Glucose Tolerance in Patients with Cystic Fibrosis - Results from the German Cystic Fibrosis Registry.

BACKGROUND: Oral glucose tolerance (OGT) deteriorates progressively in cystic fibrosis (CF). Clinical registries provide a unique basis to study real-world data. PATIENTS & METHODS: OGT tests (OGTTs) documented in the German CF-registry in 2016 were classified according WHO, modified by ADA: normal glucose tolerance (NGT), indeterminate glycaemia (INDET), impaired fasting glucose (IFG), impaired glucose tolerance (IGT), IFG+IGT, diabetes mellitus (DM). To study the association with lung function, multivariable regression adjusted for age, sex, and CFTR mutation was performed. RESULTS: Overall, OGTT screening was done in 35% of CF patients ≧10 years. Of the 996 patients (46.4% females; median age (IQR): 19 (14-27) years) with evaluable OGTTs, 56.2% had either NGT or INDET, whereas 34% had a pre-diabetic OGTT (IFG; IGT; IFG+IGT) and 9.8% a diabetic OGTT. 7 patients had glucose tolerance abnormalities <10 years. DM was more common in females or patients with F508del homozygote mutation, whereas IFG was more frequent in males (all p<0.05). Nearly 75% of patients after transplantation and about half with enteral/parental nutrition and/or steroid use had either a pre-diabetic or diabetic glucose tolerance. In the adjusted model, age (p<0.001) and OGTT category (p=0.013) had both a significant impact on %FEV1. CONCLUSION: Our data of the German CF-registry highlights incidence of glucose tolerance abnormalities in second decade of life in CF patients. However, it also underlines the need for improvement of the documentation and/or performance of OGTT screening in real-world CF care. HINTERGRUND: Bei Mukoviszidose (zystischer Fibrose: CF) verschlechtert sich die orale Glukosetoleranz (OGT) im Krankheitsverlauf. PATIENTEN & METHODEN: OGT Tests (OGTTs), die 2016 im Deutschen CF-Register dokumentiert waren, wurden gemäß WHO (modifiziert nach ADA) kategorisiert: Normale Glukosetoleranz (NGT), intermittierende Glykämie (INDET), eingeschränkte Nüchternglukosetoleranz (IFG), gestörte Glukosetoleranz (IGT), IFG+IGT, Diabetes Mellitus (DM). Um den Zusammenhang mit der Lungenfunktion zu analysieren, wurde eine multivariable Regressionsanalyse adjustiert für Alter, Geschlecht und CFTR Mutation durchgeführt. ERGEBNISSE: Insgesamt wurden 35% der CF-Patienten ≥10 Jahre mittels OGTT gescreent. Von den 996 Patienten (46,4% weiblich, medianes Alter (IQR): 19 (14-27) Jahre) mit auswertbaren OGTTs hatten 56,2% entweder NGT oder INDET, wohingegen bei 34% ein prädiabetischer (IFG; IGT; IFG+IGT) und bei 9,8% ein diabetischer OGTT beobachtet wurde. Bei 7 Patienten zeigten sich vor dem 10. LJ Abnormalitäten im Glukosestoffwechsel. DM war häufiger bei Frauen und Patienten mit homozygoter F508del Mutation, wobei IFG öfters bei Männern vorlag (alle p<0,05). Ca. 75% der Patienten mit Transplantation und etwa die Hälfte der Patienten mit künstlicher Ernährung und/oder Steroidgabe hatten eine prädiabetische oder diabetische Glukosetoleranz. Das Alter (p<0,001) und die OGTT Kategorie (p=0,013) zeigten im adjustierten Modell eine signifikante Assoziation mit %FEV1. SCHLUSSFOLGERUNG: Unsere Daten unterstreichen das Auftreten von Abnormalitäten im Glukosestoffwechsel bei CF im 2. Lebensjahrzehnt. Jedoch weißt es auf die Notwendigkeit eines regelmäßigen Diabetesscreenings und/oder Dokumentation von OGTTs bei CF hin.

Lower HbA1c in patients with type 1 diabetes and celiac disease who reached celiac-specific antibody-negativity-A multicenter DPV analysis.

