1c ≤6.5% vs placebo at 68 weeks (glycaemic endpoints secondary; primary was weight).

Population1206 adults with T2D, BMI ≥27, HbA1c 7-10%; 68-week double-blind placebo-controlled phase 3a RCT, 12 countries; CGM substudy

Fundingindustry-Novo Nordisk

Scope limitsPrimary endpoints were weight, not glycaemia; HbA1c reported as proportion reaching ≤6.5% rather than mean Δ in abstract. Placebo-controlled (no semaglutide head-to-head arm here).

Comparatorsplacebo

CagriSema INVESTIGATIONAL

Glycaemic control Decrease

Very low evidence

Per Novo Nordisk press release, in REIMAGINE 2 CagriSema 2.4/2.4 mg gave superior HbA1c reduction vs semaglutide 2.4 mg in T2D at 68 weeks (head-to-head).

Novo Nordisk press release: CagriSema demonstrated superior HbA1c reduction of 1.91%-poin... Source

PopulationAdults with T2D on metformin ± SGLT2i; 68-week phase 3 RCT; comparator semaglutide 2.4 mg

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

Scope limitsidentifier not fully verified

Comparatorssemaglutide 2.4 mg

Cotadutide MARKETED

Glycaemic control Decrease

Moderate evidence

Cotadutide reduced post-MMTT glucose AUC vs placebo in overweight/obese T2D (phase 2a, 41 days).

Ambery P et al. Lancet 2018;391:2607-2618 Source

PopulationOverweight/obese T2D, phase 2a (n=51) and phase 2b (n=834), up to 54 wk, RCT

Fundingindustry-AstraZeneca

Scope limitsshort duration; small sample (N~51)

Comparatorsplacebo; liraglutide 1.8 mg

CT-388/enicepatide INVESTIGATIONAL

Glycaemic control Decrease

Low evidence

Improved glycaemic parameters during fasting and oral glucose tolerance testing in phase 1; HbA1c reductions reported in a phase 1b T2D cohort (conference).

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

PopulationPhase 1 overweight/obese (NCT04838405); ADA abstract 763-P = 12-wk cohort adults with obesity + T2D

Fundingindustry - Roche

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

Comparatorsplacebo

LY3537021 MARKETED

Glycaemic control Mixed

Low evidence

Transient reductions in fasting glucose in T2D participants that were not sustained vs placebo by day 29.

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

PopulationPhase 1 MAD, T2D participants (NCT04586907); placebo comparator

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

Scope limitsGlycaemic benefit of selective GIPR agonism appears weaker/less durable than its weight effect in this short study — recorded neutrally.

Comparatorsplacebo

MariTide MARKETED

Glycaemic control Decrease

Moderate evidence

HbA1c reduction in the obesity + T2D cohort.

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

PopulationObesity + T2D cohort, N=127; 52 wk; phase 2 RCT; placebo comparator

Fundingindustry - Amgen

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

Comparatorsplacebo

Mazdutide INVESTIGATIONAL

Glycaemic control Decrease

Moderate evidence

In a phase 3 trial in Chinese adults with T2D, both mazdutide doses were non-inferior and superior to dulaglutide 1.5 mg for HbA1c reduction at 28 weeks (head-to-head).

Guo L et al. Mazdutide versus dulaglutide in Chinese adults with type 2 diabetes. Nature ... Source

Population731 Chinese adults with T2D on background oral antidiabetics, randomised 1:1:1; 28-week phase 3 RCT

Fundingindustry - Innovent Biologics (mazdutide licensed from Eli Lilly in China)

Scope limitsComparator dulaglutide at 1.5 mg (not max 4.5 mg). Chinese-only population may limit generalisability.

Comparatorsdulaglutide 1.5 mg

Mazdutide INVESTIGATIONAL

Glycaemic control Not directional

Very low evidence

DREAMS-3, the first head-to-head mazdutide-vs-semaglutide trial in Chinese adults with T2D + obesity, is designed but results pending (registry/protocol only).

