Combo Diabetes Drug for Type 2 Diabetes

(PRECIDENTD Trial)

Recruiting at 7 trial locations

Overseen By Jeffrey Whittle, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 4

Recruiting

Sponsor: Brigham and Women's Hospital

Must be taking: SGLT2i, GLP-1 RA

Disqualifiers: Type 1 diabetes, Pancreatitis, Heart failure, others

No Placebo Group

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

PRECIDENTD is a randomized, open label, pragmatic clinical trial designed to compare rates of the total number of cardiovascular, kidney, and death events among two alternative treatments for patients with type 2 diabetes (T2D) and either established atherosclerotic cardiovascular disease (ASCVD) or at high risk for ASCVD. To accomplish this objective, we will randomly assign 6,000 patients with established T2D and ASCVD or high-risk for ASCVD in a 1:1 allocation to sodium-glucose cotransporter-2 inhibitor (SGLT2i) or glucagon-like peptide-1 receptor agonists (GLP-1RA). Participants will be followed for the occurrence of the trial primary endpoint of the total (first and recurrent) number of episodes of myocardial infarction (MI), stroke, arterial revascularization, hospitalization for heart failure, development of end-stage kidney disease, kidney transplantation, and mortality, counting all events from randomization until end of study.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop all current medications, but if you are already taking an SGLT2 inhibitor or GLP-1 receptor agonist, you must be willing to stop them to participate. Other diabetes medications are allowed, but adjustments may be needed for safety.

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

Research shows that combining empagliflozin, a drug that helps remove excess sugar through urine, with GLP-1 receptor agonists like liraglutide, can improve blood sugar control in people with type 2 diabetes. Additionally, studies found that using exenatide and dapagliflozin together can reduce blood sugar and weight more effectively than using either drug alone. ^{1 2 3 4 5}

Is the combo diabetes drug safe for humans?

The combination of empagliflozin (a type of SGLT2 inhibitor) and GLP-1 receptor agonists like liraglutide has been studied for safety in people with type 2 diabetes. Empagliflozin is generally safe, with common side effects including urinary and genital tract infections. Studies show it does not increase the risk of low blood sugar (hypoglycemia). ^{1 3 6 7 8}

How is the combo diabetes drug for type 2 diabetes different from other drugs?

This combo diabetes drug is unique because it combines a GLP-1 receptor agonist and an SGLT2 inhibitor, which work together to improve blood sugar control through complementary mechanisms. The GLP-1 receptor agonist helps the body produce more insulin when needed, while the SGLT2 inhibitor helps remove excess sugar through urine, offering a more comprehensive approach to managing type 2 diabetes. ^{3 4 8 9 10}

Eligibility Criteria

PRECIDENTD is for adults with type 2 diabetes who either have heart disease or are at high risk for it. They must be willing to switch their current medication and not start any excluded treatments during the trial. Key eligibility includes having a certain HbA1c level, being within specific age ranges, and agreeing to data collection. Pregnant women, those with recent severe heart failure or very low kidney function, active foot ulcers, or certain insulin uses are excluded.

Inclusion Criteria

I am between 40 and 80 years old with a history of heart or artery disease.

I am willing to change my current diabetes medication for the study.

My HbA1c level is above 6.5% without diabetes medication or above 6% with it.

Exclusion Criteria

My kidney function is reduced, with an eGFR below 45.

I, or my partner, am not willing to use birth control.

I was hospitalized for heart failure in the last year or my heart pumps less blood than normal.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants are randomly assigned to either SGLT2i or GLP-1 RA therapy and followed for cardiovascular, kidney, and death events

3 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Combination drug (Drug)
• GLP-1 receptor agonist (GLP-1 Receptor Agonist)
• SGLT2 inhibitor (SGLT2 Inhibitor)

Trial Overview The trial tests three treatments: an SGLT2 inhibitor (SGLT2i), a GLP-1 receptor agonist (GLP-1 RA), and their combination in patients with type 2 diabetes at risk of cardiovascular events. It's randomized and open label; participants will be assigned equally to one of the treatment groups and monitored for heart attacks, strokes, hospitalizations due to heart failure, end-stage kidney disease, transplants, and death.

Participant Groups

Group I: Sodium-glucose cotransporter-2 inhibitor (SGLT2i) Active Control 1 Intervention

Therapy with an SGLT2i with proven cardiovascular benefit. This means either canagliflozin, dapagliflozin, or empagliflozin

Group II: Glucagon-like peptide-1 receptor agonist (GLP-1 RA) Active Control 1 Intervention

Therapy with a GLP-1 RA with proven cardiovascular benefit. This means either dulaglutide, liraglutide, or semaglutide.