OBJECTIVES: To study celiac-specific antibody status over 3 years in patients with type 1 diabetes and biopsy-proven celiac disease (T1D + CD). Furthermore, to determine clinical differences after diagnosis between patients reaching constant antibody-negativity (Ab-neg) and staying antibody-positive (Ab-pos). METHODS: A total of 608 pediatric T1D + CD patients from the multicenter DPV registry were studied longitudinally regarding their CD specific antibody-status. Differences between Ab-neg (n = 218) and Ab-pos (n = 158) patients 3 years after biopsy were assessed and compared with 26 833 T1D patients without CD by linear and logistic regression adjusted for age, gender, diabetes duration and migration background. RESULTS: Thirty-six percent of T1D + CD patients reached and sustained antibody-negativity 3 years after CD diagnosis. The median time until patients returned to Ab-neg was 0.86 (0.51;1.16) years. Three years after diagnosis, HbA1c was lowest in Ab-neg and highest in Ab-pos patients compared to T1D-only patients (adjusted mean (95%CI): 7.72 (7.51-7.92) % vs 8.44 (8.20-8.68) % vs 8.19 (8.17-8.21) %, adjusted P < 0.001, respectively). Total cholesterol, LDL-cholesterol and frequency of dyslipidemia were significantly lower in Ab-neg compared to T1D-only patients (167 (161-173) mg/dl vs 179 (178-179) mg/dl, P < .001; 90 (84-96) mg/dl vs 99 (98-99) mg/dl, P = .005; 15.7 (10.5-22.9) % vs 25.9 (25.2-26.6) %, P = .017). In longitudinal analyses over 6 years after diagnosis, a constantly higher HbA1c (P < .001) and a lower height-SDS (P = .044) was observed in Ab-pos compared to Ab-neg patients. CONCLUSION: Only one third of T1D + CD patients reached constant Ab-negativity after CD diagnosis. Achieving Ab-negativity after diagnosis seems to be associated with better metabolic control and growth, supposedly due to a higher adherence to therapy in general.

Characteristics of cystic fibrosis-related diabetes: Data from two different sources the European cystic fibrosis society patient registry and German/Austrian diabetes prospective follow-up registry.

BACKGROUND: Standardized patient registries provide a unique basis to get insight into cystic fibrosis (CF)-related diabetes (CFRD), the most common comorbidity in CF. METHODS: A total of 3853 CFRD patients from the European CF Society Patient Registry (ECFSPR) and 752 from the German/Austrian diabetes prospective follow-up (diabetes patienten verlaufsdokumentation [DPV]) were studied. To adjust for age and sex, multivariable regression was used (SAS 9.4). RESULTS: DPV subjects were younger (26.5 [20.2-32.6] vs 28.3 [21.7-36.0] years, P < 0.001) and more often female (59.6 vs 50.9%, P < 0.001). In both registries, F508del homozygotes were most frequent, with higher proportion in DPV (80.9 vs 57.8%, P = 0.003). After adjustment, lung-transplantation (LTX) was more common in ECFSPR (18.9 vs 4.9%, P < 0.001), although duration since LTX (4.8 ± 0.2 vs 5.5 ± 0.7 years, P = 0.33) did not differ. In DPV patients without LTX, a lower BMI (19.6 ± 0.1 vs 21.0 ± 0.1 kg/m2 , P < 0.001), higher proportion of underweight (41.2 vs 20.2%, P < 0.001) and a tendency towards worse lung function (%FEV1 : 42.3 ± 4.2 vs 48.3 ± 0.5%, P = 0.16) were observed. CONCLUSIONS: Between both registries, demographic and clinical differences of CFRD were present. Besides different kind of data sources, diverse treatment structures between countries may play a role. The results may further indicate a more serious illness in patients treated in specialized diabetes clinics, documenting their data in DPV.

Screening for coeliac disease in 1624 mainly asymptomatic children with type 1 diabetes: is genotyping for coeliac-specific human leucocyte antigen the right approach?

