Parallel-group randomized controlled trial of Pioglitazone versus empagliflozin for T3cDM: The PEP-DM Trial

ABSTRACT Chronic pancreatitis (CP) and recurrent acute pancreatitis (RAP) continue to increase worldwide and in the U.S. and are associated with Diabetes Mellitus (CP-DM). Observational studies indicate higher morbidity in individuals with CP-DM compared to Type 2 Diabetes mellitus (T2DM). Observational mostly retrospective studies also describe worse glycemic control in CP-DM compared to T2DM; earlier and increased need for insulin, and an increased risk of severe hypoglycemia requiring assistance from third party in CP-DM when compared to T2DM significantly impacting the quality of life of these patients. Therefore, there is a need to test better and specific antihyperglycemic therapy for CP-DM with scientifically rigorous clinical trials. To our knowledge, very few or no randomized controlled trials (RCTs) have evaluated the efficacy of antihyperglycemic therapies when compared to control or to each other in CP-DM. Animal model data indicate that pioglitazone (PIO) may be a safe and effective treatment for hyperglycemia in pancreatitis. Extensive human investigations indicate that PIO improves insulin resistance and insulin secretion in T2DM. When tested in T2DM, RCTs of PIO have shown antihyperglycemic efficacy, durability, and favorable impact on cardiovascular (CV) disease and hyperlipidemia. PIO also decreases systemic inflammation. Safety of PIO has been extensively studied and confirmed though it should be used with caution in the long-term. SGLT2 inhibitors particularly Empagliflozin (EMPA) also improve hyperglycemia, decrease blood pressure, and body weight and decrease CV and renal adverse events in T2D. They could also be associated with unique adverse events. We are proposing a pilot, parallel group, randomized, dose escalation clinical trial of PIO versus EMPA lasting 24 weeks with dose escalation at 12 weeks or earlier based on pre-specified rules at 2 of the sites (Mayo Clinic, Rochester, MN and U of Pittsburgh, Pittsburgh, PA) in the NIH funded consortium for chronic pancreatitis, diabetes mellitus and pancreatic cancer (CPDPC). Specific Aim 1 will test the hypothesis that HbA1c lowering with PIO is non-inferior to EMPA in CP-DM with primary end point of the trial being improvement in Hemoglobin A1c. Secondary end points are multiple and include other measures of efficacy, mechanism, and safety. This is a pilot clinical trial for CP-DM without a precedent for this type of study; this is a challenge and precedent in itself for trial design but successful completion of this trial will enable the design and conduct of a multi-center RCT intervention to be conducted by the CPDPC in a larger CP-DM population to improve glycemic control.