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Abnormal glucose tolerance and the 50-gram glucose challenge test in Cystic fibrosis
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Journal of Cystic Fibrosis xxx (xxxx) xxx
Contents lists available at ScienceDirect
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Short Communication
Abnormal glucose tolerance and the 50-gram glucose challenge test in Cystic fibrosis Saba Sheikh a,∗, A Russell Localio b, Andrea Kelly c, Ronald C Rubenstein a a
Division of Pulmonary Medicine and The Cystic Fibrosis Center, The Children’s Hospital of Philadelphia, Philadelphia, PA United States Division of Biostatistics, Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, PA United States c Division of Endocrinology and Diabetes, The Children’s Hospital of Philadelphia, Philadelphia, PA United States b
a r t i c l e
i n f o
Article history: Received 17 April 2019 Revised 6 December 2019 Accepted 7 January 2020 Available online xxx Keywords: Cystic Fibrosis Cystic Fibrosis Related Diabetes Oral glucose tolerance test Glucose challenge test
a b s t r a c t Diabetes has emerged as a major co-morbidity in cystic fibrosis (CF). The 75 g oral glucose tolerance test (OGTT) is used to screen for CF-related diabetes (CFRD) but is inconvenient, and adherence to screening is poor. The 50 g glucose challenge test (GCT) is shorter, performed non-fasting, and may serve to pre-screen the subset of individuals requiring confirmatory OGTT. We performed a pilot study in twenty-seven CF individuals across the glucose tolerance spectrum to test whether the GCT could identify subjects with abnormal glucose tolerance defined as 2-h OGTT glucose ≥7.8 mmol/L (2 h-AGT) or 1-h defined as 1-hr OGTT glucose ≥11.1 mmol/L (1 h-AGT). A GCT threshold of 8.1 mmol/L was 73% sensitive and 63% specific for 2hr-AGT and 80% sensitive and 65% specific for 1hr-AGT. Therefore, a screening GCT may reduce need for confirmatory OGTT for identifying AGT but a larger study is warranted to identify a robust cutoff for CFRD. © 2020 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.
1. Introduction Cystic fibrosis related diabetes (CFRD), a common complication in cystic fibrosis, is associated with worse clinical outcomes [1–4], and increases disease burden while adversely impacting quality of life [5]. Early diagnosis and treatment of CFRD may mitigate the associated decline in lung function, decreases in body mass index (BMI), and increased mortality [6–8]. Earlier glucose derangements during 75 g oral glucose challenge test (OGTT) such as impaired glucose tolerance (IGT; 2-hr OGTT glucose ≥7.8 mmol/L and <11.1 mmol/L) and isolated 1-hr glucose elevations are also associated with lower forced expiratory volume in 1 s (FEV1%-predicted) [1,9,10], greater decline in FEV1%-predicted over time [1] and increased risk of subsequent diabetes [11,12].
Abbreviations: AGT, Abnormal glucose tolerance; BMI, Body mass index; CF, Cystic Fibrosis; CFRD, Cystic Fibrosis Related Diabetes; CHOP, Children’s Hospital of Philadelphia; FEV1, Forced expiratory volume in 1 s; GCT, 50 g glucose challenge test; GDM, Gestational Diabetes Mellitus; HUP, Hospital of University of Pennsylvania; IGT, Impaired glucose tolerance; INDET, Indeterminate glucose tolerance; NGT, Normal glucose tolerance; NPV, Negative predictive value; OGTT, 75 g oral glucose tolerance test; PPV, Positive predictive value. ∗ Corresponding author at: 3501 Civic Center Boulevard, 11th Floor Colket Building, Division of Pulmonary Medicine, Philadelphia, PA 19104 United States E-mail address: [email protected] (S. Sheikh).
CFRD diagnosis can be established with identification of 2-hr OGTT glucose ≥11.1 mmol/L. The annual OGTT recommended by the CF Foundation starting by age 10 years [13] requires overnight fasting and multiple blood draws over a two-hour period. Adherence is poor [14]; reasons may include 1) patient specific factors such as fasting requirement, time commitment, number of blood draws, development of nausea, development of hypoglycemia, and insufficient concern for diabetes and 2) CF center specific factors such as poor adoption of guidelines and insufficient patient education. An alternate, firststep screening test used in gestational diabetes mellitus (GDM), is the non-fasting 1-hr 50 g glucose challenge test (GCT), the results of which correlate well with pregnancy specific outcomes [15–17]. In pregnancy, an abnormal GCT is followed by a confirmatory 100 g OGTT. A single, small study in adults (n = 31) has evaluated the GCT in CF and demonstrated 100% sensitivity and 50% specificity for positive OGTT (≥7.8 mmol/L) at 7.8 mmol/L threshold for GCT [18]. The objective of this study was to identify a glucose threshold during the GCT using a hospital grade bedside glucometer that identifies the subset of CF children and young adults with abnormal glucose tolerance defined as 2 h OGTT glucose ≥7.8 mmol/L (2 h AGT) or 1 h OGTT glucose ≥11.1 mmol/L (1-hr AGT). We hypothesize that the GCT can accurately identify patients with 1 and/or 2 h-AGT and those who require confirmatory OGTT (a twostep diagnostic approach).
https://doi.org/10.1016/j.jcf.2020.01.003 1569-1993/© 2020 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.
