Cystic Fibrosis-related Diabetes Research Articles

USING REAL-WORLD DATA TO IDENTIFY THE PREVALENCE OF HEART DISEASE IN PATIENTS WITH CYSTIC FIBROSIS

SESSION TITLE: Genetic and Autoimmune DisordersSESSION TYPE: Rapid Fire Original InvPRESENTED ON: 10/17/2022 12:15 pm - 1:15 pmPURPOSE: Cystic fibrosis (CF) is an autosomal recessive disease which is caused by mutations in the conductance regulator (CFTR) gene. It is a disease which primarily affects the respiratory, endocrine, reproductive, and gastrointestinal system. There is limited information on the impact of CF on the cardiovascular system.CF might affect the cardiovascular system directly by CFTR gene dysfunction in the heart and coronary arteries and indirectly with related conditions such as hypoxia, chronic inflammation, CF related diabetes, and pulmonary hypertension. Chronic inflammation, diabetes, and CFTR dysfunction in the vascular endothelium might lead to coronary artery disease. Hypoxia, electrolyte (chloride and bicarbonate) transport alterations could lead to arrhythmias.We aimed to identify the prevalence of cardiac complications, including heart failure (HF), acute myocardial infarction (AMI), and arrhythmias in patients with CF.METHODS: We identified patients with CF that were 18 years old or older by using the TriNetX research database which provides information from electronic medical records from several health care institutions primarily based in the United States. We analyzed the research network database From January 1, 2016, to December 31, 2021, and calculated prevalence as well as 5-year incidence of heart disease.RESULTS: A total of 17,070 patients were included in our study. 54% of the patients were females. The most prevalent cardiovascular disorders diagnosed in this cohort where heart failure [prevalence 11.338% (1921), incidence 8.542% (1403)], atrial fibrillation [prevalence (7.437% /1260), incidence (5.729% /953)], acute myocardial infarction prevalence [(3.813%/646), incidence (3.15% /530)], and supraventricular tachycardia prevalence [(3.76% /637), incidence (3.206% /540)], these were followed by atrial flutter [prevalence (2.16% /366), incidence (1.754%/296)], and ventricular tachycardia [prevalence (1.771% /300), incidence (1.369% /231)].Overall, males had higher incidence and prevalence in all outcomes except for supraventricular tachycardia 3.944% vs 3.548% and 3.371% vs 3.016% for incidence and prevalence respectively.CONCLUSIONS: CF patients have a high incidence and prevalence of heart failure, acute myocardial infarction, and arrhythmias.CLINICAL IMPLICATIONS: When compared to studies done in the general population, heart failure and arrhythmias appear to be higher in patients with CF. AMI appears to have a similar prevalence to the general population.DISCLOSURES: No relevant relationships by Kunal BhutaNo relevant relationships by Debanik ChaudhuriNo relevant relationships by Andres Cordova SanchezNo relevant relationships by Subash Nepal SESSION TITLE: Genetic and Autoimmune Disorders SESSION TYPE: Rapid Fire Original Inv PRESENTED ON: 10/17/2022 12:15 pm - 1:15 pm PURPOSE: Cystic fibrosis (CF) is an autosomal recessive disease which is caused by mutations in the conductance regulator (CFTR) gene. It is a disease which primarily affects the respiratory, endocrine, reproductive, and gastrointestinal system. There is limited information on the impact of CF on the cardiovascular system. CF might affect the cardiovascular system directly by CFTR gene dysfunction in the heart and coronary arteries and indirectly with related conditions such as hypoxia, chronic inflammation, CF related diabetes, and pulmonary hypertension. Chronic inflammation, diabetes, and CFTR dysfunction in the vascular endothelium might lead to coronary artery disease. Hypoxia, electrolyte (chloride and bicarbonate) transport alterations could lead to arrhythmias. We aimed to identify the prevalence of cardiac complications, including heart failure (HF), acute myocardial infarction (AMI), and arrhythmias in patients with CF. METHODS: We identified patients with CF that were 18 years old or older by using the TriNetX research database which provides information from electronic medical records from several health care institutions primarily based in the United States. We analyzed the research network database From January 1, 2016, to December 31, 2021, and calculated prevalence as well as 5-year incidence of heart disease. RESULTS: A total of 17,070 patients were included in our study. 54% of the patients were females. The most prevalent cardiovascular disorders diagnosed in this cohort where heart failure [prevalence 11.338% (1921), incidence 8.542% (1403)], atrial fibrillation [prevalence (7.437% /1260), incidence (5.729% /953)], acute myocardial infarction prevalence [(3.813%/646), incidence (3.15% /530)], and supraventricular tachycardia prevalence [(3.76% /637), incidence (3.206% /540)], these were followed by atrial flutter [prevalence (2.16% /366), incidence (1.754%/296)], and ventricular tachycardia [prevalence (1.771% /300), incidence (1.369% /231)]. Overall, males had higher incidence and prevalence in all outcomes except for supraventricular tachycardia 3.944% vs 3.548% and 3.371% vs 3.016% for incidence and prevalence respectively. CONCLUSIONS: CF patients have a high incidence and prevalence of heart failure, acute myocardial infarction, and arrhythmias. CLINICAL IMPLICATIONS: When compared to studies done in the general population, heart failure and arrhythmias appear to be higher in patients with CF. AMI appears to have a similar prevalence to the general population. DISCLOSURES: No relevant relationships by Kunal Bhuta No relevant relationships by Debanik Chaudhuri No relevant relationships by Andres Cordova Sanchez No relevant relationships by Subash Nepal

