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 therapyPopulation 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 complication4.4% (1992) to 12% (2002)(173% increase)

Prevalence increases with age14% of CF patient > 13 years old25% 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

Type 1 Type 2 CFRDMost common age of onset <20 >40 18-21Usual Body Habitus Normal Obese ThinInsulin secretion AbsentInsulin sensitivity

Autoimmune etiology Yes No NoKetoacidosis Yes Rare RareMicrovascular complications Yes Yes YesMacrovascular complications Yes Yes No?

Comparison of CFRD to Types 1 and 2 Diabetes

Factors Unique to CF

Under nutritionChronic inflammation with intermittent acute

infectionGlucagon deficiencyAltered gut nutrient absorption and transit timeLiver diseaseIncreased energy expenditureThin, 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 cellsCFRD 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 CFInsulin Secretion in CF

CONT CF-PS CF-no DM CFRD

CONTCF-PSCF-no DMCFRD

(PS=pancreatic sufficient)

Insulin

Or

C-Peptide

Insulin Sensitivity in CF

0

2000

4000

6000

8000

CONT CF CFRD

Rd

AU

C m

g/

kg

/m

in

*

*

CFRD: Caveats

DKA rarePoor 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 CFRDUniversity of Minnesota 1988-2003

Total Cohort 47.0 YearsWomen with Diabetes 30.7 Years

Women without Diabetes 47.0 Years Men with Diabetes 47.4 YearsMen 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 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 controlis difficult to maintain in young adulthoodwhen 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 15.2

Mean Age of diagnosis 14.0

Mean A1c 7.2/ 6.7*%

*Minus A1c=12%

Lanng data, DenmarkWeight 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 CenterOver 500 children and young adults

6% with CFRD (15% reported in literature, 40% with ‘prediabetes’)

Newborn Colorado screening program

National Jewish Hospital CF Program200 adults with CF50% with CFRD

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 %

CFRDPediatrics Clinic - BDC

Total patients = 26; (12 male, 14 female)

Mean age at last visit = 16.3Seen 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 DeficiencyInsulin 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 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.

                                                                  

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

Gender difference in survival with CFRD

Males without CFRD – 49.5 yearsMales with CFRD – 47.4 years

Females without CFRD – 47.0 yearsFemales 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 CFRD1. Prevalence of CFRD is higher in patients with

more severe pulmonary disease.

2. CFRD population has worse pulmonary funtionFEV1 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 percentile2. Lower mean weight-for-age percentile3. 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 population12% 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 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% <.001BD (Inhaled) 91.5% 84.3% <.001NSAID 10.6% 9.6% .206

(table cont.)

Therapy CFRD Group

(n=7067)

Non-CFRD group (n=1180)

Age-Adjusted p value

Oral supplement 40.5% 32.7% <.001Enteral Supplements

11.7% 7.7% <.001

Parental supplements

2.4% 0.9% <.001

Steroids(oral) 27.6% 17.9% <.001Steroids (Inhaled)

48.9% 39.6% <.001

Contraceptives 12.7% 7.0% <.001

Oxygen 24.2% 9.7% <.001Diuretic 5.5% 1.0% <.001

Long term side effects of CFRD

Decreased life expectancy from pulmonary complicationswithout diabetes, 60% live to 30 years25% with diabetes survive to age 30

Also subject to the microvasular complications of diabetes hyperglycemiaRetinopathy, nephropathy, gastroparesis

Current Goals of TherapyDetermine 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

0

40

80

120

160

200

240

280

0 30 60 90 120

CFRD with FHCFRD without FHIGTNGT

Evaluation for Diabetes in CF

Annual random glucose beginning at age 10If the random glucose is > 125

Obtain oral glucose tolerance test

At all admissions for illness, check random glucose

DiabetesFasting glucose > 1252 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 ratePatients with delayed pubertyPatients with declining pulmonary function

studiesPatients whose fasting glucose level exceeds

125All women planning pregnancy or pregnant.

Oral Glucose Tolerance Categories in Cystic Fibrosis

Category FBG 2-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 necessaryThe 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

5 to 9 10 to 19 20 to 29 30 +

CFRD-FHCFRD-no FHIGTNGT

57%

34%

---6%

3% |

36%

38%

15%

11%

23%

38%

20%

15%

30%

27%

27%

16%

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 testReferred to diabetes team

PhysicianDietitianDiabetes nurse - liaison with the

diabetes teamMedical 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 CFRDEnergy 100% of RDA or less if

overweight120-150% 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.

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