1 2 3 Cystic fibrosisrelated diabetes (CFRD) is a distinct - PDF document

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• Cystic fibrosis–related diabetes (CFRD) is a distinct clinical entity from type 1 or type 2 diabetes, affecting approximately 35% of the cystic fibrosis (CF) population, with a peak age of onset in the 20-to 24-year range • Unlike type 2 diabetes, CFRD is characterized by a severe but incomplete insulin deficiency, and insulin resistance is modest, fluctuating with infection. Notably, A1C is not a reliable indicator of blood glucose in CFRD, and metabolic syndrome, macrovascular complications, and cardiovascular disease are not dominant causes of death as in type 2 diabetes. Neither type 2 diabetes nor CFRD have an autoimmune etiology as does type 1 diabetes Reference Moran A, Becker D, Casella SJ, et al. Epidemiology, pathophysiology, and prognostic implications of cystic fibrosis-related diabetes: a technical review. Diabetes Care . 2010;33(12):2677-2683. 4

Key Points • Oral glucose tolerance test (OGTT) results are used to diagnose glucose metabolism disorders, including CFRD • For healthy outpatients, OGTT is the assessment of choice for CFRD, although assessments such as fasting plasma glucose (FPG) may be indicated during hospitalizations or acute illnesses. Diagnostic criteria for CFRD based on OGTT results are shown in the table Reference Kelly A, Moran A. Update on cystic fibrosis-related diabetes. J Cyst Fibros. 2013;12(4):318-331 5

• In one study of 527 patients with CF at a single center, 33% of patients had diabetes, and prevalence increased steadily with age peaking at 45% to 50% by age 40. Incidence was roughly 15% among adolescents and 50% among adults with CF in this study, with comparable incidences in both sexes in most of the age groups 1,2 • Cases of diabetes have occurred in children as young as infants with CF, whereas overt diabetes is comparatively rare in non-CF pediatric populations, occurring at a rate of approximately 1.5% among individuals younger than 10 years of age, and typically being associated with type 1 autoimmune diabetes 2 • Other studies have shown CFRD to occur in as many as 1 of 5 younger patients with CF, and incidences of CFRD as high as 45% have been reported by age 20 years 2 References 1. Moran A, Dunitz J, Nathan B, et al. Cystic fibrosis-related diabetes: current trends in prevalence, incidence, and mortality. Diabetes Care . 2009;32(9):1626-1631. 2. Ode KL, Moran A. New insights into cystic fibrosis-related diabetes in children. Lancet Diabetes Endocrinol . 2013;1(1):52-58. 6

Key Point • Glucose abnormalities may precede the onset of CFRD in children under 10 years of age 1 Additional Information • In one study of 152 patients with CF at a single center, a high prevalence of glucose metabolism derangements (GMDs) was observed in patients with CF with pancreatic insufficiency (PI) between the ages of 6 and 10 years • The results suggest that, despite current recommendations of the Cystic Fibrosis Foundation, the American Diabetes Association, and the Pediatric Endocrine Society, screening for GMDs may be indicated in patients younger than 10 years of age, particularly in those with PI 2 • In a prospective multicenter study in children ages 3 months to 5 years with and without CF, at their first visit, 9 of the 23 subjects with CF with full data available met criteria for abnormal glucose tolerance (AGT) ( P =0.03 vs control). One had indeterminate glucose tolerance (INDET), 6 had impaired glucose tolerance (IGT), and 2 met criteria for CFRD. None of the controls had AGT. In subjects who had multiple visits, 3 additional subjects with CF subsequently developed IGT ( P =0.01 for having exhibited AGT at any visit CF vs control) 3 • These findings emphasize the need for early monitoring for CFRD in patients with CF References 1. Ode KL, Moran A. New insights into cystic fibrosis-related diabetes in children. Lancet Diabetes Endocrinol. 2013;1(1):52-58. 2. Mozzillo E, Raia V, Fattorusso V, et al. Glucose derangements in very young children with cystic fibrosis and pancreatic insufficiency. Diabetes Care. 2012;35(11):e78. 3. Yi Y, et al. abnormal glucose tolerance in infants and young children with cystic fibrosis. Am J Respir Crit Care Med . 2016 Jul 22. doi: 10.1164/rccm.201512-2518OC. [Epub ahead of print]. 7

