Clinical Care Guidelines for Cystic Fibrosis-Related Diabetes
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Reviews/Commentaries/ADA Statements
P O S I T I O N S T A T E M E N T
Clinical Care Guidelines for Cystic
Fibrosis–Related Diabetes
A position statement of the American Diabetes Association and a clinical
practice guideline of the Cystic Fibrosis Foundation, endorsed by the
Pediatric Endocrine Society
ANTOINETTE MORAN, MD1 KAREN A. ROBINSON, PHD6 guidelines were used when available and
CAROL BRUNZELL, RD, LD, CDE1 KATHRYN A. SABADOSA, MPH7 appropriate, and these are indicated as
RICHARD C. COHEN, MD2 ARLENE STECENKO, MD8 consensus statements. The committee
MARCIA KATZ, MD3 BONNIE SLOVIS, MD9 also made consensus recommendations
BRUCE C. MARSHALL, MD4 THE CFRD GUIDELINES COMMITTEE for topics not included in the evidence
GARY ONADY, MD, PHD5
reviews or for which limited evidence was
available in the literature. Recommenda-
tions will be updated as warranted by new
C
ystic fibrosis–related diabetes partners, and health care professionals evidence, and the guidelines will be re-
(CFRD) is the most common co- and include recommendations for screen- viewed 3 years after release date to deter-
morbidity in people with cystic fi- ing, diagnosis, and medical management mine if an update is needed. A summary
brosis (CF), occurring in ⬃20% of of CFRD. This report focuses on aspects of of the committee’s recommendations is
adolescents and 40 –50% of adults (1). care unique to CFRD. A comprehensive presented in Table 2.
While it shares features of type 1 and type summary of recommendations for all peo-
2 diabetes, CFRD is a distinct clinical en- ple with diabetes can be found in the ADA
SCREENING — CFRD is often clini-
tity. It is primarily caused by insulin in- Standards of Medical Care, published
cally silent. In other populations, the pri-
sufficiency, although fluctuating levels of annually in the January supplement to
mary consequences of unrecognized
insulin resistance related to acute and Diabetes Care (5).
diabetes are macrovascular and microvas-
chronic illness also play a role. The addi-
cular disease. In CF, the nutritional and
tional diagnosis of CFRD has a negative METHODS — In 2009, CFF in collab-
pulmonary consequences of diabetes are
impact on pulmonary function and sur- oration with ADA and PES convened a
of greater concern. CFRD is associated
vival in CF, and this risk disproportion- committee of CF and diabetes experts to
with weight loss, protein catabolism, lung
ately affects women (2– 4). In contrast to update clinical care guidelines for CFRD.
function decline, and increased mortality
patients with other types of diabetes, Investigators at Johns Hopkins University
(2,3,7–17), and thus regular screening is
there are no documented cases of death conducted evidence reviews on relevant
warranted.
from atherosclerotic vascular disease in clinical questions identified by the guide-
patients with CFRD, despite the fact that lines committee. The reviews were pro-
some now live into their sixth and seventh vided to the committee to use in Screening tests for CFRD
decades. developing recommendations. Where Although hemoglobin A1C (A1C) may
These guidelines are the result of a possible, the evidence for each recom- become the standard screening test for
joint effort between the Cystic Fibrosis mendation was considered and graded by type 2 diabetes (5), the committee con-
Foundation (CFF), the American Diabe- the committee using the ADA (5) and the cluded that it is not sufficiently sensitive
tes Association (ADA), and the Pediatric U.S. Preventive Services Task Force (USP- for diagnosis of CFRD and thus should
Endocrine Society (PES). They are in- STF) (6) grading systems (Table 1). Rec- not be used as a screening test. Eight stud-
tended for use by CF patients, their care ommendations from existing published ies were identified that assessed A1C as a
screening test in this population (7,18 –
● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●
24). The authors of one prospective co-
From the 1Division of Pediatric Endocrinology, University of Minnesota, Minneapolis, Minnesota; 2Kaiser hort study of 62 participants with CF and
Permanente, Portland, Oregon; the 3Department of Medicine, Baylor College of Medicine, Houston,
Texas; 4Cystic Fibrosis Foundation, Bethesda, Maryland; 5Wright State University Boonshoft School of 107 healthy control subjects reported that
Medicine, Dayton, Ohio; the 6Department of Medicine, Johns Hopkins University, Baltimore, Maryland; A1C levels were higher in the CF group
the 7Department of Community and Family Medicine, The Dartmouth Institute for Health Policy and than among the control subjects, leading
Clinical Practice, Lebanon, New Hampshire; the 8Department of Medicine, Emory University, Atlanta, them to suggest that the use of A1C was
Georgia; and the 9Department of Medicine, Vanderbilt University, Nashville, Tennessee.
Corresponding author: Antoinette Moran, moran001@umn.edu.
appropriate (18). However, six studies
Reviewed by the Professional Practice Committee, July 2010; accepted after revisions by the Executive (including two prospective cohort stud-
Committee of the American Diabetes Association Board of Directors, September 2010; open for public ies [7,21], two cross-sectional studies
comments on the Cystic Fibrosis Foundation Web site, July 2010; and endorsed by the Board of Directors [19,20], one case-control study [23], and
of the Pediatric Endocrine Society, September 2010. one case series [22[) with a total of 477
DOI: 10.2337/dc10-1768
© 2010 by the American Diabetes Association. Readers may use this article as long as the work is properly participants demonstrated low degrees of
cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons. correlation between A1C and glucose tol-
org/licenses/by-nc-nd/3.0/ for details. erance status (7,19 –23). Additionally, a
See accompanying articles, pp. 2660, 2677, 2716. cross-sectional study of 191 participants
care.diabetesjournals.org DIABETES CARE, VOLUME 33, NUMBER 12, DECEMBER 2010 2697Clinical care of CFRD
Table 1—Evidence-grading system for clinical practice recommendations
ADA classification system
Level of
evidence Description
A Clear evidence from well-conducted, generalizable, randomized, controlled trials that are adequately powered, including
● Evidence from a well-conducted multicenter trial
● Evidence from a meta-analysis that incorporated quality ratings in the analysis
Compelling nonexperimental evidence, i.e., “all-or-none” rule developed by the Centre for Evidence-Based Medicine at Oxford
Supportive evidence from well-conducted, randomized, controlled trials that are adequately powered, including
● Evidence from a well-conducted trial at one or more institutions
● Evidence from a meta-analysis that incorporated quality ratings in the analysis
B Supportive evidence from well-conducted cohort studies, including
● Evidence from a well-conducted prospective cohort study or registry
● Evidence from a well-conducted meta-analysis of cohort studies
Supportive evidence from a well-conducted case-control study
C Supportive evidence from poorly controlled or uncontrolled studies, including
● Evidence from randomized clinical trials with one or more major or three or more minor methodological flaws that could
invalidate the results
● Evidence from observational studies with high potential for bias (such as case series with comparison with historical controls)
Conflicting evidence with the weight of evidence supporting the recommendation
E Expert consensus or clinical experience
USPSTF recommendation classification system
Estimate of effect
Quality of evidence Substantial Moderate Small Zero/negative*
High A B C D
Moderate B B C D
Low Insufficient (I)
*A study with significant findings against something is given a grade of D.
