Introduction

CFTR modulators represent a groundbreaking therapeutic approach in cystic fibrosis (CF) management, targeting the underlying cause of the disease. These therapies have the potential to directly influence pancreatic beta-cell function and pathways involved in insulin secretion, thereby improving the glycemic status of people with CF (pwCF).

Aims & Methods

We aimed to evaluate the effect of CFTR modulator therapy on endocrine pancreatic function in patients with CF. A systematic search of three databases (PubMed, Embase, and CENTRAL) was conducted up to March 6, 2024, to identify studies examining the impact of CFTR modulators on glucose metabolism in pwCF comparing variables before and after CFTR modulator therapy. Outcomes of interest included measures from oral glucose tolerance tests (OGTT), continuous glucose monitoring (CGM), and glycated hemoglobin (HbA1c). Meta-analysis was initiated using random-effects models to estimate pooled mean differences (MD) and 95% confidence intervals (CIs). Subgroup analyses were created based on CFTR modulators and length of therapy. Covariate regression analyses were made to assess the relationship between therapy length and pooled MD. A p-value less than 0.05 was considered to be statistically significant. The study protocol was registered in PROSPERO with registration number CRD42024516198.

Results

Conclusion

Our results revealed an improvement in the 120-minute OGTT plasma glucose level in the elexacaftor/tezacaftor/ivacaftor subgroup. The absence of significant changes in other analyses may indicate that these medications could potentially slow or halt the deterioration of glucose metabolism. Further prospective studies are required to overcome the limitation of a relatively small patient number and to validate our findings.

Introduction

The consequences of chronic pancreatitis (CP) may not be exclusively limited to the pancreas or restricted to the gastrointestinal tract but could also be systemic. To date, the relationship between chronic pancreatitis and cardiovascular risk factors has not been studied extensively. We conducted a systematic review and meta-analysis to examine if the combination of chronic inflammatory changes may possibly place CP patients at risk for cardiovascular disease.

Aims & Methods

We systematically searched PubMed, Scopus, and Cochrane Register of Controlled Trials for observational studies that compared major cardiovascular outcomes in patients with chronic pancreatitis. The outcomes explored were: (1) acute coronary disease/myocardial infarction; (2) hypertension; (3) hyperlipidemia; and (4) diabetes mellitus. We computed odds ratio (OR) for binary endpoints, with 95% confidence intervals (CI). Heterogeneity was examined I² statistics; p values less than 0.10 and I² > 25% were considered significant for heterogeneity.

Results

Four observational studies comprising a total of 57,721 patients with chronic pancreatitis were included in this meta-analysis. The most consistent finding across studies was a significantly higher risk of diabetes mellitus in patients with chronic pancreatitis compared to a control group without chronic pancreatitis (OR 4.77; 95% CI 1.32–17.28; p=0.017; I²=100%). In contrast, no statistically significant associations were found between chronic pancreatitis and other cardiovascular outcomes, including cerebrovascular disease (OR 1.59; 95% CI 0.98–2.57; p=0.05; I²=99.4%), acute coronary syndrome/myocardial infarction (OR 1.35; 95% CI 1.00–1.82; p=0.049; I²=95.4%), hypertension (OR 0.52; 95% CI 0.30–7.61; p=0.608; I²=99.9%) or hyperlipidemia (OR 2.60; 95% CI 0.36–18.77; p=0.342; I²=100%).

Conclusion

The results of our meta-analysis suggest that chronic pancreatitis is not associated with increased risk of cardiovascular disease despite being associated with a higher risk of diabetes mellitus.

Introduction

Pancreatic steatosis (PS) has been increasingly recognized and associated with some relevant metabolic implications. However, data on its correlation with exocrine pancreatic function remain limited. We conducted a systematic review and meta-analysis to evaluate whether PS is associated with exocrine pancreatic insufficiency (EPI).

Aims & Methods

This study aimed to investigate whether imaging-detected PS is related to exocrine pancreatic dysfunction, assessed by fecal elastase-1 (FE-1) levels. We searched PubMed, EMBASE, and Cochrane Central for studies including adults with and without PS identified on imaging, and reporting FE-1 concentrations. Data were pooled using random-effects models.

Results

Three studies evaluating a total of 1,864 patients were included. Fecal elastase levels were significantly lower in patients with PS compared to controls, indicating worse exocrine pancreatic function in this group (MD -199.78; 95% CI -303.66 to -95.91; p < 0.05; I² = 97%). Moreover, PS was associated with a significantly increased risk of exocrine pancreatic insufficiency (RR 3.13; 95% CI 1.17–8.40; p = 0.023; I² = 81%), reinforcing the link between fat accumulation in the pancreas and impaired exocrine function.