OBJECTIVES: To investigate the frequency of coeliac disease (CD)-specific human leucocyte antigen (HLA) genotypes in paediatric patients with type 1 diabetes (T1D), who are known to have a higher prevalence of CD than the general population, and to evaluate whether HLA genotyping is a suitable first-line screening method for CD. STUDY DESIGN: The study was a multicentre observational analysis of patients with T1D aged <20 years of whom a subgroup had undergone HLA genotyping. Patient data were retrieved from the Diabetes Prospective Follow-up database, a large diabetes follow-up registry. The present analysis included data from 439 centres throughout Germany, Austria, Switzerland and Luxembourg. RESULTS: In March 2017, the database contained 75 202 patients with T1D (53% male, mean age (SD) 14.6 (4.1) years, mean age at diagnosis 8.8 (4.3) years and mean diabetes duration 5.8 (4.3) years). 1624 patients had undergone coeliac-specific HLA genotyping, of whom 1344 (82.8%) were positive for HLA-DQ2, HLA-DQ8 or both, while 17.2% had no coeliac-specific HLA-markers. 26.6% of at-risk patients had a clinical suspected diagnosis of CD, and 3.6% had biopsy-proven CD. CONCLUSIONS: Genotyping for HLA-DQ2, HLA-DQ8 or both is positive in the vast majority (>80%) of patients with T1D. Therefore, screening for coeliac-specific HLA genotypes as a first-line test is not a suitable method to exclude CD in T1D. Regular screening for coeliac-specific antibodies in T1D is still recommended.

Comparative Characteristics of Patients with Type 2 Diabetes Mellitus Treated by Bariatric Surgery Versus Medical Treatment: a Multicentre Analysis of 277,862 Patients from the German/Austrian DPV Database.

INTRODUCTION: Bariatric surgery is a well-established treatment option for serious obesity and concomitant type 2 diabetes mellitus (T2DM). In this analysis, we investigated predictors for bariatric surgery in everyday clinical practice. MATERIALS AND METHODS: In the DPV-registry, patients with T2DM from Germany and Austria treated by bariatric surgery were compared to non-surgery controls by descriptive statistics and regression analysis. RESULTS: Among 277,862 patients with T2DM, 0.07% underwent bariatric surgery. Surgery patients were predominantly female [61.20%], younger [median age (Q1;Q3) 54.74(47.40;61.61) vs. 70.04 (60.36;77.58) years] and had a longer diabetes duration [11.21 (7.15;17.93) vs. 8.36 (2.94;14.91) years]. They had a higher BMI [40.02 vs. 30.61 kg/m2, adjusted p < 0.0001] and a slightly lower HbA1c [7.25 vs. 7.56%, adjusted p < 0.05]. There was a trend using more often insulin therapy (52.79 vs.50.08%, n.s.) with no difference in insulin dose/kg × day [0.56 vs. 0.58, n.s.]. Sleeve gastrectomy was performed most frequently, followed by Roux-en-Y gastric bypass, gastric banding, gastric balloon and others. A 2-year follow-up data in 29 patients demonstrated significant reductions in BMI [45.23 to 38.00 kg/m2, p < 0.005] and HbA1c [7.98 to 6.98%, p < 0.005], and a trend for reduced insulin requirements [62.07 vs. 44.83%, n.s.]. CONCLUSION: Despite favourable 2-year outcomes, bariatric surgery is still used rarely in patients with T2DM and obesity. BMI rather than metabolic control seems to represent the major selector for or against bariatric surgery in T2DM.

Trajectories of Body Mass Index from Childhood to Young Adulthood among Patients with Type 1 Diabetes-A Longitudinal Group-Based Modeling Approach Based on the DPV Registry.

