+ Cystic Fibrosis Related diabetes By Abdulmajeed AlSubaihin Clinical Fellow Pediatric Endocrinology

+ Presentation Outline Introduction Pathophysiology Clinical impact Management guidelines

+ Cystic Fibrosis is an autosomal recessive disease caused by mutations in CFTR Gene on chromosome 7 The most common life limiting genetic condition in Caucasians.

+ Ratjen F. N Engl J Med 2006;354:

+ Pulmonary disease Hepatobiliary disease Pancreatic insufficiency Pancreatitis Meconium ileus and distal ileal obstruction Nephrolitihiasis Rectal prolapse Infertility Clinical Features

+ Cystic fibrosis–related diabetes (CFRD) is the most common comorbidity in subjects with cystic fibrosis (CF)

+ Prevalence The Cystic Fibrosis Foundation Patient Registry, which collects information from 22,732 people with CF of all ages in the United States and Canada, has shown that the diagnoses of glucose intolerance and diabetes in CF are becoming more prevalent

+ Prevalence Moran et al. Epidemiology, pathophysiology, and prognostic implications of cystic fibrosis-related diabetes: a technical review. Diabetes Care Dec;33(12): Diabetes Care.

+ Pathophysiology Yung et al Cystic fibrosis-related diabetes: the role of peripheral insulin resistance and beta-cell dysfunction. Diabet Med Mar;19(3): Diabet Med.

+ Pathophysiology Hardin et al. J Pediatr. Insulin resistance is associated with decreased clinical status in cystic fibrosisJ Pediatr Jun;130(6):

+ Hardin et al. J Pediatr. Insulin resistance is associated with decreased clinical status in cystic fibrosisJ Pediatr Jun;130(6):

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+ DF508 cells had lower membrane resting potentials Glibenclamide failed to induce depolarization when CFTR is inhibited

+ Impaired first phase response In Vitro Glucose Challenge

+ In Vivo Glucose Challenge

+ VX-809 Ivacaftor Nelson Textbook of Pediatrics

+ VX-809 rescue

+ Trust me I’ve tried that out and it seems to be working

+ 2 siblings, 24 and 21 years of age, CF (DF508/S549R), with INDET and CFRD respectively, treated Ivacaftor for 16 weeks. Not on insulin or glucose lowering drugs.

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+ 48 CF patients (CFRD =19) compared to 18 healthy controls Age range years All fasted overnight and received a standard meal at the test time. Serial GLP-1 levels were taken CFRD patients were instructed to hold insulin during the fast time. None had T1DM related Autoantibodies

+ CFRD vs Controls (AUC, P= 0.001) CF vs Controls (AUC, P= 0.02) CFRD vs CF (AUC, P=0.06) Difference is not statistically significant

+ Lek et al, Current Diabetes Reviews, 2010

+ CFRD is part of a spectrum

+ CFRD spectrum FP1h2h NGT< 11.1 mmol/L<7.8 mmol/L IGT≥ 7.8 and < 11.1 mmol/L Indet≥ 11.1 mmol/L< 7.8 mmol/L CFRD -FH< 7 mmol/L≥11.1 mmol/L CFRD +FH≥ 7 mmol/L≥11.1 mmol/L

+ Clinical Impact Cystic Fibrosis Foundation Patient Registry reported that people with CF and diabetes have a 6-fold greater mortality rate than people without diabetes. Similarly to type 2 DM, 10 year duration of CFRD is associated with: 50% risk of mild neuropathy 16% risk of Retinopathy 14% risk of Neuropathy Schwarzenberg et al. Microvascular complications in cystic fibrosis– related diabetes. Diabetes Care2007

+ Clinical Impact Finkelstein et al. Diabetes Mellitus Associated with Cystic Fibrosis. J Pediatr Mar;112(3): J Pediatr.

+ Clinical Impact Cross-sectional analysis of 7566 people enrolled in the European Epidemiologic Registry of Cystic Fibrosis (ERCF) found that FEV1 % predicted was lower in people with diabetes than in those without diabetes at all ages

+ Lanng et al Eur J Pediatr (1992) 151 :

+ Lanng et al, Acta Paediatr 83:

+ Glucose and Lung Function High glucose concentration on mucosal surfaces and bacterial colonization. Hyperglycemia induced inflammatory response

+ Clinical Features

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+ Screening Screening of CFRD gains its importance as: CFRD has an insidious course CFRD does not usually present with florid clinical diabetes picture (polyuria, polydipsia, DKA) Impact of CFRD on pulmonary functions and outcome begins in the prediabetes phase.

+ Screening Screening ToolLimitations Hgb A1CNot sufficiently sensitive for diagnosis of CFRD, low positive predictive value Random GlucoseLow sensitivity FructosamineLow sensitivity Urine GlucoseLow Sensitivity CGMIntermittent hyperglycemia is of unknown clinical significance FPGIdentifies only 50% of CFRD patients Self monitoring (SMBG) International Organization for Standardization only requires that 95% of readings be within 20% of the actual glucose level Adapted from: Moran et al. Clinical Care Guidelines for Cystic Fibrosis–Related Diabetes DIABETES CARE, VOLUME 33, NUMBER 12, DECEMBER 2010

+ Screening-OGTT Advantages: Correlated with pulmonary outcomes Predicted microvascular complications and early death Identified patients who benefited from insulin therapy Disadvantages: Variability of results Combersome

+ Screening- OGTT 2h OGTT as per WHO recommendation( 1.75 gram/Kg, maximum = 75 grams) Following 8 hours of fasting, water is allowed To be done at baseline, 6 weeks following last CF exacerbation. Screening is recommended annualy starting at 10 years of age

+ Screening- Frequently ill CF patients with acute pulmonary exacerbation requiring intravenous antibiotics and/or systemic glucocorticoids should be screened for CFRD by monitoring fasting and 2-h postprandial plasma glucose levels for the first 48 h. If elevated blood glucose levels are found by SMBG, the results must be confirmed by a certified laboratory.

+ Screening- Continuous Drip Screening for CFRD by measuring mid- and immediate postfeeding plasma glucose at the time of gastrostomy tube feeding initiation and then monthly at home. Elevated glucose levels detected by SMBG must be confirmed by a certified laboratory.

+ Screening- Pregnancy Women with CF who are planning a pregnancy or confirmed pregnant should be screened for preexisting CFRD with a 2-h 75-g fasting OGTT if they have not had a normal CFRD screen in the last 6 months. Screening for gestational diabetes mellitus is recommended at both 12–16 weeks’ and 24–28 weeks’ using a 2-h 75-g OGTT with blood glucose measures at 0, 1, and 2 h. Screening for CFRD using a 2-h 75-g fasting OGTT is recommended 6–12 weeks after the end of the pregnancy in women with gestational diabetes mellitus>

+ 7mmol/l 11.1mmol/l

+ Management Multidisciplinary setting Insulin therapy is the first line of management No evidence supporting one insulin regimen. Insulin regimens are to be individualized. No evidence supporting oral agents. Patients on insulin should perform SMBG at least 3 times per day. Follow up quarterly with HgbA1c Goal Hgb A1c is =< 7%

+ Conclusion CFRD remains the most common CF comorbidity. Mechanisms include insulin insufficiency due to reduced beta cell mass and possibly some insensitivity to glucose at the beta cell surface. CFRD outcomes are not limited to Micro/Macrovascular complications of diabetes, it also involves pulmonary/nutritional status. Screening is recommended by using 2h OGTT. Treatment is recommended using insulin at CFRD phase with or without fasting hyperglycemia.

+ Thank you