Conclusion

This meta-analysis demonstrates a significant association between PS and impaired pancreatic exocrine function, compared to individuals without known pancreas disease. These findings underscore the importance of a comprehensive metabolic assessment in patients with PS, given its potential role in pancreatic dysfunction.

Introduction

With chronic inflammation, recurrent infections, and dysbiosis, people with CF (pwCF) are predisposed to autoimmunity. However, the role of autoimmune-mediated pancreatic beta-cell damage is yet unclear in the development of cystic fibrosis-related abnormal glucose tolerance (CF-AGT).

Aims & Methods

We aimed to assess the prevalence of various islet autoantibodies (AABs) according to glucose tolerance and age and the risk associated with islet AAB positivity for developing CF-AGT. A systematic search across four databases (CENTRAL, Embase, PubMed, Web of Science) identified studies reporting on AABs against glutamic acid decarboxylase (GADA), insulin (IAA), islet cell (ICA), insulinoma-associated protein 2 (IA-2A), and zinc transporter 8 (ZnT8A) in pwCF (CRD42020155846). Prevalence and odds ratios (OR) were calculated with 95% confidence intervals (CI) using a random effects model with subgroup analysis by glucose tolerance and age.

Results

Conclusion

Introduction

​In people with cystic fibrosis (CF), CFTR modulator therapy has resulted in marked improvements in pulmonary exacerbations, lung function, body weight, and quality of life. However, it remains unclear how restoring CFTR function modifies existing airway infection and inflammation. Understanding the dynamics of airway microbiome changes in response to modulator therapy plays an essential role in developing strategies for managing airway infections.

Aims & Methods

Our aim was to conduct a systematic review and meta-analysis of all available studies.
We conducted a systematic search on the 26^th January, 2024 in MEDLINE, Embase, Web of Science, Scopus and CENTRAL. We performed a random-effects meta-analysis of any provided data pertaining to lower airway microbiota composition before versus after the initiation of CFTR modulator therapy. We calculated mean difference (MD) and standardized MD (SMD) with 95% confidence intervals (CI) and visualized the results on forest plots. Chi-squared tests were performed and I² values calculated to assess statistical heterogeneity.

Results

30 studies were eligible for inclusion, with most prospectively examining people with CF before and 4-12 months after the initiation of CFTR modulator therapy. The initiation of CFTR modulator therapy was associated with an increase in lower airway alpha-diversity (Shannon index; SMD: +0.39 (95% CI: +0.20 - +0.59), p<0.0001), evenness (Pielou index; SMD: +0.84 (95% CI: +0.55 - +1.12), p<0.00001) as well as a reduction in the relative abundance of classical CF lung pathogen species Pseudomonas (MD: -7.1% (95% CI: -1.2% - -13.1%), p=0.02) and Staphylococcus (MD: -4.3% (95% CI: -2.0% - -6.6%), p=0.0003).

Conclusion

Our results demonstrate a clear and statistically significant association between the initiation of CFTR modulator therapy and the stabilization of lower airway microbiota in terms of increased biodiversity, more balanced distribution of microbial species and reduction in the abundance of potentially pathogenic species, all of which contribute to a lower risk of respiratory tract infections.

Introduction

We aimed to assess the role of islet autoimmunity and family history of diabetes in the presence of CFRD in children with CF.

Aims & Methods

Data from 78 children were analysed from the CF-related Pancreatic Disorders Registry. Pancreatic islet autoantibodies (AABs) (glutamic acid decarboxylase (GAD), insulin (IAA), islet antigen-2 (IA-2) and zinc transporter 8 (ZnT8) were measured and family history of diabetes was collected in a cross-sectional manner. Family history of T1DM and T2DM was assessed using the criterion by Blackman et al., 2009 and Ferrat et al., 2020. Fischer, Kruskal-Wallis and Mann-Witney U test were used.

Results

Males comprised 55% of the study population, with a median age of 8.7 years (IQR: 5.4–14.0 years). 51 children were on CFTR modulator therapy. Children with CFRD were significantly older with a median age of 15.9 years (IQR: 7.5–18.7) for any AAB-positive CFRD compared to 8.0 years (IQR: 6.2–12.4) for non-CFRD, and 12.1 years (IQR: 9.9–13.5) for AAB-negative CFRD compared to 7.9 years (IQR: 4.0–13.6) for non-CFRD. Any AAB and single AAB positivity was significantly associated with CFRD (Table 1). Only two children reported T1DM in any relative. Family history of diabetes showed no association with CFRD. Any AAB positivity frequency was comparable among children with positive and negative family history (Blackman criteria p=0.136; Ferrat criteria p=0.133).

Conclusion

Islet AAB positivity is associated with CFRD in children with CF. CFRD, regardless of autoantibody status, is more common in older individuals, which aligns with known disease progression in cystic fibrosis. The usefulness of family history of diabetes as a prognostic factor in the development of CFRD is limited.