Figure 1. Normal function of the entero-insular axis in the regulation of glucose levels following meal ingestion, sites of impairment in pancreatic insufficient cystic fibrosis (PI-CF), and current targets for intervention.
At Penn Medicine, Michael R. Rickels, MD, and Andrea Kelly, MD, are conducting a research study [Clinicaltrials.gov NCT04731272] to investigate the effects of dulaglutide on pancreatic islet function and blood glucose levels in adults with cystic fibrosis (CF) and abnormal glucose tolerance. [1] Dr. Rickels is the Willard and Rhoda Ware Professor in Diabetes and Metabolic Diseases at the Hospital of the University of Pennsylvania, and Dr. Kelly is Professor of Pediatrics at the Children's Hospital of Philadelphia. Dulaglutide is a long-acting recombinant polypeptide analogue of human glucagon-like peptide-1 (GLP-1) currently FDA approved for use in type 2 diabetes.
Cystic Fibrosis and the Pancreas
CF is a genetic disorder caused by mutations affecting the cystic fibrosis transmembrane conductance regulator gene (CFTR), and so named for the cysts and fibrosis that develop in the pancreas of affected individuals. Soon after birth, about 85% of individuals with CF develop pancreatic insufficiency (PI-CF), a deficiency of pancreatic digestive enzymes. The minority of CF patients who are pancreatic sufficient (PS) are at risk for acute or chronic deterioration in pancreatic function and may develop PI at any age.
Cystic Fibrosis Related Diabetes
Approximately 40% - 50% of adults with PI-CF will develop cystic fibrosis-related diabetes (CFRD), a co-morbidity associated with increased pulmonary exacerbation rates, greater prevalence of important sputum pathogens, poorer nutritional status, and six-fold greater mortality. Unlike type 1 diabetes mellitus, CFRD does not have its origin in the immune system; however, typically patients with CFRD become dependent on insulin treatment with no alternative therapies yet available.
The pathogenesis of CFRD in PI-CF is multifactorial, complicated and progressive. Among much else, for example, it is known that CF patients experience impaired fat digestion, and that reduced incretin secretion from the gastrointestinal epithelium as a consequence of impaired nutrient digestion in individuals with PI-CF leads to reduced levels of the incretin hormones GLP-1 and glucose-dependent insulinotropic polypeptide (GIP). Both GLP-1 and GIP augment insulin production and glucose-dependent insulin secretion by pancreatic islet β-cells, with reciprocal effects on islet α-cells ( i.e. GLP-1 inhibits and GIP stimulates glucagon secretion). Recent work by Drs. Rickels and Kelly has shown that the insulinotropic action of GLP-1 to enhance islet β-cell function is preserved while that for GIP is absent in individuals with PI-CF (Figure 1), making GLP-1 a potentially even more important target for improving insulin secretion in CF. [2]
Investigating GLP-1 Agonist Therapy in Adult PI-CF
Identifying interventions to preserve β-cell function are crucial for delaying and potentially preventing CFRD development. NCT04731272, the clinical trial now underway at Penn Endocrinology, Diabetes and Metabolism will assess whether β-cell function may improve with longer-term exposure to GLP-1 agonist dulaglutide intervention in PI-CF. Dulaglutide has been shown to mimic the effects of GLP-1 on augmentation of glucose-dependent insulin secretion and is available for weekly administration by injection rather than by continuous infusion. The intended population for this study includes men and women age ≥18 years at baseline with confirmed PI-CF and abnormal glucose tolerance, including those with early CFRD.
Objectives
The investigators propose that weekly administration of 0.75 mg dulaglutide via single-dose autoinjector pen in patients with PI-CF will improve both defective early-phase insulin secretion and glucose tolerance during a mixed-meal tolerance test.
Methods
This will be a proof-of-concept 6-week randomized, observation-controlled crossover study; the primary outcome will be the impact of dulaglutide upon meal-related early-phase insulin secretion. Translation of the observation of robust augmentation of β-cell function to secrete insulin by GLP-1 infusion to proof-of-concept for improved meal-related insulin secretion and tolerability of weekly GLP-1 agonist will provide the foundation for a multi-center study to test the efficacy of chronic GLP-1 therapy in preserving β-cell function in PI-CF and in hopefully helping to interrupt progression of abnormal glucose tolerance to CFRD.
Location
The GLP-1 Agonist Therapy in Cystic Fibrosis-Related Glucose Intolerance study is taking place at the Hospital of the University of Pennsylvania in Philadelphia and in collaboration with the Children's Hospital of Philadelphia.
Contact Information
Potential participants and referring clinicians for this study may contact:
Paola Alvarado, MS 215-746-2081, Paola.Alvarado@Pennmedicine.upenn.edu
Cornelia Dalton-Bakes, MSc 215-746-2085, corneliv@pennmedicine.upenn.edu
References
- GLP-1 Agonist Therapy in Cystic Fibrosis-Related Glucose Intolerance. ClinicalTrials.gov Identifier: NCT04731272. Available at https://clinicaltrials.gov/ct2/show/NCT04731272.
- Nyirjesy SC, Peleckis AJ, Eiel JN, Gallagher K, Doliba A, Tami A, Flatt AJ, De Leon DD, Hadjiliadis D, Sheikh S, Stefanovski D, Gallop R, D'Alessio DA, Rubenstein RC, Kelly A, Rickels MR. Effects of GLP-1 and GIP on Islet Function in Glucose Intolerant, Pancreatic Insufficient Cystic Fibrosis. Diabetes 07.07.2022; doi: 10.2337/db22-0399. Online ahead of print.
About Penn Endocrinology, Diabetes and Metabolism
The Division of Endocrinology, Diabetes and Metabolism at Penn Medicine and the Perelman School of Medicine comprises the Rodebaugh Diabetes Center, the Penn Pituitary Center, Penn Metabolic Medicine, the Penn Thyroid Center, the Penn Bone Center, the Pennsylvania Hospital Diabetes Education Center and Penn Endocrinology Services. The combined disciplines of these centers includes national leaders in the diagnosis, treatment and management of patients with endocrine disorders including diabetes, thyroid disorders, adrenal disorders, pituitary disorders, obesity and metabolism disorders.
Faculty Team
Hospital of the University of Pennsylvania
Department of Medicine
Division of Endocrinology, Diabetes & Metabolism
Michael R. Rickels, MD, MS
Willard and Rhoda Ware Professor in Diabetes and Metabolic Diseases
Director of Clinical Science, Endocrine Division
Serena Cardillo, MD
Professor of Clinical Medicine
Director of Education, Endocrine Division
Amy J. Peleckis, MS, CRNP
Technical Director, Human Metabolism Resource
Translational Research Program, Institute for Diabetes, Obesity & Metabolism
Division of Pulmonary, Allergy & Critical Care Medicine
Denis Hadjiliadis, MD, PhD
Professor of Medicine
Program Director, Adult Cystic Fibrosis
Daniel J. Dorgan. MD
Associate Professor of Clinical Medicine
Director, Advanced Lung Disease Clinical Research Group
Children's Hospital of Philadelphia
Department of Pediatrics
Division of Endocrinology and Diabetes
Andrea Kelly, MD, MSCE
Professor of Pediatrics
Director of Research, Endocrine Division
Diva D. De Leon, MD, MSCE
Professor of Pediatrics
Chief, Endocrine Division
Division of Pulmonary and Sleep Medicine
Saba S. Sheikh, MBBS, MSCE
Assistant Professor of Pediatrics
Director of the Therapeutic Development Network, Cystic Fibrosis Center