Cystic fibrosis

Cystic Fibrosis-Related Diabetes in Children -- Gaps in the
Evidence?
Malay Rana; Craig F. Munns, MBBS, PhD, FRACP; Hiran Selvadurai, MBBS, PhD, FRACP; Kim C. Donaghue, MBBS, PhD, FRACP; Maria E. Craig, MBBS, PhD, FRACP Abstract
As the life span of patients with cystic fibrosis has increased, so has the prevalence of cystic fibrosis- related diabetes mellitus. However, screening practices for cystic fibrosis-related diabetes mellitus vary widely, which affects accurate estimates of the health burden of this comorbidity. The management of prediabetes and hyperglycemia is an increasingly important aspect of care in patients with cystic fibrosis, but few studies have specifically addressed the management of cystic fibrosis-related diabetes mellitus. Previous studies support the use of insulin for the treatment of patients with this disorder, but the evidence for its use in patients with cystic fibrosis and impaired glucose tolerance is poor. Nutritional management is currently guided by dietary recommendations for individuals with cystic fibrosis, with little evidence specific to the dietary management of patients with cystic fibrosis-related diabetes mellitus. Additionally, microvascular complications have become more frequent as a result of the rise in life expectancy of these patients, yet to date no intervention studies have addressed prevention or management of diabetic complications in patients with cystic fibrosis. A strong evidence base is needed to guide the management of patients with cystic fibrosis-related diabetes mellitus and Introduction
Cystic fibrosis is an autosomal recessive genetic dis order that affects 1 in 2,500 white individuals.[1] Over 1,000 mutations that cause cystic fibrosis have been identified at the cystic fibrosis locus on chromosome 7q31.2. The most common is a deletion of phenylalanine in amino acid position 508 (Phe508del), which is found in approximately 94% of affected individuals.[2] The molecular defect in cystic fibrosis results in abnormal production of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, a cAMP-regulated chloride ion channel. Impairment of this channel leads to defective transport of water and ions across epithelial membranes in the respiratory, gastrointestinal, hepatobiliary and reproductive systems. Cystic fibrosis is characterized by dehydration of mucous secretions that can lead to obstruction, progressive scarring and destruction of end-organs.[3] Cystic fibrosis-related diabetes mellitus has become a more frequent comorbidity, as the life expectancy of patients with cystic fibrosis has increased from <1 year in the 1950s to >37 years in 2007.[2] This comorbidity is typically diagnosed in late adolescence or early adulthood, with a median age range at Current diagnosis and management of patients with cystic fibrosis-related diabetes mellitus is based predominantly on consensus guidelines of the International Society for Pediatric and Adolescent Diabetes (ISPAD).[1] This Review outlines current knowledge on the epidemiology, pathophysiology, diagnosis, complications and management of cystic fibrosis-related diabetes mellitus and highlights Epidemiology
The prevalence of cystic fibrosis-related diabetes mellitus increases with age, affecting 2% of children aged <10 years and 19% of adolescents aged 10-19 years.[7] Prevalence continues to increase throughout adulthood, with rates of around 40% in individuals aged 20-29 years, 50% in those aged 30-39 years and around 52% in those over 40 years of age.[6,7] The prevalence of cystic fibrosis-related diabetes mellitus has risen over time—from 1% in 1962 to 31% in 2007[3,6]—probably owing to an increase in diagnosis and long-term survival of patients with cystic fibrosis. By contrast, few studies have examined the incidence of cystic fibrosis-related diabetes mellitus in children and adolescents and the change in incidence over time. A retrospective study of 527 pediatric and adult patients with cystic fibrosis in the US determined an incidence of 2.7 per 100 patient-years, with a peak in incidence observed in women aged 30-39 years. The incidence decreased by 40%, from four cases per 100 patient-years during 1998-2002 to 2.7 cases per 100 patient-years during 2003-2008, possibly owing to a new annual screening program introduced in the 1990s, which enabled identification of patients with long-standing cystic fibrosis-related diabetes mellitus.[7] In the UK, the incidence of cystic fibrosis- related diabetes mellitus was 0.8 and 1.6 per 100 patient-years for boys and girls aged 0-9 years, respectively, which rose to 3.9 per 100 patient-years in boys and 6.0 per 100 patient-years in girls aged 10-19 years.