Carbohydrate metabolism impairment in children and adolescents with cystic fibrosis

IntroductionDevelopment of cystic fibrosis-related diabetes (CFRD) is associated with worsening of nutritional status and lung function, as well as increased mortality. The relevance of diagnosing the «pre-diabetic» status in these patients has not been addressed and the utility of HbA1c measurement in these patients is under discussion. AimTo study and characterise the different categories of carbohydrate metabolism impairment in paediatric patients with cystic fibrosis. Patients and methodsA transversal study for characterisation of carbohydrate metabolism impairment according to clinical and anthropometric status and genetic background in 50 paediatric patients with cystic fibrosis (CF) was undertaken. Oral glucose tolerance tests (OGTT) for determination of glucose and insulin levels measurement and continuous subcutaneous glucose monitoring (CSGM) were performed. Results6% of patients presented with CFRD, 26% impaired glucose tolerance, 10% an indeterminate glucose alteration and 2% impaired fasting glucose. The severity of glycaemic impairment correlated positively with age and negatively with standardised height (p < 0.05) with intergroup differences in HbA1c levels (p < 0.01), with the latter correlating with the duration of hyperglycaemia throughout CSGM. No intergroup differences in mutation prevalence, pulmonary function test, nutritional status or disease exacerbations in the previous year were found. The daily enzyme replacement dose correlated with the glucose area under the curve (AUC, p < 0.05) but not with insulin-AUC. ConclusionsAn older age and greater enzyme replacement need are correlated with more severe carbohydrate metabolism impairment and lower standardized height in paediatric CF patients, with HbA1c correlating with the duration of hyperglycaemia. The study of the full glucose/insulin AUCs throughout the OGTT affords no additional information compared to glucose determination at 120 min in these patients.

5 Comparison of meal-time dosing of rapid-acting insulin using carbohydrate counting versus fixed doses using continuous glucose monitoring in patients with cystic fibrosis–related diabetes

5 Comparison of meal-time dosing of rapid-acting insulin using carbohydrate counting versus fixed doses using continuous glucose monitoring in patients with cystic fibrosis–related diabetes

8 Predicting high blood glucose levels through voice characteristic analysis in patients with cystic fibrosis–related diabetes

8 Predicting high blood glucose levels through voice characteristic analysis in patients with cystic fibrosis–related diabetes

3 Cystic fibrosis–related diabetes—adherence to screening at a large clinical center

3 Cystic fibrosis–related diabetes—adherence to screening at a large clinical center

99 Improving screening for cystic fibrosis–related diabetes in a pediatric cystic fibrosis clinic

99 Improving screening for cystic fibrosis–related diabetes in a pediatric cystic fibrosis clinic

96 Improving cystic fibrosis–related diabetes treatment initiation through pulmonary nurse intervention

96 Improving cystic fibrosis–related diabetes treatment initiation through pulmonary nurse intervention

431 Lung infection in a chronic cystic fibrosis–related diabetes murine model

431 Lung infection in a chronic cystic fibrosis–related diabetes murine model

9 Automated insulin delivery with the iLet bionic pancreas for the management of cystic fibrosis–related diabetes

9 Automated insulin delivery with the iLet bionic pancreas for the management of cystic fibrosis–related diabetes

344 Implementation of a tiered system of screening for cystic fibrosis related diabetes using oral glucose tolerance testing and continuous glucose monitoring

344 Implementation of a tiered system of screening for cystic fibrosis related diabetes using oral glucose tolerance testing and continuous glucose monitoring

354 Racial disparities in cystic fibrosis–related diabetes outcomes

354 Racial disparities in cystic fibrosis–related diabetes outcomes

60 Improving cystic fibrosis–related diabetes annual screening in adults with cystic fibrosis

60 Improving cystic fibrosis–related diabetes annual screening in adults with cystic fibrosis

13 A North American provider survey of cystic fibrosis–related diabetes screening practices

13 A North American provider survey of cystic fibrosis–related diabetes screening practices

The long-term effects of insulin use in incident cystic fibrosis-related diabetes: a target trial emulated using longitudinal national registry data.

