advances in treatment have led to an increase in survival in people with cystic fibrosis ( cf ) . as patients age with cf , they experience an increased rate of complications , including cystic fibrosis related diabetes ( cfrd ) .
cfrd results from the progressive inflammatory destruction of the pancreas [ 2 , 3 ] and leads to the development of insulin insufficiency with varying levels of insulin resistance during acute illness .
the ferret cf model also shows that early inflammation leads to pancreatic cell destruction and replacement with fibrosis .
while patients with cf have not been observed to develop macrovascular complications of diabetes , microvascular complications are seen .
importantly , diagnosis of cfrd is associated with poor nutrition status and decreased lung function and survival [ 711 ] .
recommendations for diagnosis , screening , and management of cfrd were written in a jointly created clinical care guideline by the cystic fibrosis foundation ( cff ) , the american diabetes association ( ada ) , and the pediatric endocrine society ( pes ) . based on the guideline , screening for cfrd
should be performed annually on patients with cf > 10 years of age using the 2-hour 75-gram oral glucose tolerance test ( ogtt ) .
patients with 2  h ogtt plasma glucose > 200  mg / dl meet criteria for the diagnosis of cfrd . because of
the time - consuming nature of the test , and requirement that patients fast prior to testing , adherence to the guidelines has been challenging ; approximately one - quarter of adults with cf were tested in 2014 .
this result suggests that an alternative means of evaluation is needed for the timely diagnosis of cfrd .
although infrequently used in us cf centers , cgm has been validated in children and adolescents with cf [ 13 , 14 ] .
additionally , two small studies showed that early glucose abnormalities are detectable by cgm in children and adults with cf and are associated with historical decline and contemporaneously worse health outcomes [ 15 , 16 ] .
one study in children with cf < 18 years of age showed that abnormal cgm was the strongest predictor of abnormal glucose metabolism at 2.5-year follow - up .
however , these studies did not answer the question of whether abnormal cgm predicts future health outcomes in adults with cf .
our objectives for this study were to determine whether abnormal cgm results are associated with subsequent development of cfrd , lung function , and bmi decline and increased rate of cf pulmonary exacerbations .
to evaluate the correlation between cgm and ogtt for detection of cfrd in adult patients with cf , we conducted a prospective single center trial in 2009 - 2010 in which 21 adult patients due for routine ogtt underwent simultaneous 3-day cgm and 2-hour 75  g ogtt . subsequently , to determine whether abnormal cgm predicted health decline , we performed a retrospective observational study . medical records and data from medical charts and
the cff registry were reviewed from 2008 to 2015 to obtain clinical information ( diagnosis of cfrd , pulmonary function , bmi , and pulmonary exacerbations ) .
the original protocol was approved by the national jewish health institutional review board ( njh irb ) , and subjects provided written informed consent . prior to the conduct of the retrospective review , the new proposal underwent expedited review and approval by the njh irb .
, the following definitions were used : fasting glucose > 126  mg / dl or 2-hour glucose > 200  mg / dl indicated cfrd , fasting glucose 100125  mg / dl indicated impaired fasting glucose ( ifg ) , and 2-hour glucose 140199  mg / dl indicated impaired glucose tolerance ( igt ) [ 12 , 19 ] . in order to explore the correlation between 1-hour ogtt glucose levels and cgm results , 1-hour ogtt results were also interpreted using the 2-hour ogtt definitions . for subjects without diabetes who did not have ogtt in the observation period ( n = 5/10 ) ,
the alternative guideline criteria were used to determine the development of cfrd : hemoglobin a1c ( a1c ) 6.5% or rpg 200  mg / dl in conjunction with polyuria and polydipsia .
one touch glucometer and medtronic cgm system were used to obtain cgm data . a board - certified endocrinologist ( jj ) who was blinded to the ogtt results interpreted cgm data .
although there are no officially defined criteria for interpreting cgm , for our pilot study , a priori we used the american diabetes association criteria for ogtt   to define the following criteria to interpret cgm , all values were required on two separate dates : fasting glucose > 126  mg / dl or random glucose > 200  mg / dl indicated cfrd ; random glucose > 140  mg / dl indicated igt ; fasting glucose > 100  mg / dl indicated ifg .