Please cite this article as: S. Sheikh, A.R. Localio and A. Kelly et al., Abnormal glucose tolerance and the 50-gram glucose challenge test in Cystic fibrosis, Journal of Cystic Fibrosis, https://doi.org/10.1016/j.jcf.2020.01.003
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S. Sheikh, A.R. Localio and A. Kelly et al. / Journal of Cystic Fibrosis xxx (xxxx) xxx Table 1 Subject characteristics.
Age (y) Male sex Pancreatic insufficiency FEV1%-predicted BMI-Z GCT (mmol/L) OGTT 60 min (mmol/L) OGTT 120-min (mmol/L) ∗
NGT (N = 14)
INDET (N = 2)
IGT (N = 8)
CFRD (N = 3)
p-value
14.5 (9.6–20.8) 9 (60%) 12 (86%) 100 (86–134) 0.5 (−0.7–1.4) 7.7 (5.1–9.8) 8.1 (4.6–10.9) 4.9 (2.2–7.5)
24.6 and 25.1 1 (50%) 2 (100%) 65∗ −1.2 and −0.003 4.5 and 10.2 11.4 and 15.3 4.7 and 7.1
19.2 (12.7–39.2) 4 (40%) 8 (100%) 99 (59–125) 0.3 (−0.4–1.3) 8.4 (6.3–13.0) 12.4 (9.9–14.0) 10.4 (8.0–10.9)
23.2 (18.3–24.3) 2 (67%) 3 (100%) 89 (69–96) 0.1 (0.05–0.3) 12.5 (12.4–15.3) 13.7 (12.9–22.1) 17.2 (11.6–18.9)
0.01 0.57 0.42 0.22 0.07 0.02 0.0003 0.0002
N = 1 for FEV1%-predicted; to convert mmol/L to mg/dL multiply by 18.
2. Materials and methods 2.1. Subjects Individuals with CF, age ≥8y were recruited from The Children’s Hospital of Philadelphia (CHOP) and Hospital of University of Pennsylvania (HUP) Cystic Fibrosis Center. The diagnosis of CF was confirmed by documentation of a positive sweat test and/or diagnostic CF genotyping. Inclusion criteria included FEV1%-predicted ≥40% and OGTT within previous 4 months. Exclusion criteria were known cirrhosis or portal hypertension, history of transplant, or presence of other medical conditions not associated with CF that could affect glucose tolerance. Medical records were reviewed to determine pancreatic insufficiency status. Glucose tolerance during OGTT was categorized as normal glucose tolerance (NGT) for 1-h glucose <11.1 mmol/L and 2-h glucose <7.8 mmol/L; Indeterminate, INDET for 1-h glucose ≥11.1 mmol/L and 2-h glucose <7.8 mmol/L; IGT for 2-h glucose ≥7.8 mmol/L and <11.1 mmol/L; and CFRD for 2-h glucose ≥11.1 mmol/L or fasting glucose ≥7.0 mmol/L.
were collected were approved by the Institutional Review Boards at CHOP and HUP. Informed consent was obtained from young adult participants (age≥18 y) and from parents/guardians of participants (age<18 y). Assent was obtained from participants age <18 y. 3. Results Twenty-seven individuals (44% male), across the spectrum of glucose tolerance participated (Table 1). Median FEV1%-predicted was 96% and BMI-Z was 0.4. The majority were pancreatic insufficient (93%). Median time between GCT and OGTT was 49 days (range 2–109). Subjects with NGT were more likely to be younger (p = 0.01; Table 1). A GCT glucose of ≥8.1 mmol/L yielded a sensitivity for 2 h-AGT of 73%, specificity 63%, PPV 57%, and NPV 77% (Table 2). Thus, using this threshold, 67% individuals would be accurately classified (true negatives and true positives, Fig. 1). This GCT threshold would miss
2.2. Study procedures 2.2.1. Anthropometry Weight and height were measured to nearest 0.1 kg and 0.1 cm, respectively. BMI (weight/height2 ) was converted to age and sex adjusted Z score using reference data [19]. For subjects >20y, Zscores were calculated at age 20 y. 2.2.2. Spirometry Standard spirometry was performed. FEV1 was reported as percentage of predicted value (FEV1%-predicted) based upon the Global Lung Initiative prediction equations [20]. 50 g glucose challenge test: Non-fasting subjects ingested 50 g dose of aqueous oral dextrose (50 g dextrose/148 mL) within 5 min. Venous blood glucose was obtained 60 min later and measured using a Nova glucose meter (NovaBio, MA), which accurately measures blood glucose [21]. 2.2.3. Statistical analysis Continuous variables were summarized using median, minimum, and maximum, and categorical variables were described using proportions. Medians were compared using a non-parametric test; p < 0.05 (two-tailed) was considered statistically significant. Because of our limited sample size, we used 2 × 2 tables and graphical displays for GCT cutoffs between 7.2–8.3 mmol/L selected from GDM, and identified the GCT glucose threshold that would be highly sensitive for 2-h AGT. Specificity, accuracy, positive and negative predictive values (PPV and NPV, respectively) were calculated after a threshold with high sensitivity was identified. A ROC analysis was performed separately and yielded similar results (not shown). All analyses were performed using STATA 15 (StataCorp LP, College Station, TX, USA). Study protocols under which these data
Fig. 1. shows glucose during GCT (left) and 2-h OGTT (right) by individual subject. Lines connect each subject’s glucose on the two tests; solid gray lines with open circles identify subjects who were true positive (TP) for 2h-AGT (2-h OGTT glucose ≥7.8 mmol/L, n = 8); solid gray lines with open triangles subjects who were true negative (TN, n = 10), dashed black lines with X subjects who were false positive (FP, n = 6) and dashed black lines with open squares subjects who were false negative (FN, n = 3).
