Cystic Fibrosis-Related Diabetes
(CFRD)
Robert Slover, M.D.
Keystone
2006
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
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
Survival of Patients with Cystic Fibrosis
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
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
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
Comparison of CFRD to Types 1 and 2 Diabetes
Type 1
<20
Type 2
>40
CFRD
18-21
Usual Body Habitus
Normal
Obese
Thin
Insulin secretion
Absent
Most common age of
onset
Insulin sensitivity
Autoimmune etiology
Yes
No
No
Ketoacidosis
Microvascular
complications
Yes
Yes
Rare
Yes
Rare
Yes
Macrovascular
complications
Yes
Yes
No?
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
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?
Insulin Secretion in CF
Insulin
CONT
CF-PS
CF-no DM
CFRD
Or
C-Peptide
CONT
CF-PS
CF-no DM
(PS=pancreatic sufficient)
CFRD
Insulin Sensitivity in CF
Rd AUC mg/kg/min
8000
*
6000
*
4000
2000
0
CONT
CF
CFRD
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’
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.
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
Outcome of those with CFRD
diagnosed in childhood
Mean Current age
Mean Age of diagnosis
Current A1c
19.2 yrs (12-29)
14.2 yrs (8-19)
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
Adolescent Outcome
Those with Current age <20
Mean Age
Mean Age of diagnosis
Mean A1c
15.2
14.0
7.2/ 6.7*%
*Minus A1c=12%
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.
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
Outcomes in CFRD in Denver
Median age of diagnosis:
Mean Current age
Mean Duration
Mean A1c
15.0 (11-40)
26.1 (12-54)
5.6
7.0 %
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%
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.
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.
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.
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 centermatched 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.
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 28:2141-2144, 2005
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
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.
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
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.
Nutritional Status of patients
with CFRD
1. Lower mean height-for-age percentile
2. Lower mean weight-for-age percentile
3. Lower BMI
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
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
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.
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
Medical interventions and comorbid
medical conditions in CFRD
Therapy
CFRD Group
(n=7067)
Non-CFRD
Age-Adjusted p
group (n=1180) 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%
91.5%
10.6%
13.7%
84.3%
9.6%
<.001
<.001
.206
BD (Inhaled)
NSAID
(table cont.)
Therapy
CFRD Group
(n=7067)
Non-CFRD
group (n=1180)
Age-Adjusted p
value
Oral supplement
40.5%
11.7%
32.7%
7.7%
<.001
<.001
Parental
supplements
2.4%
0.9%
<.001
Steroids(oral)
27.6%
48.9%
17.9%
39.6%
<.001
<.001
Contraceptives
12.7%
7.0%
<.001
Oxygen
24.2%
9.7%
<.001
Diuretic
5.5%
1.0%
<.001
Enteral
Supplements
Steroids
(Inhaled)
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
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
Glucose Tolerance in CF
280
240
200
CFRD with FH
CFRD without FH
IGT
NGT
160
120
80
40
0
0
30
60
90
120
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
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.
Oral Glucose Tolerance Categories
in Cystic Fibrosis
Category
FBG
mg/dl (mM)
Normal Glucose Tolerance (NGT)
2-h PG
mg/dl (mM)
<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
necessary
≥126 (7.0)
OGTT not
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.
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.
Glucose Tolerance Prevalence
3%
|
---6%
11%
15%
34%
15%
16%
20%
27%
38%
38%
27%
57%
36%
23%
5 to 9
10 to 19
20 to 29
30%
30 +
CFRD-FH
CFRD-no FH
IGT
NGT
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
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
Team Care of CFRD
Diabetic glucose tolerance test
Referred to diabetes team
Physician
Dietitian
Diabetes nurse - liaison with the
diabetes team
Medical social worker
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.
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
Principles of Dietary treatment in CFRD
compared with DM (cont.)
Refined CHO
Restriction 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 intake
Increased intake
CHO, carbohydrate
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!