[8] An increased incidence with age is also seen in Denmark, with a mean annual incidence of cystic fibrosis-related diabetes mellitus of 5 and 9 per 100 patient-years for patients aged >10 years and >20 years, respectively.[9] Furthermore, in France, the cumulative incidence over a 17- year period increased from 20% at 15 years of age to 45% at 20 years of age and 70% in patients The main risk factors for cystic fibrosis-related diabetes mellitus include age, female sex, pancreatic exocrine insufficiency, poor pulmonary function and previous organ transplant.[11] Of the five classes of CFTR mutations, class I mutations result in premature transcription termination and an unstable truncated CFTR transcript or no CFTR protein expression, whereas class II mutations, including Phe508del, cause protein misfolding that leads to the retention of the misfolded protein in the endoplasmic reticulum and premature degradation. Both types of mutation are independent risk factors for the development of cystic fibrosis-related diabetes mellitus, as they cause total or partial absence of the CFTR protein and are associated with severe cystic fibrosis genotypes.[8] Pathophysiology
The pathogenesis of cystic fibrosis-related diabetes mellitus is multifactorial, with genetic and environmental factors contributing to the disease risk. Genetics
The Phe508del mutation of CFTR is the most common mutation in patients with cystic fibrosis-related diabetes mellitus, with homozygous mutations more frequent than heterozygous mutations.[12] Despite sharing some pathophysiological features with type 1 diabetes mellitus ( Table 1 ), no association between cystic fibrosis-related diabetes mellitus and major type 1 diabetes mellitus susceptibility genes, such as human leukocyte antigen class II or insulin variable number of tandem repeats, has been found.[1] However, some evidence points to an association between cystic fibrosis-related diabetes mellitus and type 1 diabetes mellitus susceptibility genes associated with inflammation, such as tumor necrosis factor (TNF) and heat shock protein, as well as the type 2 diabetes mellitus susceptibility gene calpain 10,[1] which is a marker for insulin secretion. The clinical significance of these genes and their role in the pathogenesis of cystic fibrosis-related diabetes mellitus are yet to be Inflammation and Immunity
Inflammation plays a role in the pathophysiology of cystic fibrosis-related diabetes mellitus; however, in contrast to type 1 diabetes mellitus, T cells do not seem to mediate β-cell damage. Glucose abnormalities can be further pronounced in patients with chronic inflammation and acute-on-chronic pulmonary exacerbations (a sudden worsening of lung function, including shortness of breath, increased cough and quantity and color of sputum) owing to increased insulin resistance. Autoantibodies frequently found in patients with type 1 diabetes mellitus are not often detected in patients with cystic fibrosis-related diabetes mellitus, and auto-immunity does not seem to have an appreciable role in its pathogenesis.[13] Serum antibody responses to bacterial antigens, such as IgG antibodies to the Pseudomonas aeruginosa antigen 60 kDa chaperonin (also known as groEL protein), have been implicated in the development of cystic fibrosis-related diabetes mellitus and, in one study,[14] were significantly elevated 3-12 months before onset of this comorbidity. This finding suggests that a chronic microbial infection is the cause of the progressive destruction or downregulation of pancreatic β-cell function in cystic fibrosis. The mechanism is unclear, although one could speculate that (β-cell destruction occurs via molecular mimicry; for example, the groEL protein has a 52% sequence homology with the human heat shock protein 60 (HSP60),[15] a peptide which induces diabetes mellitus in animal models and is linked to the appearance of T cells that specifically recognize hsp60.[16] Furthermore, high levels of antibodies to HSP60 have been detected in patients with cystic fibrosis.[17] Further studies are needed to determine whether these antibodies have a notable role in the pathogenesis of cystic fibrosis-related diabetes mellitus. Histopathology
The mechanisms that lead to β-cell death in cystic fibrosis-related diabetes mellitus are not well- understood and several concurrent processes may play a part. Obstruction of the pancreatic duct leads to interstitial edema and ischemic damage to the endocrine pancreas. Nevertheless, the degree of pancreatic fibrosis and islet-cell destruction are only marginally associated.[5] Apoptosis of β cells might occur as a consequence of endoplasmic reticulum stress[18] or accumulation of intracellular islet amyloid polypeptide owing to membrane disruption.[19] Future studies are needed to clarify the relative contribution of these or alternative mechanisms to the development of cystic fibrosis-related diabetes Dynamics of Insulin