each subject 's highest lung function and bmi for the year prior to ogtt / cgm testing , and for each of the 5 years following ogtt / cgm testing , were extracted from the cf registry .
the number of exacerbations each subject had for each of the 5 years following ogtt / cgm testing was also extracted from the cf registry , and the average number of exacerbations per year was calculated . during the period of retrospective review
, three subjects died and three patients moved away from the center ; all available data points were included for these subjects .
six patients began chronic use of cystic fibrosis transmembrane conductance regulator ( cftr ) modulators during the period of retrospective review ( two patients began ivacaftor , and four patients began lumacaftor / ivacaftor ) .
the highest fev1 and bmi for the year prior to initiation of cftr modulators were used for analysis of decline in these parameters over time .
means and standard deviations are reported for demographic information ( graph pad prism v6.07 ) .
agreement between test methods ( ogtt and cgm ) was evaluated using both pearson correlation and the bland - altman method .
test was used to evaluate whether abnormal cgm predicts subsequent development of cfrd . using two - sample t - tests , average lung function , bmi , and average exacerbation rate were compared between subjects who developed cfrd and those who did not develop cfrd .
standard error of the mean is reported for group means compared by t - tests .
pearson correlation was calculated to evaluate the relationship between maximum cgm and lung function and bmi decline .
the average age of the subjects was 32.4 years ( sd 13.1 ; median 27.0 , range 2065 ) .
fifty - two percent ( 11/21 ) of subjects were homozygous for the f508del mutation ; 90% ( 19/21 ) of subjects had at least one copy of the f508del mutation .
average percent of predicted fev1 and average bmi of subjects at the time of enrollment was 68.8 ( sd 5.5 ; range , 22109 ) and 21.6 ( range 17.129.1 ; sd 0.72 ) , respectively ( table 1 ) .
one patient did not have adequate data for ogtt interpretation due to improper collection of the timed samples .
two patients did not have adequate data for interpretation by cgm due to failure of the device and/or data retrieval .
for these 18 patients ( mean results for test methods shown in figure 1 ) , there was a modest correlation between interpreted results from ogtt and cgm ( r = 0.52 , 95% ci 0.07 to 0.79 , p = 0.03 ; not shown ) ; only 3/18 ( 17% ) comparisons yielded the same result ( two subjects with impaired glucose tolerance and one subject with cfrd ) . in 14 of 15 ( 93% ) subjects for whom results differed between the two tests
one - hour ogtt glucose interpretation yielded the same result as that of cgm in 11/17 ( 65% ) subjects .
there was a strong positive correlation between one - hour ogtt interpretation and that of cgm ( r = 0.77 , 95% ci 0.46 to 0.91 , p = 0.0003 ; not shown ) . in 5/6 ( 83% ) of the subjects for whom results differed between the two tests ,
we also compared maximum cgm glucose to blood glucose based on 1-hour and 2-hour ogtt using the bland - altman method ( figure 2 ) .
the comparison between ogtt and maximum cgm values showed poor agreement between the two methods ( bias 96.06 , sd 56.91 , 95% limit of agreement 207.6 to 15.49 ) .
in contrast , the comparison between 1-hour ogtt and maximum cgm values showed some agreement ( bias 32.81 , sd 41.18 , 95% limit of agreement 113.5 to 47.9 ) .
one subject met criteria for cfrd by ogtt ( as well as by the cgm criteria defined for this study : glucose > 200  mg / dl on two dates ) at the time of the prospective study . of those remaining subjects with complete cgm and ogtt data ( n = 17 ) , 7/17 ( 41% ) subjects were diagnosed with cfrd within 4 years of their study enrollment ( 5 subjects were diagnosed by symptoms in combination with rpg > 200  mg / dl , and 2 subjects were diagnosed by subsequent ogtt ) ( table 2 ) .
all of the subjects who were subsequently diagnosed with cfrd had abnormal cgm results at the time of the original study ; cgm results were interpreted as consistent with igt in 3 subjects and with cfrd in 4 subjects .