Combination drug is already approved in Canada, Japan for the following indications:

Approved in Canada as Jardiance for:

• Type 2 diabetes mellitus
• Heart failure with reduced ejection fraction

Approved in Japan as Jardiance for:

• Type 2 diabetes mellitus

Who Is Running the Clinical Trial?

Brigham and Women's Hospital

Lead Sponsor

Trials

1,694

Recruited

14,790,000+

Patient-Centered Outcomes Research Institute

Collaborator

Trials

592

Recruited

27,110,000+

Findings from Research

In a 28-week study involving 695 patients with type 2 diabetes, the combination of exenatide and dapagliflozin significantly reduced HbA1c levels more than either drug alone, demonstrating enhanced efficacy in glycaemic control.

The dual treatment was well tolerated, with no major hypoglycaemia reported, and common side effects included gastrointestinal issues and urinary tract infections, indicating a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exenatide once weekly plus dapagliflozin once daily versus exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled with metformin monotherapy (DURATION-8): a 28 week, multicentre, double-blind, phase 3, randomised controlled trial. Frías, JP., Guja, C., Hardy, E., et al.[2022]

Empagliflozin effectively lowers glycated hemoglobin levels, plasma glucose, body weight, and blood pressure in patients with type 2 diabetes, whether used alone or in combination with other medications, based on clinical trials lasting at least 12 weeks.

In addition to its glucose-lowering effects, empagliflozin significantly reduces the risk of cardiovascular and all-cause mortality, making it a valuable option for patients with type 2 diabetes, especially those at high cardiovascular risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Options for empagliflozin in combination therapy in type 2 diabetes mellitus. Hershon, KS.[2022]

In a 52-week phase 4 trial involving Japanese patients with type 2 diabetes, empagliflozin as an add-on to liraglutide was well tolerated, with 59.4% to 66.7% of patients reporting at least one adverse event, indicating a manageable safety profile.

The combination therapy resulted in significant improvements in glycaemic control (reduction in HbA1c), body weight, and blood pressure, demonstrating its efficacy in enhancing diabetes management compared to liraglutide alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Efficacy of Empagliflozin as Add-On Therapy to GLP-1 Receptor Agonist (Liraglutide) in Japanese Patients with Type 2 Diabetes Mellitus: A Randomised, Double-Blind, Parallel-Group Phase 4 Study. Terauchi, Y., Utsunomiya, K., Yasui, A., et al.[2020]

Dapagliflozin, when combined with metformin, is slightly more effective and less costly than DPP4 inhibitors for treating type-2 diabetes, providing an additional 0.019 quality-adjusted life-years (QALY) and saving €42 overall.

In comparison to other treatments like sulphonylureas and thiazolidinediones, dapagliflozin also proved to be cost-effective, with costs per QALY gained of €3,560 and €2,007, respectively, making it a viable option for managing type-2 diabetes in Spain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Cost-effectiveness analysis of dapagliflozin compared to DPP4 inhibitors and other oral antidiabetic drugs in the treatment of type-2 diabetes mellitus in Spain]. Abad Paniagua, EJ., Casado Escribano, P., Fernández Rodriguez, JM., et al.[2021]

Empagliflozin effectively reduces blood sugar levels in patients with type 2 diabetes by preventing glucose reabsorption, leading to a loss of about 70 grams of glucose per day, which also contributes to weight loss.

In addition to its blood sugar-lowering effects, empagliflozin has been shown to slightly decrease blood pressure and has been approved for use in the European Union since May 2014, often in combination with other diabetes medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Empagliflozin - the new representative of SGLT2 transporter inhibitors for the treatment of patients with diabetes 2 type]. Prázný, M., Slíva, J.[2018]

Empagliflozin, a newly approved SGLT2 inhibitor for type 2 diabetes, effectively lowers blood sugar levels, with an average reduction in HbA1c of about -0.8% and a decrease in fasting plasma glucose by approximately -2 mmol/L, as shown in multiple international studies.

The drug is generally safe, with a low risk of hypoglycemia and common side effects including urinary and genital tract infections, making it suitable as a first-line treatment or as an add-on therapy to other diabetes medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of empagliflozin in the management of type 2 diabetes by patient profile. Hedrington, MS., Davis, SN.[2020]

In a 3-year study involving 362 patients with type 2 diabetes, both empagliflozin and dapagliflozin effectively improved glycemic control, with empagliflozin showing a greater reduction in HbA1c (-1.7%) compared to dapagliflozin (-1.1%).