The insulin response is impaired in patients with cystic fibrosis with exocrine pancreatic insufficiency. The peak of plasma insulin concentration is lower and the time to reach it is delayed,[20] as is first- phase C-peptide response to oral glucose,[21] compared with healthy individuals. A spectrum of progressive glucose abnormalities is present in patients with cystic fibrosis—from normoglycemia to intermittent postprandial hyperglycemia, impaired glucose tolerance, cystic fibrosis-related diabetes mellitus without fasting hyperglycemia and, finally, cystic fibrosis-related diabetes mellitus with fasting hyperglycemia. The degree of dysglycemia can fluctuate within an individual over time depending on their health status.[1] Insulin resistance contributes to the worsening of glucose tolerance in patients with cystic fibrosis and impaired glucose tolerance or cystic fibrosis-related diabetes mellitus. Its role in the etiology of cystic fibrosis-related diabetes mellitus, however, is undetermined, with conflicting results from studies indicating either increased insulin resistance in patients with this disorder compared with nondiabetic patients[22] or no difference.[20] An exaggerated insulin clearance rate,[23] elevated hepatic gluconeogenesis[22] and increased glucose absorption[24] might play a part in the pathophysiology of cystic fibrosis-related diabetes mellitus (Figure 1). Figure 1.
Pathophysiology of Cystic Fibrosis-related Diabetes Mellitus. The predicted three-dimensional structure of human CFTR[49] was derived on the basis of experimental information.[50] Courtesy of C. M. Soares and M. D. Amaral (University of Lisbon, Portugal). Permission for histology pictures was obtained from the Department of Pathology, University of Iowa (The University of Iowa, CFTR, cystic fibrosis transmembrane conductance regulator; IL-6, interleukin 6; Lung Disease
Severe lung disease (defined as a forced expiratory volume in 1 second (FEV1) <40% of the predicted FEV1) might be associated with poor glycemic control in patients with cystic fibrosis. A previous study[11] demonstrated that pulmonary disease is more severe in patients with cystic fibrosis-related diabetes mellitus than in normoglycemic individuals with cystic fibrosis, with a greater decline in lung function, more frequent pulmonary exacerbations and an increased frequency of pathogens in the sputum. Patients who undergo lung transplantation are more prone to develop cystic fibrosis-related diabetes mellitus, possibly owing to the use of immunosuppressive medication after transplant surgery.[25] Further studies will have to ascertain whether the control of cystic fibrosis-related diabetes mellitus can slow the progression of lung disease. Screening and Diagnosis
The risk of cystic fibrosis-related diabetes mellitus is low in children aged <10 years, but the incidence increases by 5% every year after this age.[26] The ISPAD guidelines recommend annual oral glucose tolerance testing in patients with cystic fibrosis >10 years of age, during a period when they are clinically well;[1] however, clinical practice varies widely.[26-28] Diagnosis depends on screening practices, as many cases are detected even before symptoms develop. Indeed, in a prospective study of 191 patients with cystic fibrosis, only one-third of those with cystic fibrosis-related diabetes mellitus had symptoms of polyuria or polydypsia at diagnosis.[9] Possible barriers to screening for cystic fibrosis- related diabetes mellitus include lack of resources and patient discomfort as the result of fasting or venipuncture. Repeated blood samples, which are necessary with an oral glucose tolerance test, although minimally invasive, can be particularly problematic when managing young children with cystic fibrosis. Lack of proximity to major cystic fibrosis centers for patients who live in remote areas might Glucose tolerance in patients with cystic fibrosis is classified as normal glucose tolerance, impaired glucose TNF IL-6 tolerance, cystic fibrosis-related diabetes mellitus without fasting hyperglycemia and cystic fibrosis-related diabetes mellitus with fasting hyperglycemia ( Table 2 ). Measures frequently used in clinical practice for the diagnosis and screening of cystic fibrosis-related diabetes mellitus include oral glucose tolerance tests, random and fasting plasma glucose levels, HbA1c levels and continuous glucose monitoring.[1,4] Abnormalities in any one of these investigations is diagnostic of cystic fibrosis-related diabetes mellitus. However, only limited evidence supports the use of one test Oral Glucose Tolerance Test
