Cystic Fibrosis Related Diabetes: An Update

1. Cystic Fibrosis Related Diabetes: An Update Julie Matel, MS, RD, CDE

2. Cystic Fibrosis Related Diabetes

3. CFRD Is a Distinct Form of Diabetes Type 1 Type 2 CFRD Most common age of onset Usual body habitus Insulin Secretion Insulin Sensitivity Autoimmune etiology Ketoacidosis Microvascular complications Macrovascular complications <20 Normal Absent ↓ Yes Yes Yes Yes >40 Obese ↓ ↓ ↓ ↓ No Rare Yes Yes 22-24 Normal ↓ ↓ No Rare Yes No Moran A, et al. Diabetes Res Clin Pract. 1999.

4. Microvascular Complications in Subjects with Diabetes > 10 Years Duration 98 patients with CFRD with FH, 39 patients >10 yrs duration Schwarzenberg, Moran et al. Diabetes Care. 2007

5. Clinical Signs and Symptoms of Diabetes in CF Excessive thirst or excessive urination Failure to gain or maintain weight despite nutritional intervention Failure to grow Delayed progression of puberty Chronic decline in pulmonary function Moran A, et al. Diabetes Res Clin Pract. 1999.

6. Decline in Pulmonary Functions and Nutritional Status Precedes Development of Diabetes “Prediabetic state may be deleterious because a greater decline in pulmonary function and nutritional state was found as early as 6 years before the diagnosis of diabetes.” Bismuth, E. et al J Pediatr 2008;152:540-5

7. CFRD has an impact on patient outcomes… Reduced survival In a study of 448 people with CF, less than 25% with diabetes survived to age 30, whereas nearly 60% of people without diabetes reached this age Finkelstein et al J Pediatr 1988 Decreased Pulmonary Function Cross sectional analysis of 7566 people enrolled in the European Epidemiologic Registry of CF found lower FEV1% in those with DM vs those without DM at all ages (72% vs 52%) Koch et al Pediatr Pulmonol 2001

8. Screening for CFRD High Risk: Pre- and 2hr post-prandial glucose Hospitalized Oral or iv corticosteroids Pregnancy At least annual glucose screening for all patients with CF >10 years of age (LPCH >6 years of age) Hemoglobin A1c > 6.5 diagnostic for diabetes Hemoglobin A1c < 6.5 does not rule out diabetes or glucose impairment related to CF Moran A, et al. Diabetes Res Clin Pract. 1999.

9. Oral Glucose Tolerance Test Fasting, 30 minute, 1 hour, 2 hour blood draws after glucose beverage Most sensitive way to detect CFRD without fasting hyperglycemia Early Identification is important High risk for progression to fasting hyperglycemia High risk for excessive decline in pulmonary function Moran A, et al. Diabetes Res Clin Pract. 1999. Milla CE, et al. Am J Respir Crit Care Med. 2000.

10. Glucose Tolerance Categories in CF with OGTT

11. Glucose Tolerance Prevalence in Patients with CF 100 23 30 36 80 57 60 27 38 Percent Prevalence Within Age Group 38 40 27 34 20 20 15 6 15 16 11 3 0 5-9 10-19 20-29 30+ Age (years) Normal glucose tolerance Impaired glucose tolerance CFRD without fasting hyperglycemia Moran A, et al. J Pediatr. 1998. CFRD with fasting hyperglycemia

12. Insulin Secretion is Decreased in CF Patients With and Without Diabetes Insulin or C-peptide * * Control CF-PS CF-no DM CFRD PS=pancreatic sufficient DM=diabetes mellitus *P<0.001 vs control Moran A, et al. J Pediatr. 1991. .

13. Metabolic Consequences of Insulin deficiency in CF Malnourished or very sick CF patient 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, providing rationale for insulin treatment even in the face of relatively normal blood glucose levels. Moran et al: Diabetes 50:1336-1343,2001 Hardin et al: Pediatrics 101:433-437,1998

14. Insulin Therapy to Improve BMI in Cystic Fibrosis-Related Diabetes Without Fasting Hyperglycemia • n= 81 • People with CF and CFRD without fasting hyperglycemia were treated with insulin vs. Repaglinide or placebo • Insulin group showed improved BMI after one year of therapy whereas the group treated with Repaglinide did not Moran A. et al. Diabetes Care. 2009.

15. Goals of Medical Nutrition Therapy Achievement of optimal nutritional status Provision of sufficient calories Calorie restriction is never appropriate Near-normalization of blood glucose Management of hyperglycemia and hypoglycemia Necessary for energy balance Insulin is an anabolic hormone Flexible meal planning approach to optimize energy intake Meal plan should be based on usual food intake and patterns

16. Key Dietary Considerations No restrictions on calorie or total carbohydrate intake Consistent carbohydrate diets may not be feasible Consume high fat diet (35-40% of calories) Best option is carbohydrate counting with short acting pre-meal insulin to match carbohydrate intake Allows adequate calorie intake/flexible schedule

17. Improved Outcomes with More Aggressive Management • Minnesota data

18. Cystic Fibrosis-Related Diabetes: Current Trends in Prevalence, Incidence, and Mortality • Over the past 15 years, > 50% decrease in mortality in male and females with diabetes with absence of a sex difference • Mortality remains significantly higher in CF patients with diabetes compared to those without, but the gap has narrowed Moran A. et al. Diabetes Care. 2009.

19. What does more aggressive management mean? • Routine screening with annual oral glucose tolerance test (OGTT) for patients aged > 6 years • Careful inpatient glucose monitoring and use of insulin as needed • Early institution of intensive insulin therapy has become more routine in the last 5 years • Pre-meal insulin is prescribed for those with CFRD without fasting hyperglycemia

20. LPCH/Stanford Protocol for Diabetes Management • Annual OGTT for patients > 6 years • Endocrine consult for those with OGTT indicating CFRD without fasting hyperglycemia or CFRD • Inpatient Screening for CFRD • Monitor fasting BG and 2 hour post meal for 48 hours upon admission to the hospital

21. Summary • Early screening may help identify folks at risk for developing glucose abnormalites • Early treatment of glucose abnormalities may improve nutrition and pulmonary outcomes • New diabetes screening and treatment guidelines are being developed by a CFF consensus committee so…. Stay Tuned!