Cystic Fibrosis-Related Diabetes (CFRD)

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
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Prevalence of CFRD (2003)

• 16.9 of CF patients gt13 in the US have CFRD
  requiring insulin therapy
• Population of 21,742 at 117 US care centers
• 2003 CF Foundation Patient Registry Annual Report

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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 gt 13 years old
• 25 of CF patients 35-44 years old
• Estimates have been as high as 43 of CF patients
  gt 30 years

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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
• Caloric intake needs to be maintained to meet
  metabolic demands of CF
• 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
• Insulin is required for CFRD

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Comparison of CFRD to Types 1 and 2 Diabetes
Type 1 Type 2 CFRD
Most common age of onset lt20 gt40 18-21
Usual Body Habitus Normal Obese Thin
Insulin secretion Absent
Insulin sensitivity
Autoimmune etiology Yes No No
Ketoacidosis Yes Rare Rare
Microvascular complications Yes Yes Yes
Macrovascular complications Yes Yes No?
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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

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Cystic Fibrosis Related DiabetesInsulin
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?

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Insulin Secretion in CF
Insulin Or C-Peptide
(PSpancreatic sufficient)
12
Insulin Sensitivity in CF


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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

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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.

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Median Survival in CFRDUniversity 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
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Outcome of those with CFRD diagnosed in childhood

• Mean Current age 19.2 yrs (12-29)
• Mean Age of diagnosis 14.2 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
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Adolescent Outcome

• Those with Current age lt20
• Mean Age 15.2
• Mean Age of diagnosis 14.0
• Mean A1c 7.2/
  6.7

Minus A1c12
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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.

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CFRDDenver

• The Childrens 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

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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

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CFRDPediatrics 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

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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.

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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.

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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.

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                   Figure 2 Adverse impact of
CFRD on female predicted FEV1 percentage when
stratified by chronic P. aeruginosa (PA)
infection. A Chronic P. aeruginosafree females
and males. B Chronic P. aeruginosapresent
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 281581-87, 2005.
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Survival Curves for Subjects with CF
                                                
                   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 282141-2144, 2005
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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 282141, 2005

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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.

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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

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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 (Plt0.001)
• 3. More pulmonary exacerbations treated with
  parental antibiotics.
• 4. Higher prevalence of pseudomonas, Burkhdderia
  cepacia, Candida, and Aspergillus.

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Nutritional Status of patients with CFRD

• 1. Lower mean height-for-age percentile
• 2. Lower mean weight-for-age percentile
• 3. Lower BMI

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Epidemiology of CFRD

• Marshal et al. Journal of Pediatrics 146681, May
  2005
• Data gathered from 8247 patients in the
  Epidemiologic Study of Cystic Fibrosis

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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

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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.

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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

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Medical interventions and comorbid medical
conditions in CFRD
Therapy CFRD Group (n7067) Non-CFRD group (n1180) Age-Adjusted p value
Pulmozyme (dornase) 57.6 49.8 lt.001
Airway Clearance 90.7 84.3 lt.001
Mast Cell Stabilizer 20.3 17.5 lt.001
BD (oral) 21.5 13.7 lt.001
BD (Inhaled) 91.5 84.3 lt.001
NSAID 10.6 9.6 .206
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(table cont.)
Therapy CFRD Group (n7067) Non-CFRD group (n1180) Age-Adjusted p value
Oral supplement 40.5 32.7 lt.001
Enteral Supplements 11.7 7.7 lt.001
Parental supplements 2.4 0.9 lt.001
Steroids(oral) 27.6 17.9 lt.001
Steroids (Inhaled) 48.9 39.6 lt.001
Contraceptives 12.7 7.0 lt.001
Oxygen 24.2 9.7 lt.001
Diuretic 5.5 1.0 lt.001
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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

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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

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Glucose Tolerance in CF
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Evaluation for Diabetes in CF

• Annual random glucose beginning at age 10
• If the random glucose is gt 125
• Obtain oral glucose tolerance test
• At all admissions for illness, check random
  glucose
• Diabetes
• Fasting glucose gt 125
• 2 hour glucose gt 200

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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.

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Oral Glucose Tolerance Categories in Cystic
Fibrosis

• Category FBG 2-h PG
• mg/dl (mM) mg/dl (mM)

Normal Glucose Tolerance (NGT)
lt126 (7.0) lt140 (7.8) Impaired
Glucose Tolerance lt126 (7.0)
140-199 (7.8-11.1) CFRD Without Fasting
Hyperglycemia lt126 (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.
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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 gt 200mg/dl (11.1 mM).
• Casual glucose levels 200 mg/dl (11.1 mM) on
  two or more occasions with symptoms.

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Glucose Tolerance Prevalence
3
---6
11
15
16
15
20
34
27
38
38
27
57
36
30
23
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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
  patients eating pattern and lifestyle

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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

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Team Care of CFRD

• Diabetic glucose tolerance test
• Referred to diabetes team
• Physician
• Dietitian
• Diabetes nurse - liaison with the diabetes
  team
• Medical social worker

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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.

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Principles of Dietary treatment in CFRD compared
with DM
Nutrient NON-CFRD CFRD
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
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Principles of Dietary treatment in CFRD compared
with DM (cont.)
Refined CHO Restriction to lt 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 intake Increased intake
CHO, carbohydrate
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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!