Please cite this article as: S. Sheikh, A.R. Localio and A. Kelly et al., Abnormal glucose tolerance and the 50-gram glucose challenge test in Cystic fibrosis, Journal of Cystic Fibrosis, https://doi.org/10.1016/j.jcf.2020.01.003
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3
Table 2 Characteristics for abnormal GCT test at ≥ 8.1 mmol/L. Cell counts
2-h AGT (mmol/L)
GCT (mmol/L)
≥ 7.8 8 3 11 Accuracy (%)
≥ 8.1 < 8.1 Total
< 7.8 6 10 16 67
1-h AGT (mmol/L) Total 14 13 27 70
≥ 11.1 8 2 10
< 11.1 6 11 17
Total 14 13 27
GCT test characteristics
2-h AGT
1-h AGT
Sensitivity (%) Specificity (%) PPV (%) NPV (%)
73 63 57 77
80 65 57 85
2-h defined as 2-h OGTT glucose ≥7.8 mmol/L with or without abnormal 1-h OGTT glucose (≥11.1 mmol/L); 1-hr AGT defined as 1-h OGTT glucose ≥11.1 mmol/L with or without abnormal 2-h OGTT glucose (≥7.8 mmol/L); GCT: glucose challenge test; PPV: positive predictive value; NPV; negative predictive value.
3 individuals with AGT (false negatives) (Fig. 1), but no individual with CFRD would be missed. Of the 14 (52%) who would proceed to confirmatory testing (true positives and false positives), 8 (57%) would be confirmed as having AGT (Fig. 1). This GCT ≥ 8.1 mmol/L threshold would also be 80% sensitive and 65% specific for 1 h-AGT (Table 2). 4. Conclusions The OGTT is the gold standard for CFRD diagnosis and, while cumbersome, is also the currently recommended annual screening test for CFRD [13]. Since this test is burdensome, a simpler test, such as the shorter GCT may be more well-received by patients and caregivers. Based on the data here, the more convenient GCT that does not require fasting or baseline measurement of glucose may help to identify patients with abnormal glucose at 1- (with 80% sensitivity at the current cutoff). Furthermore, adopting a twostep approach, in which OGTT is only performed if GCT is positive, could potentially reduce the need for OGTT in a portion of CF patients (48%) undergoing screening for CFRD. However, based on the current data set, this screening threshold is associated with a false negative rate of 20–27% for identifying abnormal glucose tolerance. Despite strong recommendations since 2010 to screen annually, only 29.1% of patients 10–17 y and 61.7% of patients >18 y with CF underwent OGTT in 2017 [14]. Registry data demonstrated that HbA1C was obtained during the same year in 85% of patients age 10–17 y and 100% of those ≥18 y. These data suggest CFRD screening is important to CF Centers and patients but that the barrier may be the test itself. Existing literature has not investigated specific reasons for poor adherence, but anecdotally, both test and patient related factors are important: fasting, nausea, and time and financial commitment in the context of similar demands imposed by routine clinical care. Therefore, an easier alternate that is also sensitive could be the solution to improving CFRD screening. Potentially further simplifying the process for completion in the CF Clinic setting, a bedside meter could be used to measure the 1-h glucose. A similar screening algorithm using glycated hemoglobin levels (HbA1C) has been proposed to screen for CFRD given its ease and sensitivity [22]. However, since it is less sensitive at detecting early glucose abnormalities, investigating GCT in conjunction with HbA1C may establish improvement over a single screening test. The data included here, however, are insufficient to recommend replacement of the OGTT as 1) CF-relevant outcomes are known to be associated with OGTT glucose, 2) a larger validation sample is needed to replicate these results, and 3) comparison between GCT vs. OGTT vs. a two-step approach is necessary. Future studies should evaluate the performance, feasibility, and acceptance of this proposed two-step approach vs. OGTT alone in a larger and more broadly representative population that includes patients with severe lung disease in whom AGT may be more common. Future studies are also needed to assess the threshold for defining abnormality. A lower threshold would improve sensitivity, thereby reducing the number of false negatives, but will increase the number of false positives. Studies are needed to establish an acceptable