with CF demonstrated a low positive pre- A1C and other tests, the oral glucose tol- glucose (maximum 75 g) dissolved in wa-
dictive value of the A1C test (24). erance test (OGTT) is the screening test of ter and sits or lies quietly for 2 h. Glucose
choice for CFRD. Although it is an imper- levels are measured at baseline and 2 h.
Use of A1C as a screening test for fect test due to the inherent variability of Unless the patient is experiencing classi-
CFRD is not recommended. (ADA-B; the test and the variability observed in indi- cal symptoms of polyuria and polydipsia
USPSTF-D) vidual CF patients over time, longitudinal in the presence of a glucose level ⬎200
studies demonstrate that a diabetes diagno- mg/dl (11.1 mmol/l) or has two more di-
Fructosamine, urine glucose, and random agnostic criteria for diabetes (such as both
sis by OGTT correlates with clinically im-
glucose levels have low sensitivity in the fasting and 2-h glucose elevation or a di-
CF population (20,23,25). Continuous portant CF outcomes including the rate of
lung function decline over the next 4 years abetes pattern on OGTT in the presence
glucose monitoring is not recommended of an A1C level ⬎6.5%), the test should
as a screening tool because intermittent (12), the risk of microvascular complica-
tions (27), and the risk of early death (1,2). be confirmed by repeat testing.
hyperglycemia detected in this fashion is
not diagnostic for diabetes and there are In a multicenter, multinational study, the
OGTT identified patients who benefited Screening for CFRD should be
no outcome data to determine its clinical performed using the 2-h 75-g OGTT.
significance. Fasting plasma glucose from insulin therapy (28).
(ADA-E; Consensus)
(FPG) identifies patients with CFRD with The OGTT should be performed in
but not those without fasting hyperglyce- the morning during a period of stable The age of screening for CFRD
mia (FH), and thus this test will miss the baseline health (at least 6 weeks since an Three studies with a total of 811 partici-
diagnosis of diabetes in approximately acute exacerbation) using the World pants were identified that provided infor-
half of CF patients (1). Self-monitoring of Health Organization protocol (5). Pa- mation about the appropriate age at which
blood glucose (SMBG) with home meters tients fast for at least 8 h (water is permit- to start screening for CFRD (1,21,24).
is also not sufficiently accurate to screen ted) and should consume a minimum of These studies—a retrospective cohort study
for CFRD given that the International Or- 150 g (600 kcal) of carbohydrate per day (1), a prospective cohort study (21), and a
ganization for Standardization only re- for the preceding 3 days (generally not an cross-sectional study (24)—reported a sig-
quires that 95% of readings be within issue because CF patients have high- nificantly higher prevalence and incidence
20% of the actual glucose level (26). calorie diets). The patient drinks a stan- of CFRD beyond the first decade of life.
Because of the poor performance of dard beverage containing 1.75 g/kg Screening included both pancreatic suffi-
2698 DIABETES CARE, VOLUME 33, NUMBER 12, DECEMBER 2010 care.diabetesjournals.orgMoran and Associates
Table 2—Summary of recommendations for the clinical care of CFRD
Screening recommendations
1. The use of A1C as a screening test for CFRD is not recommended. (ADA-B; USPSTF-D)
2. Screening for CFRD should be performed using a 2-h 75-g OGTT. (ADA-E; Consensus)
3. Annual screening for CFRD should begin by age 10 years in all CF patient s who do not have CFRD. (ADA B; USPSTF-B)
4. CF patients with acute pulmonary exacerbation requiring intravenous antibiotics and/or systemic glucocorticoids should be screened for
CFRD by monitoring fasting and 2-h postprandial plasma glucose levels for the first 48 h. If elevated blood glucose levels are found by
SMBG, the results must be confirmed by a certified laboratory. (ADA-E; Consensus)
5. Screening for CFRD by measuring mid- and immediate postfeeding plasma glucose levels is recommended for CF patients on
continuous enteral feedings, at the time of gastrostomy feeding initiation and then monthly by SMBG. Elevated glucose levels detected
by SMBG must be confirmed by a certified laboratory. (ADA-E; Consensus)
6. Women with CF who are planning a pregnancy or confirmed pregnant should be screened for preexisting CFRD with a 2-h 75-g fasting
OGTT if they have not had a normal CFRD screen in the last 6 months. (ADA-E; Consensus)
7. Screening for gestational diabetes mellitus is recommended at both 12–16 weeks’ and 24–28 weeks’ gestation in pregnant women with
CF not known to have CFRD, using a 2-h 75-g OGTT with blood glucose measures at 0, 1, and 2 h. (ADA-E; Consensus)
8. Screening for CFRD using a 2-h 75-g fasting OGTT is recommended 6–12 weeks after the end of the pregnancy in women with
gestational diabetes mellitus (diabetes first diagnosed during pregnancy). (ADA-E; Consensus)
9. CF patients not known to have diabetes who are undergoing any transplantation procedure should be screened preoperatively by OGTT
if they have not had CFRD screening in the last 6 months. Plasma glucose levels should be monitored closely in the perioperative
critical care period and until hospital discharge. Screening guidelines for patients who do not meet diagnostic criteria for CFRD at the
time of hospital discharge are the same as for other CF patients. (ADA-E; Consensus)
Diagnosis recommendations
1. During a period of stable baseline health the diagnosis of CFRD can be made in CF patients according to standard ADA criteria. Testing
should be done on 2 separate days to rule out laboratory error unless there are unequivocal symptoms of hyperglycemia (polyuria and
polydipsia); a positive FPG or A1C can be used as a confirmatory test, but if it is normal the OGTT should be performed or repeated. If
the diagnosis of diabetes is not confirmed, the patient resumes routine annual testing. (ADA-E; Consensus)
● 2-h OGTT plasma glucose ⱖ200 mg/dl (11.1 mmol/l)
● FPG ⱖ126 mg/dl (7.0 mmol/l)
● A1C ⱖ 6.5% (A1C ⬍6.5% does not rule out CFRD because this value is often spuriously low in CF.)
