Pioglitazone Versus Empagliflozin for Chronic Pancreatitis/Recurrent Acute Pancreatitis/Acute Pancreatitis Associated Diabetes Mellitus

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) or Acute Pancreatitis (AP) 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.

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, or acute pancreatitis followed by diabetes (AP-DM) 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 \0.4 mmol/L) at screening.