GLP-1 Agonist Therapy in Cystic Fibrosis-Related Glucose Intolerance

Inclusion Criteria:

1. Male or female, aged ≥18 years on date of consent

2. Confirmed diagnosis of CF, defined by positive sweat test or Cystic Fibrosistransmembrane conductance regulator (CFTR) mutation analysis according toCystic Fibrosis Foundation (CFF) diagnostic criteria.

3. Pancreatic insufficiency defined by clinical requirement for pancreatic enzymereplacement.

4. Abnormal glucose tolerance defined by OGTT criteria for EGI, IGT, or CFRD, ordiagnosed CFRD.

5. There will be no restriction on enrollment of individuals with CFRD but withoutfasting hyperglycemia (fasting hyperglycemia is defined as fasting glucose ≥126mg/dL)

6. Individuals with CFRD and fasting hyperglycemia (defined as above or by the useof basal insulin therapy) must also have a HbA1c ≤8% and a random (non-fasting)C-peptide ≥1.2 ng/mL17; enrollment of this subgroup will be limited to n =10.

5. Ability to take subcutaneous medication and be willing to adhere to the weeklyadministration regimen and complete study specific procedures (MMTT)

6. For females of reproductive potential: use of highly effective contraceptionfor at least 1 month prior to screening and agreement to use such a methodduring study participation and for an additional 6 weeks after the end ofdulaglutide or observation administration; oral contraceptives, intra-uterinedevices, Norplant®, Depo-Provera®, and barrier devices with spermicide areacceptable contraceptive methods; condoms used alone are not acceptable

Exclusion Criteria:

1. BMI <19 kg/m2

2. Presence of first-degree atrioventricular block or other evidence for cardiacconduction system or structural heart defects

3. Pregnancy or lactation; a negative urine pregnancy test will be required atenrollment

4. Known allergic reactions to any GLP-1 agonist, and any history of severehypersensitivity reactions (anaphylaxis or angioedema)

5. Personal or family history of medullary thyroid cancer or multiple endocrineneoplasia syndrome type 2 (MEN2)

6. Pulmonary exacerbation requiring IV antibiotics or systemic glucocorticoidswithin 4 weeks prior to study procedures

7. Gastrointestinal symptom exacerbation defined by current nausea/vomiting ordiarrhea

8. Established diagnosis of non-CF diabetes (e.g. type 1 diabetes) or CFRD withfasting hyperglycemia (fasting glucose ≥126 mg/dL [use of prandial insulin orrepaglinide will be permitted])

9. History of clinically symptomatic pancreatitis within the last year

10. Prior lung, liver or other solid organ transplant

11. Severe CF liver disease, as defined by the presence of portal hypertension

12. History of fundoplication-related dumping syndrome

13. Hemoglobin <10 g/dL, within 90 days of study procedures or at screening

14. Abnormal renal function, within 90 days of study procedures or at screening;defined as creatinine >2x upper limit of normal (ULN) or potassium >5.5mEq/L onnon-hemolyzed specimen

15. History of any illness or condition that, in the opinion of the investigatormight confound the results of the study or pose an additional risk to thesubject