Orforglipron vs Dapagliflozin for Type 2 Diabetes

(ACHIEVE-2 Trial)

Recruiting at 24 trial locations

Overseen By Joseph Soufer

Age: 18+

Sex: Any

Travel: May Be Covered

Trial Phase: Phase 3

Sponsor: Eli Lilly and Company

Must be taking: Metformin

Must not be taking: Antihyperglycemics

Disqualifiers: Type 1 diabetes, Hepatitis, 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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: 46 weeks

888 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests two medications, orforglipron and dapagliflozin, to determine which better controls blood sugar in people with type 2 diabetes who aren't getting enough help from metformin. The goal is to find the safest and most effective way to manage blood sugar over about 46 weeks. Participants will take either orforglipron (a new potential drug) at one of three doses or dapagliflozin (also known as Farxiga). Ideal candidates have type 2 diabetes, have been on a steady dose of metformin, and struggle with blood sugar control. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking diabetes treatment advancements.

Will I have to stop taking my current medications?

You will need to continue taking metformin, as the trial requires participants to have been on a stable dose of metformin for at least 90 days before starting and to maintain it during the study. If you are taking other diabetes medications, you may need to stop them, as the trial excludes those who have used other antihyperglycemic medications in the 90 days before starting.

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

Research has shown that orforglipron, the main treatment in this trial, is generally well-tolerated by patients. Studies have found that orforglipron can help lower blood sugar levels and reduce body weight. Reported side effects are similar to those of other diabetes medications in the same category, with most being mild to moderate.

Dapagliflozin, the other treatment being compared, has already received FDA approval for treating type 2 diabetes, indicating it has passed safety tests for this condition. Common side effects include urinary tract infections and increased urination, but these are usually manageable.

Both treatments show promise in managing blood sugar with a reasonable safety profile. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about orforglipron for treating Type 2 Diabetes because it offers a unique approach compared to existing treatments like metformin and insulin. Unlike these standard treatments, orforglipron is an oral medication that acts as a GLP-1 receptor agonist, which is a different mechanism of action that can improve blood sugar control and potentially aid in weight loss. This dual benefit of glucose regulation and weight management sets orforglipron apart from many current diabetes medications, making it a promising option for patients seeking comprehensive management of their condition.

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

In this trial, participants will receive either orforglipron or dapagliflozin to manage type 2 diabetes. Previous studies have shown that orforglipron helps people with type 2 diabetes manage their blood sugar levels, leading to significant reductions in HbA1c, a key measure of blood sugar, with decreases of up to 2.1%. This medication works like some injectable treatments but is available as a convenient pill. Dapagliflozin has effectively lowered blood sugar and offers additional benefits, such as improving kidney function and reducing the risk of heart-related deaths or hospitalizations. Both treatments have successfully managed type 2 diabetes, making them strong options for better diabetes care. ^{6 7 8 9 10}

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 haven't been able to control their blood sugar levels using metformin alone. Participants should be stable on their current metformin dose.

Inclusion Criteria

I have been diagnosed with Type 2 Diabetes.

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

Exclusion Criteria

I have had pancreatitis before.

I am currently receiving or planning to receive treatment for eye conditions related to diabetes.

I have taken diabetes medication other than metformin in the last 90 days.

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 dapagliflozin orally to assess safety and efficacy in improving blood sugar control

46 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Dapagliflozin
• Orforglipron

Trial Overview The study compares the safety and effectiveness of a new diabetes medication, Orforglipron, with an existing one, Dapagliflozin. It aims to see which is better at controlling blood sugar over about 46 weeks.

How Is the Trial Designed?

Group I: Orforglipron Dose 3 Experimental Treatment 1 Intervention

Participants will receive orforglipron orally.

Group II: Orforglipron Dose 2 Experimental Treatment 1 Intervention

Participants will receive orforglipron orally.

Group III: Orforglipron Dose 1 Experimental Treatment 1 Intervention

Participants will receive orforglipron orally.

Group IV: Dapagliflozin Active Control 1 Intervention

Participants will receive dapagliflozin orally.

Dapagliflozin is already approved in European Union, United States, Canada for the following indications:

Approved in European Union as Forxiga for:

• Type 2 diabetes
• Heart failure
• Chronic kidney disease

Approved in United States as Farxiga for:

• Type 2 diabetes
• Heart failure
• Chronic kidney disease

Approved in Canada as Farxiga for:

• Type 2 diabetes
• Heart failure
• Chronic kidney disease

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

Dapagliflozin (DAPA) is an effective SGLT2 inhibitor for treating type 2 diabetes, showing favorable pharmacokinetics and pharmacodynamics that help lower blood sugar levels while having beneficial effects on other metabolic risk factors.

While DAPA is generally safe, it carries an increased risk of genital and urinary infections, and concerns about bladder cancer and cardiovascular safety remain, prompting the FDA to seek further data on these issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics, pharmacodynamics and clinical efficacy of dapagliflozin for the treatment of type 2 diabetes. Maranghi, M., Carnovale, A., Durante, C., et al.[2021]

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 1 study involving 92 healthy adults, orforglipron (LY3502970) demonstrated a favorable safety profile, with gastrointestinal issues being the most common side effects, and showed a long half-life of 25-68 hours, allowing for convenient once-daily oral dosing.