false positive rate. Our chosen threshold attempts to balance the rate of false positives with the number of missed diagnoses of IGT. An additional limitation is that this study was not designed to assess real world improvement in adherence to screening. The American Congress of Obstetrics and Gynecology recommends GCT as part one of a two-step approach for screening GDM [23]. Despite these recommendations, randomized trials have not been conducted to establish the threshold that best identifies women with GDM and GCT thresholds vary among institutions. Moreover, institutions report a range of sensitivities and specificities for thresholds between 7.2–7.8 mmol/L [23]. A GCT threshold that best identifies maternal and fetal complications and improves pregnancy specific outcomes has similarly not been established. Interestingly, a subset of patients with GDM who have a positive GCT but normal OGTT are noted to have worse pregnancy outcomes compared to those pregnant women whose GCT is negative [15]. Similarly, examining relationships of GCT with in CF-relevant outcomes in a large sample of CF individuals should also be evaluated. In conclusion, adopting a two-step CFRD screening approach that employs the GCT has the potential to improve screening practices in CF by easing patient burden of testing. Studies are needed to confirm test performance and proposed benefit to patientcentered outcomes. Declaration of Competing Interest None. Acknowledgments The authors would like to thank the Center for Human Phenomic Science where the study procedures were performed, Paige Notrianni for database management and Christina Kubrak for her coordinator support. The authors would like to especially thank the patients involved. Funding source SS was supported by a CF Foundation third year fellowship training grant (SHEIKH12A0) and an National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) career development grant (K23 DK107937). AK and RCR were supported by NIDDK (R01 DK097830-05). References [1] Milla CE, Warwick WJ, Moran A. Trends in pulmonary function in patients with cystic fibrosis correlate with the degree of glucose intolerance at baseline. Am J Respir Crit Care Med 20 0 0;162(3 Pt 1):891–5. [2] Marshall BC, Butler SM, Stoddard M, Moran AM, Liou TG, Morgan WJ. Epidemiology of cystic fibrosis-related diabetes. J Pediatr 2005;146(5):681–7. [3] Koch C, Rainisio M, Madessani U, Harms HK, Hodson ME, Mastella G, et al. Presence of cystic fibrosis-related diabetes mellitus is tightly linked to poor lung function in patients with cystic fibrosis: data from The European Epidemiologic Registry of Cystic Fibrosis. Pediatr Pulmonol 2001;32(5):343–50.
Please cite this article as: S. Sheikh, A.R. Localio and A. Kelly et al., Abnormal glucose tolerance and the 50-gram glucose challenge test in Cystic fibrosis, Journal of Cystic Fibrosis, https://doi.org/10.1016/j.jcf.2020.01.003
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[4] Lanng S, Thorsteinsson B, Nerup J, Koch C. Influence of the development of diabetes mellitus on clinical status in patients with cystic fibrosis. Eur J Pediatr 1992;151(9):684–7. [5] Abbott J, Morton AM, Hurley MA, Conway SP. Longitudinal impact of demographic and clinical variables on health-related quality of life in cystic fibrosis. BMJ Open 2015;5(5):e007418. [6] Lanng S, Thorsteinsson B, Nerup J, Koch C. Diabetes mellitus in cystic fibrosis: effect of insulin therapy on lung function and infections. Acta Paediatr 1994;83(8):849–53. [7] Mohan K, Israel KL, Miller H, Grainger R, Ledson MJ, Walshaw MJ. Long-term effect of insulin treatment in cystic fibrosis-related diabetes. Respiration 2008;76(2):181–6. [8] Rolon MA, Benali K, Munck A, Navarro J, Clement A, Tubiana-Rufi N, et al. Cystic fibrosis-related diabetes mellitus: clinical impact of prediabetes and effects of insulin therapy. Acta Paediatr 2001;90(8):860–7. [9] Brodsky J, Dougherty S, Makani R, Rubenstein RC, Kelly A. Elevation of 1-hour plasma glucose during oral glucose tolerance testing is associated with worse pulmonary function in cystic fibrosis. Diabetes Care 2011;34(2):292–5. [10] Tofe S, Moreno JC, Maiz L, Alonso M, Escobar H, Barrio R. Insulin-secretion abnormalities and clinical deterioration related to impaired glucose tolerance in cystic fibrosis. Eur J Endocrinol 2005;152(2):241–7. [11] Sheikh S, Putt ME, Forde KA, Rubenstein RC, Kelly A. Elevation of one hour plasma glucose during oral glucose tolerance testing. Pediatr Pulmonol 2015;50(10):963–9. [12] Ode KL, Frohnert B, Laguna T, Phillips J, Holme B, Regelmann W, et al. Oral glucose tolerance testing in children with cystic fibrosis. Pediatr Diabetes 2010;11(7):487–92. [13] Moran A, Brunzell C, Cohen RC, Katz M, Marshall BC, Onady G, et al. 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. Diabetes Care 2010;33(12):2697–708.
