Pioglitazone Versus Empagliflozin for Chronic Pancreatitis/Recurrent Acute Pancreatitis Associated Diabetes Mellitus (PEP-DM)

Randomized, Parallel Group, Dose Escalation Trial of Pioglitazone Versus Empagliflozin for Chronic Pancreatitis/Recurrent Acute Pancreatitis Associated Diabetes Mellitus: The PEP-DM 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.

Study Overview

• Status: Recruiting
• Conditions: Diabetes Mellitus; Pancreatitis, Chronic; Pancreatitis, Acute
• Intervention / Treatment: Drug: Pioglitazone (PIO); Drug: Empagliflozin (EMPA)

Detailed Description

This trial will test the efficacy of PIO versus EMPA in improving glycemic control in CP-DM. The anticipated enrollment will consist of 40 subjects, age 18-80 years who have been diagnosed with CP or RAP with DM, at two clinical sites in the United States. The primary objective is to evaluate the efficacy of PIO vs. EMPA to improve glycemic control in people with CP or RAP associated with DM.

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Ravinder Jeet Kaur, M.B.B.S; Phone Number: 507-255-1455; Email: Kaur.ravinder@mayo.edu

Study Locations

• United States
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Recruiting
      • Mayo Clinic
      • Contact: Corey Kurek, B.S.; Phone Number: 507-255-0316; Email: Reid.Corey@mayo.edu
      • Principal Investigator: Yogish C Kudva
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15219
      • Not yet recruiting
      • University of Pittsburgh Medical Center
      • Principal Investigator: Dhiraj Yadav, MD, MPH
      • Contact: Shari Reynolds, BS, CCRP; Phone Number: 412-383-0570; Email: reynoldssl2@upmc.edu
      • Sub-Investigator: Frederico G.S. de Toledo, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age ≥18-80 years at the time of enrollment.
2. RAP or CP with DM diagnosed before or after CP diagnosis (Confirmed CP on imaging or RAP based on PROCEED study criteria, and confirmed DM as per ADA criteria or clinically diagnosed with DM and on antihyperglycemic therapy)
3. Able to provide written informed consent and participate in longitudinal follow-up
4. A Stable retinal exam within 1 year prior to enrollment unless new onset diabetes was diagnosed within 6 months prior to study enrollment. If an eye exam within the past year is not available but the most recent exam is stable, a standard of care eye exam needs to be scheduled during the study period.
5. HbA1c level 6.5-10.5% at screening visit.

6. Current ongoing treatment with metformin and/or insulin and other antihyperglycemic medications will be accepted at screening. Patients will be willing to safely withdraw one or more study medication or mealtime insulin under the supervision of the study team by the time of screening. The patients clinical team will be informed promptly. Patients not on any antihyperglycemic medications are also eligible.

   a. If on a GLP-1 medication (e.g., semaglutide [Ozempic, Wegovy, Rybelsus], liraglutide, dulaglutide, exenatide, tirzepatide, etc.), the patient must be on a stable dose for at least 3 months prior to enrollment, with stable weight status at the time of enrollment and the GLP-1 dose cannot be escalated during the study period.

7. Willing to perform blood glucose and ketone testing on study provided meters as per study protocol.

Exclusion Criteria:

1. Inability to take PIO or EMPA due to prior hypersensitivity or allergic reaction or current use of medications with potential for drug-drug interactions (Pioglitazone: Drug information - UpToDate, Empagliflozin: Drug information - UpToDate)
2. Patients on PIO or EMPA at the time of screening
3. Diagnosed with Type 1 Diabetes
4. Pregnancy or lactation in women (positive urine pregnancy test at screening will lead to exclusion)
5. History of bleeding disorders (e.g., Hemophilia A (factor VIII deficiency), hemophilia B (factor IX deficiency), von Willebrand disease, platelet disorders etc)
6. Presence of hepatic impairment, ALT >3 x ULN with no etiology known at the time of enrollment or any evidence of acute/chronic liver disease
7. Ongoing treatment for any malignancy requiring systemic treatment (non-melanoma skin cancers treated in dermatologists' office would be acceptable)
8. Presence of osteoporosis without definitive treatment according to PI discretion.
9. Recent inflammatory illness within the 30 days preceding enrollment (e.g.: URTI, episode of AP, etc)
10. History of heart failure classified by NYHA as Class III or greater
11. History of kidney dysfunction classified by an eGFR of <30 mL/min/min
12. Participation in any clinical trial within 30 days before screening for an approved or non-approved investigational medical product.
13. Active alcohol dependence or chemical dependence including tobacco based on investigator discretion
14. On a ketogenic diet
15. Autoimmune pancreatitis, obstructive pancreatitis, and prior surgery of pancreas (Whipple procedure, total pancreatectomy, and distal pancreatectomy)
16. Any condition which could jeopardize participant safety as per investigator opinion, (hemolytic anemia limiting A1c reliability, any evidence of fluid overload, presence of Congestive heart failure etc).
17. Recent DKA or signs of decompensated diabetes in last 6 months or increased β hydroxybutyrate levels (>0.4 mmol/L) at screening.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pioglitazone (PIO); 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.	Drug: Pioglitazone (PIO); Subjects will take 30 mg tablet, once daily in the morning, taken with or without food for 12 weeks and after 12 weeks dose will be escalated to 45 mg based on Hemoglobin A1c (HbA1c) levels (HbA1c >7.0% at 12 weeks, escalate the dose) once daily in the morning, taken with or without food till 24 weeks.
Experimental: Empagliflozin (EMPA); 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.	Drug: Empagliflozin (EMPA); Subjects will start with 10 mg dose, once daily in the morning, taken with or without food for 12 weeks and after 12 weeks dose will be escalated to 25 mg based on Hemoglobin A1c (HbA1c) levels (HbA1c >7.0% at 12 weeks, escalate the dose) once daily in the morning, taken with or without food.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hemoglobin A1c (HbA1c)	Hemoglobin is a protein within red blood cells. As glucose enters the bloodstream, it binds to hemoglobin, or glycates. The more glucose that enters the bloodstream, the higher the amount of glycated hemoglobin. An HbA1C level below 5.7 percent is considered normal. Reported as percentage of glycated hemoglobin	Baseline to 24 weeks
Area under curve (AUC) for glucose	Pre-post study difference in AUC for glucose	Baseline to 24 weeks
AUC for C-peptide	Pre-post study difference in AUC for C-Peptide	Baseline to 24 weeks
AUC for Insulin	Pre-post study difference in AUC for Insulin	Baseline to 24 weeks
AUC for glucagon	Pre-post study difference in AUC for glucagon	Baseline to 24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fasting plasma glucose	Pre-post study difference in Fasting plasma glucose	Baseline to 24 weeks
Lean mass	Pre-post study difference in lean mass	Baseline to 24 weeks
Fat mass	Pre-post study difference in fat mass	Baseline to 24 weeks
Visceral fat	Pre-post study difference in visceral fat	Baseline to 24 weeks
Fecal elastase	Pre-post study difference in Fecal elastase (ELISA quantitative test, normal >200 mcg/g)	Baseline to 24 weeks
High Sensitivity C-Reactive Protein (Hs-CRP)	Pre-post study difference in Hs-CRP	Baseline to 24 weeks
Total cholesterol, LDL, HDL and Triglyceride	Pre-post study difference in Total cholesterol, LDL, HDL and Triglyceride	Baseline to 24 weeks
β-Hydroxybutyrate	Pre-post study difference in β-Hydroxybutyrate	Baseline to 24 weeks
Body weight	Pre-post study difference in body weight	Baseline to 24 weeks
Blood Pressure	Pre-post study difference in Blood Pressure	Baseline to 24 weeks
Body Mass Index (BMI)	Pre-post study difference in BMI	Baseline to 24 weeks
Insulin sensitivity	Change in sensitivity from baseline vs 24 weeks (Homeostatic Model Assessment, Matsuda Index)	Baseline to 24 weeks
Patient-Reported Outcomes Measurement Information System - 29 Profile v2.1 (PROMIS-29 Profile v2.1)	The PROMIS-29 Profile assesses following domains: Physical function; Pain interference; Anxiety; Depression; Fatigue; Sleep disturbance; Ability to participate in social roles and activities PROMIS-29 is scored using T-scores. Higher T-scores indicate a higher level of the underlying construct. Each domain has a set of questions, typically 4 to 6 items, and responses are rated on a 5-point Likert scale (e.g., "Never," "Rarely," "Sometimes," "Often," "Always" or "Not at all," "A little bit," "Somewhat," etc.). The responses are then scored on a T-score scale (with a mean of 50 and a standard deviation of 10 in the general population). T-scores Interpretation: A T-score of 50 is the average score for the general population.; T-scores above 50 indicate better functioning or less severe symptoms.; T-scores below 50 indicate worse functioning or more severe symptoms.	Baseline to 24 weeks
Beta cell function	Change in Beta cell function from baseline vs 24 weeks using oral disposition index	Baseline to 24 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ketosis	Percentage of participants experiencing Ketosis based on meter data	Baseline to 24 weeks
Diabetic Ketoacidosis (DKA) events	Number of DKA events	Baseline to 24 weeks
Insulin needs	Percentage of participants experiencing requirement for insulin	Baseline to 24 weeks
Chronic pancreatitis exacerbation	Percentage of participants experiencing CP exacerbation	Baseline to 24 weeks
Acute pancreatitis episodes	Percentage of participants experiencing AP episodes	Baseline to 24 weeks
Exocrine pancreatic insufficiency	Percentage of participants experiencing incident exocrine pancreatic insufficiency	Baseline to 24 weeks
Vitamin D	Decrease in vitamin D	Baseline to 24 weeks
Bone fractures	Percentage of participants experiencing bone fractures	Baseline to 24 weeks
Adverse events	Adverse events: Anemia, edema, urinary tract infection, Vaginal yeast infection	Baseline to 24 weeks

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Collaborators: University of Pittsburgh Medical Center
• Investigators: Principal Investigator: Yogish Kudva, Mayo Clinic

Study record dates

Study Major Dates

• Study Start (Actual): May 29, 2025
• Primary Completion (Estimated): May 31, 2027
• Study Completion (Estimated): May 31, 2027

Study Registration Dates

• First Submitted: December 5, 2024
• First Submitted That Met QC Criteria: December 9, 2024
• First Posted (Actual): December 12, 2024

Study Record Updates

• Last Update Posted (Actual): April 3, 2026
• Last Update Submitted That Met QC Criteria: March 30, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: diabetes; pancreatitis; pioglitazone; diabetes mellitus; empagliflozin
• Additional Relevant MeSH Terms: Endocrine System Diseases; Pathologic Processes; Chronic Disease; Disease Attributes; Metabolic Diseases; Digestive System Diseases; Glucose Metabolism Disorders; Pancreatic Diseases; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Pancreatitis; Pancreatitis, Chronic; Diabetes Mellitus; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Thiazoles; Azoles; Thiazolidinediones; Pioglitazone; empagliflozin
• Other Study ID Numbers: 24-003868

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No