1. Cystic Fibrosis-Related Diabetes (CFRD) Robert Slover, M.D. Keystone 2006

2. Why do we care if CF patients have diabetes? They are already burdened with complex medical cares. Arguably, they may not live long enough to develop diabetes microvascular complications

3. CF Foundation Patients Registry: More than 22,000 US Patients The mortality rate is 6-fold greater in patients with CFRD They are more likely to be underweight and to have severe pulmonary disease than CF patients without diabetes

4. Survival of Patients with Cystic Fibrosis

5. Prevalence of CFRD (2003) 16.9 % of CF patients >13 in the US have CFRD requiring insulin therapy Population of 21,742 at 117 US care centers 2003 CF Foundation Patient Registry Annual Report

6. Cystic Fibrosis Related Diabetes (CFRD) in the US Most common co morbid complication 4.4% (1992) to 12% (2002) (173% increase) Prevalence increases with age 14% of CF patient > 13 years old 25% of CF patients 35-44 years old Estimates have been as high as 43% of CF patients > 30 years

7. CFRD: Not Type 1 or Type 2 Most like type 2 diabetes, but requires insulin treatment like type 1 diabetes rather than diet and oral therapy like type 2 1.Caloric intake needs to be maintained to meet metabolic demands of CF 2.Oral medications used in type 2 diabetes cannot be used in CF Major side effect may be liver damage Sulfoylureas interfere with the chloride transporter 3.Insulin is required for CFRD

8. Type 1Type 2CFRD Most common age of onset <20>4018-21 Usual Body Habitus NormalObeseThin Insulin secretion Absent Insulin sensitivity Autoimmune etiology YesNo Ketoacidosis YesRare Microvascular complications Yes Macrovascular complications Yes No? Comparison of CFRD to Types 1 and 2 Diabetes

9. Factors Unique to CF Under nutrition Chronic inflammation with intermittent acute infection Glucagon deficiency Altered gut nutrient absorption and transit time Liver disease Increased energy expenditure Thin, low lipid levels, normal blood pressure

10. Cystic Fibrosis Related Diabetes: Insulin Deficiency Autoimmune induced insulin deficiency is the cause of type 1 diabetes Insulin deficiency in CFRD is due to scarring and destruction of the pancreatic islets and their beta cells CFRD is not associated with the autoimmune process and the autoantibodies seen in type 1 diabetes Scarring (fibrosis) occurs due to thickened exocrine secretions?

11. Insulin Secretion in CF (PS=pancreatic sufficient) Insulin Or C-Peptide

12. Insulin Sensitivity in CF * *

13. CFRD: Caveats DKA rare Poor fatty acid metabolism Pancreatic insufficiency associated associated with CFRD A1c may underestimate abnormal glucose metabolism Increased red cell turnover so A1c is ‘diluted’

14. Survival in CFRD, University of Minnesota 1988-2003 Retrospective study of 1081 CF patients followed at the University of Minnesota over the last 25 years. Classified based on presence of diabetes with fasting hyperglycemia. 123 patients with CFRD with FH identified (58 male, 65 female) Mean age at diagnosis 23 +/- 9 years.

15. Median Survival in CFRD University of Minnesota 1988-2003 Total Cohort 47.0 Years Women with Diabetes 30.7 Years Women without Diabetes 47.0 Years Men with Diabetes 47.4 Years Men without Diabetes 49.5 Years * Female gender and FEV1 at time of diagnosis associated with death by Cox proportional hazards regression

16. Outcome of those with CFRD diagnosed in childhood Mean Current age 19.2 yrs (12-29) Mean Age of diagnosis14.2 yrs (8-19) Current A1c 8.6 % (5.3-12) These data suggest that diabetes control is difficult to maintain in young adulthood when diabetes duration exceeds 3-5 years. This may be related to our current, more aggressive approach to CFRD management

17. Adolescent Outcome Those with Current age <20 Mean Age 15.2 Mean Age of diagnosis 14.0 Mean A1c 7.2/ 6.7*% *Minus A1c=12%

18. Lanng data, Denmark Weight loss and decline in pulmonary function began 4-6 years before the onset of diabetes. After two years of insulin therapy, weight returned to levels seen six years earlier and the decline in pulmonary function stabilized Suggests a cause and effect relationship between clinical decline and the pre-diabetic state.

19. CFRD:Denver The Children’s Hospital CF Center Over 500 children and young adults 6% with CFRD (15% reported in literature, 40% with ‘prediabetes’) Newborn Colorado screening program National Jewish Hospital CF Program 200 adults with CF 50% with CFRD

20. Outcomes in CFRD in Denver Median age of diagnosis: 15.0 (11-40) Mean Current age 26.1 (12-54) Mean Duration 5.6 Mean A1c 7.0 %

21. CFRD Pediatrics Clinic - BDC Total patients = 26; (12 male, 14 female) Mean age at last visit = 16.3 Seen in past year = 16; (6 male, 10 female) Last mean A1C (all patients) = 5.9% Latest A1C mean (seen in past year) = 6.0% A1C range at last visit = 4.8% - 9.3%

22. How might early diabetes cause CF clinical decline? Insulin Deficiency Insulin is an anabolic hormone which promotes conservation of body protein, fat and carbohydrate stores. Malnutrition and protein catabolism are clearly associated with death in CF.

