To the Editor:
Cystic fibrosis (CF)–related diabetes (CFRD) is a common extrapulmonary comorbidity among adults with CF, affecting one-third of adults and portending a worse prognosis. CFRD is part of the spectrum of glucose intolerance and results from dysfunction and loss of pancreatic islet cells and insulin resistance (1). CFRD was known to be associated with more severe lung function decline (2, 3), at least before highly effective CFTR (CF transmembrane conductance regulator) modulator therapy (HEMT) was available. The first available modulator, ivacaftor, improves function of CFTR and has led to dramatic improvements in lung function among those with qualifying CFTR mutations (4, 5). However, long-term follow-up of patients on ivacaftor showed that improvements in lung function were not preserved over time (6). By Year 5, the rate of decline approximated that of a comparator group not on HEMT. In addition, the effect of HEMT on glucose tolerance is not well defined. Although ivacaftor was associated with improvements in insulin secretion, it did not improve glucose tolerance (7).
Understanding the effect of HEMT on lung function decline in those with CFRD has important implications for the CF community, given an expected increase in survival with HEMT and thus a rising incidence of CFRD with age. Here we present an analysis of the CF Foundation Patient Registry (CFFPR), focusing on those on ivacaftor with the hypothesis that, over time, the presence of CFRD as compared with its absence (non-CFRD) was associated with a greater decline in lung function.
Source data were obtained from the CFFPR (8). Patients on ivacaftor were defined as those 12 years of age and older with any use of ivacaftor in the initial period of U.S. Food and Drug Administration approval for those with at least one copy of CFTR mutation G551D. Encounters during pregnancy or after lung transplant were censored to avoid abrupt changes in lung function that were not related to disease progression. CFRD status included those with fasting hyperglycemia or 2-hour plasma glucose ⩾200 on an oral glucose tolerance test and was defined before the first encounter with ivacaftor use. Those with normal and impaired glucose tolerance at baseline were defined as non-CFRD even if they went on to develop CFRD during the study period. Baseline values were determined at the encounter of first ivacaftor use. FEV1% predicted values were equally spaced within each year as exact dates were unavailable (deidentified). Demographics and baseline characteristics were summarized with descriptive statistics. For comparisons between groups, Pearson’s chi-square test or Wilcoxon rank sum tests were used as appropriate. A linear mixed model was used to examine the association of CFRD with the time trend of FEV1% predicted. Factors known to affect lung function decline, including age, sex, baseline FEV1% predicted, body mass index (BMI), pancreatic insufficiency, and Pseudomonas aeruginosa culture status, were also included in the model.
A total of 732 CFFPR participants were identified as meeting ivacaftor user criteria (Table 1). Of those ivacaftor users, 175/732 (24%) were categorized as CFRD and 557/732 (76%) as non-CFRD. Of those categorized as non-CFRD, there were 239/557 (43%) who developed CFRD during the study period. Those with CFRD were older (median age 27 vs. 23 years, P < 0.0001) and had lower baseline FEV1% predicted (61% vs. 80%, P < 0.0001) with no significant difference in sex (percentage male 53 vs. 52, P = 0.97) or BMI (median 22.3 vs. 21.7, P = 0.81). In terms of comorbidities, there were significantly more in the CFRD group with pancreatic insufficiency (98% vs. 86%, P < 0.0001) and sputum cultures positive for P. aeruginosa (74% vs. 59%, P < 0.0001).
Table 1.
Baseline Demographics and Clinical Characteristics
| CFRD (n = 175) | Non-CFRD (n = 557) | P Value | |
|---|---|---|---|
| Age, yr, median (IQR) | 27 (19–38) | 23 (17–31) | <0.0001 |
| Sex, F, % | 47 | 48 | 0.97 |
| Race, % | 0.83 | ||
| White | 97 | 98 | |
| Black | 2 | 1 | |
| Other | 1 | 1 | |
| FEV1% predicted, median (IQR) | 61 (41–84) | 80 (58–99) | <0.0001 |
| G551D, % homo/heterozygous | 89 | 86 | 0.35 |
| F508del, % heterozygous | 77 | 70 | 0.06 |
| BMI, kg/m2, median (IQR) | 22.3 (19.7–24.8) | 21.7 (19.8–24.8) | 0.81 |
| Pancreatic insufficiency, % | 98 | 86 | <0.0001 |
| P. aeruginosa colonization, % | 74 | 59 | <0.0001 |
| Hb A1C, median (IQR)* | 6.7 (5.8–8.1) | 5.5 (5.3–5.9) | <0.0001 |
Definition of abbreviations: BMI = body mass index; CFRD = cystic fibrosis–related diabetes; IQR = interquartile range; P. aeruginosa = Pseudomonas aeruginosa.