The oral glucose tolerance test was considered to have a high sensitivity for the diagnosis of cystic fibrosis-related diabetes mellitus without fasting hyperglycemia, according to a consensus statement in 1999.[4] However, in patients with cystic fibrosis and normal oral glucose tolerance test results, abnormal glucose peaks have been demonstrated with the use of continuous glucose monitoring devices.[29] Some patients displayed marked hyperglycemia with a decline in weight and lung function that could be corrected by insulin administration.[30] The 2-h value of the oral glucose tolerance test cannot distinguish children with declining from those with stable weight SD scores. By contrast, a peak blood glucose level ≥8.2 mmol/l during an oral glucose tolerance test and a blood glucose level >7.8 mmol/l for ≥4.5% of the time with continuous glucose monitoring are associated with declining weight SD scores and lung function in the preceding year.[31] These parameters may, therefore, assist in the early diagnosis of cystic fibrosis-related diabetes mellitus in children with declining lung function and Measuring insulin concentrations every 30 min during the oral glucose tolerance test might be clinically useful to assess the degree of insulin deficiency.[1] The oral glucose tolerance test has poor specificity; over half (58%) of the patients with cystic fibrosis who initially showed impaired glucose tolerance upon oral glucose tolerance testing reverted back to normal glycemic status, and only 14% developed cystic fibrosis-related diabetes mellitus.[9] Half of the patients who initially had a cystic fibrosis-related diabetes mellitus profile in an oral glucose tolerance test lost this profile over a 10-year period, and 18% achieved normal glucose tolerance.[32] Therefore, appropriate criteria that account for cystic fibrosis-specific outcomes, such as weight and lung function, need to be determined when the oral glucose tolerance test is used to diagnose patients with cystic fibrosis-related diabetes mellitus. Random and Fasting Blood Glucose
Random blood glucose levels of ≥11.1 mmol/l on more than two occasions and fasting blood glucose levels of ≥7.0 mmol/l are both diagnostic of cystic fibrosis-related diabetes mellitus. Nevertheless, normal fasting or random glucose levels do not exclude a diagnosis of cystic fibrosis-related diabetes mellitus.[1] The development of a random glucose profile over a period of time might be more HbA1c values can be unreliable in the diagnosis of cystic fibrosis-related diabetes mellitus and, hence, are not recommended as a diagnostic or screening tool.[1] HbA1c levels are often normal, regardless of the degree of hyperglycemia, with only 16% of patients with cystic fibrosis having elevated values at the time of the diagnosis of diabetes mellitus.[1] This finding may be because red blood cells in patients with cystic fibrosis have an altered mass and shorter lifespan from chronic inflammation, which affects the degree of glycosylation. Furthermore, in early cystic fibrosis-related diabetes mellitus, intermittent hyperglycemia may not be high enough or long enough to raise HbA1c levels. However, HbA1c values can be elevated in some patients with cystic fibrosis with normal baseline and/or 2-h blood glucose levels as determined by oral glucose tolerance testing.[9] Consensus guidelines recommend the use of HbA1c levels to monitor established cystic fibrosis-related diabetes mellitus,[4,26] but the relationship between HbA1c and cystic fibrosis-related complications is undetermined. Although HbA1c levels are unreliable as a screening tool in cystic fibrosis-related diabetes mellitus, the American Diabetes Association guidelines33 recommend the use of HbA1c values in the diagnosis of type 2 diabetes mellitus. A lower HbA1c threshold than the one used for the diagnosis of type 2 diabetes mellitus, determined by considering the decline in cystic fibrosis-specific outcomes such as BMI and lung function, could assist in the diagnosis of cystic fibrosis-related diabetes mellitus in conjunction with Continuous Glucose Monitoring
Continuous glucose monitoring can detect hyperglycemia earlier than the oral glucose tolerance test, but current guidelines do not recommend its use in routine clinical practice. In one study of adolescents and young adults with cystic fibrosis,[34] continuous glucose monitoring detected hyperglycemia in all patients with cystic fibrosis-related diabetes mellitus, half of which showed impaired glucose tolerance and one-third of which displayed normal glucose tolerance. This method could, therefore, aid in the diagnosis of cystic fibrosis-related diabetes mellitus when used in conjunction with oral glucose tolerance tests and the clinical scenario.[29] Complications and Mortality
