Orforglipron research findings - The Echo Compendium

Orforglipron INVESTIGATIONAL

comparative-efficacy Decrease

High evidence

PLACEBO-controlled (ACHIEVE-1, early T2D, diet/exercise only). Oral orforglipron 3/12/36 mg gave HbA1c change -1.24/-1.47/-1.48 pp vs placebo -0.41 at 40 weeks; weight...

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

Full findingPLACEBO-controlled (ACHIEVE-1, early T2D, diet/exercise only). Oral orforglipron 3/12/36 mg gave HbA1c change -1.24/-1.47/-1.48 pp vs placebo -0.41 at 40 weeks; weight -4.5/-5.8/-7.6% vs placebo -1.7%. No direct active comparator in this trial.

Population559 adults with early T2D (diet/exercise only), double-blind placebo-controlled phase 3, 40 weeks, 1:1:1:1

Fundingindustry-Eli Lilly

Scope limitsOrforglipron weight loss (~7.6% at 40 wk) sits BELOW injectable sema/tirz on the cross-trial ladder; useful for placing the oral small-molecule rung. Placebo-controlled only - any sema/tirz comparison is INDIRECT/cross-trial. 'Why' OPEN.

Comparatorsplacebo

Orforglipron INVESTIGATIONAL

comparative-efficacy Decrease

High evidence

PLACEBO-controlled add-on (ACHIEVE-5, T2D on insulin glargine). Orforglipron 3/12/36 mg added to titrated glargine gave HbA1c -1.58/-1.88/-1.82 pp vs placebo -0.79 at...

Giorgino F, D'Souza S, et al. JAMA 2026 (ACHIEVE-5) Source

Full findingPLACEBO-controlled add-on (ACHIEVE-5, T2D on insulin glargine). Orforglipron 3/12/36 mg added to titrated glargine gave HbA1c -1.58/-1.88/-1.82 pp vs placebo -0.79 at 40 weeks; weight -2.6/-4.8/-5.4% vs placebo +0.2%. No active drug comparator.

Population546 adults with T2D inadequately controlled on insulin glargine (+/- metformin/SGLT2i), double-blind phase 3, 40 weeks

Fundingindustry-Eli Lilly

Scope limitsInsulin-background population - weight loss attenuated vs monotherapy ACHIEVE-1. Placebo-controlled; cross-class comparison remains indirect.

Comparatorsplacebo

Orforglipron INVESTIGATIONAL

comparative-efficacy Mixed

Moderate evidence

Head-to-head, the oral non-peptide orforglipron was non-inferior and superior to ORAL semaglutide on HbA1c, but with more GI adverse events, more discontinuations and...

Orforglipron versus oral semaglutide head-to-head (ACHIEVE-3), Lancet 2026 Source

Full findingHead-to-head, the oral non-peptide orforglipron was non-inferior and superior to ORAL semaglutide on HbA1c, but with more GI adverse events, more discontinuations and a larger heart-rate rise.

PopulationPeer-reviewed RCT / meta-analysis

FundingEli Lilly

Scope limitsOPEN-LABEL design -> graded moderate, not high. The first oral-vs-oral incretin head-to-head; superior efficacy is paired with worse tolerability and a larger pulse increase.

Orforglipron INVESTIGATIONAL

comparative-efficacy Decrease

Moderate evidence

ACHIEVE-2 (T2D on metformin): orforglipron non-inferior and statistically superior to dapagliflozin for HbA1c reduction at 40 weeks (active-comparator head-to-head).

Welch M et al. Orforglipron compared with dapagliflozin... (ACHIEVE-2): a phase 3 trial. ... Source

PopulationACHIEVE-2, N=962 (49% female; mean age 56.1; HbA1c 8.14%; BMI 32.6; T2D ~8 y), metformin background; 40 wk; phase 3 open-label (dose-blinded) RCT (NCT06192108)

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

Scope limitsconference/abstract-level; open-label (unblinded)

Comparatorsdapagliflozin 10 mg

Orforglipron INVESTIGATIONAL

Gastrointestinal tolerability Increase

High evidence

In a weight-maintenance setting (after injectable tirzepatide or semaglutide), most common AEs with orforglipron were GI, mostly mild-to-moderate.

Aronne LJ et al., Nat Med 2026 (ATTAIN-MAINTAIN) Source

PopulationATTAIN-MAINTAIN: 376 adults (205 prior tirzepatide; 171 prior semaglutide); 52 weeks; phase 3b RCT, orforglipron daily vs placebo

Fundingindustry-Eli Lilly

Scope limitsPMID confirmed. Maintenance-phase tolerability after switching from injectables.

