CF Related Diabetes

1. CF Related Diabetes ADEU November 2010

2. Cystic Fibrosis • Genetic disorder • Exocrine pancreas dysfunction • Autosomal recessive inheritance • Several identified genes • Presentation • Newborn screening • Failure to thrive in infancy • Chronic pulmonary disease in older individuals

3. Cystic Fibrosis • Treatment • Nutritional support • High caloric diet- carbohydrate and protein • Exocrine pancreatic enzymes • Pulmonary toilet • Monitor and aggressively treat pulmonary infection • Course • Failure to thrive/ poor growth • Progressive pulmonary disease • Diabetes • Early death due to pulmonary disease • Genetic testing has demonstrated significant variability in presentation and course

4. History of CF • 1980s • Children and Teens died of respiratory failure • Diabetes was a pre-morbid event • 1990s • Aggressive nutritional support • Extended lifespan • Increased incidence of diabetes • <25% of patients with CFRD reach age of 30 years vs 60% of those without • 2000s • Increased life span, Average life expectancy 37.4 yrs • Impact of diabetes?

5. Incidence of CFRD • CFRD increases with age • 2% children • 19% adolescents • 40-50% adults • Normal OGTT (standard definition) • 60% children • 30% of adults 20-40 years • 20% of adults > 40 years

6. CFRD – Etiology • Originally hypothesized to be due to fibrosis and destruction of islet cells in pancreas • Autopsy data demonstrated that CF patients with AND without diabetes had the same islet cell mass • Family history of type 2 diabetes increases the risk of CFRD • Genetic predisposition towards type 2 diabetes?

7. Impact of Diabetes in CF • Insulin deficiency • Catabolic state- malnutrition • Until recently focus has been here • Hyperglycemia • Airway glucose concentrations increased • Immune function • Long term complications • Microvascular disease in CFRD is less common and less severe in CF • Not described in CF patients without fasting hyperglycemia

8. Impact of Diabetes on CF patients • CF patients die of pulmonary disease rather than atherosclerotic cardiac disease • Insulin deficiency • Poor nutrition is linked to decline in pulmonary function • Insulin is anabolic involved in conservation of lean body mass and weight • Patients with IGT (on OGTT) have more rapid decline in pulmonary function than NGT • CFRD without fasting hyperglycemia is bad prognostic indicator

9. Definition of CFRD • Same as the ADA definition • Oral glucose tolerance test • Glucose load is low compared to normal intake • Random glucose over 200mg/dl and symptoms • Overnight tube feedings may make it hard to see symptoms • Is this the best or right definition for CF?

10. CFRD- how to define it? • “Normal glucose tolerance” on OGTT • Increased 30, 60, and 90 minute glucoses • Increase area under the curve glucose • CGMS • Mean glucose levels higher in CF (106 vs 92 mg/dl) • 33% of CF patients had a glucose >200 mg/dl (vs 5% of control patients) / day

11. Risk of Diabetes in CF • Family history of type 2 diabetes increases risk to CF patients • OR- 3.1 (p = 0.009) • Sibling-twin data from a study on type 2 diabetes demonstrated genetic component • Concordance rate for monozygotic twins higher than dizygotic twins or sib pairs (p=0.002) • Genetic variant associated with Type 2 commonly found in CFRD • Presence associated with earlier age of diagnosis of diabetes • TCF7L2 = transcriprtion factor 7-like 2

12. Etiology of CFRD • Originally thought to be due to purely mechanical issues • Destruction of pancreas, loss of ß cell mass • Autopsy data demonstrated essentially equivalent mass in non-diabetic CF and diabetic CF patients • Autopsy data demonstrated amyloid deposits similar to that seen in type 2 DM patients but not in type 1 nor in pancreatitis patients

13. Hyperglycemia in CF • OGTT demonstrates glucose “area under the curve” is higher in non-diabetic CF patients than controls matched for for age and BMI • Higher 30, 60 and 90 minute glucose levels • CGMS demonstrates CF patients with normal OGTT have “diabetic” glucose values in normal life • Average glucose higher (106 vs 92 mg/dl) • 33% of CF patients had one or more glucose over 200 mg/dl vs 5% of controls • Hgb A1C and OGTT may underestimate glucose abnormalities in CF patients

14. Hyperglycemia in CF • Blood glucose over 144 mg/dl associated with increased airway glucose levels • CGMS demonstrates levels higher than this 50% of the time in CFRD, 6% of the time in CF with normal GT, and 1% of the time in controls • Staph aureus and Pseudomonas growth was accelerated when cultured in a similar glucose environment • Potential impact: increased bacterial growth, increased glycation products, increased inflammatory process, decrased immune function

15. CFRD • Increases with age • 2% of children, 50% of adults • At younger ages, more individuals have normal fasting glucose (CFRD FH-) • Mortality is decreasing (1992-7 vs 2003-8) • Pre-screening, mortality was 20% within 5 years of diagnosis, now 3% • Lung function continues to be worse in CFRD patients

16. When to Treat CFRD • Macrovascular complications really aren’t seen in CF • Microvascular complications are seen in CFRD FH+ • What about CFRD FH- • Multicenter trial of CFRD FH-, IGT • Oral replaglinide, pre-meal insulin aspart, oral placebo • End point BMI • Pre-treatment BMI decreased in all groups, reversed in insulin group only • No difference in pulmonary function over 1 year but study time frame is likely too short to see difference

17. Diagnosis and Treatment • Oral glucose tolerance test • End point • Area under the curve? • CFRD FH+ • Basal-bolus insulin similar to type 1 DM • Consider Insulin pump • CFRD FH- • Watch BMI trajectory • Consider pre-meal bolus insulin

18. Summary • CFRD is a significant contributor to burden of disease in CF • Increased illness, earlier death • CFRD may look more like type 2 diabetes than type 1 and may have identifiable risk factors • Appropriate diagnosis and timing of intervention is a work in progress • Therapy is classic basal-bolus insulin