Pioglitazone vs Empagliflozin for Diabetes

(PEP-DM Trial)

Recruiting in Palo Alto (17 mi)

+1 other location

Overseen by Yogish Kudva, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Mayo Clinic

Must be taking: Metformin

Disqualifiers: Type 1 diabetes, Pregnancy, Bleeding disorders, Hepatic impairment, others

No Placebo Group

Prior Safety Data

Trial Summary

What is the purpose of this trial?

The purpose of this study is to evaluate efficacy of pioglitazone (PIO) versus empagliflozin (EMPA) to improve glycemic control in people with Chronic Pancreatitis (CP) or Recurrent Acute Pancreatitis (RAP) associated with Diabetes Mellitus (DM). To evaluate mixed meal response in PIO versus EMPA group to better understand physiology of both therapies in CP-DM.

Will I have to stop taking my current medications?

The trial requires that participants are not on any antihyperglycemic medication except Metformin. If you are taking other diabetes medications, you may need to stop them to join the study.

What data supports the effectiveness of the drug empagliflozin for diabetes?

Empagliflozin, also known as Jardiance, is effective in treating type-2 diabetes by improving blood sugar control, and it has also been shown to reduce the risk of hospitalization in people with heart failure, even if they do not have diabetes. ^{1 2 3 4 5}

Is empagliflozin safe for humans?

Empagliflozin (Jardiance) is generally considered safe for humans and is used to treat type 2 diabetes and heart failure. However, it may cause side effects like fluid deficits, so patients should be monitored for these. ^{3 4 5 6 7}

How does the drug combination of Pioglitazone and Empagliflozin differ from other diabetes treatments?

The combination of Pioglitazone and Empagliflozin is unique because it combines two different mechanisms: Pioglitazone reduces insulin resistance and improves lipid profiles, while Empagliflozin helps lower blood sugar by preventing glucose reabsorption in the kidneys, leading to glucose excretion and weight loss. This dual approach may offer enhanced glycemic control and additional benefits like reduced cardiovascular risk and slight blood pressure reduction. ^{2 8 9 10 11}

Research Team

Yogish Kudva, MD

Principal Investigator

Mayo Clinic

Eligibility Criteria

This trial is for individuals with diabetes that's related to chronic or recurrent acute pancreatitis. Participants should have a history of these conditions and need better blood sugar control.

Inclusion Criteria

I am between 18 and 70 years old.

Able to provide written informed consent and participate in longitudinal follow-up

Fasting plasma glucose <220 mg/dL at screening visit

Exclusion Criteria

I am not on any systemic treatment for cancer, except for non-melanoma skin cancers.

I have a history of bleeding disorders like Hemophilia or von Willebrand disease.

My kidney function is very low.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either Pioglitazone or Empagliflozin to improve glycemic control in CP-DM

24 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Empagliflozin (SGLT2 Inhibitor)
• Pioglitazone (Thiazolidinediones)

Trial Overview The study aims to compare the effectiveness of two diabetes medications, Pioglitazone (PIO) and Empagliflozin (EMPA), in managing blood sugar levels in patients with pancreatitis-associated diabetes.

Participant Groups

Group I: Pioglitazone (PIO) Experimental Treatment 1 Intervention

PIO (Actos) is a thiazolidinedione and an agonist for peroxisome proliferator activated receptor (PPAR) gamma indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 DM in multiple clinical settings. Its use has limitation for type 1 DM or for treatment of diabetic ketoacidosis. It is contraindicated to use in established NYHA class III or IV heart failure.

Group II: Empagliflozin (EMPA) Experimental Treatment 1 Intervention

EMPA is a sodium-glucose co-transporter 2 inhibitor, FDA approved drug. It is indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in adults with heart failure, to reduce the risk of cardiovascular death in adults with type 2 DM and established cardiovascular disease and as an adjunct to diet and exercise to improve glycemic control in adults with type 2 DM. It is not recommended in patients with type 1 DM. It may increase the risk of diabetic ketoacidosis. Not recommended for use to improve glycemic control in adults with type 2 DM with an eGFR less than 30mL/min/1.73m2.

Empagliflozin 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
• Chronic kidney disease

Approved in Japan as Jardiance for:

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

Who Is Running the Clinical Trial?

Mayo Clinic

Lead Sponsor

Trials

3,427

Recruited

3,221,000+

Dr. Gianrico Farrugia

Mayo Clinic

Chief Executive Officer since 2019

MD from University of Malta Medical School

Dr. Richard Afable

Mayo Clinic

Chief Medical Officer

MD from Loyola Stritch School of Medicine

University of Pittsburgh Medical Center

Collaborator

Trials

78

Recruited

77,600+

Leslie C. Davis

University of Pittsburgh Medical Center

Chief Executive Officer since 2021

BA in Economics from Wesleyan University, MBA in Health Administration from The Wharton School

Don Yealy

University of Pittsburgh Medical Center

Chief Medical Officer since 2023

MD from the Pritzker School of Medicine, University of Chicago

Findings from Research

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 the EMPEROR-Reduced study involving over 3700 participants with chronic heart failure and reduced ejection fraction, empagliflozin significantly reduced the risk of hospitalization for heart failure complications (13.2% vs. 18.3% for placebo) over an average of 16 months.