Comparatorsplacebo

Orforglipron INVESTIGATIONAL

Gastrointestinal tolerability Increase

High evidence

GI AEs most common, mostly mild-to-moderate, concentrated in escalation; per-symptom rates and AE-related discontinuation dose-related.

Lilly ATTAIN-1 (NEJM 2025) and ATTAIN-2 results Source

PopulationATTAIN-1: adults with obesity (no diabetes); phase 3 RCT, orforglipron 6/12/36 mg vs placebo

Fundingindustry - Eli Lilly

Scope limitsidentifier not fully verified; no outcome data yet (ongoing)

Comparatorsplacebo

Orforglipron INVESTIGATIONAL

Gastrointestinal tolerability Increase

High evidence

Predominantly mild-to-moderate GI adverse events, mostly during dose escalation; higher AE-related discontinuation than placebo/active comparators.

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

PopulationPooled across ATTAIN-2, ACHIEVE-1, ACHIEVE-2 phase 3 RCTs

Fundingindustry-Eli Lilly

Scope limitsSafety profile stated as consistent with the GLP-1RA class. No drug-induced-liver-injury signal reported for orforglipron (contrast with Pfizer oral GLP-1s).

Comparatorsplacebo; dapagliflozin

Orforglipron INVESTIGATIONAL

Gastrointestinal tolerability Increase

Low evidence

Review-channel: safety profile consistent with GLP-1 class, dominated by manageable GI events mitigated by slow escalation; small mild-pancreatitis signal noted...

Pillai AA et al., Cardiol Rev 2025 (orforglipron review) Source

Full findingReview-channel: safety profile consistent with GLP-1 class, dominated by manageable GI events mitigated by slow escalation; small mild-pancreatitis signal noted (logged as class context).

PopulationACHIEVE-3 (T2D) and ATTAIN-2 (obesity+T2D) programme; phase 3

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

Scope limitsPer-symptom GI rates not quantified here (see C-ORF-SAFETY-GI05).

Comparatorsoral semaglutide; placebo

Orforglipron INVESTIGATIONAL

Weight change Decrease

High evidence

Once-daily oral non-peptide GLP-1RA (LY3502970, Lilly). In ATTAIN-1 phase 3 obesity (no T2D), 36 mg reduced body weight by 12.4% vs 0.9% placebo at 72 weeks. In...

Eli Lilly press + ATTAIN-1/ATTAIN-2 (NEJM; Lancet 2025), ACHIEVE-1 (NEJM 2025) Source

Full findingOnce-daily oral non-peptide GLP-1RA (LY3502970, Lilly). In ATTAIN-1 phase 3 obesity (no T2D), 36 mg reduced body weight by 12.4% vs 0.9% placebo at 72 weeks. In ATTAIN-2 (obesity + T2D), top dose gave 10.5% weight loss and HbA1c -1.8%. In ACHIEVE-1 (early T2D), HbA1c fell 1.2/1.5/1.5% (3/12/36 mg) vs 0.4% placebo with weight loss 4.5/5.8/7.6% vs 1.7% placebo.

PopulationATTAIN-1: obesity/overweight + comorbidity, 72 wk, placebo-controlled (3/12/36 mg). ATTAIN-2: obesity + T2D. ACHIEVE-1: T2D on diet/exercise

Fundingindustry - Eli Lilly (disclosed in publication)

Scope limitsMECHANISM: oral non-peptide (small-molecule) GLP-1R agonist, once daily, no food/water restriction claimed (vs oral peptide semaglutide). Lilly states safety consistent with injectable class; global regulatory submission stage. GI tolerability typical of class.

Comparatorsplacebo

Orforglipron INVESTIGATIONAL

Weight change Decrease

High evidence

ATTAIN-1 (obesity, no diabetes): superior body-weight reduction vs placebo at all three doses at 72 weeks.

Lilly ATTAIN-1 (NEJM 2025) and ATTAIN-2 results Source

PopulationATTAIN-1, adults with obesity (or overweight + comorbidity) without diabetes; 72 wk; phase 3 double-blind placebo-controlled RCT (NCT05869903); doses 6/12/36 mg vs placebo

Fundingindustry - Eli Lilly

Scope limitsidentifier not fully verified; no outcome data yet (ongoing)

Comparatorsplacebo

Orforglipron INVESTIGATIONAL

Weight change Decrease

High evidence

ATTAIN-2 (obesity + T2D): dose-dependent weight reduction superior to placebo at 72 weeks.