OBJECTIVE: To identify distinct longitudinal patterns of body mass index (BMI) z score in type 1 diabetes from childhood to young adulthood and secondly to determine sex differences as well as associated clinical covariates. STUDY DESIGN: A total of 5665 patients with type 1 diabetes (51% male) with follow-up from 8 to 20 years of age from the multicenter diabetes prospective registry DPV were studied (baseline diabetes duration ≥1 years, BMI z score aggregated per year of life). Latent class growth modeling (SAS: PROC TRAJ) was applied to analyze BMI z score over time. RESULTS: Six distinct BMI z score trajectories were identified (group 1: 7% of patients, group 2: 22%, group 3: 20%, group 4: 16%, group 5: 25%, and group 6: 10%). Group 1, 2, 5, and 6 had an almost stable BMI z score, either in the low, near-normal, high stable, or chronic overweight range. Group 3 (60% girls) increased their BMI during puberty, whereas group 4 (65% boys) had a BMI decrease. Similar patterns were observed for girls only, whereas boys followed nearly stable trajectories without fluctuation over time. Between the near-normal and the other groups, significant differences (P < .05) in sex ratio, migration background, mental health, height z score, glycated hemoglobin A1c, diabetes treatment, dyslipidemia, hypertension, and smoking were observed. CONCLUSIONS: In youth with type 1 diabetes, a great heterogeneity of BMI z score trajectories exists that highlight the importance of personalized sex-specific intervention programs for subjects at risk for unfavorable BMI development.

Repaglinide versus insulin for newly diagnosed diabetes in patients with cystic fibrosis: a multicentre, open-label, randomised trial.

BACKGROUND: As survival among patients with cystic fibrosis has improved in recent decades, complications have become increasingly relevant. The most frequent complication is cystic-fibrosis-related diabetes. The recommended treatment is injected insulin, but some patients are treated with oral antidiabetic drugs to ease the treatment burden. We assessed the efficacy and safety of oral antidiabetic drugs. METHODS: We did a multicentre, open-label, comparative, randomised trial in 49 centres in Austria, France, Germany, and Italy. Eligible patients had cystic fibrosis, were older than 10 years, and had newly diagnosed diabetes. We used a central randomisation schedule derived from a Geigy random number table to assign patients 1:1 to receive insulin or repaglinide, stratified by sex and age (10-15 years or >15 years). The primary outcome was glycaemic control assessed by mean change in HbA1c concentration from baseline after 24 months of treatment. Differences between groups were assessed by linear models. The primary and safety analyses were done in the modified intention-to-treat population (including patients who stopped treatment early because of lack of efficacy). This trial is registered with ClinicalTrials.gov, number NCT00662714. FINDINGS: We enrolled 34 patients in the repaglinide group and 41 in the insulin group, of whom 30 and 37, respectively, were included in the analyses. At 24 months, glycaemic control was similar in the repaglinide and insulin groups (mean change in HbA1c concentration from baseline 0·2% [SD 0·7%], 1·7 mmol/mol [8·1 mmol/mol] with repaglinide vs -0·2% [1·3%], -2·7 mmol/mol, [14·5 mmol/mol] with insulin; mean difference between groups -0·4%, (95% CI -1·1 to 0·2 [-4·4 mmol/mol, -11·5 to 2·7], p=0·15). The most frequent adverse events were pulmonary events (43 [40%] of 107 in the repaglinide group and 60 [45%] of 133 in the insulin group), and the most frequent serious adverse events were pulmonary events leading to hospital admission (five [50%] of ten and seven [54%] of 13, respectively). INTERPRETATION: Repaglinide for glycaemic control in patients with cystic-fibrosis-related diabetes is as efficacious and safe as insulin. FUNDING: Mukoviszidose eV, Vaincre la Mucoviscidose, ABCF Association, and Novo Nordisk.

Prevalence of Celiac Disease in 52,721 Youth With Type 1 Diabetes: International Comparison Across Three Continents.