Luo Y et al. Mazdutide versus Semaglutide for T2D and obesity: rationale, design and base... Source

Population349 Chinese adults with T2D (≤10 y) and obesity (BMI ≥28); 32-week open-label active-controlled phase 3 RCT; comparator semaglutide 1 mg

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

Scope limitsopen-label (unblinded)

Comparatorssemaglutide 1 mg

Orforglipron INVESTIGATIONAL

Glycaemic control Decrease

High evidence

ACHIEVE-1 (early T2D, drug-naive): HbA1c reduction superior to placebo at 40 weeks; mean week-40 HbA1c 6.5-6.7%.

Rosenstock J, Hsia S, et al. N Engl J Med 2025 (ACHIEVE-1) Source

PopulationACHIEVE-1, N=559 adults, early T2D managed by diet/exercise, baseline HbA1c ~8.0%; 40 wk; phase 3 double-blind placebo-controlled RCT (NCT05971940); 3/12/36 mg vs placebo

Fundingindustry-Eli Lilly

Scope limitsNo severe hypoglycaemia. Body-weight also fell (-4.5% to -7.6% vs -1.7% placebo) — see WL record.

Comparatorsplacebo

Orforglipron INVESTIGATIONAL

Glycaemic control Decrease

Low evidence

In a phase 2 T2D dose-response study, orforglipron (≥12 mg) gave significant HbA1c reductions vs placebo and numerically exceeded dulaglutide 1.5 mg at 26 weeks.

Frías JP et al. Efficacy and safety of oral orforglipron in patients with type 2 diabetes... Source

Population383 adults with T2D (diet/exercise ± metformin, HbA1c 7.0-10.5%, BMI ≥23); 26-week double-blind phase 2 RCT; USA, Hungary, Poland, Slovakia

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

Scope limitsDulaglutide comparison descriptive (not a powered head-to-head). Dose-ranging with two escalation regimens for 36 mg and 45 mg cohorts.

Comparatorsplacebo; dulaglutide 1.5 mg

Pramlintide MARKETED

Glycaemic control Decrease

High evidence

Modest HbA1c reduction as mealtime-insulin adjunct in T1D/T2D

SYMLIN (pramlintide acetate) FDA label, 2015 Source

PopulationT1D/T2D on mealtime insulin, FDA registration trials, ≥6 mo, RCT placebo-controlled

Fundingregulatory agency (FDA/EMA/MHRA/WHO)

Scope limitsMarketed precedent; effect small relative to newer agents

Comparatorsplacebo + insulin

Retatrutide INVESTIGATIONAL

Glycaemic control Decrease

Moderate evidence

In the phase-2 T2D trial, retatrutide produced dose-dependent HbA1c reductions at 24 weeks (HbA1c is a SURROGATE endpoint), significantly greater than placebo at all...

Rosenstock J, Frias J, Jastreboff AM, et al. Lancet 2023 Source

Full findingIn the phase-2 T2D trial, retatrutide produced dose-dependent HbA1c reductions at 24 weeks (HbA1c is a SURROGATE endpoint), significantly greater than placebo at all doses bar 0.5 mg and greater than dulaglutide 1.5 mg at the 8 mg slow-escalation and 12 mg doses, with no hypoglycaemia reported. (High HbA1c target attainment is reported, but as secondary/figure data - see magnitude, flagged not-abstract-verified.)

PopulationRosenstock phase-2 (NCT04867785): 281 adults with T2D (HbA1c 7.0-10.5%, BMI 25-50), on diet/exercise +/- stable metformin; 36-week double-blind placebo- and dulaglutide-1.5mg-controlled RCT, USA; 24-week primary.

Fundingindustry - Eli Lilly and Company

Scope limitsDEEPENED (D3): adds HbA1c target-attainment and fasting-glucose detail to the existing row. GLUCAGON-OFFSET caveat: the GCGR arm RAISES hepatic glucose in isolation, so net HbA1c lowering is a COMBINATION result; the incretin and weight-loss effects are PRESUMED to outweigh any glucagon-driven rise, but the trial cannot partition this and does NOT establish that an offset 'holds' (weight-mediation and HbA1c-floor equally explain the absence of net blunting). Cross-ref thread-3. Dulaglutide capped at 1.5 mg (below the 4.5 mg max), so the active-comparator superiority is framed cautiously. Background med reduction/insulin-sparing was NOT a reported endpoint. Validation: PMID 37385280 confirmed as the Rosenstock Lancet 2023 reta T2D trial, DISTINCT from the Jastreboff NEJM obesity trial (37366315). NOTE: the HbA1c-change and dulaglutide figures are abstract-verified; the target-attainment percentages (<7.0% ~80%, <=6.5% up to 82%) and the ~69 mg/dL FPG drop are SECONDARY/figure data not in the abstract (directionally consistent, flagged not-abstract-verified).

