glycaemic

Albiglutide WITHDRAWN

glycaemic 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

Comparatorsplacebo

Dulaglutide MARKETED

glycaemic 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)

Comparatorsplacebo; exenatide

Dulaglutide MARKETED

glycaemic 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)

Comparatorsplacebo

Dulaglutide MARKETED

glycaemic 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)

Comparatorsmetformin

Dulaglutide MARKETED

glycaemic 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)

Comparatorssitagliptin; placebo

Dulaglutide MARKETED

glycaemic 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)

Comparatorsliraglutide

Dulaglutide MARKETED

glycaemic 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)

Comparatorsplacebo

Dulaglutide MARKETED

glycaemic 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

Comparatorsdulaglutide 1.5 mg; dulaglutide 3.0 mg

Ecnoglutide MARKETED

glycaemic 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

Exenatide MIXED STATUS

glycaemic 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)

Comparatorsexenatide IR (twice daily)

Liraglutide MARKETED

glycaemic 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)

Comparatorsplacebo/comparator arm

Lixisenatide WITHDRAWN

glycaemic 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

Comparatorsplacebo

Retatrutide INVESTIGATIONAL

glycaemic 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)

Comparatorsplacebo; dulaglutide

Retatrutide INVESTIGATIONAL

glycaemic 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

Comparatorsplacebo

Amycretin INVESTIGATIONAL

glycaemic 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

Comparatorsplacebo

Cagrilintide INVESTIGATIONAL

glycaemic 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

Comparatorssemaglutide 2.4 mg; CagriSema

CagriSema INVESTIGATIONAL

glycaemic 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

Comparatorsplacebo

CagriSema INVESTIGATIONAL

glycaemic 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)

Comparatorssemaglutide 2.4 mg

Cotadutide DISCONTINUED

glycaemic 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

Comparatorsplacebo; liraglutide 1.8 mg

Enicepatide INVESTIGATIONAL

glycaemic 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

Comparatorsplacebo

LY3537021 INVESTIGATIONAL

glycaemic 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)

Comparatorsplacebo

MariTide INVESTIGATIONAL

glycaemic 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

Comparatorsplacebo

Mazdutide MARKETED

glycaemic 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)

Comparatorsdulaglutide 1.5 mg

Orforglipron MARKETED

glycaemic 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

Comparatorsplacebo

Orforglipron MARKETED

glycaemic 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)

Comparatorsplacebo; dulaglutide 1.5 mg

Pramlintide DISCONTINUED

glycaemic 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)

Comparatorsplacebo + insulin

Retatrutide INVESTIGATIONAL

glycaemic Decrease

Moderate evidence

In the phase 2 type 2 diabetes trial, retatrutide produced dose-dependent HbA1c reductions at 24 weeks. Reductions were significantly greater than placebo at all doses...

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

Full findingIn the phase 2 type 2 diabetes trial, retatrutide produced dose-dependent HbA1c reductions at 24 weeks. Reductions were significantly greater than placebo at all doses except 0.5 mg and greater than dulaglutide 1.5 mg at the 8 mg slow-escalation and 12 mg doses; no hypoglycaemia was reported.

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

Comparatorsplacebo; dulaglutide 1.5 mg

Retatrutide INVESTIGATIONAL

glycaemic 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

Comparatorsplacebo

Retatrutide INVESTIGATIONAL

glycaemic 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

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

Retatrutide INVESTIGATIONAL

glycaemic 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

Comparatorsplacebo; dulaglutide 1.5 mg

Tirzepatide MARKETED

glycaemic 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

Comparatorssemaglutide 1 mg

Most represented records

Evidence spread