Participants taking orforglipron experienced significant weight loss (up to 5.4 kg) and reductions in fasting glucose levels over 4 weeks, indicating its potential efficacy as a glucagon-like peptide-1 receptor agonist for managing weight and blood sugar.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Orforglipron (LY3502970), a novel, oral non-peptide glucagon-like peptide-1 receptor agonist: A Phase 1a, blinded, placebo-controlled, randomized, single- and multiple-ascending-dose study in healthy participants. Pratt, E., Ma, X., Liu, R., et al.[2023]

GLP-1 receptor agonists, specifically exenatide and liraglutide, significantly improve the chances of achieving the HbA(1c) target of <7% in patients with type 2 diabetes, with exenatide LAR showing the highest success rate at 63%.

While these medications are effective, they are associated with a higher risk of hypoglycemia when used alongside sulfonylureas, but they also promote weight loss compared to placebo or other diabetes treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

GLP-1 receptor agonists and HBA1c target of Esposito, K., Mosca, C., Brancario, C., et al.[2022]

Dapagliflozin effectively lowers blood sugar levels and glycated hemoglobin (HbA1c) in patients with type 2 diabetes, with a low risk of hypoglycemia and additional benefits like weight loss and reduced blood pressure.

While it is generally safe, dapagliflozin can increase the risk of genital infections, particularly in women, and its efficacy may be reduced in patients with kidney issues; ongoing trials are investigating its potential cardiovascular and renal protective effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Dapagliflozin (forxiga®) : SGLT 2 cotransporter inhibitor as glucose-lowering agent in type 2 diabetes]. Scheen, AJ.[2021]

In a study involving 9901 participants with type 2 diabetes, long-term use of the GLP-1 receptor agonist dulaglutide significantly reduced the risk of adverse renal outcomes compared to placebo, with a hazard ratio of 0.85, indicating a 15% lower risk.

The most notable benefit was observed in the prevention of new macroalbuminuria, where dulaglutide reduced the incidence by 23% (hazard ratio 0.77), highlighting its potential to protect kidney function in diabetic patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWIND randomised, placebo-controlled trial. Gerstein, HC., Colhoun, HM., Dagenais, GR., et al.[2020]

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]

Dapagliflozin is an effective treatment for type 2 diabetes, proven through multiple controlled clinical trials that assess its efficacy, safety, and tolerability.

It is approved by the FDA for use as a standalone therapy or in combination with other glucose-lowering medications, including insulin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dapagliflozin: A Sodium Glucose Cotransporter 2 Inhibitor for the Treatment of Diabetes Mellitus. Davis, PN., Ndefo, UA., Oliver, A.[2021]

In a study of 20,762 patients with type 2 diabetes, GLP-1 receptor agonists (GLP-1 RA) were found to significantly reduce the risk of non-fatal myocardial infarction and major adverse cardiovascular events (MACE) compared to SGLT-2 inhibitors (SGLT-2i).

Both GLP-1 RA and SGLT-2i had low incidences of serious adverse events (<1%), indicating that GLP-1 RA is not only more effective but also equally safe for patients, especially those without prior cardiovascular diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness and safety of GLP-1 receptor agonists versus SGLT-2 inhibitors in type 2 diabetes: an Italian cohort study. Baviera, M., Foresta, A., Colacioppo, P., et al.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10847023/

Long-term benefits of dapagliflozin on renal outcomes ... Initiating dapagliflozin improved kidney function outcomes and albuminuria in patients with T2D and a low renal risk.

2. nejm.org nejm.org/doi/full/10.1056/NEJMoa1812389

Dapagliflozin and Cardiovascular Outcomes in Type 2 ... With respect to efficacy, dapagliflozin resulted in a lower rate of cardiovascular death or hospitalization for heart failure than placebo (4.9% ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8855933/

Effectiveness and safety of dapagliflozin in real-life patients In this study, the effectiveness and safety of dapagliflozin were analysed in nearly 600 patients with T2D, showing a high capacity of dapagliflozin to reduce ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S2772417424000396

A new hope for the therapeutic treatment of type 2 diabetes ... Although dapagliflozin did not reduce the rate of major adverse cardiac events (MACE), it did reduce the rate of cardiovascular death and hospitalization for ...

5. diabetesjournals.org diabetesjournals.org/care/article/46/1/156/147950/Efficacy-and-Safety-of-Dapagliflozin-by-Baseline

Efficacy and Safety of Dapagliflozin by Baseline Insulin ... In a phase 3 study, dapagliflozin improved glycemic control, stabilized insulin dosing, and reduced weight without increasing severe ...

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/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 ...

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

Orforglipron (LY3502970), a novel, oral non‐peptide glucagon ... Orforglipron may provide a safe and effective once-daily oral treatment alternative to injectable GLP-1RAs or peptide oral formulations without water and food ...

9. clinicaltrials.gov clinicaltrials.gov/study/NCT05048719

NCT05048719 | A Study of LY3502970 in Participants With ... Efficacy and safety of oral orforglipron in patients with type 2 diabetes: a multicentre, randomised, dose-response, phase 2 study. Lancet. 2023 Aug 5;402 ...

10. 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.