Key inclusion and exclusion criteria for the ATTAIN-2 study are presented in Key Inclusion and Exclusion Criteria in ATTAIN-2.

The ATTAIN-2 trial randomized over 1600 participants across the US, Argentina, Australia, Brazil, China, Czechia, Germany, Greece, India, South Korea and Puerto Rico in a 1:1:1:2 ratio to receive either

• orforglipron 6 mg
• orforglipron 12 mg
• orforglipron 36 mg, or
•  placebo.1

During the study, orforglipron was taken once per day without food and water restrictions.1,3

The primary objective of the study was to demonstrate that orforglipron (6 mg, 12 mg, 36 mg) is superior to placebo in the mean percent change in body weight from baseline at 72 weeks.1,2

All participants receiving orforglipron started the study at a dose of 1 mg once-daily and then increased the dose in a step-wise approach at 4-week intervals to their final randomized treatment arms of 

• 6 mg (via steps at 1 mg and 3 mg)
• 12 mg (via steps at 1 mg, 3 mg and 6 mg), or
• 36 mg (via steps at 1 mg, 3 mg, 6 mg, 12 mg and 24 mg).1 

Dose reduction was only allowed for gastrointestinal (GI) tolerability if other mitigations failed.1

Two statistical estimands, efficacy or treatment-regimen, were used to evaluate efficacy data in ATTAIN-2.1

• The efficacy estimand represents efficacy had all randomized participants remained on study intervention (with possible dose interruptions and/or modifications) for 72 weeks without initiating prohibited weight management treatments (and glycemic rescue therapy for glycemic endpoints only).1
• The treatment-regimen estimand represents the estimated average treatment effect regardless of adherence to study intervention or initiation of prohibited weight management treatments (or glycemic rescue therapy for glycemic endpoints only).1

In ATTAIN-2, treatment with orforglipron met the primary endpoint of superior body weight reduction compared to placebo.1

As described in Efficacy Endpoint Results at Week 72 in ATTAIN-2 (Efficacy Estimand), for the efficacy estimand, body weight was reduced from baseline to week 72 in a dose-dependent manner by 5.5% to 10.5% (12.1 lbs to 22.9 lbs) with orforglipron compared with 2.2% (5.1 lbs) with placebo.1

In a key secondary endpoint for the efficacy estimand, HbA1c was reduced from an average baseline of 8.1% to week 72 by 1.3% to 1.8% across orforglipron doses, compared with a 0.1% reduction with placebo (Efficacy Endpoint Results at Week 72 in ATTAIN-2 (Efficacy Estimand)).1

Key secondary results for the efficacy estimand are summarized in Efficacy Endpoint Results at Week 72 in ATTAIN-2 (Efficacy Estimand).

For the treatment-regimen estimand, each dose of orforglipron led to statistically significant improvements across primary and all key secondary endpoints. From baseline to week 72, the mean percent change in body weight was -5.1% to -9.6% (-11.7 lbs to -21.2 lbs) with orforglipron compared with -2.5% (-6.0 lbs) with placebo as described in Efficacy Endpoint Results at Week 72 in ATTAIN-2 (Treatment-Regimen Estimand).1

For the treatment-regimen estimand, HbA1c was reduced from baseline to week 72 by 1.2% to 1.7% with orforglipron compared with 0.5% with placebo (Efficacy Endpoint Results at Week 72 in ATTAIN-2 (Treatment-Regimen Estimand)).1

Key secondary endpoints for the treatment-regimen estimand are described in Efficacy Endpoint Results at Week 72 in ATTAIN-2 (Treatment-Regimen Estimand).

In ATTAIN-2, in addition to body weight and HbA1C reductions, orforglipron showed clinically meaningful benefits across key cardiovascular risk factors, including

• non-HDL cholesterol
• systolic blood pressure, and
• triglycerides.1

In a pre-specified exploratory analysis, treatment with orforglipron 36 mg reduced high-sensitivity C-reactive protein (hsCRP) levels, a marker of inflammation, by 50.6%.1

The overall safety profile of orforglipron in ATTAIN-2 was consistent with the established glucagon-like peptide-1 (GLP-1) receptor agonist class.1

The most commonly reported adverse events were GI-related and generally mild-to-moderate in severity. Most Common Adverse Events For Participants Treated with Orforglipron in in ATTAIN-2 presents the most common adverse events for participants treated with orforglipron.1

Treatment discontinuation rates due to adverse events were 6.1%, 10.6%, and 10.6% with orforglipron 6 mg, 12 mg, and 36 mg, respectively, compared with 4.6% with placebo.1

Overall treatment discontinuation rates were balanced across the treatment groups with 19.1%, 22.3%, and 20.5% with orforglipron 6 mg, 12 mg, and 36 mg, respectively, compared with 20.0% with placebo.1

No hepatic safety signal was observed.1