● Classical symptoms of diabetes (polyuria and polydipsia) in the presence of a casual glucose level ⱖ200 mg/dl (11.1 mmol/l)
2. The diagnosis of CFRD can be made in CF patients with acute illness (intravenous antibiotics in the hospital or at home, systemic
glucocorticoid therapy) when FPG levels ⱖ126 mg/dl (7.0 mmol/l) or 2-h postprandial plasma glucose levels ⱖ200 mg/dl (11.1 mmol/
l) persist for more than 48 h. (ADA-E; Consensus)
3. The diagnosis of CFRD can be made in CF patients on enteral continuous drip feedings when mid- or postfeeding plasma glucose levels
exceed 200 mg/dl (11.1 mmol/l) on 2 separate days. (ADA-E; Consensus)
4. Diagnosis of gestational diabetes mellitus should be made based on the recommendations of the IADPSG (45) where diabetes is
diagnosed based on 0-, 1-, and 2-h glucose levels with a 75-g OGTT if any one of the following is present:
● FPG ⱖ92 mg/dl (5.1 mmol/l)
● 1-h plasma glucose ⱖ180 mg/dl (10.0 mmol/l)
● 2-h plasma glucose ⱖ153 mg/dl (8.5 mmol/l) (ADA-E; Consensus)
CF patients with gestational diabetes mellitus are not considered to have CFRD, but require CFRD screening 6–12 weeks after the end
of the pregnancy. (ADA-E; Consensus)
5. Distinguishing between CFRD with and without FH is not necessary. (ADA-B, USPSTF-D)
6. The onset of CFRD should be defined as the date a person with CF first meets diagnostic criteria, even if hyperglycemia subsequently
abates. (ADA-E; Consensus)
Management recommendations
1. Patients with CFRD should ideally be seen quarterly by a specialized multidisciplinary team with expertise in diabetes and CF. (ADA-E;
Consensus)
2. Patients with CFRD should receive ongoing diabetes self-management education from diabetes education programs that meet national
standards for DSME. (ADA-E; Consensus)
3. Patients with CFRD should be treated with insulin therapy. (ADA-A; USPSTF-B)
4. Oral diabetes agents are not as effective as insulin in improving nutritional and metabolic outcomes in CFRD and are not recommended
outside the context of clinical research trials. (ADA-A; USPSTF-D)
5. Patients with CFRD who are on insulin should perform SMBG at least three times a day. (ADA-E; Consensus)
6. Patients with CFRD should strive to attain plasma glucose goals as per the ADA recommendations for all people with diabetes, bearing
in mind that higher or lower goals may be indicated for some patients and that individualization is important. (ADA-E; Consensus)
7. A1C measurement is recommended quarterly for patients with CFRD. (ADA-E; Consensus)
8. For many patients with CFRD, A1C treatment goal is ⬍7%, bearing in mind that higher or lower goals may be indicated for some
patients and that individualization is important. (ADA-B; USPSTF-B)
9. CFF evidence-based guidelines for nutritional management are recommended for patients with CFRD. (ADA-E; Consensus)
10. Patients with CFRD should be advised to do moderate aerobic exercise for at least 150 min per week. (ADA-E; Consensus)
(continued on following page)
care.diabetesjournals.org DIABETES CARE, VOLUME 33, NUMBER 12, DECEMBER 2010 2699Clinical care of CFRD
Table 2—Continued
Diabetes complications recommendations
1. Education about the symptoms, prevention, and treatment of hypoglycemia, including the use of glucagon, is recommended for
patients with CFRD and their care partners. (ADA-E; Consensus)
2. Patients with CFRD should have their blood pressure measured at every routine diabetes visit as per ADA guidelines. Patients found to
have systolic blood pressure ⱖ130 mmHg or diastolic blood pressure ⱖ80 mmHg or ⬎90th percentile for age and sex for pediatric
patients should have repeat measurement on a separate day to confirm a diagnosis of hypertension. (ADA-E; Consensus)
3. Annual monitoring for microvascular complications of diabetes is recommended using ADA guidelines, beginning 5 years after the
diagnosis of CFRD or, if the exact time of diagnosis is not known, at the time that FH is first diagnosed. (ADA-E; Consensus)
4. Patients with CFRD diagnosed with hypertension or microvascular complications should receive treatment as recommended by ADA for
all people with diabetes, except that there is no restriction of sodium and, in general, no protein restriction. (ADA-E; Consensus)
5. An annual lipid profile is recommended for patients with CFRD and pancreatic exocrine sufficiency or if any of the following risk
factors are present: obesity, family history of coronary artery disease, or immunosuppressive therapy following transplantation. (ADA-E;
Consensus)
cient and insufficient patients. The commit- confirmed by laboratory plasma glucose not produce the extra insulin required to
tee concluded that these findings suggest measurement. meet this demand (31–33). In addition to
that annual screening for CFRD should start the usual concerns about the effect of hy-
CF patients with acute pulmonary
by age 10 years in all CF patients. Because perglycemia on the fetus, diabetes can ex-
exacerbation requiring intravenous
clinical deterioration in nutritional and pul- acerbate the difficulties many women
antibiotics and/or systemic
monary status begins 6 –24 months prior to with CF have in achieving a positive pro-
glucocorticoids should be screened for
a diagnosis of CFRD (29,30), early detec- tein balance and sufficient weight gain
CFRD by monitoring fasting and 2-h
tion by annual screening is warranted. during pregnancy (32).
