The purpose of this study is to assess the efficacy of metformin to improve airway ion channel function in those with CF-related diabetes (CFRD)

Up to 30 patients with CFRD on highly effective CFTR modulator therapy who meet criteria and agree to participation in the study will be placed on metformin. There will be a dose-escalation starting with 500mg twice daily for a week, followed by 500mg in the AM and 1000mg in the PM for another week and finally followed by 1000mg twice daily for 14 weeks. To minimize risk of B12 deficiency, a known side effect of long-term metformin use, we will also provide a supplement of 1000 μg oral cyanocobalamin daily for the duration of the trial

Inclusion criteria:

1. Age >18 years with a prior diagnosis of CF.

2. Use of ivacaftor or elexacaftor/tezacaftor/ivacaftor or vanzacaftor/tezacaftor/deutivacaftor for 30 days prior to day 0

3. Diagnosis of CFRD with evidence of continued glucose intolerance at least 6 months after starting qualifying modulator therapy will be based upon one of the following:

   1. Insulin use
   2. Hemoglobin A1C >6.5%
   3. Fasting glucose >126 mg/dl
   4. Non-fasting glucose >200 mg/dl (random or as part of a 2-hr OGTT)

Exclusion criteria:

1. Prior lung or liver transplant
2. Use of supplemental oxygen
3. BMI <18
4. CF pulmonary exacerbation requiring hospitalization or intravenous antibiotics in the preceding 30 days
5. Systemic corticosteroid or regular non-steroidal anti-inflammatory use in the preceding 30 days
6. Cardiac, renal (creatinine clearance <45 mL/minute), neurologic, psychiatric, endocrine or neoplastic diseases that are judged to interfere with participation in the study
7. Alanine aminotransferase, aspartate aminotransferase or alkaline phosphatase >1.5X the upper limit of normal; bilirubin >3 mg/dL
8. Taking medications that interact with metformin.
9. Vitamin B12 deficiency
10. Pregnancy or lactation
11. Inability or unwillingness to comply with an approved contraceptive method during the study period (females of childbearing age)
12. Use of medications known to be strong CYP inducers or moderate to strong CYP inhibitors
13. In the opinion of the investigator any severe or acute or chronic condition or laboratory abnormality that may increase the risk associated with trial participation or make the subject inappropriate for enrollment
14. Participation in another interventional trial that, in the opinion of the investigator, has the potential to affect the primary outcome