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

Inclusion Criteria:

• Age ≥18-70 years at the time of enrollment.

• RAP or CP with DM diagnosed before or after CP diagnosis (Confirmed CP on imaging orRAP based on PROCEED study criteria, and confirmed DM as per ADA criteria orclinically diagnosed with DM and on antihyperglycemic therapy)

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

• Stable last annual retinal exam within 1 year prior to enrollment.

• HbA1c level 7-10% at screening visit.

• Fasting plasma glucose <220 mg/dL at screening visit.

• Not on any antihyperglycemic medication except Metformin

• Willing to perform blood glucose and ketone testing on study provided meters as perstudy protocol.

Exclusion Criteria:

• Inability to take PIO or EMPA due to prior hypersensitivity or allergic reaction orcurrent use of medications with potential for drug-drug interactions (Pioglitazone:Drug information - UpToDate, Empagliflozin: Drug information - UpToDate)

• Diagnosed with Type 1 Diabetes

• Pregnancy or lactation in women (positive urine pregnancy test at screening willlead to exclusion)

• History of bleeding disorders (e.g., Hemophilia A (factor VIII deficiency),hemophilia B (factor IX deficiency), von Willebrand disease, platelet disorders etc)

• Presence of hepatic impairment, ALT >3 x ULN with no etiology known at the time ofenrollment or any evidence of acute/chronic liver disease

• Ongoing treatment for any malignancy requiring systemic treatment (non-melanoma skincancers treated in dermatologists' office would be acceptable)

• Presence of osteoporosis (the threshold of bone density value below the -2.5 SDS ofT-score or presence of one or more fragility fractures), on electronic medicalrecord.

• Recent inflammatory illness within the 30 days preceding enrollment (e.g.: URTI,episode of AP, etc)

• History of heart failure classified by New York Heart Association as Class III orgreater

• History of kidney dysfunction classified by eGFR of <30 mL/min/min

• Participation in any clinical trial within 30 days before screening for an approvedor non-approved investigational medical product.

• Active alcohol dependence or chemical dependence including tobacco based oninvestigator discretion

• On a ketogenic diet

• Autoimmune pancreatitis, obstructive pancreatitis, and prior surgery of pancreas

• Any condition which could jeopardize participant safety as per investigator opinion, (hemolytic anemia limiting HbA1c reliability, any evidence of fluid overload,presence of Congestive heart failure etc).

• Recent DKA or signs of decompensated diabetes in last 6 months or increased βhydroxybutyrate levels (>0.4 mmol/L) at screening.