• Studies of CFRD prevalence have shown that elevations in fasting plasma glucose are less common among younger patients, and instead predominate in the older age groups • In a study of 527 patients with CF at a single center, 33% of patients had diabetes, and incidence increased steadily with age. The prevalence of CFRD with fasting hyperglycemia increased with age and predominated after the age of 40 years, whereas CFRD without fasting hyperglycemia was more prevalent in the younger age groups Reference Moran A, Dunitz J, Nathan B, et al. Cystic fibrosis-related diabetes: current trends in prevalence, incidence, and mortality. Diabetes Care . 2009;32(9):1626-1631. 8

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• The results from a prospective, 4-year study of patients with CF without diabetes has shown a pattern of decline in pulmonary function, as assessed by ppFEV 1 , that was directly proportional to the severity of glucose intolerance at baseline • The study group comprised 152 patients (n=77 female; n=75 male) without fasting hyperglycemia and having stable lung health status. Patients were found on OGTT to have either normal glucose tolerance (45.4%), impaired glucose tolerance (38.8%), or CFRD without fasting hyperglycemia (15.8%) • There was a difference among the groups based on OGTT; whereas patients with normal glucose tolerance had no decline in their percent FEV 1 rates, those with impaired glucose tolerance or CFRD without fasting hyperglycemia had significant declines of -1.36 and -2.44/year, respectively • These differences were observed after adjustment for sex and baseline body mass index (BMI), microbiology, and FEV 1 • Similar findings were observed for insulin AUC, and after adjustment for sex and baseline BMI, microbiology, and FEV 1 , with those subjects in the lowest quartiles having the highest degree of decline relative to those in the higher quartiles • The results suggest that the degree of glucose tolerance impairment and the degree of insulin deficiency correlates with the rate of lung functional decline in patients with CF, suggesting a direct cause/effect relation Reference 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. 2000;162(3 Pt 1):891-895. 10

Key Point • CFRD is important to recognize as a condition in patients with CF, as it has been associated with increased mortality Additional Information • In a retrospective cohort study of 8029 individuals with CF in the UK Cytsic Fibrosis Registry from 1996 to 2005, a total of 5892 patients were included in an analysis of mortality rates 1 • Results showed that individuals with diabetes had higher age-adjusted mortality rates compared with those without diabetes (4.2 vs 1.5 per 100 person-years, respectively). Absolute mortality rates were also significantly higher across all age groups ( P =0.009), with the greatest relative difference occurring in the <10-year age group 1 • In a more recent study of 664 patients followed from 2008 through 2012, there remained a significantly higher incidence of mortality for patients with CFRD, regardless of genotype, compared with patients with CF without CFRD 2 References 1. Chamnan P, Shine BS, Haworth CS, Bilton D, Adler AI. Diabetes as a determinant of mortality in cystic fibrosis. Diabetes Care. 2010;33(2):311-316. 2. Lewis C, Blackman SM, Nelson A, et al. Diabetes-related mortality in adults with cystic fibrosis. Role of genotype and sex. Am J Respir Crit Care Med. 2015;191(2):194-200. 11

Key Point • CFRD is important to recognize as a condition in patients with CF, as it has been associated with increased mortality. The difference in mortality rate between patients with and without CFRD is higher in male patients compared with female patients Additional Information • In a study of 664 patients followed from 2008 through 2012, there was a significantly higher incidence of mortality for patients with CFRD, regardless of genotype, compared with patients with CF without CFRD Reference Lewis C, Blackman SM, Nelson A, et al. Diabetes-related mortality in adults with cystic fibrosis. Role of genotype and sex. Am J Respir Crit Care Med. 2015;191(2):194-200. 12

Key Point • The early appearance of impaired glucose metabolism was associated with a higher rate of lung transplantation Additional Information • Early appearance was defined as before 15 years for IGT and before 18 years for diabetic OGTT • In the entire cohort, rates of transplantation did not differ between boys and girls Reference Bismuth E, Laborde K, Taupin P, et al. Glucose tolerance and insulin secretion, morbidity, and death in patients with cystic fibrosis. J Pediatr. 2008;152(4):540- 545. 13