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

PopulationATTAIN-2, N=1613 (47% female; mean baseline weight 101.4 kg, BMI 35.6, HbA1c 8.05%); 72 wk; phase 3 RCT (NCT05872620); 6/12/36 mg vs placebo

Fundingindustry-Eli Lilly

Scope limitsWeight loss attenuated in T2D (as expected for class). All prespecified weight/cardiometabolic measures incl. HbA1c improved.

Comparatorsplacebo

Orforglipron INVESTIGATIONAL

Weight change Decrease

High evidence

ACHIEVE-1 secondary: body-weight reduction at 40 weeks in early T2D.

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

PopulationACHIEVE-1, N=559; 40 wk; phase 3 RCT (NCT05971940)

Fundingindustry-Eli Lilly

Comparatorsplacebo

Thin or bounded evidence here means uncertainty remains visible. It is not evidence that an effect has been ruled out.

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

Thin or bounded evidence here means uncertainty remains visible. It is not evidence that an effect has been ruled out.

Orforglipron INVESTIGATIONAL

Safety signals Increase

High evidence

AE-related discontinuation rose with orforglipron dose; GI events the commonest AEs, mostly mild-to-moderate, in escalation.

Lilly ATTAIN-1 (NEJM 2025) and ATTAIN-2 results Source

PopulationATTAIN-1 (obesity, no diabetes) and ATTAIN-2 (obesity + T2D) phase 3 trials

Fundingindustry - Eli Lilly

Scope limitsidentifier not fully verified; no outcome data yet (ongoing)

Comparatorsplacebo

Thin or bounded evidence here means uncertainty remains visible. It is not evidence that an effect has been ruled out.

Orforglipron INVESTIGATIONAL

Blood pressure Decrease

Moderate evidence

Orforglipron produced significant placebo-adjusted BP decreases in phase 2 T2D and obesity; plateau at >=12 mg.

Wharton S et al., Cardiovasc Diabetol, 2025;24(1):240 Source

PopulationPhase 2 pooled: T2D N=361 (26 wk) and obesity N=234 (36 wk); orforglipron 3-45 mg vs placebo (+dulaglutide in T2D).

Fundingindustry - Eli Lilly and Company

Scope limitssurrogate/exploratory endpoint

Comparatorsplacebo; dulaglutide 1.5 mg (T2D study)

Thin or bounded evidence here means uncertainty remains visible. It is not evidence that an effect has been ruled out.

Orforglipron INVESTIGATIONAL

Lipids and lipoproteins Decrease

Moderate evidence

Orforglipron significantly lowered LDL-C, TG, ApoB and ApoC3 versus placebo in phase 2 (plateau at >=12 mg).

Wharton S et al., Cardiovasc Diabetol, 2025;24(1):240 Source

PopulationPhase 2 pooled: T2D N=361 (26 wk), obesity N=234 (36 wk); orforglipron 3-45 mg vs placebo (+dulaglutide in T2D).

Fundingindustry - Eli Lilly and Company

Scope limitssurrogate/exploratory endpoint

Comparatorsplacebo; dulaglutide 1.5 mg (T2D study)

Thin or bounded evidence here means uncertainty remains visible. It is not evidence that an effect has been ruled out.

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)

Thin or bounded evidence here means uncertainty remains visible. It is not evidence that an effect has been ruled out.

Orforglipron INVESTIGATIONAL

Appetite and food intake Decrease

Low evidence

In a phase 1a single/multiple-ascending-dose study in healthy participants, 4 weeks of orforglipron produced body-weight reductions up to 5.4 kg vs 2.4 kg placebo,...

Pratt E et al., Diabetes Obes Metab 2023;25(9):2634-2641 Source

Full findingIn a phase 1a single/multiple-ascending-dose study in healthy participants, 4 weeks of orforglipron produced body-weight reductions up to 5.4 kg vs 2.4 kg placebo, decreased fasting glucose, and delayed gastric emptying on Day 28 — pharmacodynamics consistent with class GLP-1R appetite/satiety effects (intake not formally measured here).

PopulationHealthy adults, n=92 (32 SAD, 60 MAD), phase 1a

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

Scope limitssmall sample (N~92); surrogate/exploratory endpoint

Comparatorsplacebo

Thin or bounded evidence here means uncertainty remains visible. It is not evidence that an effect has been ruled out.

Orforglipron INVESTIGATIONAL

Insulin and beta-cell function Decrease

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,...

Frías 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