postprandial plasma glucose levels for
Women with CF not known to have
the first 48 h. If elevated blood glucose
Annual screening for CFRD should CFRD who are contemplating pregnancy
levels are found by SMBG, the results
begin by age 10 years in all CF should be evaluated prior to conception
must be confirmed by a certified
patients who do not have CFRD. to rule out preexisting CFRD or be tested
laboratory. (ADA-E; Consensus)
(ADA-B; USPSTF-B) immediately upon confirmation of the
Screening of CF patients during pregnancy if they have not had an OGTT
Screening of CF patients during continuous drip enteral feedings in the previous 6 months. Because women
acute illness Supplemental continuous drip feedings are with CF are at high risk for development
CF patients experience frequent pulmo- commonly prescribed for malnourished CF of hyperglycemia during pregnancy (ges-
nary exacerbations, some of which patients. Although there are few data avail- tational diabetes mellitus), the 2-h 75-g
require treatment either in the hospital or able specific to this situation, mid-feeding OGTT should be performed at the end of
at home with intravenous antibiotics. hyperglycemia may compromise efforts to both the first and second trimesters.
Treatment at times includes systemic glu- gain weight. The Committee felt that glu-
cocorticoids. In clinical experience, hyper- cose levels in the middle and immediately Women with CF who are planning a
glycemia that develops during acute illness after the gastrostomy tube feeding should pregnancy or confirmed pregnant
occasionally resolves after a day or two of be measured in the hospital and at these should be screened for preexisting
medical therapy, but usually lasts for at least same time points once a month at home CFRD with a 2-h 75-g fasting OGTT
2– 6 weeks. CF patients are frequently ill, using SMBG. SMBG levels are not suffi- if they have not had a normal CFRD
and hyperglycemia returns with each sub- ciently accurate to make a diagnosis of screen in the last 6 months. (ADA-E;
sequent bout of illness, often several times a CFRD, and hyperglycemia detected by Consensus)
year. Insulin deficiency and insulin resis- SMBG should be confirmed by laboratory
tance generally progress over time. Long- plasma glucose measurement.
term microvascular (27) and pulmonary Screening for gestational diabetes
(1,2) outcomes correlate with duration of Screening for CFRD by measuring mellitus is recommended at both
CFRD first diagnosed during acute illness, mid- and immediate postfeeding 12–16 weeks’ and 24 –28 weeks’
even with intervening periods of normal or plasma glucose levels is recommended gestation in pregnant women with
impaired glucose tolerance (IGT). for CF patients on continuous enteral CF not known to have CFRD, using
During acute illness and/or a pulse of feedings, at the time of gastrostomy a 2-h 75-g OGTT with blood glucose
systemic glucocorticoid therapy, glucose tube feeding initiation and then measures at 0, 1, and 2 h. (ADA-E;
levels should be monitored for at least the monthly at home. Elevated glucose Consensus)
first 48 h, preferably fasting and 2 h post- levels detected by SMBG must be
prandially. If glucose levels do not meet confirmed by a certified laboratory. Screening for CFRD using a 2-h 75-g
diagnostic criteria for CFRD, testing can (ADA-E; Consensus) fasting OGTT is recommended 6 –12
be discontinued after 48 h. For patients weeks after the end of the pregnancy
receiving therapy at home, SMBG can be Screening CF patients who are in women with gestational diabetes
performed. However, SMBG levels are not pregnant or planning a pregnancy mellitus (diabetes first diagnosed
sufficiently accurate to make a diagnosis Pregnancy is a state of marked insulin re- during pregnancy). (ADA-E;
of CFRD, and hyperglycemia should be sistance, and many women with CF can- Consensus)
2700 DIABETES CARE, VOLUME 33, NUMBER 12, DECEMBER 2010 care.diabetesjournals.orgMoran and Associates
Figure 1—Criteria for the diagnosis of CFRD under different conditions.
Screening CF patients undergoing Screening guidelines for patients tal children with CF both IGT and INDET
transplantation who do not meet diagnostic criteria are associated with early-onset CFRD (40).
There is an almost universal require- for CFRD at the time of hospital dis-
ment for insulin in the immediate criti- charge are the same as for other CF
cal care postoperative period in CF patients. (ADA-E; Consensus) Criteria for the diagnosis of CFRD in
patients undergoing transplantation stable outpatients
procedures, and many have long-term ADA has established diagnostic criteria
insulin requirements after transplanta- DIAGNOSIS (Fig. 1) for diabetes that include specific fasting
tion (34 –36). A diagnosis of CFRD glucose levels, 2-h OGTT glucose levels
prior to transplantation may increase The spectrum of glucose tolerance (5), and A1C levels. They are based on the
complications of surgery and has a neg- abnormalities in CF population risk of microvascular disease,
ative impact on survival, at least in the Diabetes is part of a continuum of glucose and patients with CF are also at risk for
early postoperative period when infec- tolerance abnormalities defined by ADA these complications (27,41– 43). The
tion, bleeding, and multiorgan failure (supplementary Table 1, available at http:// committee questioned whether the diag-
are the most common causes of death care.diabetesjournals.org/cgi/content/full/ nostic thresholds should be lower for the
(34,37). Aggressive management may dc10-1768/DC1). Few CF patients have CF population as CFRD is known to have
have a positive impact on outcomes truly “normal” glucose tolerance. Many pa- a negative impact on CF pulmonary status
(35). tients with normal fasting and 2-h glucose (2,10,11), given that pulmonary disease
levels have elevation in the middle of the is the chief morbidity in CFRD. Even less
OGTT (indeterminate glycemia [INDET]) severe glucose tolerance abnormalities
CF patients not known to have dia- or when assessed randomly or by continu- such as IGT are associated with lung func-
betes who are undergoing any trans- ous glucose monitoring. Impaired fasting tion decline (12,17). However, sufficient
plantation procedure should be glucose (IFG) (100 –125 mg/dl [5.6 – 6.9 outcome-based data are not available at
screened preoperatively by OGTT if mmol/l[) may also be present (20,38). The present to determine whether more strin-
they have not had CFRD screening in clinical significance of IFG or INDET in CF gent diagnostic glucose thresholds more
the last 6 months. Plasma glucose is not known. In the general population, appropriately reflect risk for the CF
levels should be monitored closely they are considered pre-diabetic condi- population.