Comparatorsplacebo; dulaglutide 1.5 mg

Retatrutide INVESTIGATIONAL

Glycaemic control Decrease

High evidence

TRANSCEND-T2D-1, the first phase-3 confirmation: in adults with T2D inadequately controlled by diet and exercise, retatrutide produced graduated, dose-dependent HbA1c...

Bajaj HS et al., Lancet, 2026 Source

Full findingTRANSCEND-T2D-1, the first phase-3 confirmation: in adults with T2D inadequately controlled by diet and exercise, retatrutide produced graduated, dose-dependent HbA1c reductions significantly greater than placebo at 40 weeks, corroborating the phase-2 dose-response. Headline caveats: HbA1c is a SURROGATE (not a hard CV/microvascular outcome), and this is MONOTHERAPY in short-duration (mean 2.5 y), diet-and-exercise-only, placebo-only T2D, so generalisability to established/treated T2D is not established.

PopulationTRANSCEND-T2D-1 (NCT06354660): 537 adults with T2D on diet/exercise only (HbA1c 7.0-9.5%, mean diabetes duration 2.5 y), retatrutide 4/9/12 mg vs placebo; 40-week phase-3 double-blind monotherapy RCT.

Fundingindustry-Eli Lilly

Scope limitsNEW compendium row for TRANSCEND-T2D-1 (already in the per-receptor corpus as L2-040 / T7-039 - cross-ref, confirm same PMID 42250575 / NCT06354660). Pivotal phase-3 but monotherapy in a SHORT-duration (mean 2.5 y), diet-and-exercise-only population, placebo-only (no active comparator) - generalisability to established/treated T2D is limited. Glucagon-offset caveat as in GLY-01. VALIDATOR: confirm PMID 42250575 and reconcile with L2-040.

Comparatorsplacebo

Retatrutide INVESTIGATIONAL

Glycaemic control Decrease

Moderate evidence

CROSS-TRIAL juxtaposition (NOT head-to-head, NOT a non-inferiority test): the bare HbA1c point estimates from three SEPARATE trials are reta 12 mg -2.02 to -2.16%...

Rosenstock J, Frias J, Jastreboff AM, et al. Lancet 2023 Source

Full findingCROSS-TRIAL juxtaposition (NOT head-to-head, NOT a non-inferiority test): the bare HbA1c point estimates from three SEPARATE trials are reta 12 mg -2.02 to -2.16% (phase-2), tirzepatide 15 mg -2.30% (SURPASS-2), semaglutide 1.0 mg -1.55% (SUSTAIN-1). The point estimates OVERLAP, but with different populations, baselines, durations and designs the comparison cannot establish non-inferiority or superiority in EITHER direction and NO potency rank-order can be drawn. The only within-trial (true) comparison is reta superior to dulaglutide 1.5 mg (a submaximal dose). Class glycaemic rank-ordering, and whether reta's glucagon arm costs net glycaemia, remain UNESTABLISHED until the registered reta-vs-sema head-to-head (TRANSCEND-T2D-2) reports.

PopulationCROSS-TRIAL juxtaposition: reta phase-2 (N=281, 24-36 wk) vs SURPASS-2 (tirz, N=1879 on metformin, 40 wk) vs SUSTAIN-1 (sema, N=388 drug-naive, 30 wk). Different populations/baselines/durations.

