Orforglipron vs Semaglutide for Type 2 Diabetes

(ACHIEVE-3 Trial)

No longer recruiting at 165 trial locations

Overseen By Chad Crystal

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Eli Lilly and Company

Must be taking: Metformin

Disqualifiers: Type 1 diabetes, Heart failure, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 61 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests two treatments, orforglipron (a new potential drug) and semaglutide, to evaluate their effectiveness and safety for people with Type 2 diabetes who struggle with blood sugar control despite using metformin. Participants will take one of these medications in pill form for about 61 weeks. The trial suits those who have managed Type 2 diabetes with metformin for at least three months but still find it challenging to maintain steady blood sugar levels. As a Phase 3 trial, this study represents the final step before FDA approval, allowing participants to contribute to the development of potentially groundbreaking treatments.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you must continue taking metformin at a stable dose if you are already on it.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that orforglipron, a newer treatment for Type 2 diabetes, is generally safe. In studies, many participants experienced side effects, similar to those of other treatments in the GLP-1 receptor agonist group. These side effects can include nausea or diarrhea, but they are usually manageable.

Semaglutide, another diabetes treatment, has a well-established safety record, as it is already approved for treating Type 2 diabetes. Most side effects are mild and can include nausea, vomiting, or diarrhea, but they typically improve over time.

Both orforglipron and semaglutide have been tested in people and are generally well-tolerated. Prospective trial participants should discuss any concerns with their doctor. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Orforglipron for Type 2 Diabetes because it represents a promising new oral treatment option. Unlike traditional injectable treatments like insulin or GLP-1 receptor agonists such as injectable semaglutide, Orforglipron can be taken orally, making it potentially more convenient and accessible for patients. This ease of administration could lead to better adherence and outcomes. Additionally, Orforglipron may offer a unique mechanism of action that targets pathways differently than current medications, potentially improving blood sugar control and offering an alternative for those who struggle with existing therapies.

What evidence suggests that this trial's treatments could be effective for Type 2 diabetes?

This trial will compare Orforglipron and Semaglutide for managing type 2 diabetes. Research has shown that Orforglipron, which participants in this trial may receive, can significantly lower blood sugar levels in people with type 2 diabetes. Studies have found it can reduce A1C, a measure of long-term blood sugar control, by 1.3% to 1.6%, which is promising for effective diabetes management.

Semaglutide, another treatment option in this trial, is a well-known treatment for type 2 diabetes and effectively controls blood sugar levels. It has helped many people achieve better blood sugar control when used regularly. Both treatments in this trial aim to assist those struggling to manage their diabetes with current medications in maintaining healthy blood sugar levels. ^{2 3 4 6 7}

Who Is on the Research Team?

Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST)

Principal Investigator

Eli Lilly and Company

Are You a Good Fit for This Trial?

This trial is for adults with Type 2 Diabetes who have been taking metformin consistently and haven't achieved desired blood sugar control. Participants should not have had any significant weight changes or started new diets or intense exercise programs recently. They can't join if they have Type 1 Diabetes, recent severe diabetes complications, certain cancers, high serum calcitonin levels, advanced heart failure, are undergoing treatment for diabetic eye disease, or have severely reduced kidney function.

Inclusion Criteria

I have been taking at least 1500 mg of metformin daily for the last 90 days.

Your long-term blood sugar level (HbA1c) is between 7.0% and 10.5%.

I have Type 2 Diabetes.

Exclusion Criteria

I am getting or planning to get treatment for eye problems related to diabetes.

I have been cancer-free or in remission for less than 5 years.

I have had a severe diabetic complication in the last 6 months.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either orforglipron or semaglutide orally to assess efficacy and safety

61 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Orforglipron
• Semaglutide

Trial Overview The study compares the effectiveness and safety of a new medication called Orforglipron to an existing drug named Semaglutide in managing blood sugar levels over approximately 61 weeks in people whose Type 2 Diabetes isn't well-controlled by metformin alone.

How Is the Trial Designed?

Group I: Orforglipron Dose 2 Experimental Treatment 1 Intervention

Participants will receive orforglipron orally.

Group II: Orforglipron Dose 1 Experimental Treatment 1 Intervention

Participants will receive orforglipron orally.

Group III: Semaglutide Dose 1 Active Control 1 Intervention

Participants will receive semaglutide orally.

Group IV: Semaglutide Dose 2 Active Control 1 Intervention

Participants will receive semaglutide orally.

Who Is Running the Clinical Trial?

Eli Lilly and Company

Lead Sponsor

Trials

2,708

Recruited

3,720,000+

Dr. Daniel Skovronsky

Eli Lilly and Company

Chief Medical Officer since 2018

MD from Harvard Medical School

David A. Ricks

Eli Lilly and Company

Chief Executive Officer since 2017

BSc from Purdue University, MBA from Indiana University

Published Research Related to This Trial

In a 26-week phase 2 trial involving 383 participants with type 2 diabetes, orforglipron significantly reduced HbA1c levels by up to -2.10% compared to placebo and showed greater weight loss of up to -10.1 kg, indicating its efficacy as a treatment option.

The safety profile of orforglipron was comparable to other GLP-1 receptor agonists, with most adverse events being mild to moderate gastrointestinal issues, suggesting it may be a safer and more convenient alternative to injectable treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of oral orforglipron in patients with type 2 diabetes: a multicentre, randomised, dose-response, phase 2 study. Frias, JP., Hsia, S., Eyde, S., et al.[2023]

Semaglutide (Ozempic®) is a new subcutaneous treatment for type 2 diabetes that effectively lowers blood glucose levels by stimulating insulin release and also helps reduce body weight.