OBJECTIVE: Celiac disease (CD) has a recognized association with type 1 diabetes. We examined international differences in CD prevalence and clinical characteristics of youth with coexisting type 1 diabetes and CD versus type 1 diabetes only. RESEARCH DESIGN AND METHODS: Data sources were as follows: the Prospective Diabetes Follow-up Registry (DPV) (Germany/Austria); the T1D Exchange Clinic Network (T1DX) (U.S.); the National Paediatric Diabetes Audit (NPDA) (U.K. [England/Wales]); and the Australasian Diabetes Data Network (ADDN) (Australia). The analysis included 52,721 youths <18 years of age with a clinic visit between April 2013 and March 2014. Multivariable linear and logistic regression models were constructed to analyze the relationship between outcomes (HbA1c, height SD score [SDS], overweight/obesity) and type 1 diabetes/CD versus type 1 diabetes, adjusting for sex, age, and diabetes duration. RESULTS: Biopsy-confirmed CD was present in 1,835 youths (3.5%) and was diagnosed at a median age of 8.1 years (interquartile range 5.3-11.2 years). Diabetes duration at CD diagnosis was <1 year in 37% of youths, >1-2 years in 18% of youths, >3-5 years in 23% of youths, and >5 years in 17% of youths. CD prevalence ranged from 1.9% in the T1DX to 7.7% in the ADDN and was higher in girls than boys (4.3% vs. 2.7%, P < 0.001). Children with coexisting CD were younger at diabetes diagnosis compared with those with type 1 diabetes only (5.4 vs. 7.0 years of age, P < 0.001) and fewer were nonwhite (15 vs. 18%, P < 0.001). Height SDS was lower in those with CD (0.36 vs. 0.48, adjusted P < 0.001) and fewer were overweight/obese (34 vs. 37%, adjusted P < 0.001), whereas mean HbA1c values were comparable: 8.3 ± 1.5% (67 ± 17 mmol/mol) versus 8.4 ± 1.6% (68 ± 17 mmol/mol). CONCLUSIONS: CD is a common comorbidity in youth with type 1 diabetes. Differences in CD prevalence may reflect international variation in screening and diagnostic practices, and/or CD risk. Although glycemic control was not different, the lower height SDS supports close monitoring of growth and nutrition in this population.

Does ß-Cell Autoimmunity Play a Role in Cystic Fibrosis-Related Diabetes? Analysis Based on the German/Austrian Diabetes Patienten Verlaufsdokumentation Registry.

OBJECTIVE: Research on ß-cell autoimmunity in cystic fibrosis (CF)-related diabetes (CFRD) is still rare. We aimed to analyze the frequency of ß-cell autoimmunity and the influence on age at diabetes onset, insulin requirement, type of insulin therapy, and hypoglycemic or ketoacidotic events in patients with CFRD compared with antibody-negative patients with CFRD in the Diabetes Patienten Verlaufsdokumentation (DPV) registry. RESEARCH DESIGN AND METHODS: We analyzed data of 837 patients with CFRD in the German/Austrian DPV database by multivariable mixed-regression modeling. RESULTS: In our cohort, 8.5% of patients with CFRD (n = 72) were found to be ß-cell antibody positive. There was a female preponderance in this patient group: 65.3 vs. 57.6%. Diabetes onset (median [interquartile range]) was earlier (14.00 [10.15-15.90] vs. 16.10 [13.50-21.20] years; P < 0.005), and insulin dose/kg body weight was higher (0.95 [0.61-1.15] vs. 0.67 [0.33-1.04] IU/kg; P < 0.05). There were also differences in the type of insulin treatment. Insulin pump therapy was used significantly more often in patients with CFRD with ß-cell autoimmunity (18.2 vs. 6.4%; P < 0.05). The differences for multiple daily injections (ICT) and conventional therapy (CT) were not significant (ICT: 67.7 vs. 79.0%; CT: 15.2 vs. 14.6). Oral antidiabetic agents were rarely used in both groups. Rate of severe hypoglycemia with coma and rate of ketoacidosis were higher in antibody-positive patients (hypoglycemia with coma: 8.0 vs. 1.4, P < 0.05; ketoacidosis: 9.3 vs. 0.9, P < 0.05). CONCLUSIONS: Presence of ß-cell autoantibodies in our cohort of patients with CFRD (8.5%) appeared to be greater than in the general population and was associated with female sex, earlier onset of diabetes, and higher insulin requirement. Insulin pump therapy was used significantly more often in patients with ß-cell antibodies. Severe hypoglycemia and ketoacidosis were significantly more frequent in CFRD with ß-cell autoimmunity compared with ß-cell antibody-negative patients with CFRD.