Fundingindustry - Eli Lilly and Company

Scope limitsCROSS-TRIAL caveat is LOAD-BEARING: this is a juxtaposition of three separate RCTs, NOT a head-to-head; do not present as evidence reta is more/less potent than tirzepatide. No direct reta-vs-tirz or reta-vs-sema T2D efficacy exists yet (the reta-vs-sema head-to-head TRANSCEND-T2D-2 is registered but UNREAD, see C2-RETATRUTIDE-GLY-06). GRADE: although anchored on primary RCTs, the CROSS-TRIAL juxtaposition itself is a LOW-confidence indirect comparison (per-source grading limit, OQ-DB-01: the moderate grade attaches to Rosenstock, NOT to the juxtaposition drawn across trials). COI: reta and tirzepatide (SURPASS-2) are BOTH Eli Lilly-sponsored (same sponsor on both sides of the comparison); semaglutide (SUSTAIN-1) is Novo - this is NOT independent benchmarking. The glucagon-offset inference is NOT drawn in this row (it lives, bounded, in GLY-04). Competitive context: orforglipron/mazdutide/CagriSema T2D HbA1c sit in an overlapping ~-1.2 to -2.2% band (existing rows). Validation: SURPASS-2 PMID 34170647 and SUSTAIN-1 PMID 28110911 confirmed.

Comparatorsplacebo; dulaglutide 1.5 mg; tirzepatide (separate trial); semaglutide (separate trial)

Retatrutide INVESTIGATIONAL

Glycaemic control Decrease

Moderate evidence

Glucagon-offset net-efficacy and glycaemic-ceiling observation (NEUTRAL): no NET glycaemic blunting was observed at any dose (the glycaemic outcome is a combination...

Rosenstock J, Frias J, Jastreboff AM, et al. Lancet 2023 Source

Full findingGlucagon-offset net-efficacy and glycaemic-ceiling observation (NEUTRAL): no NET glycaemic blunting was observed at any dose (the glycaemic outcome is a combination result - no per-arm penalty can be observed OR excluded from trial data). There is a directional signal that retatrutide's WEIGHT efficacy outruns its HbA1c efficacy relative to a submaximal-dose pure incretin (at 12 mg, ~8.4x dulaglutide's weight effect but only ~1.5x its HbA1c effect), and HbA1c plateaued across 8-12 mg. Recorded as an observation, NOT a per-receptor decomposition.

PopulationReta phase-2 (NCT04867785), 281 adults with T2D, 36 wk, vs placebo and dulaglutide 1.5 mg.

Fundingindustry - Eli Lilly and Company

Scope limitsDO NOT OVER-CLAIM (cross-ref thread-3, human-court ruling 2026-06-19): the weight>HbA1c disproportion and the HbA1c plateau are NOT a clean measure of glucagon-driven glycaemic blunting - both are equally consistent with weight-mediation (OQ-T3-A) and with HbA1c being floor-limited near target (HbA1c <=6.5% in up to 82%). A reta-direct clamp + EGP tracer study would only BOUND, not partition, the offset. The class caveat (GLP-1/glucagon duals can show blunted glycaemia if glucagon weighting is too high) does NOT visibly manifest for reta at studied doses, which is CONSISTENT WITH an intact incretin-vs-glucagon balance but does NOT establish it: the 8-12 mg HbA1c plateau is equally consistent with (a) HbA1c floor-limited near target, (b) weight-mediation, (c) the disproportion ratio being inflated by the submaximal dulaglutide 1.5 mg comparator, OR (d) the glucagon arm beginning to blunt glycaemia at the top dose - these cannot be partitioned, so do NOT conclude the offset is definitively intact at the highest doses. Cross-ref OQ-SW-A (dose-headroom).

Comparatorsplacebo; dulaglutide 1.5 mg

Retatrutide INVESTIGATIONAL

Glycaemic control Not directional

Very low evidence

REGISTRY (no results): TRIUMPH-2 (NCT05929079) is a phase-3 master protocol of once-weekly retatrutide in adults with T2D who have obesity/overweight, including an...

Eli Lilly. TRIUMPH-2 master protocol of retatrutide in T2D with obesity/overweight (incl.... Source

Full findingREGISTRY (no results): TRIUMPH-2 (NCT05929079) is a phase-3 master protocol of once-weekly retatrutide in adults with T2D who have obesity/overweight, including an obstructive sleep apnoea (OSA) subset. Confirmed as a reta phase-3 T2D trial; its primary endpoint is body weight (and AHI for the OSA arm), NOT HbA1c, so its glycaemic outcomes are secondary and unreported.