[14] Cystic Fibrosis Foundation Patient Registry. 2017 Annual data report. 2017. [15] Stamilio DM, Olsen T, Ratcliffe S, Sehdev HM, Macones GA. False-positive 1-hour glucose challenge test and adverse perinatal outcomes. Obstet Gynecol 2004;103(1):148–56. [16] Jimenez-Moleon JJ, Bueno-Cavanillas A, Luna-del-Castillo Jde D, Garcia– Martin M, Lardelli-Claret P, Galvez-Vargas R. Impact of different levels of carbohydrate intolerance on neonatal outcomes classically associated with gestational diabetes mellitus. Eur J Obstet Gynecol Reprod Biol 2002;102(1):36–41. [17] Tan PC, Ling LP, Omar SZ. The 50-g glucose challenge test and pregnancy outcome in a multiethnic Asian population at high risk for gestational diabetes. Int J Gynaecol Obstet 2009;105(1):50–5. [18] Lee KM, Miller RJ, Rosenberg FM, Kreisman SH. Evaluation of glucose tolerance in cystic fibrosis: comparison of 50-g and 75-g tests. J Cyst Fibros 2007;6(4):274–6. [19] Kuczmarski RJ, Ogden CL, Grummer-Strawn LM, Flegal KM, Guo SS, Wei R, et al. CDC growth charts: United States. Adv Data 20 0 0(314):1–27. [20] Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, et al. Multi-ethnic reference values for spirometry for the 3-95-yr age range: the global lung function 2012 equations. Eur Respir J 2012;40(6):1324–43. [21] Rabiee A, Magruder JT, Grant C, Salas-Carrillo R, Gillette A, DuBois J, et al. Accuracy and reliability of the Nova StatStrip(R) glucose meter for real-time blood glucose determinations during glucose clamp studies. J Diabetes Sci Technol 2010;4(5):1195–201. [22] Gilmour JA, Sykes J, Etchells E, Tullis E. Cystic fibrosis-related diabetes screening in adults: a gap analysis and evaluation of accuracy of glycated hemoglobin levels. Can J Diabetes 2019;43(1):13–18. [23] Committee on Practice B-O. ACOG practice bulletin no. 190: gestational diabetes mellitus. Obstet Gynecol 2018;131(2):e49–64.
Please cite this article as: S. Sheikh, A.R. Localio and A. Kelly et al., Abnormal glucose tolerance and the 50-gram glucose challenge test in Cystic fibrosis, Journal of Cystic Fibrosis, https://doi.org/10.1016/j.jcf.2020.01.003
JID: JCF
[m5G;January 21, 2020;1:20]
Journal of Cystic Fibrosis xxx (xxxx) xxx
Contents lists available at ScienceDirect
Journal of Cystic Fibrosis journal homepage: www.elsevier.com/locate/jcf
Short Communication
Abnormal glucose tolerance and the 50-gram glucose challenge test in Cystic fibrosis Saba Sheikh a,∗, A Russell Localio b, Andrea Kelly c, Ronald C Rubenstein a a
Division of Pulmonary Medicine and The Cystic Fibrosis Center, The Children’s Hospital of Philadelphia, Philadelphia, PA United States Division of Biostatistics, Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, PA United States c Division of Endocrinology and Diabetes, The Children’s Hospital of Philadelphia, Philadelphia, PA United States b
a r t i c l e
i n f o
Article history: Received 17 April 2019 Revised 6 December 2019 Accepted 7 January 2020 Available online xxx Keywords: Cystic Fibrosis Cystic Fibrosis Related Diabetes Oral glucose tolerance test Glucose challenge test
a b s t r a c t Diabetes has emerged as a major co-morbidity in cystic fibrosis (CF). The 75 g oral glucose tolerance test (OGTT) is used to screen for CF-related diabetes (CFRD) but is inconvenient, and adherence to screening is poor. The 50 g glucose challenge test (GCT) is shorter, performed non-fasting, and may serve to pre-screen the subset of individuals requiring confirmatory OGTT. We performed a pilot study in twenty-seven CF individuals across the glucose tolerance spectrum to test whether the GCT could identify subjects with abnormal glucose tolerance defined as 2-h OGTT glucose ≥7.8 mmol/L (2 h-AGT) or 1-h defined as 1-hr OGTT glucose ≥11.1 mmol/L (1 h-AGT). A GCT threshold of 8.1 mmol/L was 73% sensitive and 63% specific for 2hr-AGT and 80% sensitive and 65% specific for 1hr-AGT. Therefore, a screening GCT may reduce need for confirmatory OGTT for identifying AGT but a larger study is warranted to identify a robust cutoff for CFRD. © 2020 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.
1. Introduction Cystic fibrosis related diabetes (CFRD), a common complication in cystic fibrosis, is associated with worse clinical outcomes [1–4], and increases disease burden while adversely impacting quality of life [5]. Early diagnosis and treatment of CFRD may mitigate the associated decline in lung function, decreases in body mass index (BMI), and increased mortality [6–8]. Earlier glucose derangements during 75 g oral glucose challenge test (OGTT) such as impaired glucose tolerance (IGT; 2-hr OGTT glucose ≥7.8 mmol/L and <11.1 mmol/L) and isolated 1-hr glucose elevations are also associated with lower forced expiratory volume in 1 s (FEV1%-predicted) [1,9,10], greater decline in FEV1%-predicted over time [1] and increased risk of subsequent diabetes [11,12].