in the perioperative critical care pe- tions, associated with a high risk of future During a period of stable baseline
riod and until hospital discharge. development of diabetes (39). In prepuber- health, the diagnosis of CFRD can be
care.diabetesjournals.org DIABETES CARE, VOLUME 33, NUMBER 12, DECEMBER 2010 2701Clinical care of CFRD
made in CF patients according to stan- Gestational diabetes mellitus in CF Distinguishing between CFRD with
dard ADA criteria. Testing should be In the general population, the Hypergly- and without FH is not necessary.
done on two separate days to rule out cemia and Adverse Pregnancy Outcome (ADA-B; USPSTF-D)
laboratory error unless there are un- (HAPO) study showed a continuous risk
equivocal symptoms of hyperglycemia of adverse perinatal and maternal out- Date of onset of CFRD
(polyuria and polydipsia); a positive comes with increasing glycemia at 24 –28 Defining the date of onset of CFRD is
FPG or A1C can be used as a confirma- weeks’ gestation (45), and a recent multi- important because long-term outcomes
tory test, but if it is normal the OGTT center, randomized study has demon- are related to disease duration. Glucose
should be performed or repeated. If the strated that aggressive treatment of mild tolerance gradually worsens with age in
diagnosis of diabetes is not confirmed, gestational diabetes mellitus improves CF as a result of steadily declining insu-
the patient resumes routine annual test- lin production (1,47). At any point in
outcomes (46).
ing. (ADA-E; Consensus) time, however, an individual’s glucose
tolerance may acutely fluctuate depend-
● 2-h OGTT plasma glucose ⱖ200 mg/dl ing on his or her general state of health.
Diagnosis of gestational diabetes
(11.1 mmol/l) The committee defined the onset of
mellitus should be made based on CFRD as the first time a patient meets
● FPG ⱖ126 mg/dl (7.0 mmol/l) the recommendations of the
● A1C ⱖ6.5% (A1C ⬍6.5% does not rule diabetes diagnostic criteria. Longitudi-
International Association of the nal studies of patients whose date of di-
out CFRD because this value is often Diabetes and Pregnancy Study
spuriously low in CF.) agnosis was considered to be either the
Groups (IADPSG) (45) where first time they had a positive OGTT or
● Classical symptoms of diabetes (poly-
diabetes is diagnosed based on 0-, the first time they had persistent hyper-
uria and polydipsia) in the presence of a
1-, and 2-h glucose levels with a 75-g glycemia during acute illness have
casual glucose level ⱖ200 mg/dl (11.1
mmol/l) OGTT if any one of the following is shown that duration of CFRD deter-
present: mined by these criteria correlates with
clinically relevant outcomes including
Diagnosing CFRD during acute microvascular complications (27) and
illness or continuous feedings ● FPG >92 mg/dl (5.1 mmol/l)
● 1-h plasma glucose >180 mg/dl mortality (1,2). Hyperglycemia may re-
There are special situations when a diag- solve without treatment during periods
nosis of CFRD must be considered in pa- (10.0 mmol/l)
● 2-h plasma glucose >153 mg/dl of stable health, but insulin secretion
tients who are not in their baseline state of remains insufficient to control glucose
(8.5 mmol/l)
health. CF patients frequently first de- under stress, and hyperglycemia will
velop hyperglycemia during stressors recur.
such as acute illness or continuous enteral Although in the general population
nutrition. Blood glucose levels may nor- CF patients with gestational
critically ill patients who experience
malize when the stress is not present. In diabetes mellitus are not considered
stress hyperglycemia are not given a di-
the past, this was called “intermittent to have CFRD but require CFRD agnosis of diabetes, our recommenda-
CFRD” (44). Longitudinal outcome data screening 6–12 weeks after the end tion differs for CF patients who develop
have shown that CF morbidity and mor- of the pregnancy. (ADA-E; hyperglycemia during acute exacerba-
tality are associated with CFRD first diag- Consensus) tions of their chronic illness. In CF, ill-
nosed in the acute illness setting when ness-associated hyperglycemia is a
hyperglycemia has persisted beyond 48 h reflection of insulin insufficiency as well
Differentiating CFRD with and with-
(1,2,27). Based on this experience, the as resistance and is a recurrent event.
out FH
committee developed the following Defining the disease by this criterion en-
The 1998 CFF CFRD Consensus Con-
recommendations. courages early intervention to improve
ference recommended that CFRD pa-
tients with and without FH (FH⫹ and long-term outcomes.
The diagnosis of CFRD can be made FH-, respectively) be categorized sepa-
in CF patients with acute illness rately because differences in their treat- The onset of CFRD should be
(intravenous antibiotics in the ment needs were unknown (44). defined as the date a person with CF
hospital or at home, systemic first meets diagnostic criteria, even if
However, in a recent retrospective co-
glucocorticoid therapy) when FPG hyperglycemia subsequently abates.
hort study, 78 patients with CFRD FH-
levels >126 mg/dl (7.0 mmol/l) or (ADA-E; Consensus)
and 77 with CFRD FH⫹ were treated
2-h postprandial plasma glucose with insulin with similar positive effects
levels >200 mg/dl (11.1 mmol/l) MANAGEMENT OF CFRD
on nutritional status and lung function
persist for more than 48 h. (ADA-E; (1). In addition, in a randomized con-
Consensus) The care team
trolled trial, insulin therapy reversed As per ADA guidelines, CFRD should be
The diagnosis of CFRD can be made in chronic weight loss in patients with managed by a multidisciplinary team of
CF patients on enteral continuous drip CFRD FH- (28), suggesting that both health professionals with expertise in CF
feedings when mid- or postfeeding groups of CFRD patients should receive and diabetes (5). The diabetes team
plasma glucose levels exceed 200 mg/dl insulin treatment and that there is no should be intimately familiar with CFRD,
(11.1 mmol/l) on two separate days. need to distinguish them diagnosti- recognizing differences between this and
(ADA-E; Consensus) cally. type 1 and type 2 diabetes pathophysiol-
2702 DIABETES CARE, VOLUME 33, NUMBER 12, DECEMBER 2010 care.diabetesjournals.orgMoran and Associates
ogy and treatment. Good communication improved nutritional status (seven stud- or blood glucose/A1C control comparing
between diabetes and CF care providers is ies), (28,29,49 –53), improved blood glu- those who received oral hypoglycemic
essential. Poor team communication and cose/A1C control (two studies) (50,53), agents with those who received insulin.