Patients with cystic fibrosis and diabetes mellitus have a six-fold increased mortality rate compared with those without diabetes mellitus.[4] Although women still have a poorer prognosis than men, the gap in mortality between the sexes, as well as the gap between patients with diabetes mellitus and those without, seems to have narrowed in past years. Over an 11-year period, mortality decreased from 6.9 to 3.2 deaths per 100 patient-years in women and 6.5 to 3.8 deaths per 100 patient-years in men.[7] The reduction in mortality could result from the use of more aggressive treatment to manage pulmonary exacerbations of cystic fibrosis, such as use of intravenous antibiotics, or the early diagnosis of cystic fibrosis-related diabetes mellitus and its control, including early intervention with Lung Function
Cystic fibrosis-related diabetes mellitus is associated with decreased lung function in both the prediabetic and diabetic stages. A cross-sectional analysis of 7,566 patients with cystic fibrosis revealed that the rate of decline in pulmonary function is directly proportional to the degree of glucose intolerance and insulin deficiency. The mean predicted FEV1 value, which was 72% in individuals with cystic fibrosis without diabetes mellitus, was 52% in those patients with this comorbidity.[35] The greater decline in lung function might be a consequence of hyperglycemia, which can lead to structural changes in lung tissue and predispose to infection. Insulin deficiency, which leads to the disinhibition of protein catabolism, also probably affects lung function negatively.[35] Several case reports[30] and small prospective studies[36,37] have demonstrated improvement in lung function of patients with cystic fibrosis-related diabetes mellitus with early insulin treatment. Randomized controlled trials examining the effects of early insulin therapy on lung function, however, are lacking. Vascular Complications
The vascular complications of cystic fibrosis-related diabetes mellitus are similar to those of type 1 and type 2 diabetes mellitus, albeit with a lower prevalence. As these diabetes-related complications develop over time, their presence in patients with cystic fibrosis has only emerged over the past few years, as the life expectancy of these individuals has gradually risen.[38] The most frequent microvascular complications in patients with cystic fibrosis-related diabetes mellitus include retinopathy (10-25%), nephropathy (13-21%) and neuropathy (3-30%).[38,39] Risk factors for microvascular complications include long duration of diabetes mellitus and poor glycemic control, but intervention studies have not yet taken place. Macrovascular complications are rare in patients with cystic fibrosis,[3] which might be owing to the lower life expectancy and lower rates of risk factors such as hypercholesterolemia and hypertension compared with the general population. Management
Guidelines for the management of cystic fibrosis-related diabetes mellitus vary from other forms of diabetes mellitus due to unique dietary requirements and slower disease onset,[1] but many recommendations lack evidence and are currently based on expert consensus.[40] A high-calorie, high- fat diet is standard in the management of cystic fibrosis,[41] but is contrary to guidelines for the management of type 1 diabetes mellitus. Recommendations for carbohydrate intake are contentious. Low glycemic index foods that are consumed evenly throughout the day provide better glycemic control,[40] but can lead to increased satiety, which results in less food being eaten throughout the day.[42] By contrast, high-carbohydrate foods provide more calories and can be combined with varying insulin doses to suit the meal. However, consuming large quantities of high-carbohydrate foods at one time can cause sudden glucose peaks.[40] Insulin may help stabilize lung function and improve nutritional status in patients with cystic fibrosis- related diabetes mellitus. A retrospective analysis[43] found a long-term benefit of insulin treatment on the nutritional state of patients, but only a temporary benefit on lung function, which returned to the pretreatment baseline after 34 months. A randomized controlled trial of the short-acting insulin aspart in adults with cystic fibrosis-related diabetes mellitus without fasting hyperglycemia over 1 year demonstrated notable improvements in BMI, but no substantial effect on the rate of decline in lung function.