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.

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.

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.