one hundred percent of the subjects whose cgm results were consistent with cfrd went on to develop cfrd in the follow - up study period .
abnormal cgm ( glucose > 200  mg / dl on two dates ) correctly identified those subjects who would subsequently be diagnosed with cfrd (  = 17.27 , df = 2 , p = 0.0002 ) .
two of the 7 subjects had normal ogtts at the time of the original study ; the remainder of the subjects had ifg / igt by ogtt .
one - hour glucose results were normal in 2 subjects , but the remaining 5 subjects had 1-hour ogtt results consistent with cfrd .
thus , the 1-hour ogtt result was also useful in determining which subjects would develop cfrd (  = 13.26 , df = 2 , p = 0.001 ) .
of the 10 subjects who have not met criteria for cfrd since study enrollment ( two of these subjects died , and 3 moved from the center ) , 5 subjects ( 50% ) had at least one ogtt in the 4 - 5 years subsequent to study enrollment .
although 3 of 5 of the subjects had normal ogtts at enrollment ( cgm results indicated igt in all three subjects ) , those 3 subjects have subsequently been diagnosed with igt by ogtt .
all 10 subjects who have not met criteria for cfrd since study enrollment have had at least one rpg and/or a1c measured in the 4 - 5 years subsequent to enrollment .
none of the 10 subjects met criteria for cfrd based on an a1c 6.5% or rpg 200  mg / dl in conjunction with polyuria and polydipsia . using current glucose metabolism as the outcome ( table 2 )
, we calculated the sensitivity , specificity , and positive ( ppv ) and negative predictive values ( npv ) for cfrd of subjects ' initial testing ( cgm , 1-hour ogtt and 2-hour ogtt results ) .
the sensitivity , specificity , ppv , and npv of cgm for subsequent diagnosis of cfrd were 0.63 ( ci 0.30.86 ) , 1.0 ( ci 0.711.0 ) , 1 ( ci 0.541.0 ) , and 0.77 ( ci 0.490.92 ) , respectively . the sensitivity , specificity , ppv , and npv of 1-hour ogtt for subsequent diagnosis of cfrd were 0.75 ( ci 0.40.92 ) , 1.0 ( ci 0.691.0 ) , 1 ( ci 0.591.0 ) , and 0.82 ( ci 0.520.95 ) , respectively .
finally , the sensitivity , specificity , ppv , and npv of 2-hour ogtt for the subsequent diagnosis of cfrd were 0.13 ( ci 0.030.48 ) , 1.0 ( ci 0.711.0 ) , 1 ( ci 0.151.0 ) , and 0.59 ( ci 0.350.78 ) , respectively .
there was no difference in baseline lung function between the patients who went on to develop cfrd and those who did not ( 67.1  10.7 versus 66.3  7.9 , p = 0.95 ) .
there was a trend towards a correlation between maximum cgm values and decline in lung function over time in the group as a whole ( r = 0.45 ; 95% ci 0.01 to 0.76 , p = 0.06 ) , but there was no correlation between these values in those later diagnosed with dm ( r = 0.03 , 95% ci 0.69 to 0.72 , p = 0.9416 ) .
there was no difference in baseline bmi between the patients who went on to develop cfrd and those who did not ( 20.80  1.08 versus 22.83  1.13 , p = 0.22 ) .
there was no correlation between maximum cgm and decline in bmi over time in the group as a whole ( r = 0.33 , 95% ci 0.160.69 , p = 0.18 ) , although there was a trend towards decline in bmi in those later diagnosed with cfrd ( r = 0.67 , 95% ci 0.93 to 0.07 , p = 0.07 ) .
there was no difference between rate of exacerbations in subjects who went on to develop cfrd versus those who did not ( 1.21  0.29 versus 1.71  0.26 , p = 0.22 ) .
there was no correlation between maximum cgm and rate of exacerbations in the group as a whole ( r = 0.34 , 95% ci 0.70 to 0.15 , p = 0.16 ) , nor in those who later were diagnosed with cfrd ( r = 0.59 , 95% ci 0.20 to 0.91 , p = 0.12 ) .