[44] The study period of 1 year or the insulin dose used (0.5 units per 15 g carbohydrate consumed) may not have been sufficient for an improvement in lung function to take effect. More randomized controlled studies over longer time periods are required. Metabolic benefits have been demonstrated with the use of insulin pump therapy, which is safe and effective in patients with cystic Oral hypoglycemic agents are not recommended for the treatment of patients with cystic fibrosis- related diabetes mellitus,[4] given their undesirable adverse effects, such as gastrointestinal symptoms with the use of metformin[1,46] and the association between thiazolidinediones and osteoporosis.[1] Agents that reduce insulin resistance are unlikely to be effective on their own, as insulin resistance is not the main etiological factor in cystic fibrosis-related diabetes mellitus.[46] Several studies that examined oral hypoglycemic agents enrolled small numbers of patients and demonstrated increases in insulin secretion but no weight gain in individuals with cystic fibrosis.[4] A prospective case-based study of 20 patients with cystic fibrosis-related diabetes mellitus found no substantial difference between insulin therapy and oral hypoglycemic agents to achieve overall glycemic control.[47] A small, short-term, randomized controlled study of seven patients found repaglinide was less effective at correcting postprandial glucose than insulin lispro.[48] A 1-year randomized controlled trial comparing insulin aspart and repaglinide in 61 patients with cystic fibrosis-related diabetes mellitus without fasting hyperglycemia demonstrated marked and sustained improvement in BMI with insulin over 1 year, but only temporary improvement with repaglinide in the first 6 months.[44] The BMI of patients who received repaglinide did not differ after 1 year of treatment compared to the year before the trial.[44] Although the insulin group could not be blinded and, hence, could have been more attentive to carbohydrate intake than the repaglanide group, the conclusions of this study[44] warrant consideration, particularly given its size and study design and the lack of other trials comparing insulin and oral hypoglycemic agents. Treatment for impaired glucose tolerance and/or intermittent hyperglycemia is controversial and is currently not recommended, unless signs of poor growth, inability to gain weight or unexpected decline in pulmonary function persist.[1] Insulin treatment of patients with cystic fibrosis and impaired glucose tolerance has shown improvements in their weight and lung function,[37] but this finding has not been confirmed by randomized controlled studies, although several are currently ongoing. To reduce the effects of hyperglycemia on the lungs, treatment of patients with impaired glucose tolerance during acute pulmonary exacerbations may also be necessary. Management
Guidelines for the management of cystic fibrosis-related diabetes mellitus vary from other forms of diabetes mellitus due to unique dietary requirements and slower disease onset,[1] but many recommendations lack evidence and are currently based on expert consensus.[40] A high-calorie, high- fat diet is standard in the management of cystic fibrosis,[41] but is contrary to guidelines for the management of type 1 diabetes mellitus. Recommendations for carbohydrate intake are contentious. Low glycemic index foods that are consumed evenly throughout the day provide better glycemic control,[40] but can lead to increased satiety, which results in less food being eaten throughout the day.[42] By contrast, high-carbohydrate foods provide more calories and can be combined with varying insulin doses to suit the meal. However, consuming large quantities of high-carbohydrate foods at one time can cause sudden glucose peaks.[40] Insulin may help stabilize lung function and improve nutritional status in patients with cystic fibrosis- related diabetes mellitus. A retrospective analysis[43] found a long-term benefit of insulin treatment on the nutritional state of patients, but only a temporary benefit on lung function, which returned to the pretreatment baseline after 34 months. A randomized controlled trial of the short-acting insulin aspart in adults with cystic fibrosis-related diabetes mellitus without fasting hyperglycemia over 1 year demonstrated notable improvements in BMI, but no substantial effect on the rate of decline in lung function.