Orforglipron for Type 2 Diabetes and Obesity

(ACHIEVE-4 Trial)

Not currently recruiting at 534 trial locations

Overseen By Joseph Soufer

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Eli Lilly and Company

Must be taking: Oral antihyperglycemics

Must not be taking: Weight loss drugs

Disqualifiers: Type 1 diabetes, Pancreatitis, 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: 27

Duration: 104 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called orforglipron for individuals with type 2 diabetes and obesity who are also at risk of heart problems. The goal is to determine if orforglipron is safe and effective compared to insulin glargine, a standard diabetes treatment. Participants will either take orforglipron pills or receive insulin glargine injections. Suitable candidates include those with type 2 diabetes who are on oral diabetes medications, have a BMI over 25, and have heart or kidney issues. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to access a potentially groundbreaking treatment.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop your current medications, but you must be on a stable treatment of 1 to 3 specific diabetes drugs (metformin, SGLT-2 inhibitors, and/or sulfonylureas) for at least 90 days before joining.

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

Research shows that orforglipron, a new pill for treating type 2 diabetes and obesity, is currently undergoing safety testing in clinical trials. Early results suggest it is well-tolerated, and its long-lasting effects require only once-daily dosing, without the need to take it with food or water. This convenience surpasses some treatments that require injections. Although more detailed safety information is still being collected, its presence in the later stages of testing indicates safety in earlier studies. Participants in these studies have not reported any major side effects. However, ongoing monitoring ensures it remains safe for a broader population. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for type 2 diabetes?

Orforglipron is unique because it offers a new approach to managing Type 2 Diabetes and obesity. Unlike traditional treatments like metformin or insulin injections, Orforglipron is taken orally, which could make it more convenient for patients. It works as a non-peptide GLP-1 receptor agonist, a novel mechanism that enhances the body's insulin response and helps control blood sugar levels. Researchers are excited about its potential to not only manage diabetes but also aid in weight loss, offering a two-pronged benefit for patients struggling with these interconnected conditions.

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

Research has shown that orforglipron, one of the treatments in this trial, effectively lowers blood sugar levels. It reduces A1C, a measure of long-term blood sugar, by 1.3% to 1.6%. Orforglipron also aids in weight loss, which helps manage type 2 diabetes and obesity. Previous studies suggest it works similarly to injected treatments already used for these conditions. This trial will compare orforglipron, taken orally, with insulin glargine, an injected treatment, to evaluate their effectiveness. Orforglipron could be a promising option for those seeking a non-injection alternative. ^{1 3 6 7 8}

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 and obesity or overweight, who also have a higher risk of heart disease. Participants should not be on insulin therapy but may be taking other diabetes medications.

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 insulin glargine for the duration of the study

104 weeks

Up to 27 visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Insulin Glargine
• Orforglipron

Trial Overview The study tests the safety and effectiveness of a daily oral medication called Orforglipron compared to Insulin Glargine, an injectable insulin, over about two years with up to 27 visits.

How Is the Trial Designed?

Group I: Orforglipron Experimental Treatment 1 Intervention

Participants will receive escalated doses of orforglipron orally.

Group II: Insulin Glargine Active Control 1 Intervention

Participants will receive insulin glargine subcutaneously (SC). Doses will be individualized and titrated according to a treat-to-target algorithm.

Insulin Glargine is already approved in European Union, United States, Canada, Japan, China, Switzerland for the following indications:

Approved in European Union as Lantus for:

• Type 1 diabetes
• Type 2 diabetes

Approved in United States as Lantus for:

• Type 1 diabetes
• Type 2 diabetes

Approved in Canada as Lantus for:

• Type 1 diabetes
• Type 2 diabetes

Approved in Japan as Lantus for:

• Type 1 diabetes
• Type 2 diabetes

Approved in China as Lantus for:

• Type 1 diabetes
• Type 2 diabetes

Approved in Switzerland as Lantus for:

• Type 1 diabetes
• Type 2 diabetes

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

GLP-1 receptor agonists, while effective in reducing weight and postprandial blood glucose levels, do not significantly lower HbA1c levels compared to insulin glargine, indicating similar efficacy in glycemic control.

Insulin glargine was found to be more effective in reducing fasting blood glucose but was associated with a higher incidence of nocturnal hypoglycemia and influenza, while GLP-1 receptor agonists had more gastrointestinal side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Glucagon-like peptide-1 receptor agonists versus insulin glargine for type 2 diabetes mellitus: A systematic review and meta-analysis of randomized controlled trials. Li, WX., Gou, JF., Tian, JH., et al.[2021]

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]

In a 24-week phase III study involving 756 patients with type 2 diabetes, LY2963016 insulin glargine (LY IGlar) demonstrated non-inferiority to the reference product Lantus(®) (IGlar) in reducing HbA1c levels, indicating it is equally effective for glucose control.

Both LY IGlar and IGlar had similar safety profiles, with no significant differences in adverse events, weight change, or hypoglycemia, suggesting that LY IGlar is a safe alternative to IGlar for patients with type 2 diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Similar efficacy and safety of LY2963016 insulin glargine and insulin glargine (Lantus®) in patients with type 2 diabetes who were insulin-naïve or previously treated with insulin glargine: a randomized, double-blind controlled trial (the ELEMENT 2 study). Rosenstock, J., Hollander, P., Bhargava, A., et al.[2022]

GLP-1 receptor agonists, like liraglutide, not only help manage type 2 diabetes by stimulating insulin release and inhibiting glucagon but also promote weight loss, leading to their approval for weight management.

These medications have additional nonglycemic effects on various body systems, including cardiovascular, neurological, and renal functions, which could be beneficial for patients beyond just weight loss.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

GLP-1 receptor agonists: Nonglycemic clinical effects in weight loss and beyond. Ryan, D., Acosta, A.[2018]

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]

In a phase 2 trial involving 272 adults with obesity, the oral GLP-1 receptor agonist orforglipron resulted in significant weight loss, with participants losing between 8.6% to 14.7% of their body weight by week 36, compared to only 2.3% in the placebo group.

Orforglipron was generally well-tolerated, with mild to moderate gastrointestinal side effects being the most common adverse events, leading to discontinuation in 10-17% of participants, similar to the safety profile of injectable GLP-1 receptor agonists.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daily Oral GLP-1 Receptor Agonist Orforglipron for Adults with Obesity. Wharton, S., Blevins, T., Connery, L., et al.[2023]

Citations

1. 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.

2. 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 ...

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. 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.

5. 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.

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37344954/

Orforglipron (LY3502970), a novel, oral non-peptide ... Orforglipron's long half-life (25-68 hours) allows once-daily oral dosing, without water and food restrictions. Orforglipron had a ...

7. pnas.org pnas.org/doi/10.1073/pnas.2014879117

Structural basis for GLP-1 receptor activation by ... Therapeutically, the GLP-1 mimetic exenatide was the first GLP-1R agonist approved for the treatment of type 2 diabetes mellitus (T2DM) (4, 5).

8. lilly.com lilly.com/news/stories/what-to-know-about-orforglipron

What to Know About Orforglipron Oral GLP-1 Is orforglipron safe to take? Orforglipron is currently being evaluated for safety in the treatment of weight loss and type 2 diabetes through clinical trials ...