Cystic fibrosis-related diabetes (CFRD) is a common complication of cystic fibrosis and is associated with deleterious clinical outcomes. Insulin is recommended as a treatment by international guidelines. However, there are scarce clinical trial data to support the use of insulin, and little is known about the long-term outcomes of treatment. The aim of this study was to compare the long-term impacts of insulin use versus non-use in CFRD. We used data from the national UK Cystic Fibrosis Registry and adopted a target trial framework. Eligible individuals included those 12 years and older with a new diagnosis of CFRD. Outcomes were change in % predicted forced expiratory volume in 1 s (FEV1 %) and body mass index z-scores (BMI) over a 5-year follow-up period. Treatment strategies were to receive insulin or not for the duration of follow-up. Treatment effect estimates were obtained using two methods to control for confounding: inverse-probability-of-treatment weighted estimation of marginal structural models and the G-formula. We identified 1613 individuals diagnosed with CFRD between 2008 and 2016 and included 1196 and 1192 in the FEV1 % and BMI outcome analyses respectively. We found no evidence of an effect of insulin on FEV1 % over the 5-year study period. Similarly, we found no overall effect of insulin on BMI; however, there was some evidence for a positive treatment effect in patients with lower baseline BMI. Using well-established national registry data, we found no evidence of long-term treatment effects for insulin on FEV1 % or BMI in people with incident CFRD.

394 Development of a programmable automated cell culture system to mimic cystic fibrosis-related diabetes conditions in vitro

394 Development of a programmable automated cell culture system to mimic cystic fibrosis-related diabetes conditions in vitro

Mediation of the total effect of cystic fibrosis-related diabetes on mortality: A UK Cystic Fibrosis Registry cohort study.

To investigate whether the effect of cystic fibrosis-related diabetes (CFRD) on the composite outcome of mortality or transplant could act through lung function, pulmonary exacerbations and/or nutritional status. A retrospective cohort of adult cystic fibrosis (CF) patients who had not been diagnosed with CFRD were identified from the UK Cystic Fibrosis Registry (n= 2750). Rate of death or transplant was compared between patients who did and did not develop CFRD (with insulin use) during follow-up using Poisson regression, separately by sex. Causal mediation methods were used to investigate whether lung function, pulmonary exacerbations and nutritional status lie on the causal pathway between insulin-treated CFRD and mortality/transplant. At all ages, the mortality/transplant rate was higher in both men and women diagnosed with CFRD. Pulmonary exacerbations were the strongest mediator of the effect of CFRD on mortality/transplant, with an estimated 15% [95% CI: 7%, 28%] of the effect at 2 years post-CFRD diagnosis attributed to exacerbations, growing to 24% [95% CI: 9%, 46%] at 4 years post-diagnosis. Neither lung function nor nutritional status were found to be significant mediators of this effect. Estimates were similar but with wider confidence intervals in a cohort that additionally included people with CFRD but not using insulin. There is evidence that pulmonary exacerbations mediate the effect of CFRD on mortality but, as they are estimated to mediate less than one-quarter of the total effect, the mechanism through which CFRD influences survival may involve other factors.

The utility of glucose area under the curve from the oral glucose tolerance test as a screening tool for cystic fibrosis-related diabetes.

Consistently abnormal glucose levels on oral glucose tolerance test (OGTT) are the most effective screening tool for cystic fibrosis-related diabetes (CFRD). However, some cystic fibrosis (CF) patients demonstrate abnormal glucose profiles not reaching levels required for CFRD diagnosis and are, therefore, left untreated. Since CFRD is associated with disease deterioration, early diagnosis and treatment are desirable. To explore the association between the area under the curve of glucose (G-AUC) obtained during a five-point2-hstandard OGTT and CF disease severity parameters. All CF patients referred for an annual routine OGTT at the Hadassah CF Center between 2002 and 2018, were included. Disease severity parameters were correlated with the G-AUC. Two hundred forty-twoOGTTs were performed in 81 patients (mean age 19.7 ± 9.0 years); 54% were normal, 14% showed impaired glucose tolerance (IGT), 5% had values in the indeterminate range (INDET), 11% had both IGT and INDET and 16% were diagnosed with CFRD. A gradual increase in mean G-AUC was observed among the groups. In multivariate regression models, G-AUC ≥ 295 mg h/dl was independently associated with an increased number of pulmonary exacerbations (PEx). Not all the patients having this value met the CFRD definition. Patients who do not fulfill the criteria for CFRD may have abnormal glucose metabolism identifiable by abnormally high G-AUC values, which may be associated with more PEx. The potential advantage of treating these patients with insulin and the subsequent reduction in PEx needs further investigation.