PopulationTRIUMPH-2 (NCT05929079): adults with T2D for >=90 days, BMI >=27, incl. an OSA subset; retatrutide (3 doses) vs placebo; phase-3.

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

Scope limitsRegistered per the D3 remit. Promissory note (very-low). Primary is weight/AHI not HbA1c; glycaemic data will be a secondary readout. Also the anchor for the OSA indication (backlog D8). VALIDATOR: confirm NCT05929079 population + primary endpoint on clinicaltrials.gov.

Comparatorsplacebo

Retatrutide INVESTIGATIONAL

Glycaemic control Not directional

Very low evidence

REGISTRY (no results): NCT06260722 is TRANSCEND-T2D-2, a phase-3 OPEN-LABEL trial of once-weekly retatrutide versus once-weekly semaglutide in adults with T2D...

Eli Lilly. TRANSCEND-T2D-2: retatrutide vs semaglutide in T2D inadequately controlled on ... Source

Full findingREGISTRY (no results): NCT06260722 is TRANSCEND-T2D-2, a phase-3 OPEN-LABEL trial of once-weekly retatrutide versus once-weekly semaglutide in adults with T2D inadequately controlled on metformin +/- an SGLT2 inhibitor, with an HbA1c primary endpoint. This is the within-class HEAD-TO-HEAD that will, for the first time, pit the triple agonist directly against the leading GLP-1 monoagonist on glycaemia - until it reports, every reta-vs-sema glycaemic comparison is cross-trial only.

PopulationTRANSCEND-T2D-2 (NCT06260722): adults with T2D, HbA1c 7.0-10.5%, on stable metformin +/- SGLT2i, BMI >=25; retatrutide (2 doses) vs semaglutide; phase-3 open-label.

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

Scope limitsopen-label (unblinded)

Comparatorssemaglutide

Retatrutide INVESTIGATIONAL

Glycaemic control Not directional

Very low evidence

REGISTRY (no results): NCT06297603 is TRANSCEND-T2D-3, a phase-3 double-blind trial of once-weekly retatrutide versus placebo in adults with T2D AND moderate-to-severe...

Eli Lilly. TRANSCEND-T2D-3: retatrutide vs placebo in T2D with renal impairment on basal ... Source

Full findingREGISTRY (no results): NCT06297603 is TRANSCEND-T2D-3, a phase-3 double-blind trial of once-weekly retatrutide versus placebo in adults with T2D AND moderate-to-severe renal impairment, inadequately controlled on basal insulin (+/- metformin and/or SGLT2i), with an HbA1c primary. It IS a reta-vs-placebo T2D trial, but in a renal-impairment, basal-insulin-background subgroup - NOT the generic T2D-vs-placebo cohort the backlog implied.

PopulationTRANSCEND-T2D-3 (NCT06297603): adults with T2D, HbA1c 7.0-10.5%, moderate-to-severe renal impairment, on stable basal insulin +/- metformin and/or SGLT2i; retatrutide (3 doses) vs placebo; phase-3 double-blind.

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

Scope limitsRegistered per the D3 remit; BRIEF CORRECTED - this is a renal-impairment / basal-insulin population (TRANSCEND-T2D-3), the closest of the registered set to an insulin-background / insulin-sparing context, though no insulin-reduction endpoint is stated. Also relevant to the renal effect-domain. Promissory note (very-low). VALIDATOR: confirm NCT06297603 population (renal impairment + basal insulin) and HbA1c primary.

Comparatorsplacebo

Tirzepatide MARKETED

Glycaemic control Decrease

Moderate evidence

In SURPASS-2, all three tirzepatide doses were non-inferior and superior to semaglutide 1 mg for HbA1c reduction from baseline at 40 weeks (head-to-head).

Frias JP, Davies MJ, Rosenstock J, et al. N Engl J Med 2021 (SURPASS-2) Source

Population1879 adults with T2D on metformin; mean age 56.6 y, mean weight 93.7 kg; 40-week open-label phase 3 RCT; comparator semaglutide 1 mg SC once weekly

Fundingindustry-Eli Lilly

Scope limitsopen-label (unblinded); post-hoc (not prespecified)

Comparatorssemaglutide 1 mg

Most represented records

Evidence spread