the goal of the prospective pilot study was to compare the ability of the gold standard ogtt versus cgm to evaluate glucose metabolism in cf .
subsequently , we sought to determine if glucose abnormalities detected by cgm predicted decline in health . in our small study population , abnormal cgm results were not associated with decline in lung function or bmi or increased rate of exacerbations over the 5 years following the study .
however , abnormal glucose metabolism ( glucose > 200  mg / dl on two dates ) identified by cgm accurately identified those who would later be diagnosed with cfrd .
the sensitivity of cgm was similar to that of 1-hour ogtt , and both were better than that of 2-hour ogtt for subsequent development of cfrd .
numerous studies have shown that development of cfrd is associated with lung function and bmi decline [ 4 , 8 , 9 , 20 ] ; these adverse health effects can begin in the years prior to diagnosis .
a recent review of diabetes - related mortality in cf showed that the overall mortality for patients with cfrd was 1.8 per 100 person - years , compared with 0.5 in patients with cf without diabetes ( p = 0.0002 ) .
importantly , the increased morbidity and mortality can be improved with use of insulin therapy in patients with cfrd [ 4 , 2127 ] .
in addition to those patients who are diagnosed with cfrd , 1020% of patients with cf who do not meet criteria for diagnosis of cfrd have impaired glucose tolerance when it is evaluated .
other investigators have shown that patients with elevated 1-hour ogtt values are at increased risk of developing cfrd [ 28 , 29 ] .
furthermore , patients with one - hour ogtt glucose greater than 140  mg / dl have been shown to be at risk for lung function decline directly related to the degree of one - hour glucose elevation . while treatment of patients with igt is not well studied ,
2 case series have shown reversal of decline in lung function and bmi decline with use of insulin therapy in cf patients with igt [ 31 , 32 ] .
thus , impaired glucose metabolism is a prevalent issue leading to increased morbidity and mortality that can be reversed with treatment when it is diagnosed .
although rates of screening for cfrd using ogtt have increased since the guidelines   were published , rates of screening are still quite low . in 2014 , only approximately 54% of children between 10 and 17 years of age and 28% of adults 18 years of age underwent cfrd screening with the recommended ogtt .
at our center in 2014 , approximately 36% of patients 10 years of age underwent ogtt screening .
because of the difficulty in obtaining annual screening ogtt , it would be ideal to use a sensitive test that does not require fasting ( in a patient population that suffers from malnutrition ) and an additional 2 - 3 hours in clinic .
although aic is quick and easy to assess , it is not recommended for cfrd screening because it demonstrates a low degree of correlation with ogtt and is insensitive for the diagnosis of cfrd [ 33 , 34 ] .
in contrast to the performance of a1c against ogtt , we showed a strong correlation with cgm and 1-hour ogtt and a moderate degree of correlation with 2-hour ogtt results .
cgm detected a greater degree of glucose excursions > 140  mg / dl than ogtt . because there are no dietary restrictions during cgm , cf patients ' recommended diet
however , a glucose > 140  mg / dl occurs very rarely in nondiabetic individuals tested by cgm .
furthermore , the test can be performed with relative ease , with a small increase in overall cost of diabetes screening .
o'riordan and colleagues sought to validate the use of cgm in a prospective cohort of children and adolescents with cf .
they demonstrated that cgm performed on two occasions over a 12-month period was reliable when compared with ogtt ( bland - altman agreement 0.81  mmol / l ; 95% ci for bias  2.90 
nineteen of the twenty - one patients in our study had adequate data for analysis .
subsequent to the validation of cgm in children and adolescents with cf , other researchers have examined whether abnormal glucose metabolism by cgm predicts clinical outcomes .
prospectively studied 33 children with cf who were scheduled to undergo ogtt as part of routine health screening .
they found that the amount of time a patient experienced elevated blood glucose , specifically a blood glucose of > 7.8  mmol / l ( 140.4  mg / dl ) for 4.5% of the time , was associated with declining nutritional status and lung function in the preceding 12 months .