23. Metabolic Consequences of Insulin Deficiency in CF Malnourished or very sick CF patients are severely protein catabolic. Healthy, well-nourished CF patients have subtle defects in protein and fat breakdown that may compromise nutrition. Increased protein and fat breakdown can be prevented if high enough insulin levels are achieved.

24. Hypothesis Insulin deficiency leads to protein catabolism in CF, even in the face of relatively normal blood glucose levels, and thus negatively affects morbidity and mortality.

25. Figure 2— Adverse impact of CFRD on female predicted FEV1 percentage when stratified by chronic P. aeruginosa (PA) infection. A: Chronic P. aeruginosa–free females and males. B: Chronic P. aeruginosa–present females and males. Box plots in the left and middle panels show median FEV1 in female and male subjects with CFRD ( ) compared with control subjects with NGT ( ). 95% CIs are also indicated (). Left panels show all patients, middle panels show F508/ F508 patients, and right panels show FEV1 for age-, sex-, and center- matched CFRD and NGT patients. Median FEV1 is indicated by black bar. The number of patients in each group is shown on the abscissa. Sims E, Green M, Mehta A, Diabetes Care 28:1581-87, 2005.

26. Figure 1— Survival curves for male subjects with CF but without diabetes (green, median survival 49.5 years), male subjects with CF and diabetes (blue, median 47.4 years), female subjects with CF but without diabetes (black, median 47.0 years), and female subjects with CF and diabetes (red, median survival 30.7 years). Milla CE, Billings J and Moran A. Diabetes Care 28:2141-2144, 2005 Survival Curves for Subjects with CF

27. Gender difference in survival with CFRD Males without CFRD – 49.5 years Males with CFRD – 47.4 years Females without CFRD – 47.0 years Females with CFRD – 30.7 years *Milla, C. et al. Diabetes Care 28:2141, 2005

28. CFRD is Associated with decreased pulmonary function in females but not males Female patients with CFRD but without chronic P. aeruginosa infections had 20% worse percent predicted FEV1 Male patients with CFRD did not have a similar reduction in FEV1.

29. Genotype is predictive of Pancreatic status Delta F508 homozygous genotype is associated with pancreatic insufficiency in nearly all patients. This genotype is also at higher risk for CFRD

30. Pulmonary Function in CFRD 1. Prevalence of CFRD is higher in patients with more severe pulmonary disease. 2. CFRD population has worse pulmonary funtion FEV1 55.4% versus 67.5% age adjusted (P<0.001) 3. More pulmonary exacerbations treated with parental antibiotics. 4. Higher prevalence of pseudomonas, Burkhdderia cepacia, Candida, and Aspergillus.

31. Nutritional Status of patients with CFRD 1. Lower mean height-for-age percentile 2. Lower mean weight-for-age percentile 3. Lower BMI

32. Epidemiology of CFRD Marshal et al. Journal of Pediatrics 146:681, May 2005 Data gathered from 8247 patients in the Epidemiologic Study of Cystic Fibrosis

33. Gender and Age Distribution of CFRD Males: 54.4 % of CF population 12% with CFRD Females: 45.6% of CF population 17.1% with CFRD Mean age of CFRD group 25.9 (8.9) years Mean age of non-CFRD group 22.5 (8.5) years

34. Summary of the epidemiologic date in patients with CFRD 1. CFRD is associated with increased age, female gender, pancreatic insufficiency, and delta F508 genotype. 2. There is a striking correlation between CFRD and worsened clinical status, with poorer pulmonary function, increased acute pulmonary illnesses, increased prevalence of important sputum pathogens, poorer nutritional stats, and a higher prevalence of liver disease.

35. Complications of CFRD (poorly controlled) Infections due to decreased WBC phagocytosis Increased viscosity of mucous secretions with hyperglycemia and dehydration Increased protein catabolism with CF and with DM Increased fatigue with poorly controlled DM

36. Medical interventions and comorbid medical conditions in CFRD Therapy CFRD Group (n=7067) Non-CFRD group (n=1180) Age-Adjusted p value Pulmozyme (dornase) 57.6%49.8%<.001 Airway Clearance 90.7%84.3%<.001 Mast Cell Stabilizer 20.3%17.5%<.001 BD (oral) 21.5%13.7%<.001 BD (Inhaled) 91.5%84.3%<.001 NSAID 10.6%9.6%.206