Empagliflozin also showed a lower incidence of serious kidney problems (1.6% vs. 3.1% for placebo), indicating its potential safety and efficacy in managing heart failure, although it was associated with a higher rate of genital tract infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Drug treatment with empagliflozin lowered risk for hospitalization in people with heart failure with reduced ejection fraction: plain language summary of the EMPEROR-Reduced study. Zannad, F., Macari, S.[2023]

A study involving 60 healthy Chinese subjects demonstrated that the test formulation of empagliflozin is bioequivalent to the brand-name drug Jardiance, showing similar pharmacokinetic properties under both fasting and fed conditions.

Both formulations of empagliflozin were generally well tolerated, indicating a good safety profile for the drug in the tested populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics, Safety, and Bioequivalence of Two Empagliflozin Formulations after Single Oral Administration under Fasting and Fed Conditions in Healthy Chinese Subjects: An Open-label Randomized Single-dose Two-sequence, Two-treatment, Two-period Crossover Study. Chen, G., Zhang, D., Du, A., et al.[2021]

Empagliflozin, an SGLT2 inhibitor, is effective in improving blood sugar control in adults with type 2 diabetes, especially when metformin is not suitable.

In addition to managing diabetes, empagliflozin also aims to reduce cardiovascular risks associated with the condition, highlighting its dual role in treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

▼ Empagliflozin, diabetes and outcomes. [2017]

In a study of 268 patients with inadequately controlled type 2 diabetes, adding empagliflozin (25 mg/day) significantly reduced HbA1c and fasting plasma glucose levels compared to insulin glargine after 24 weeks.

Empagliflozin also led to notable improvements in body weight and systolic blood pressure, while having fewer hypoglycemic events compared to insulin, indicating it is a safe and effective add-on therapy for glycemic control.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness and safety of empagliflozin-based quadruple therapy compared with insulin glargine-based therapy in patients with inadequately controlled type 2 diabetes: An observational study in clinical practice. Ku, EJ., Lee, DH., Jeon, HJ., et al.[2022]

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]

In a study of 78 patients with uncontrolled type 2 diabetes, dapagliflozin showed the most significant reduction in HbA1c levels after 24 months, with a mean change of -1.05%, compared to sitagliptin (-0.81%) and lobeglitazone (-1.08%).

Dapagliflozin also improved body composition by decreasing whole body fat percentage and increasing muscle percentage, while sitagliptin and lobeglitazone led to increases in body fat, suggesting dapagliflozin may be a better option for patients looking to improve their body composition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of therapeutic efficacy and safety of sitagliptin, dapagliflozin, or lobeglitazone adjunct therapy in patients with type 2 diabetes mellitus inadequately controlled on sulfonylurea and metformin: Third agent study. Hong, JH., Moon, JS., Seong, K., et al.[2023]

In a study involving 4,866 patients with type 2 diabetes, the combination of metformin and pioglitazone (Competact) significantly improved glycemic control, as evidenced by a reduction in HbA1c from 7.8% to 7.0% after 4 months of treatment.

The therapy also led to significant improvements in blood pressure and lipid profiles, while not affecting body mass index (BMI), indicating its efficacy in managing multiple aspects of diabetes without weight gain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Competact, a fixed combination of pioglitazone and metformin, improves metabolic markers in type 2 diabetes patients with insufficient glycemic control by metformin alone--results from a post-marketing surveillance trial under daily routine conditions. Schöndorf, T., Karagiannis, E., Posseldt, RE., et al.[2022]

Pioglitazone is an effective second-line therapy for type 2 diabetes, offering strong blood sugar control, a lower risk of cardiovascular issues, and improved liver health compared to other treatments.

While gliptins like sitagliptin and vildagliptin also lower blood sugar effectively, they lack long-term safety data and are more expensive, making pioglitazone a more favorable option in many cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative analysis of therapeutic efficiency and costs (experience in Bulgaria) of oral antidiabetic therapies based on glitazones and gliptins. Filipova, EP., Uzunova, KH., Vekov, TY.[2022]

References

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

Pharmacokinetics and bioequivalence of a generic empagliflozin tablet versus a brand-named product and the food effects in healthy Chinese subjects. [2021]

2. 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]

3. England pubmed.ncbi.nlm.nih.gov

Drug treatment with empagliflozin lowered risk for hospitalization in people with heart failure with reduced ejection fraction: plain language summary of the EMPEROR-Reduced study. [2023]

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

Pharmacokinetics, Safety, and Bioequivalence of Two Empagliflozin Formulations after Single Oral Administration under Fasting and Fed Conditions in Healthy Chinese Subjects: An Open-label Randomized Single-dose Two-sequence, Two-treatment, Two-period Crossover Study. [2021]

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

Diabetes Drug Now Approved for Heart Failure. [2023]

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

▼ Empagliflozin, diabetes and outcomes. [2017]

7. England pubmed.ncbi.nlm.nih.gov

Effectiveness and safety of empagliflozin-based quadruple therapy compared with insulin glargine-based therapy in patients with inadequately controlled type 2 diabetes: An observational study in clinical practice. [2022]

8. 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]

9. Ireland pubmed.ncbi.nlm.nih.gov

Comparison of therapeutic efficacy and safety of sitagliptin, dapagliflozin, or lobeglitazone adjunct therapy in patients with type 2 diabetes mellitus inadequately controlled on sulfonylurea and metformin: Third agent study. [2023]

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

Competact, a fixed combination of pioglitazone and metformin, improves metabolic markers in type 2 diabetes patients with insufficient glycemic control by metformin alone--results from a post-marketing surveillance trial under daily routine conditions. [2022]

11. England pubmed.ncbi.nlm.nih.gov

Comparative analysis of therapeutic efficiency and costs (experience in Bulgaria) of oral antidiabetic therapies based on glitazones and gliptins. [2022]