additionally , in a single center cross - sectional study in stable adult and pediatric patients with cf undergoing routine annual ogtt , investigators performed cgm and evaluated the effects of cgm glucose > 11  mmol / l ( 198  mg / dl ) on health outcomes . patients with cgm glucose > 11 
mmol / l had lower lung function and increased prevalence of pseudomonas aeruginosa lung infection .
these two studies show that early glucose abnormalities are detectable by cgm in children and adults with cf and are associated with historical decline and contemporaneous worse health outcomes .
obtained ogtt and cgm on 17 children ( mean age approximately 13 years ) with cf followed by repeat ogtt in 2.5 years .
they found that altered glucose metabolism measured by cgm was the best predictor of future glucose metabolism abnormalities .
these studies did not answer the question of whether abnormal cgm predicts future health outcomes in adults with cf .
we were unable to show that maximum cgm value predicted declines in lung function and / bmi or increased rate of exacerbations . because this study was a pilot study , it was underpowered to detect such differences .  
 limitations .
although ogtt and cgm were collected prospectively , information regarding subsequent diagnosis of cfrd , lung function , and bmi was collected retrospectively . in the original study ,
cgm data was interpreted in a blinded fashion ; however , knowledge of cgm results might have led to bias / more sensitivity to symptoms by clinicians . on the other hand , abnormal ogtt results ( i.e. , impaired fasting glucose and/or impaired glucose tolerance ) should also alert clinicians / caregivers to increase monitoring of a patient 's glucose metabolism .
although a formal study of the impact of ivacaftor on glucose metabolism is underway ( nct02039986 ) , to date only a case report and a case series have been published [ 36 , 37 ] .
based on these reports , it is possible that cftr modulation may have improved glucose metabolism in our six patients who received them , thus influencing their current state of glucose metabolism .
in adult patients with cf , cgm identified a greater degree of impaired glucose metabolism than the gold standard 2-hour ogtt .
furthermore , glucose > 200  mg / dl on two dates by cgm correctly identified subjects who developed cfrd over time .
the sensitivity and negative predictive values were similar for both cgm and 1-hour ogtt for subsequent development of cfrd , and both exceeded those values for the traditional ogtt measurements .
our findings suggest that either including a 1-hour ogtt measurement or using cgm may provide a better tool for identifying patients who are at highest risk for the development of cfrd .
larger studies are required to test this hypothesis and to more accurately evaluate the ability of cgm data to predict changes in clinical endpoints such as lung function , nutritional status , and rate of pulmonary exacerbations .
impaired glucose metabolism is clearly associated with poor health outcomes in patients with cf ; therefore , such investigation may be important as we look for better ways to quickly identify and intervene in subjects at greater risk of clinical decline .
 
 rationale . cystic fibrosis related diabetes ( cfrd ) is the most common comorbidity in patients with cf . in spite of increased screening , diagnosis , and treatment of cfrd , the mortality rate in patients with cfrd still far exceeds the mortality rate in those without cfrd . 
 guidelines suggest that screening for cfrd be performed annually using the 2-hour 75-gram oral glucose tolerance test ( ogtt ) . 
 adherence to recommended screening has been poor , with only approximately one - quarter of adults with cf undergoing ogtt in 2014 . 
 use of continuous glucose monitoring ( cgm ) for diagnosis may become an alternative . objectives . our objective was to determine whether abnormal cgm predicts subsequent development of cfrd , lung function , and body mass index ( bmi ) decline and increased rate of cf pulmonary exacerbations in adults with cf . 
 methods . in a prospective single center pilot trial from september 2009 to september 2010 , 
 21 adult patients due for routine ogtt were recruited to complete simultaneous 3-day cgm and 2-hour 75 gram ogtt . 
 subsequently , clinical information was reviewed from 2008 to 2015 . 
 conclusions . 
 there was a moderate correlation between interpreted results of 2-hour ogtt and cgm ( p = 0.03 ) ; cgm indicated a greater level of glucose impairment than ogtt . 
 glucose > 200  mg / dl by cgm predicted development of cfrd ( p = 0.0002 ) . 