What is Eli Lilly’s ACHIEVE-1 Trial for the New Oral GLP-1 orforglipron?

Eli Lilly’s new GLP-1 candidate orforglipron is expected to be filed for regulatory approval towards the end of 2025, with the earliest date of approval anticipated to be mid-2026. Orforglipron is being evaluated in five global registrational trials as part of a comprehensive clinical development program, demonstrating its safety and efficacy across diverse populations. It will be one of the first oral GLP-1 treatments to be made available, and it is intended to benefit people who are averse to injectable format GLP-1’s.

This article explores the Eli Lilly sponsored ACHIEVE-1 study that establishes the promising use case for orforglipron in weight loss and HbA1c control. In addition to ACHIEVE-1, orforglipron is being studied in global registrational trials, highlighting the international scope and significance of its clinical development program.

Image of Eli Lilly Laboratory, which is sponsoring the ACHIEVE-1 Trial for Orforglipron

Introduction: Background on Orforglipron and the ACHIEVE-1 Trial

Orforglipron is a groundbreaking, orally active non-peptide glucagon-like peptide 1 (GLP-1) receptor agonist developed by Eli Lilly to address the growing need for effective treatments in type 2 diabetes and obesity. Unlike traditional injectable GLP-1 therapies, orforglipron offers the convenience of a once-daily pill, making it an attractive option for patients seeking alternatives to injections. The ACHIEVE-1 trial is a pivotal Phase 3 clinical trial designed to evaluate the efficacy and safety of orforglipron in adults with type 2 diabetes who have inadequate glycemic control. As part of Eli Lilly’s comprehensive clinical development program, this study aims to establish orforglipron as a safe and effective treatment for improving glycemic control and supporting weight management in people living with diabetes and obesity.

Mechanism of Action: How Orforglipron Works

Orforglipron exerts its effects by selectively binding to the GLP-1 receptor, a key player in regulating blood sugar and appetite. Activation of the GLP-1 receptor stimulates insulin secretion in response to elevated blood glucose, suppresses glucagon release, and slows gastric emptying. These actions collectively contribute to improved glucose control and significant weight reduction. Unlike peptide-based GLP-1 receptor agonists, orforglipron’s unique structural basis as a non-peptide molecule allows it to be administered orally, offering a more convenient option for patients and potentially improving adherence compared to injectable therapies. This innovative approach positions orforglipron as a promising addition to the latest incretin medicines for diabetes and obesity management.

Study Design and Participants

The ACHIEVE-1 trial was designed as a randomized, double-blind, placebo-controlled clinical trial to rigorously assess the efficacy and safety of orforglipron. The study enrolled adults with type 2 diabetes who had inadequate glycemic control despite lifestyle modifications, with or without the use of anti-diabetic medications (excluding those on insulin therapy). Participants were randomly assigned to receive one of several doses of orforglipron or a placebo, taken once daily. The primary endpoint was to determine whether orforglipron could achieve statistically significant efficacy results in improving glycemic control compared to placebo, as measured by reductions in HbA1c levels. This robust study design ensures that the findings are reliable and relevant for real-world diabetes care.

What was the Focus of the ACHIEVE-1 Trial?

The ACHIEVE-1 trial was centered on evaluating both the efficacy and safety of orforglipron in adults with type 2 diabetes. The primary focus was on achieving better glycemic control, as indicated by reductions in HbA1c, and on body weight reduction, which is a critical factor in diabetes and obesity management. Secondary endpoints included a thorough assessment of the safety profile, monitoring for common adverse events such as gastrointestinal symptoms, and determining the proportion of participants who achieved significant reductions in body weight. The trial also aimed to confirm that orforglipron’s safety profile is consistent with other GLP-1 receptor agonists, ensuring that the benefits of improved glycemic control and weight reduction are not offset by unexpected adverse events.

Impact on Body Weight and Metabolic Health

Clinical trials of orforglipron, including ACHIEVE-1, have demonstrated significant reductions in body weight among participants, highlighting its potential as a powerful tool for weight management in diabetes and obesity. The weight loss observed with orforglipron is attributed to its ability to decrease appetite and enhance satiety, alongside its positive effects on glucose metabolism. Achieving meaningful weight reduction not only supports better diabetes control but also contributes to improvements in other metabolic health markers, such as blood pressure and cholesterol levels. These benefits are especially important for individuals with type 2 diabetes, who often face increased risks of cardiovascular disease. By delivering both weight loss and improved metabolic health, orforglipron stands out as a promising new option in the landscape of diabetes and obesity treatments.

What was the ACHIEVE-1 trial?