37. (table cont.) Therapy CFRD Group (n=7067) Non-CFRD group (n=1180) Age-Adjusted p value Oral supplement 40.5%32.7%<.001 Enteral Supplements 11.7%7.7%<.001 Parental supplements 2.4%0.9%<.001 Steroids(oral) 27.6%17.9%<.001 Steroids (Inhaled) 48.9%39.6%<.001 Contraceptives 12.7%7.0%<.001 Oxygen 24.2%9.7%<.001 Diuretic 5.5%1.0%<.001

38. Long term side effects of CFRD Decreased life expectancy from pulmonary complications without diabetes, 60% live to 30 years 25% with diabetes survive to age 30 Also subject to the microvasular complications of diabetes hyperglycemia Retinopathy, nephropathy, gastroparesis

39. Current Goals of Therapy Determine if near-normalization of blood glucose will prevent the deterioration of lung function associated with onset of CFRD Maintain nutrition and weight with attention to appetite, and post-prandial glucose as well as fasting glucose Avoidance of diabetes and CFRD complications

40. Glucose Tolerance in CF

41. Evaluation for Diabetes in CF Annual random glucose beginning at age 10 If the random glucose is > 125 Obtain oral glucose tolerance test At all admissions for illness, check random glucose Diabetes Fasting glucose > 125 2 hour glucose > 200

42. CFRD – who should have an OGTT? Patients unable to gain or maintain appropriate weight, despite optimal nutrition. Patients with a poor growth rate Patients with delayed puberty Patients with declining pulmonary function studies Patients whose fasting glucose level exceeds 125 All women planning pregnancy or pregnant.

43. Oral Glucose Tolerance Categories in Cystic Fibrosis Category FBG2-h PG mg/dl (mM) mg/dl (mM) Normal Glucose Tolerance (NGT) <126 (7.0) <140 (7.8) Impaired Glucose Tolerance <126 (7.0) 140-199 (7.8-11.1) CFRD Without Fasting Hyperglycemia <126 (7.0) ≥200 (11.1) CFRD With Fasting Hyperglycemia ≥126 (7.0)OGTT not necessary The OGTT is performed by giving a 1.75 gr/kg body weight (max 75 gr) oral glucose load to fasting patients. FBG and 2-h PG are measured.

44. Criteria for the Diagnosis of CFRD 2-h PG ≥ 200 mg/dl (11.0 mM) during a 75 gram OGTT. FBG ≥ 126 mg/dl (7.0 mM) on two or more occasions. FBG ≥ 126 mg/dl (7.0 mM) plus casual glucose level > 200mg/dl (11.1 mM). Casual glucose levels ≥ 200 mg/dl (11.1 mM) on two or more occasions with symptoms.

45. Glucose Tolerance Prevalence 57% 34% ---6% 3% | 36% 38% 15% 11% 23% 38% 20% 15% 30% 27% 16%

46. Practical Aspects of diabetes management in CFRD Patients should be cared for by multidisciplinary teams A dedicated nurse specialist and interested physician are preferred to review in general DM clinic Aim for optimal nutritional status with weight maintenance Diet is largely unrestricted, with insulin adjusted accordingly Insulin regimens should be tailored to suit patient’s eating pattern and lifestyle

47. Practical Aspects of diabetes management in CFRD (cont.) Basal/bolus regimens are acceptable, though some individuals require only meal-time injections Intermittent insulin therapy may be necessary during steroid administration, enteral feeding and infection Insulin infusion may be required with enteral feeding regimens Subjects with CFRD should receive annual screening for microvascular complications

48. Team Care of CFRD Diabetic glucose tolerance test Referred to diabetes team Physician Dietitian Diabetes nurse - liaison with the diabetes team Medical social worker

49. Ways in Which CFRD Medical Nutrition Therapy Differs from that of Type 1 and Type 2 Diabetes High energy intake is necessary for survival – caloric restriction is never an appropriate means of glycemic control. High fat intake is recommended (40% of total calories) to provide increased calories and because macrovascular disease does not appear to be a concern. Protein reduction may not be appropriate in diabetic nephropathy because of the potential for malnutrition. Frequent intercurrent illness necessitates constant adjustment of the meal plan.

50. Principles of Dietary treatment in CFRD compared with DM NutrientNON-CFRDCFRD Energy 100% of RDA or less if overweight 120-150% RDA Fat 30% of Energy (with restriction of sat. fats 30-40% of energy (no restriction on type of fats.) Carbohydrate Promotion of complex carbohydrates spread evenly throughout the day (low glycaemic index foods). Promotion of complex carbohydrate RDA, Recommended daily allowance

51. Principles of Dietary treatment in CFRD compared with DM (cont.) Refined CHORestriction to < 25 g/day Allowed liberally throughout the day(although avoid sugary drinks between meals) Fiber Soluble and insoluble encouraged Not encouraged as may increase satiety and so decrease energy intake Salt Low intakeIncreased intake CHO, carbohydrate

52. Conclusion Aggressive glucose management in patients with CFRD results in dramatically improved quality of life and life span, especially in females. YOU can make a difference! Thank You!