inadequate or conflicting information decreased pulmonary exacerbation rates However, two randomized studies sug-
from health care providers have been (one study) (49), and decreased mortality gested that oral hypoglycemic agents were
identified as significant sources of stress (one study) (1). not as effective as insulin in improving
for patients with CFRD (48). There is little evidence regarding nutritional status (28), blood glucose/
Although there are few CF-specific the superiority of specific insulin regi- A1C control (28), and 2-h and 5-h insulin
data, it has been well established in the mens in CFRD, and clinical judgment area under the curve (57). Potential CF-
general diabetes population that patients should be used to choose the best regi- specific concerns associated with various
must be given the educational tools and men for each patient. CFRD FH⫹ is noninsulin diabetes agents are presented
support they need to assume a central role usually treated with standard basal- in supplementary Table 3.
in determining their treatment goals and bolus insulin regimens, including a
implementing the management plan (5). combination of basal and rapid-acting CF patients with CFRD should be
Initial and ongoing diabetes self- insulin by multiple daily subcutaneous treated with insulin therapy.
management education (DSME) is an in- injections, or rapid-acting insulin by (ADA-A; USPSTF-B)
tegral component of care. In addition to continuous subcutaneous infusion (in-
medical issues, the role of the patient- sulin pump) (1,50,54,55). CFRD pa- Oral diabetes agents are not as
centered medical team is to encourage tients still have endogenous insulin effective as insulin in improving
and support the patient and family. The secretion, and, except during acute ill- nutritional and metabolic outcomes
treatment team should address psychoso- ness, treatment is often similar to that of in CFRD and are not recommended
cial issues and recognize the risk of de- patients with type 1 diabetes in the hon- outside the context of clinical
pression. Emotional well-being is eymoon period. During acute illness or research trials. (ADA-A; USPSTF-D)
strongly correlated with diabetes out- systemic glucocorticoid treatment, in-
comes, and the additional diagnosis of di- sulin requirements steeply rise, two- to
abetes can be a significant burden. There fourfold. Once the illness resolves, it Management goals
may also be financial concerns associated generally takes about 4 – 6 weeks for in- ADA has established plasma glucose goals
with this diagnosis. sulin requirements to gradually return for people with diabetes (5). These are
to baseline. Careful monitoring for hy- primarily based on the need to decrease
Patients with CFRD should ideally poglycemia is required during this the risk of microvascular complications
be seen quarterly by a specialized period. Specific insulin treatment sug- and thus apply to CFRD with slight mod-
multidisciplinary team with gestions are presented in supplemen- ifications (supplementary Table 4).
expertise in diabetes and CF. tary Table 2. Whether more stringent goals should be
(ADA-E; Consensus) At the time of the last consensus con- adopted for CF patients based on the re-
ference (44), it was not clear whether lationship between hyperglycemia, nutri-
Patients with CFRD should receive CFRD patients without FH should receive tion, and pulmonary disease cannot be
ongoing DSME from diabetes insulin treatment. A recently completed determined at present.
education programs that meet trial demonstrated that treatment with To safely achieve glucose goals, ADA
national standards for DSME. (ADA- premeal rapid-acting insulin was able to recommends that all patients on insulin
E; Consensus) reverse chronic weight loss in this popu- therapy perform SMBG at least three
lation, and thus insulin therapy is indi- times daily (5). Continuous glucose mon-
Medical therapy cated (28). Whether basal insulin therapy itoring has been validated in CF and may
Patients with CFRD are insulin insuffi- alone (54) or basal-bolus insulin therapy be useful for clinical management in some
cient, and based on available data, insulin would be as beneficial as premeal insulin patients (58 – 60).
is the only recommended treatment. alone in CFRD FH- remains to be
There is evidence that CF patients on in- determined. Patients with CFRD who are on
sulin therapy who achieve glycemic con- The available data suggest that oral insulin should perform SMBG at
trol demonstrate improvement in weight, agents are not as effective as insulin in least three times a day. (ADA-E;
protein anabolism, pulmonary function, CFRD. Four studies (with a total of 153 Consensus)
and survival. Ten studies (with a total of participants) compared oral hypoglyce-
783 participants) were identified that ad- mic therapy with insulin therapy in CFRD Patients with CFRD should strive
dressed insulin therapy in CFRD, includ- (14,28,56,57). These included one ran- to attain plasma glucose goals as
ing one randomized controlled trial (28), domized controlled trial (28), one ran- per the ADA recommendations for
five before-after studies (49 –53), one ret- domized controlled crossover trial (57), all people with diabetes, bearing in
rospective cohort study (1), one prospec- one prospective cohort study (56), and mind that higher or lower goals
tive cohort study (54), and two case- one retrospective cohort study (14). Oral may be indicated for some patients
control studies (29,30). These studies hypoglycemic agents studied included and that individualization is
reported improved outcomes associated sulfonylureas (e.g., glyburide), met- important. (ADA-E; Consensus)
with the use of insulin in patients with formin, meglitinides (e.g., repaglinide),
CFRD, including those without FH. Re- and thiazolidinediones. The two observa- ADA considers A1C the primary tar-
ported outcomes included improved lung tional studies (14,56) reported no differ- get for glycemic control in type 1 and
function (five studies) (29,30,49,51,54), ences in lung function, nutritional status, type 2 diabetes (5). Although A1C levels
care.diabetesjournals.org DIABETES CARE, VOLUME 33, NUMBER 12, DECEMBER 2010 2703Clinical care of CFRD
Table 3—Dietary recommendations for CFRD
Nutrient Type 1 and type 2 diabetes CFRD
Calories As needed for growth, maintenance, or reduction diets 1.2–1.5 times DRI for age; individualized based
on weight gain and growth
Carbohydrate Individualized. Monitor carbohydrates to achieve Individualized. Carbohydrates should be
glycemic control; choose from fruits, vegetables, monitored to achieve glycemic control.
whole grains and fiber-containing foods, legumes, Artificial sweeteners should be used sparingly
and low-fat milk. Sugar alcohols and nonnutritive due to lower calorie content.
sweeteners are safe within U.S. Food and Drug
Administration–established consumption guidelines.