Abbreviations: AGT, Abnormal glucose tolerance; BMI, Body mass index; CF, Cystic Fibrosis; CFRD, Cystic Fibrosis Related Diabetes; CHOP, Children’s Hospital of Philadelphia; FEV1, Forced expiratory volume in 1 s; GCT, 50 g glucose challenge test; GDM, Gestational Diabetes Mellitus; HUP, Hospital of University of Pennsylvania; IGT, Impaired glucose tolerance; INDET, Indeterminate glucose tolerance; NGT, Normal glucose tolerance; NPV, Negative predictive value; OGTT, 75 g oral glucose tolerance test; PPV, Positive predictive value. ∗ Corresponding author at: 3501 Civic Center Boulevard, 11th Floor Colket Building, Division of Pulmonary Medicine, Philadelphia, PA 19104 United States E-mail address: [email protected] (S. Sheikh).
CFRD diagnosis can be established with identification of 2-hr OGTT glucose ≥11.1 mmol/L. The annual OGTT recommended by the CF Foundation starting by age 10 years [13] requires overnight fasting and multiple blood draws over a two-hour period. Adherence is poor [14]; reasons may include 1) patient specific factors such as fasting requirement, time commitment, number of blood draws, development of nausea, development of hypoglycemia, and insufficient concern for diabetes and 2) CF center specific factors such as poor adoption of guidelines and insufficient patient education. An alternate, firststep screening test used in gestational diabetes mellitus (GDM), is the non-fasting 1-hr 50 g glucose challenge test (GCT), the results of which correlate well with pregnancy specific outcomes [15–17]. In pregnancy, an abnormal GCT is followed by a confirmatory 100 g OGTT. A single, small study in adults (n = 31) has evaluated the GCT in CF and demonstrated 100% sensitivity and 50% specificity for positive OGTT (≥7.8 mmol/L) at 7.8 mmol/L threshold for GCT [18]. The objective of this study was to identify a glucose threshold during the GCT using a hospital grade bedside glucometer that identifies the subset of CF children and young adults with abnormal glucose tolerance defined as 2 h OGTT glucose ≥7.8 mmol/L (2 h AGT) or 1 h OGTT glucose ≥11.1 mmol/L (1-hr AGT). We hypothesize that the GCT can accurately identify patients with 1 and/or 2 h-AGT and those who require confirmatory OGTT (a twostep diagnostic approach).
https://doi.org/10.1016/j.jcf.2020.01.003 1569-1993/© 2020 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.
Please cite this article as: S. Sheikh, A.R. Localio and A. Kelly et al., Abnormal glucose tolerance and the 50-gram glucose challenge test in Cystic fibrosis, Journal of Cystic Fibrosis, https://doi.org/10.1016/j.jcf.2020.01.003
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S. Sheikh, A.R. Localio and A. Kelly et al. / Journal of Cystic Fibrosis xxx (xxxx) xxx Table 1 Subject characteristics.
Age (y) Male sex Pancreatic insufficiency FEV1%-predicted BMI-Z GCT (mmol/L) OGTT 60 min (mmol/L) OGTT 120-min (mmol/L) ∗
NGT (N = 14)
INDET (N = 2)
IGT (N = 8)
CFRD (N = 3)
p-value
14.5 (9.6–20.8) 9 (60%) 12 (86%) 100 (86–134) 0.5 (−0.7–1.4) 7.7 (5.1–9.8) 8.1 (4.6–10.9) 4.9 (2.2–7.5)
24.6 and 25.1 1 (50%) 2 (100%) 65∗ −1.2 and −0.003 4.5 and 10.2 11.4 and 15.3 4.7 and 7.1
19.2 (12.7–39.2) 4 (40%) 8 (100%) 99 (59–125) 0.3 (−0.4–1.3) 8.4 (6.3–13.0) 12.4 (9.9–14.0) 10.4 (8.0–10.9)
23.2 (18.3–24.3) 2 (67%) 3 (100%) 89 (69–96) 0.1 (0.05–0.3) 12.5 (12.4–15.3) 13.7 (12.9–22.1) 17.2 (11.6–18.9)
0.01 0.57 0.42 0.22 0.07 0.02 0.0003 0.0002
N = 1 for FEV1%-predicted; to convert mmol/L to mg/dL multiply by 18.
2. Materials and methods 2.1. Subjects Individuals with CF, age ≥8y were recruited from The Children’s Hospital of Philadelphia (CHOP) and Hospital of University of Pennsylvania (HUP) Cystic Fibrosis Center. The diagnosis of CF was confirmed by documentation of a positive sweat test and/or diagnostic CF genotyping. Inclusion criteria included FEV1%-predicted ≥40% and OGTT within previous 4 months. Exclusion criteria were known cirrhosis or portal hypertension, history of transplant, or presence of other medical conditions not associated with CF that could affect glucose tolerance. Medical records were reviewed to determine pancreatic insufficiency status. Glucose tolerance during OGTT was categorized as normal glucose tolerance (NGT) for 1-h glucose <11.1 mmol/L and 2-h glucose <7.8 mmol/L; Indeterminate, INDET for 1-h glucose ≥11.1 mmol/L and 2-h glucose <7.8 mmol/L; IGT for 2-h glucose ≥7.8 mmol/L and <11.1 mmol/L; and CFRD for 2-h glucose ≥11.1 mmol/L or fasting glucose ≥7.0 mmol/L.