Empagliflozin also led to a more significant weight loss (-4.5 kg) compared to dapagliflozin (-1.0 kg), while both medications had similar safety profiles with no significant differences in adverse events or cardiovascular outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term effectiveness and safety of quadruple combination therapy with empagliflozin versus dapagliflozin in patients with type 2 diabetes: 3-year prospective observational study. Ku, EJ., Lee, DH., Jeon, HJ., et al.[2021]

Empagliflozin, when combined with other oral diabetes medications, significantly reduced HbA1c levels, body weight, and blood pressure in 1,801 patients with type 2 diabetes over 24 weeks, demonstrating its efficacy in managing diabetes.

The safety profile of empagliflozin was favorable, with similar rates of adverse effects compared to placebo, although there was a slight increase in hypoglycemia and genital infections, indicating it is generally well-tolerated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of empagliflozin in combination with other oral hypoglycemic agents in patients with type 2 diabetes mellitus. Romera, I., Ampudia-Blasco, FJ., Pérez, A., et al.[2022]

A new combination tablet of empagliflozin and sitagliptin was successfully developed using a direct compression method, showing excellent in-vitro performance with a disintegration time of 5.32 minutes and high drug release rates (89.05% for empagliflozin and 93.76% for sitagliptin).

In vivo testing on mice demonstrated that this combination significantly reduced fasting blood glucose and cholesterol levels, achieving results comparable to metformin, indicating its potential as an effective treatment for type-2 diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Design expert software assisted development and evaluation of empagliflozin and sitagliptin combination tablet with improved in-vivo anti-diabetic activities. Hossain, MS., Jahan, S., Al Rezwan Rahman, S., et al.[2023]

Combining SGLT2 inhibitors (like canagliflozin and dapagliflozin) with DPP-4 inhibitors (like saxagliptin and linagliptin) is an effective strategy for managing type 2 diabetes, showing greater glucose-lowering effects than either medication alone.

This combination therapy is safe, does not cause hypoglycemia, and has been shown to be bioequivalent when taken as fixed-dose combinations, making it a practical option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetic Characteristics and Clinical Efficacy of an SGLT2 Inhibitor Plus DPP-4 Inhibitor Combination Therapy in Type 2 Diabetes. Scheen, AJ.[2021]

References

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

Exenatide once weekly plus dapagliflozin once daily versus exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled with metformin monotherapy (DURATION-8): a 28 week, multicentre, double-blind, phase 3, randomised controlled trial. [2022]

2. New Zealand pubmed.ncbi.nlm.nih.gov

Options for empagliflozin in combination therapy in type 2 diabetes mellitus. [2022]

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

Safety and Efficacy of Empagliflozin as Add-On Therapy to GLP-1 Receptor Agonist (Liraglutide) in Japanese Patients with Type 2 Diabetes Mellitus: A Randomised, Double-Blind, Parallel-Group Phase 4 Study. [2020]

4. Spain pubmed.ncbi.nlm.nih.gov

[Cost-effectiveness analysis of dapagliflozin compared to DPP4 inhibitors and other oral antidiabetic drugs in the treatment of type-2 diabetes mellitus in Spain]. [2021]

5. Czech Republic pubmed.ncbi.nlm.nih.gov

[Empagliflozin - the new representative of SGLT2 transporter inhibitors for the treatment of patients with diabetes 2 type]. [2018]

6. New Zealand pubmed.ncbi.nlm.nih.gov

The role of empagliflozin in the management of type 2 diabetes by patient profile. [2020]

7. Ireland pubmed.ncbi.nlm.nih.gov

Long-term effectiveness and safety of quadruple combination therapy with empagliflozin versus dapagliflozin in patients with type 2 diabetes: 3-year prospective observational study. [2021]

8. Spain pubmed.ncbi.nlm.nih.gov

Efficacy and safety of empagliflozin in combination with other oral hypoglycemic agents in patients with type 2 diabetes mellitus. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Design expert software assisted development and evaluation of empagliflozin and sitagliptin combination tablet with improved in-vivo anti-diabetic activities. [2023]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Pharmacokinetic Characteristics and Clinical Efficacy of an SGLT2 Inhibitor Plus DPP-4 Inhibitor Combination Therapy in Type 2 Diabetes. [2021]