Fat Limit saturated fat to ⬍7% of total calories; intake of No restriction on type of fat. High fat necessary
trans fat should be minimized; limit dietary for weight maintenance. Aim for 35–40%
cholesterol to ⬍200 mg/day. Consume two or more total calories.
servings per week of fish high in n-3
polyunsaturated fatty acids.
Protein 15–20% of total calories; reduction to 0.8–1.0 g/kg Approximately 1.5–2.0 times the DRI for age;
with nephropathy no reduction for nephropathy
Sodium ⬍2,300 mg/day for blood pressure control Liberal, high salt diet, especially in warm
conditions and/or when exercising
Vitamins, minerals No supplementation necessary unless deficiency noted Routine supplementation with CF-specific
multivitamins or a multivitamin and
additional fat-soluble vitamins A, D, E, and K
Alcohol If consumed, limit to a moderate amount; one drink Consult with physician because of the higher
per day for women and two or less drinks per day prevalence of liver disease in CF and possible
for men. use of hepatotoxic drugs.
Special circumstances
Gestational diabetes Restricted calories/carbohydrate for weight and blood No calorie or carbohydrate restriction;
mellitus glucose control adequate kcals for weight gain
IGT Weight loss of 5–10% recommended; low-fat diet No weight loss. Spread carbohydrates
throughout the day; consume nutrient-dense
beverages.
DRI, daily recommended intake.
may be spuriously low in CF For most patients with CFRD, the calories should almost never be restricted.
(7,20,21,23,27,59,61), they are gener- A1C treatment goal isMoran and Associates
Patients with CFRD should be patients have had the disease for at least 5 CF, hypertension is a known risk factor
advised to do moderate aerobic years and have developed FH (27,41,70). for diabetic kidney disease. As for all per-
exercise for at least 150 min per Tight glycemic control and treatment of sons with diabetes, the recommended
week. (ADA-E; Consensus) microalbuminuria with ACE inhibitors or systolic and diastolic blood pressure goals
angiotensin receptor blockers combined are ⱕ130 mmHg and ⱕ80 mmHg, re-
COMPLICATIONS with optimal control of hypertension de- spectively, or ⬍90th percentile for age
lay progression of diabetic renal disease in and sex for pediatric patients (5). Hyper-
Acute complications of CFRD the general diabetes population (5). They lipidemia is rare in CF but may occur,
Acute complications of CFRD include are assumed to also be beneficial in CFRD especially after transplantation or in pan-
hypoglycemia and, rarely, diabetic keto- although there are no specific data in this creatic-sufficient individuals. While cho-
acidosis (DKA) or hyperosmolar hyper- population. ACE inhibitors are associated lesterol levels are typically quite low,
glycemic state. Because DKA is so with development of cough in ⬃10% of isolated triglyceride elevation has been
uncommon (66), patients are not rou- subjects, and this can occur months after noted. Because CF patients are at low risk
tinely taught to measure ketones and any drug initiation—a side effect with special for atherosclerotic cardiovascular disease,
CF patient with DKA should be screened significance in CF as increased cough is it is not clear that lipid elevation requires
for diabetes autoantibodies to rule out among the symptoms of a pulmonary ex- treatment in this population, and there
type 1 diabetes. acerbation (71). Cough may also occur
are no data regarding the efficacy or safety
Hypoglycemia that is not severe (i.e., with angiotensin receptor blockers but is
of medical therapy for CF dyslipidemia.
not requiring assistance from another in- less frequent (⬃1%).
CFRD is not an autoimmune disease;
dividual) is common even in CF patients Early diabetic nephropathy is charac-
without CFRD. It occurs both in the fast- terized by microalbuminuria (a spot urine thus, there is no increased risk of other
ing state, where it may reflect malnutri- ACR of 30 –299 g/mg creatinine) (5). autoimmune endocrinopathies.
tion and/or increased energy needs due to Macroalbuminuria (ⱖ300 g/mg creati-
inflammation and infection, and post- nine) indicates clinically significant ne- Patients with CFRD should have their
prandially, where it is related to delayed phropathy that is progressing toward blood pressure measured at every
and disordered insulin secretion (67). In- renal failure. A patient must demonstrate routine diabetes visit as per ADA
sulin-induced hypoglycemia can occur in two out of three abnormal tests within a 3- guidelines. Patients found to have
CFRD as in any patient on insulin ther- to 6-month period to receive a diagnosis. systolic blood pressure >130 mmHg
apy, although severe hypoglycemia may Renal failure due solely to diabetes is un- or diastolic blood pressure >80
be less common in CF (68). While CF common in CF, but microalbuminuria mmHg or >90th percentile for age
patients do not have a good glucagon re- has been reported to occur in 4 –21% of and sex for pediatric patients should
sponse to hypoglycemia (69), they have a individuals with CFRD (27,41,70). Re- have repeat measurement on a sepa-
brisk catecholamine response and normal cent strenuous exercise, fever, hyperten- rate day to confirm a diagnosis of hy-
hypoglycemia awareness. Hypoglycemia sion, congestive heart failure, infection, pertension. (ADA-E; Consensus)
education including the use of glucagon is menstruation, and orthostatic proteinuria
important for patients and their families. can result in a positive screen. It is there- Annual monitoring for microvascular
Regular SMBG, especially during unusual fore important to exclude other causes be- complications of diabetes is recom-
activity, diet changes, or illness is the best fore concluding that microalbuminuria is mended using ADA guidelines, begin-
protection against insulin-induced hypo- CFRD related. ning 5 years after the diagnosis of
glycemia (5). Patients should be coun- Diabetic retinopathy is seen in ⬃10 – CFRD or, if the exact time of diagno-
seled regarding the hypoglycemic effects 23% of patients with CFRD and is seldom sis is not known, at the time that fast-
of alcohol and the risks of driving or op- severe, although isolated severe cases ing hyperglycemia is first diagnosed.
