Combo Diabetes Drug for Type 2 Diabetes

(PRECIDENTD Trial)

Recruiting at 7 trial locations

Overseen By Jeffrey Whittle, MD

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Brigham and Women's Hospital

Must be taking: SGLT2i, GLP-1 RA

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

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

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

Compensation: Varies

Number of Visits: Unknown

Duration: 3 years

6000 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests two treatments for people with type 2 diabetes who also have heart disease or are at high risk for it. Participants will receive either a sodium-glucose cotransporter-2 inhibitor (SGLT2i), which removes sugar through urine, or a glucagon-like peptide-1 receptor agonist (GLP-1 RA), which controls blood sugar and appetite. The goal is to determine which treatment better reduces heart and kidney issues and overall risk of death. This trial may suit individuals with type 2 diabetes who have experienced heart issues like a heart attack or stroke or are at high risk for such conditions. As a Phase 4 trial, the treatment is already FDA-approved and proven effective, and this research helps understand how it benefits more patients.

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 is the safety track record for these treatments?

Research has shown that SGLT2 inhibitors are generally safe for people with type 2 diabetes. One study found that these drugs can reduce the risk of heart-related deaths by 33%. They also improve heart and kidney health, making them a safe choice for individuals with diabetes and heart issues.

Studies have also shown that GLP-1 receptor agonists are safe. They lower the risk of major heart problems and effectively manage weight in people with type 2 diabetes. This makes them a safe option for those with diabetes and heart concerns.

Both treatments have strong evidence supporting their safety and effectiveness for people with diabetes, especially those at risk for heart problems. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about these treatments because they combine the powers of two different drug classes: GLP-1 receptor agonists and SGLT2 inhibitors, both known for their cardiovascular benefits. Unlike traditional diabetes treatments that often focus solely on lowering blood sugar, this combination aims to provide a dual action—enhancing insulin sensitivity and reducing glucose reabsorption in the kidneys. This multi-targeted approach could lead to better overall health outcomes for people with type 2 diabetes, potentially improving both blood sugar control and heart health simultaneously.

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

Research has shown that certain medications can help people with type 2 diabetes and heart disease. In this trial, participants will join different treatment arms to evaluate these medications. One group, called SGLT2 inhibitors, such as empagliflozin, can lower the risk of heart problems and death. Another group, known as GLP-1 RAs, can improve blood sugar control, aid in weight loss, and reduce blood pressure. Studies have found that GLP-1 RAs outperform many other diabetes drugs in these areas. Both types of treatments offer heart health benefits, making them promising options for people with type 2 diabetes at risk for heart issues. ^{4 6 7 8 9}

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Combination drug
• GLP-1 receptor agonist
• 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.

How Is the Trial Designed?

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 European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Jardiance for:

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

Approved in United States as Jardiance for:

• Type 2 diabetes mellitus
• Heart failure with reduced ejection fraction
• Chronic kidney disease

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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]

Citations

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Comparative effectiveness of GLP-1 receptor agonists on ... GLP-1RAs also significantly improved weight management for type 2 diabetes, with CagriSema performing the best for weight loss. The results ...

2. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK572151/

Compare and Contrast the Glucagon-Like Peptide-1 Receptor ... Clinical trials show the superiority of GLP-1RA to other antihyperglycemic drugs in improving glycemic efficacy, reducing weight and blood pressure, and having ...

3. uchicagomedicine.org uchicagomedicine.org/forefront/research-and-discoveries-articles/2024/may/research-on-glp-1-drugs

Research shows GLP-1 drugs are effective but complex Physicians and researchers agree that the drugs are highly effective for weight management and Type 2 diabetes treatment.

4. nejm.org nejm.org/doi/full/10.1056/NEJMoa2206038

Tirzepatide Once Weekly for the Treatment of Obesity A molecule that combines both GIP and GLP receptor agonism theoretically may lead to greater efficacy in weight reduction. Tirzepatide is a once ...

5. jamanetwork.com jamanetwork.com/journals/jamanetworkopen/fullarticle/2829779

Discontinuation and Reinitiation of GLP-1 Receptor Agonists This study suggests that although most patients discontinue GLP-1 RAs, discontinuation rates are significantly higher and reinitiation rates are significantly ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38286487/

Comparative effectiveness of GLP-1 receptor agonists on ... GLP-1RAs also significantly improved weight management for type 2 diabetes, with CagriSema performing the best for weight loss. The results ...

7. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK551568/

Glucagon-Like Peptide-1 Receptor Agonists - StatPearls - NCBI Glucagon-like peptide-1 (GLP-1) agonists are a class of medications utilized to treat type 2 diabetes mellitus (T2DM) and obesity.

8. diabetesjournals.org diabetesjournals.org/care/article/48/5/846/158048/Cardiovascular-and-Kidney-Outcomes-and-Mortality

Cardiovascular and Kidney Outcomes and Mortality With Long ... Glucagon-like peptide 1 receptor agonists (GLP-1RA) reduce the incidence of major adverse cardiovascular events (MACE) in type 2 diabetes (T2D).

9. fda.gov fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/fdas-concerns-unapproved-glp-1-drugs-used-weight-loss

FDA's Concerns with Unapproved GLP-1 Drugs Used for ... FDA has warned companies that have illegally sold unapproved drugs containing semaglutide, tirzepatide or retatrutide that are falsely labeled “for research ...