were collected were approved by the Institutional Review Boards at CHOP and HUP. Informed consent was obtained from young adult participants (age≥18 y) and from parents/guardians of participants (age<18 y). Assent was obtained from participants age <18 y. 3. Results Twenty-seven individuals (44% male), across the spectrum of glucose tolerance participated (Table 1). Median FEV1%-predicted was 96% and BMI-Z was 0.4. The majority were pancreatic insufficient (93%). Median time between GCT and OGTT was 49 days (range 2–109). Subjects with NGT were more likely to be younger (p = 0.01; Table 1). A GCT glucose of ≥8.1 mmol/L yielded a sensitivity for 2 h-AGT of 73%, specificity 63%, PPV 57%, and NPV 77% (Table 2). Thus, using this threshold, 67% individuals would be accurately classified (true negatives and true positives, Fig. 1). This GCT threshold would miss
2.2. Study procedures 2.2.1. Anthropometry Weight and height were measured to nearest 0.1 kg and 0.1 cm, respectively. BMI (weight/height2 ) was converted to age and sex adjusted Z score using reference data [19]. For subjects >20y, Zscores were calculated at age 20 y. 2.2.2. Spirometry Standard spirometry was performed. FEV1 was reported as percentage of predicted value (FEV1%-predicted) based upon the Global Lung Initiative prediction equations [20]. 50 g glucose challenge test: Non-fasting subjects ingested 50 g dose of aqueous oral dextrose (50 g dextrose/148 mL) within 5 min. Venous blood glucose was obtained 60 min later and measured using a Nova glucose meter (NovaBio, MA), which accurately measures blood glucose [21]. 2.2.3. Statistical analysis Continuous variables were summarized using median, minimum, and maximum, and categorical variables were described using proportions. Medians were compared using a non-parametric test; p < 0.05 (two-tailed) was considered statistically significant. Because of our limited sample size, we used 2 × 2 tables and graphical displays for GCT cutoffs between 7.2–8.3 mmol/L selected from GDM, and identified the GCT glucose threshold that would be highly sensitive for 2-h AGT. Specificity, accuracy, positive and negative predictive values (PPV and NPV, respectively) were calculated after a threshold with high sensitivity was identified. A ROC analysis was performed separately and yielded similar results (not shown). All analyses were performed using STATA 15 (StataCorp LP, College Station, TX, USA). Study protocols under which these data
Fig. 1. shows glucose during GCT (left) and 2-h OGTT (right) by individual subject. Lines connect each subject’s glucose on the two tests; solid gray lines with open circles identify subjects who were true positive (TP) for 2h-AGT (2-h OGTT glucose ≥7.8 mmol/L, n = 8); solid gray lines with open triangles subjects who were true negative (TN, n = 10), dashed black lines with X subjects who were false positive (FP, n = 6) and dashed black lines with open squares subjects who were false negative (FN, n = 3).
Please cite this article as: S. Sheikh, A.R. Localio and A. Kelly et al., Abnormal glucose tolerance and the 50-gram glucose challenge test in Cystic fibrosis, Journal of Cystic Fibrosis, https://doi.org/10.1016/j.jcf.2020.01.003
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Table 2 Characteristics for abnormal GCT test at ≥ 8.1 mmol/L. Cell counts
2-h AGT (mmol/L)
GCT (mmol/L)
≥ 7.8 8 3 11 Accuracy (%)
≥ 8.1 < 8.1 Total
< 7.8 6 10 16 67
1-h AGT (mmol/L) Total 14 13 27 70
≥ 11.1 8 2 10
< 11.1 6 11 17
Total 14 13 27
GCT test characteristics
2-h AGT
1-h AGT
Sensitivity (%) Specificity (%) PPV (%) NPV (%)
73 63 57 77
80 65 57 85
2-h defined as 2-h OGTT glucose ≥7.8 mmol/L with or without abnormal 1-h OGTT glucose (≥11.1 mmol/L); 1-hr AGT defined as 1-h OGTT glucose ≥11.1 mmol/L with or without abnormal 2-h OGTT glucose (≥7.8 mmol/L); GCT: glucose challenge test; PPV: positive predictive value; NPV; negative predictive value.