erating machinery while hypoglycemic. have been reported (27,41,43,70,72). As (ADA-E; Consensus)
They should be encouraged to exercise; in all persons with diabetes, dilated reti-
however, they should be counseled to nal exams are necessary in patients with
Patients with CFRD diagnosed with
check their glucose level before vigorous CFRD to evaluate for the presence of ret-
hypertension or microvascular com-
physical activity and to potentially con- inopathy and the need for treatment.
plications should receive treatment as
sume extra carbohydrate or alter their in- Annual neurologic assessment and
sulin dose, depending on the glucose level foot evaluation are recommended for the recommended by ADA for all people
and the intensity and duration of the general diabetes population (5). Current with diabetes, except that there is no
planned exercise. data suggest that the severity of this mi- restriction of sodium and, in general,
crovascular complication may be less in no protein restriction. (ADA-E;
Education about the symptoms, CFRD (27). Gastroparesis is common in Consensus)
prevention, and treatment of CF patients with and without CFRD, and
hypoglycemia, including the use of the role that CFRD plays in aggravating An annual lipid profile is recom-
glucagon, is recommended for this condition can be difficult to deter- mended for patients with CFRD and
patients with CFRD and their care mine (27). Gastroparesis may make good pancreatic exocrine sufficiency or if
partners. (ADA-E; Consensus) glycemic control difficult to achieve. any of the following risk factors are
Hypertension is not uncommon in present: obesity, family history of
Chronic complications of CFRD adult CF patients, particularly after trans- coronary artery disease, or immuno-
Microvascular disease does not typically plantation (41). Although atherosclerotic suppressive therapy following trans-
become clinically apparent in CFRD until vascular disease has not been described in plantation. (ADA-E; Consensus)
care.diabetesjournals.org DIABETES CARE, VOLUME 33, NUMBER 12, DECEMBER 2010 2705Clinical care of CFRD
FUTURE RESEARCH (Wright State University Boonshoft Irish Med J 2006;99:83– 86
CONSIDERATIONS — The CFRD School of Medicine, Dayton, Ohio) 9. Finkelstein SM, Wielinski CL, Elliott GR,
Guidelines Committee identified the (Chair, Management Subcommittee); Warwick WJ, Barbosa J, Wu SC, Klein DJ.
following as the most pressing research Karen A. Robinson, PhD (Johns Hopkins Diabetes mellitus associated with cystic fi-
brosis. J Pediatr 1988;112:373–377
questions in CFRD: 1) Do nondiabetic University, Baltimore, Maryland);
10. Koch C, Rainisio M, Madessani U, Harms
CF patients with abnormal glucose tol- Theresa Rodgers, RN, MSN, CRNP- HK, Hodson ME, Mastella G, McKenzie
erance benefit from diabetes therapy AC/PC (University of Alabama, Birming- SG, Navarro J, Strandvik B, Investigators
and, if so, what method of treatment has ham, Irondale, Alabama); Kathryn A. of the European Epidemiologic Registry
the greatest impact on nutritional and Sabadosa, MPH (The Dartmouth Institute of Cystic Fibrosis. Presence of cystic fibro-
pulmonary status? 2) What are the ob- for Health Policy and Clinical Practice, sis-related diabetes mellitus is tightly
stacles to OGTT screening of the CF Lebanon, New Hampshire); Terri Schin- liked to poor lung function in patients
population and how can they best be dler, MS, RD (Rainbow Babies and Chil- with cystic fibrosis: data from the Euro-
overcome? 3) What are the mechanisms dren’s Hospital, Cleveland, Ohio); Bonnie pean Epidemiologic Registry of Cystic Fi-
by which CFRD impacts pulmonary Slovis, MD (Vanderbilt University Medi- brosis. Pediatr Pulmonol 2001;32:343–
function and survival in CF? 4) Should cal Center, Nashville, Tennessee) (Com- 350
11. Marshall BC, Butler SM, Stoddard M, Mo-
target goals for glucose and/or A1C in mittee Co-Chair); Arlene Stecenko, MD ran AM, Liou TG, Morgan WJ. Epidemi-
CFRD differ from ADA target goals? 5) (Emory University School of Medicine, ology of cystic fibrosis-related diabetes.
How can we assess and improve patient Atlanta, Georgia) (Chair, Complications J Pediatr 2005;146:681– 687
acceptance of the diagnosis of CFRD to Subcommittee); Mary E. Wood, RN, MS, 12. Milla CE, Warwick WJ, Moran A. Trends
improve diabetes self-management and CDE, BC-ADM (Dartmouth-Hitchcock in pulmonary function in patients with
psychosocial well-being? Medical Center, Lebanon, New Hamp- cystic fibrosis correlate with the degree of
shire); David Young, PharmD (Inter- glucose intolerance at baseline. Am J Re-
mountain Cystic Fibrosis Adult Center, spir Crit Care Med 2000;162:891– 895
Acknowledgments — No potential conflicts Salt Lake City, Utah). 13. Peraldo M, Fasulo A, Chiappini E, Milio
of interest relevant to this article were C, Marianelli L. Evaluation of glucose tol-
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Beall, PhD (CFF, Bethesda, Maryland); Care 2009;32:1626 –1631 nary function and clinical outcome. Eur
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of Minnesota Medical Center, Fairview,
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Minneapolis, Minnesota); Preston W. 3. Miller RJ, Tildesley HD, Wilcox PG, tion in cystic fibrosis. Pediatr Pulmonol
Campbell, III, MD (CFF, Bethesda, Mary- Zhang H, Kreisman SH. Sex disparities in 2002;33:483– 491
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Hospital at Dartmouth, Lebanon, New on clinical outcomes: a matched study. Clifton I, Morton AM, Owen D, Conway
Hampshire); Melissa Chin, BA (CFF, Be- Can Respir J 2008;15:291–294 SP, Peckham DG. Nutritional decline in
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MD (Kaiser Permanente, Portland, Ore- lung function in female but not male sub- of intensive nutritional intervention. J
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