[44] The study period of 1 year or the insulin dose used (0.5 units per 15 g carbohydrate consumed) may not have been sufficient for an improvement in lung function to take effect. More randomized controlled studies over longer time periods are required. Metabolic benefits have been demonstrated with the use of insulin pump therapy, which is safe and effective in patients with cystic Oral hypoglycemic agents are not recommended for the treatment of patients with cystic fibrosis- related diabetes mellitus,[4] given their undesirable adverse effects, such as gastrointestinal symptoms with the use of metformin[1,46] and the association between thiazolidinediones and osteoporosis.[1] Agents that reduce insulin resistance are unlikely to be effective on their own, as insulin resistance is not the main etiological factor in cystic fibrosis-related diabetes mellitus.[46] Several studies that examined oral hypoglycemic agents enrolled small numbers of patients and demonstrated increases in insulin secretion but no weight gain in individuals with cystic fibrosis.[4] A prospective case-based study of 20 patients with cystic fibrosis-related diabetes mellitus found no substantial difference between insulin therapy and oral hypoglycemic agents to achieve overall glycemic control.[47] A small, short-term, randomized controlled study of seven patients found repaglinide was less effective at correcting postprandial glucose than insulin lispro.[48] A 1-year randomized controlled trial comparing insulin aspart and repaglinide in 61 patients with cystic fibrosis-related diabetes mellitus without fasting hyperglycemia demonstrated marked and sustained improvement in BMI with insulin over 1 year, but only temporary improvement with repaglinide in the first 6 months.[44] The BMI of patients who received repaglinide did not differ after 1 year of treatment compared to the year before the trial.[44] Although the insulin group could not be blinded and, hence, could have been more attentive to carbohydrate intake than the repaglanide group, the conclusions of this study[44] warrant consideration, particularly given its size and study design and the lack of other trials comparing insulin and oral hypoglycemic agents. Treatment for impaired glucose tolerance and/or intermittent hyperglycemia is controversial and is currently not recommended, unless signs of poor growth, inability to gain weight or unexpected decline in pulmonary function persist.[1] Insulin treatment of patients with cystic fibrosis and impaired glucose tolerance has shown improvements in their weight and lung function,[37] but this finding has not been confirmed by randomized controlled studies, although several are currently ongoing. To reduce the effects of hyperglycemia on the lungs, treatment of patients with impaired glucose tolerance during acute pulmonary exacerbations may also be necessary. Conclusions
Diabetes mellitus is a major complication of cystic fibrosis and is associated with an increased morbidity and mortality in this population of patients. Its pathophysiology is complex and the mechanisms leading to the development of diabetes mellitus in patients with cystic fibrosis remain poorly understood. Current guidelines recommend oral glucose tolerance testing for the diagnosis and screening of patients with cystic fibrosis-related diabetes mellitus; however, this recommendation is based on limited evidence. Alternative diagnostic criteria using peak blood glucose levels during an oral glucose tolerance test, continuous glucose monitoring or HbA1c cut-off values lower than those used for patients with type 2 diabetes mellitus need to be considered in light of current inconsistencies and lack of an evidence base. Randomized controlled studies are needed to assess the benefit of early insulin therapy in patients with cystic fibrosis and impaired glucose tolerance and the effect of different insulin regimens on cystic fibrosis-related diabetes mellitus. Finally, intervention studies will hopefully enable clinicians to address strategies for the prevention and management of microvascular complications of cystic fibrosis-related diabetes mellitus. Key Points
• The prevalence of cystic fibrosis-related diabetes mellitus has risen, as life expectancy of patients with cystic fibrosis has increased • The diagnosis of cystic fibrosis-related diabetes mellitus is currently made on the basis of consensus guidelines, and diagnostic criteria do not address cystic fibrosis-specific outcomes • Microvascular complications are becoming more prevalent in patients with cystic fibrosis, but evidence for their prevention and management is minimal • Strong evidence supports the use of insulin therapy in patients with cystic fibrosis-related diabetes mellitus; however, its use in those with impaired glucose tolerance is controversial References
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