The once-weekly injection has been approved in the US, Puerto Rico, and Canada, and is also under review in other countries, with ongoing clinical development for additional conditions like obesity and liver diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Semaglutide: First Global Approval. Dhillon, S.[2019]

In a meta-analysis of 23 randomized trials involving 22,096 patients with type 2 diabetes, semaglutide was not found to significantly increase the overall risk of diabetic retinopathy (DR) compared to control groups.

However, the analysis indicated that semaglutide was associated with a higher risk of DR in specific subgroups, particularly in patients aged 60 years or older and those with a diabetes duration of 10 years or more, suggesting that caution is warranted in these populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Semaglutide and Diabetic Retinopathy Risk in Patients with Type 2 Diabetes Mellitus: A Meta-Analysis of Randomized Controlled Trials. Wang, F., Mao, Y., Wang, H., et al.[2022]

Semaglutide, a GLP-1 receptor agonist with a long half-life, effectively promotes insulin secretion in a glucose-dependent manner, making it a valuable treatment for type 2 diabetes, approved for use worldwide and in Japan since 2018.

Oral semaglutide (Rybelsus®) is the first GLP-1 receptor agonist available in pill form, showing continuous benefits in glycemic control for patients with type 2 diabetes across various stages, as demonstrated in multiple global clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[New drug for type 2 diabetes: introduction of oral Semaglutide (Rybelsus® tablets), an oral GLP-1 receptor agonist]. Miyasaka, K.[2022]

In a Phase 1b trial involving 68 participants with type 2 diabetes, orforglipron (LY3502970) demonstrated significant reductions in HbA1c levels (by -1.5% to -1.8%) and body weight (by -0.24 to -5.8 kg) compared to placebo, which only showed a -0.4% change in HbA1c.

Orforglipron was generally well tolerated, with gastrointestinal side effects similar to those seen with other GLP-1 receptor agonists, suggesting it may be a safe and effective oral alternative to injectable treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Orforglipron (LY3502970), a novel, oral non-peptide glucagon-like peptide-1 receptor agonist: A Phase 1b, multicentre, blinded, placebo-controlled, randomized, multiple-ascending-dose study in people with type 2 diabetes. Pratt, E., Ma, X., Liu, R., et al.[2023]

Semaglutide (Ozempic®) is an effective once-weekly treatment for type 2 diabetes, showing superior glucose-lowering effects and greater weight loss compared to other GLP-1 receptor agonists in Phase III clinical trials.

It is approved for use in Belgium for patients with type 2 diabetes who have not achieved adequate control with other antidiabetic therapies, particularly in those with a body mass index of 30 kg/m² or higher.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Semaglutide, once weekly GLP-1 receptor agonist (Ozempic®)]. Scheen, AJ.[2019]

Semaglutide, administered once weekly, demonstrated superior reductions in HbA1c levels compared to liraglutide, with significant differences noted at various dosages, indicating better long-term glycemic control.

In terms of weight reduction, semaglutide also showed greater efficacy than liraglutide at certain doses, suggesting it may be a more effective option for managing both blood sugar and weight in patients with diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Weekly Semaglutide vs. Liraglutide Efficacy Profile: A Network Meta-Analysis. Alsugair, HA., Alshugair, IF., Alharbi, TJ., et al.[2021]

Citations

1. investor.lilly.com investor.lilly.com/news-releases/news-release-details/lillys-oral-glp-1-orforglipron-demonstrated-statistically

Lilly's oral GLP-1, orforglipron, demonstrated statistically ... Orforglipron is the first small molecule GLP-1 to successfully complete a Phase 3 trial, lowering A1C by an average of 1.3% to 1.6% across doses.

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40544435/

Orforglipron, an Oral Small-Molecule GLP-1 Receptor ... In adults with early type 2 diabetes, orforglipron significantly reduced the glycated hemoglobin level over a period of 40 weeks.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT05803421

NCT05803421 | A Study of Daily Oral Orforglipron ... The main purpose of this study is to determine safety and efficacy of orforglipron compared with insulin glargine in participants with type 2 diabetes and ...

4. dom-pubs.onlinelibrary.wiley.com dom-pubs.onlinelibrary.wiley.com/doi/full/10.1111/dom.15150

Orforglipron (LY3502970), a novel, oral non‐peptide glucagon ... The current data show this non-peptide agonist has the potential to achieve a similar efficacy to that of some injectable GLP-1RAs, while ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7703558/

Structural basis for GLP-1 receptor activation by ... In efficacy studies, oral administration of LY3502970 resulted in glucose lowering in humanized GLP-1R transgenic mice and insulinotropic and ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37264711/

Orforglipron (LY3502970), a novel, oral non-peptide ... Orforglipron treatment resulted in meaningful reductions in HbA1c and body weight, with an adverse event profile consistent with that of other GLP-1RAs.

7. clinicaltrials.gov clinicaltrials.gov/study/NCT06010004

NCT06010004 | A Long-term Safety Study of Orforglipron ( ... A Long-term Safety Study of Orforglipron (LY3502970) in Participants With Type 2 Diabetes (ACHIEVE-J). ClinicalTrials.gov ID NCT06010004.