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

Trial Summary

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.

What data supports the effectiveness of the drug Orforglipron for type 2 diabetes?

Research shows that Orforglipron, a new type of drug that helps control blood sugar, was effective in improving blood sugar levels in people with type 2 diabetes when compared to a placebo. It works similarly to other drugs in its class, which are known to help manage diabetes. ^{1 2 3 4 5}

Is Orforglipron safe for humans?

Orforglipron has been evaluated in clinical trials for safety in both healthy participants and those with type 2 diabetes, showing it is generally safe and well-tolerated. ^{3 4 5 6 7}

How does the drug Orforglipron differ from other treatments for type 2 diabetes?

Orforglipron is unique because it is an oral, non-peptide glucagon-like peptide-1 receptor agonist (GLP-1RA), which is different from many other GLP-1RAs that are typically injectable. This makes it more convenient for patients who prefer oral medication. Additionally, it targets the GLP-1 receptor to help control blood sugar levels, which is a different mechanism compared to dapagliflozin, an SGLT2 inhibitor that works by promoting glucose excretion through urine. ^{1 3 4 8 9}

What is the purpose of this trial?

This trial is testing two medications, orforglipron and dapagliflozin, to see which one better controls blood sugar in people with type 2 diabetes who are not well-managed on metformin alone. Orforglipron lowers blood sugar levels, while dapagliflozin helps remove sugar through urine. The study will last several months. Dapagliflozin has been shown to improve blood sugar control in various studies.

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

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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]

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 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]

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 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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Pharmacokinetics, pharmacodynamics and clinical efficacy of dapagliflozin for the treatment of type 2 diabetes. [2021]

2. England pubmed.ncbi.nlm.nih.gov

GLP-1 receptor agonists and HBA1c target of [2022]

3. England 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. [2023]

4. England 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. [2023]

5. England 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. [2023]

6. England pubmed.ncbi.nlm.nih.gov

Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWIND randomised, placebo-controlled trial. [2020]

7. England 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. [2022]

8. Belgium pubmed.ncbi.nlm.nih.gov

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

9. United States pubmed.ncbi.nlm.nih.gov

Dapagliflozin: A Sodium Glucose Cotransporter 2 Inhibitor for the Treatment of Diabetes Mellitus. [2021]