Eli Lilly sponsored the ACHIEVE-1 clinical trial, a Phase 3 clinical study that investigated orforglipron (LY3502970)—an oral, non-peptide, small-molecule GLP-1 receptor agonist being studied as a potential treatment for type 2 diabetes and obesity. As a small-molecule GLP-1 receptor agonist, orforglipron, can be readily manufactured to meet global demand. The trial design included a dose-response evaluation to determine optimal dosing.

What was the focus of the ACHIEVE-1 trial?

The ACHIEVE-1 trial focused on evaluating the safety and efficacy of orforglipron in adults with type 2 diabetes who had not achieved adequate glycaemic control through diet and exercise alone.

The ACHIEVE-1 trial involved 559 adult participants treated with orforglipron at 3 mg, 12 mg, or 36 mg, compared to placebo, over a 40-week duration. No active comparator was used in this trial.

The purpose of the ACHIEVE-1 trial was to help determine the efficacy and safety of orforglipron for:

• Reduction in HbA1c (a measure of blood glucose) from a baseline of 8.0%
• Weight loss

A key secondary endpoint was the proportion of participants achieving target A1C levels. Among participants taking orforglipron, adherence to the treatment regimen was monitored to assess efficacy and safety outcomes.

What were the body weight reduction results of the ACHIEVE-1 trial?

Orforglipron achieved significant improvements in both weight loss and HbA1c reduction in the ACHIEVE-1 trial.

Results from the ACHIEVE-1 trial showed that orforglipron led to robust efficacy outcomes across multiple endpoints:

Weight Loss Observed:

• Orforglipron doses of 3 mg, 12 mg, and 36 mg were tested, with the highest dose (36 mg) resulting in the greatest weight loss.
• Orforglipron 3 mg dose: 4.7% weight loss
• Orforglipron 12 mg dose: 6.1% weight loss
• Orforglipron 36 mg dose: 7.9% weight loss
• Placebo: 1.6% weight loss

When bodyweight was compared between groups, orforglipron demonstrated a greater reduction than placebo and other GLP-1 receptor agonists in similar studies. The lower dose was associated with fewer gastrointestinal side effects while still providing meaningful weight loss. Orforglipron compared to other GLP-1 receptor agonists showed a favorable efficacy and safety profile, particularly at the highest dose. Orforglipron versus placebo, all active doses resulted in superior weight loss, with a dose-dependent increase in efficacy.

HbA1c Reduction observed:

• Orforglipron 3 mg dose: 1.3% decrease
• Orforglipron 12 mg dose: 1.6% decrease
• Orforglipron 36 mg dose: 1.5% decrease
• Placebo: 0.1% decrease

Orforglipron compared to placebo resulted in a significant reduction in HbA1c at all tested doses. Orforglipron achieved primary endpoints for glycemic control, with orforglipron doses demonstrating a clear dose-response relationship.

Achievement of HbA1c ≤6.5%: Over 65% of participants on the 36 mg dose reached this target, meeting the defined threshold for glycemic control. This aligns with the American Diabetes Association’s defined threshold for diabetes diagnosis.

Treatment discontinuation rates due to adverse events were higher in the orforglipron groups compared to placebo, but remained within expected ranges for GLP-1 receptor agonists.

Orforglipron Safety Profile consistent as determined from ACHIEVE-1 trial

Safety data collected during the trial showed that orforglipron’s safety was consistent with other GLP-1 therapies.

The most common adverse events were:

• gastrointestinal, including diarrhea (19–26%)
• nausea (13–18%), dyspepsia (10–20%)
• constipation (8–17%), and vomiting (5–14%).

The safety profile is consistent with that of injectable GLP-1 therapies, with no new safety signals observed.

These side effects were generally mild to moderate and occurred primarily during the early stages of treatment. Importantly, no liver safety concerns were identified.

The Significance of the ACHIEVE-1 trial

ACHIEVE-1 is the first of seven Phase 3 trials in Eli Lilly’s clinical program for orforglipron, which seeks to offer an effective oral alternative to injectable GLP-1 weight loss injections for treating type 2 diabetes and obesity. Additional data readouts from ongoing and future trials are expected to provide more comprehensive efficacy and safety information to support regulatory approval and clinical decision-making.

As a convenient once daily pill with no dietary restrictions, orforglipron represents the latest incretin medicine and a significant advancement in incretin-based treatments. The latest incretin medicine meets key clinical milestones in safety, efficacy, and tolerability, positioning it as an innovative option for patients. Eli Lilly has stated in a recent press release and news release that the ACHIEVE-1 trial results highlight the importance of orforglipron in the treatment landscape. The company does not anticipate supply constraints and is confident in its ability to manufacture and launch orforglipron at scale globally. Eli Lilly intends to submit regulatory applications for orforglipron’s approval in weight management by the end of 2025, followed by an application for type 2 diabetes in 2026.