3 individuals with AGT (false negatives) (Fig. 1), but no individual with CFRD would be missed. Of the 14 (52%) who would proceed to confirmatory testing (true positives and false positives), 8 (57%) would be confirmed as having AGT (Fig. 1). This GCT ≥ 8.1 mmol/L threshold would also be 80% sensitive and 65% specific for 1 h-AGT (Table 2). 4. Conclusions The OGTT is the gold standard for CFRD diagnosis and, while cumbersome, is also the currently recommended annual screening test for CFRD [13]. Since this test is burdensome, a simpler test, such as the shorter GCT may be more well-received by patients and caregivers. Based on the data here, the more convenient GCT that does not require fasting or baseline measurement of glucose may help to identify patients with abnormal glucose at 1- (with 80% sensitivity at the current cutoff). Furthermore, adopting a twostep approach, in which OGTT is only performed if GCT is positive, could potentially reduce the need for OGTT in a portion of CF patients (48%) undergoing screening for CFRD. However, based on the current data set, this screening threshold is associated with a false negative rate of 20–27% for identifying abnormal glucose tolerance. Despite strong recommendations since 2010 to screen annually, only 29.1% of patients 10–17 y and 61.7% of patients >18 y with CF underwent OGTT in 2017 [14]. Registry data demonstrated that HbA1C was obtained during the same year in 85% of patients age 10–17 y and 100% of those ≥18 y. These data suggest CFRD screening is important to CF Centers and patients but that the barrier may be the test itself. Existing literature has not investigated specific reasons for poor adherence, but anecdotally, both test and patient related factors are important: fasting, nausea, and time and financial commitment in the context of similar demands imposed by routine clinical care. Therefore, an easier alternate that is also sensitive could be the solution to improving CFRD screening. Potentially further simplifying the process for completion in the CF Clinic setting, a bedside meter could be used to measure the 1-h glucose. A similar screening algorithm using glycated hemoglobin levels (HbA1C) has been proposed to screen for CFRD given its ease and sensitivity [22]. However, since it is less sensitive at detecting early glucose abnormalities, investigating GCT in conjunction with HbA1C may establish improvement over a single screening test. The data included here, however, are insufficient to recommend replacement of the OGTT as 1) CF-relevant outcomes are known to be associated with OGTT glucose, 2) a larger validation sample is needed to replicate these results, and 3) comparison between GCT vs. OGTT vs. a two-step approach is necessary. Future studies should evaluate the performance, feasibility, and acceptance of this proposed two-step approach vs. OGTT alone in a larger and more broadly representative population that includes patients with severe lung disease in whom AGT may be more common. Future studies are also needed to assess the threshold for defining abnormality. A lower threshold would improve sensitivity, thereby reducing the number of false negatives, but will increase the number of false positives. Studies are needed to establish an acceptable
false positive rate. Our chosen threshold attempts to balance the rate of false positives with the number of missed diagnoses of IGT. An additional limitation is that this study was not designed to assess real world improvement in adherence to screening. The American Congress of Obstetrics and Gynecology recommends GCT as part one of a two-step approach for screening GDM [23]. Despite these recommendations, randomized trials have not been conducted to establish the threshold that best identifies women with GDM and GCT thresholds vary among institutions. Moreover, institutions report a range of sensitivities and specificities for thresholds between 7.2–7.8 mmol/L [23]. A GCT threshold that best identifies maternal and fetal complications and improves pregnancy specific outcomes has similarly not been established. Interestingly, a subset of patients with GDM who have a positive GCT but normal OGTT are noted to have worse pregnancy outcomes compared to those pregnant women whose GCT is negative [15]. Similarly, examining relationships of GCT with in CF-relevant outcomes in a large sample of CF individuals should also be evaluated. In conclusion, adopting a two-step CFRD screening approach that employs the GCT has the potential to improve screening practices in CF by easing patient burden of testing. Studies are needed to confirm test performance and proposed benefit to patientcentered outcomes. Declaration of Competing Interest None. Acknowledgments The authors would like to thank the Center for Human Phenomic Science where the study procedures were performed, Paige Notrianni for database management and Christina Kubrak for her coordinator support. The authors would like to especially thank the patients involved. Funding source SS was supported by a CF Foundation third year fellowship training grant (SHEIKH12A0) and an National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) career development grant (K23 DK107937). AK and RCR were supported by NIDDK (R01 DK097830-05). References [1] Milla CE, Warwick WJ, Moran A. Trends in pulmonary function in patients with cystic fibrosis correlate with the degree of glucose intolerance at baseline. Am J Respir Crit Care Med 20 0 0;162(3 Pt 1):891–5. [2] Marshall BC, Butler SM, Stoddard M, Moran AM, Liou TG, Morgan WJ. Epidemiology of cystic fibrosis-related diabetes. J Pediatr 2005;146(5):681–7. [3] Koch C, Rainisio M, Madessani U, Harms HK, Hodson ME, Mastella G, et al. Presence of cystic fibrosis-related diabetes mellitus is tightly linked to poor lung function in patients with cystic fibrosis: data from The European Epidemiologic Registry of Cystic Fibrosis. Pediatr Pulmonol 2001;32(5):343–50.
Please cite this article as: S. Sheikh, A.R. Localio and A. Kelly et al., Abnormal glucose tolerance and the 50-gram glucose challenge test in Cystic fibrosis, Journal of Cystic Fibrosis, https://doi.org/10.1016/j.jcf.2020.01.003
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Please cite this article as: S. Sheikh, A.R. Localio and A. Kelly et al., Abnormal glucose tolerance and the 50-gram glucose challenge test in Cystic fibrosis, Journal of Cystic Fibrosis, https://doi.org/10.1016/j.jcf.2020.01.003