Glycemic indices at night measured by CGM are predictive for a lower pulmonary function in adults but not in children with cystic fibrosis

IntroductionIn patients with cystic fibrosis (CF), it is still unclear to which extent glucose abnormalities – preceding the diagnosis of cystic fibrosis related diabetes (CFRD) – are associated with pulmonary and nutritional outcome parameters. This study related circadian glycemic patterns to clinical outcomes in a group of CF patients not previously diagnosed with diabetes. MethodsContinuous glucose monitoring (CGM) readings (7 days) of 47 CF patients (26 children, 21 adults) with an impaired oral glucose tolerance test (OGTT) (n = 25) and/or increased Hb1Ac (> 5.5%) were analyzed. Biometric, pulmonary function and clinical parameters were retrospectively collected over a period of 1 year before (T-1) and 1 year after (T + 1) CGM (T0). Results96% (45/47) of CGM readings showed glucose values > 140 mg/dL ≥ 4.5% of the time and at least one ≥ 200 mg/dL. In the pediatric cohort, no significant associations were found between CGM parameters and pulmonary and nutritional outcome parameters. In the adult cohort, an area under the curve (AUC) > 140 mg/dL and%-time > 140 mg/dL during the night were associated with a lower forced expiratory volume in 1 s (FEV1)% predicted (pp) at time of evaluation but not with change in FEV1pp. ConclusionThis is the first study reporting the circadian glycemic pattern in children and adults at risk for CFRD. In the adult cohort an association between detection of abnormal glucose exposure and a lower FEV1pp was found. Our results support continued screening for glucose intolerance in patients with CF.

Association of Islet Amyloid Polypeptide to C-Peptide Ratio With Cystic Fibrosis–Related Diabetes

Early detection of cystic fibrosis (CF) related diabetes (CFRD) improves health outcomes and reduces CF-related mortality. The study aims to evaluate the ratio of islet amyloid polypeptide (IAPP) to C-peptide in CF patients with diabetes and without diabetes. Cross-sectional analysis was carried out in a prospective cohort of 33 participants (CF [n = 16] and CFRD [n = 18]). We examined the association of plasma IAPP:C-peptide ratio with clinical information, including glycated hemoglobin, and lung function markers. The median (interquartile range) IAPP:C-peptide ratio was significantly (P = 0.004) higher in people with CFRD (4.8 [4.5]) compared with participants without CFRD (12.1 [19.7]). The ratio of IAPP to C-peptide significantly accounted for a 38% variation in the diabetes status in patients with CF (r2 = 0.399, P < 0.001). Islet amyloid polypeptide is strongly correlated with serum ferritin levels (r = 0.683, P = 0.005) and forced expiratory volume in CFRD, but not in nondiabetic participants with CF. Islet amyloid polypeptide:C-peptide ratio could be a potential marker of CFRD in adults with CF. Further research requires validation of this marker in longitudinal cohort studies to confirm the capability of IAPP:C-peptide to predict CFRD.

Insulinogenic index and early phase insulin secretion predict increased risk of worsening glucose tolerance and of cystic fibrosis-related diabetes

ObjectiveMeasures of stimulated insulin secretion are emerging as important predictors of diabetes mellitus in at-risk populations. We analyzed the utility of clinical estimates of insulin secretion in a prospective cohort at risk for cystic fibrosis-related diabetes (CFRD). MethodsWe divided the profiles of 189 people with CF (pwCF) followed longitudinally in the Montreal CF cohort (mean follow up 6.6 ± 1.2 years) according to quartiles of the insulinogenic index (IGI; (I30-I0)/(G30-G0)); area under the curve for insulin normalized for glucose (AUCins/glu), and HOMA-B at baseline to compare clinical characteristics and risk of CFRD according to quartiles for each measure. We also compared characteristics of 40 pwCF found to have de novo CFRD at baseline. ResultsAt baseline, IGI and AUCins/glu were lower in subjects with de novo CFRD and those who later developed CFRD than those who never developed CFRD (p < 0.0001 for each). Subjects with the lowest quartiles of IGI, AUCins/glu, and AUCins/glu 0–30 had increased risk of developing CFRD by Kaplan-Meier analysis (p = 0.0244, p = 0.0024, and p = 0.0338, respectively). There was no significant difference in risk between quartiles of HOMA-B. Subjects in the lowest quartile of IGI showed a significant increase in 2-hour OGTT glucose and AUCglu between the initial and final study visits (p = 0.0027 and p = 0.0044, respectively). ConclusionIGI is easily measured in a clinical setting and needs to be validated in prospective studies as a potential tool to improve risk stratification in CFRD with direct relevance to pathogenesis.