CFRD n = 42, normal glucose tolerance n = 78.
When modeling lung function over time, with adjustment for relevant covariates such as age, sex, baseline FEV1% predicted, BMI, pancreatic insufficiency, and sputum P. aeruginosa status, the estimated FEV1% predicted decline of those with CFRD was 0.36 percentage points per year more than that in the non-CFRD group (P < 0.001). Trajectory for those with pancreatic insufficiency also declined 1.25 percentage points per year (P < 0.001) in lung function more than those without pancreatic insufficiency. Based on the model, the estimated mean trajectories and point-wise 95% confidence intervals for CFRD and non-CFRD for subjects with pancreatic insufficiency and sputum cultures positive for P. aeruginosa were plotted together for comparison for males and females, separately (Figure 1). A significant association between CFRD and decline in lung function trajectory persisted in alternate models adjusted for fewer covariates and when using raw lung function values (FEV1 in liters). Given the proportion of those in the non-CFRD group who developed CFRD during the study period, a sensitivity analysis was performed with censoring of those encounters after CFRD diagnosis. The estimated FEV1% predicted decline of those with CFRD remained significantly greater than that in the non-CFRD group (P < 0.001). Furthermore, when we defined participants as three separate groups, never-CFRD, later-CFRD, and baseline-CFRD, both later-CFRD and baseline-CFRD groups had significantly greater decreases over time compared with the never-CFRD group (later-CFRD: −0.17 FEV1% predicted per year, P = 0.032; baseline-CFRD: −0.45 FEV1% predicted per year, P < 0.001).
Figure 1.
CFRD is associated with a greater decline in lung function over time. Given indicator variables used in analysis, we used a representative plot for females (mean age, 26.0 yr; n = 233) and males (mean age, 27.6 yr; n = 183) with pancreatic insufficiency and sputum cultures positive for Pseudomonas aeruginosa demonstrating estimated trajectory of FEV1% predicted over the study period (coefficient −0.36, P < 0.0001). The 95% confidence intervals for each group are represented by dotted lines. Those with CFRD experienced almost a 3% greater decline in FEV1% predicted as compared with those without CFRD when controlling for age, sex, baseline FEV1% predicted, body mass index, a diagnosis of pancreatic insufficiency, and having sputum cultures positive for P. aeruginosa. CFRD = cystic fibrosis–related diabetes.
In this real-world analysis of those with CF on ivacaftor, we found that, after adjusting for relevant baseline characteristics and risk factors, a diagnosis of CFRD was still associated with greater decline in lung function despite treatment with HEMT. The underlying etiology of worse pulmonary outcomes due to CFRD is unknown, but the effects appear to persist despite correction of CFTR function. In addition, in line with other long-term studies of CFTR modulators, we found that the incidence of CFRD continues to increase with time in those on ivacaftor (6).
There were some limitations to our analysis. The true effect of CFRD on lung function trajectory may be underestimated by this analysis owing to misclassification of CFRD status given the low compliance (40% of adults with CF) with annual screening for CFRD. In addition, we were unable to determine if the degree of glycemic control in those with CFRD, as estimated by Hb A1C, had an impact on lung function trajectory because of the low number of observations in the data set. Lastly, adherence to ivacaftor was not measured. However, CFRD has not been identified as a risk factor for worse adherence to CFTR modulator therapy (9).
Although the overall rate of lung function decline for both groups in this cohort was less than that observed in premodulator studies, CFRD continues to be a risk factor for worse outcomes despite ivacaftor use (3). Future studies are needed to untangle the mechanisms by which hyperglycemia affects lung function and to evaluate therapies that can mitigate these effects.
Acknowledgments
Acknowledgment
The authors thank the Cystic Fibrosis Foundation (CFF) for the use of the CFF Patient Registry data to conduct this study. They also thank the patients, care providers, and clinic coordinators at CF centers throughout the United States for their contributions to the CFF Patient Registry.
Footnotes
Supported by Cystic Fibrosis Foundation grants BENGTA19C0 (C.D.B.), POLINE18Y7 (J.H.), and SALATH18I0 (M.A.S.); National Center for Advancing Translational Sciences grant UL1-TR002366 (C.D.B.); and NHLBI grant R01-HL157942 (M.A.S.).
Originally Published in Press as DOI: 10.1164/rccm.202104-1060LE on September 1, 2021
Author disclosures are available with the text of this letter at www.atsjournals.org.
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