Cystic fibrosis (CF) is still not curable. However, the development of CFTR modulators in recent years has given rise to treatment options that can improve FEV1, for example, by up to 15% in certain patients. As the first CF drugs to be at least partially causal, CFTR modulators have been the subject of multiple investigations.
Triple therapy with the CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) modulatorselexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) has shown beneficial effects on lung function, BMI, and quality of life. A team led by Dr. Carolin Steinack, Department of Pneumology, University Hospital Zurich, has investigated whether the combination also has positive effects on glucose tolerance [1].
In their cohort study, the investigators included 33 CF patients with at least one copy of F508del (27.8±6.3 years; 73% male; 64% F508del homozygous). Before treatment and at least 3 months after initiation, an oral glucose tolerance test (OGTT) with glucose and insulin measurements, pulmonary function test were performed, and BMI and sweat chloride levels were measured.
At a median of 184 days after initiation of therapy, 48.5% patients (n=16) improved their glucose tolerance category, 39.4% (n=13) remained unchanged, and 12.1% (n=4) worsened. OGTT glycemia value (measured after 60, 90, and 120 minutes) decreased significantly from 11.9 ± 2.7 mmol/l to 10.6 ± 2.8 mmol/l (after 60 minutes; p=0.012), 10.4 ± 3.0 mmol/l to 8.4 ± 3.6 mmol/l (after 90 minutes; p=0.002), and 7.3 ± 3.1 mmol/l to 5.7 ± 3.0 mmol/l (after 120 minutes; p=0.012) (Fig. 1). The HbA1c value also improved significantly from 5.50±0.24% to 5.39±0.25% (p=0.039).
Adults with cystic fibrosis and at least one copy of F508del may benefit from treatment with the triple CFTR modulator in terms of potential improvement in glucose tolerance without increasing insulin secretion, the Zurich scientists concluded. Early initiation of treatment is imperative to show whether decreased glucose control is preventable or even reversible, he said.
Risk of CF arthropathy reduced
A common comorbidity in adult patients with CF is musculoskeletal symptoms and arthritis, mainly affecting small joints. The potential benefit of CFTR modulator therapy on these complaints was the subject of a study by pulmonologists and rheumatologists at the Cantonal Hospital of St. Gallen [2].
For their prospective cross-sectional cohort study, the group led by Dr. Anna-Lena Walter, Department of Pneumology and Sleep Medicine, and Dr. Kristin Schmiedeberg, Department of Rheumatology, first performed rheumatologic examinations (clinical and laboratory parameters) on 25 CF patients. Twenty-two of these patients were on triple CFTR modulator therapy (ELX/TEZ/IVA, duration 13 ± 4 months). Arthralgias occurred in 48% and myalgias in 20% of patients. Arthritis affecting mainly small joints was found clinically in 24% (n=6) and confirmed by ultrasound in 3 of these patients. Myalgias were associated with swollen joints (r=0.7452, p<0.0001), pain sensitive joints (r=0.6674, p=0.0003), positive squeeze test (r=0.5898, p=0.0019) and morning stiffness (r=0.6556, p=0.0004).
Duration of CFTR modulator therapy was associated with fewer painful and swollen joints, consistent with the assumption that ameliorating mucosal airway inflammation may reduce the risk of developing CF arthropathy, the authors concluded.
Identify early parameters
Regarding long-term response to CFTR modulator therapy, there are no early parameters to date. A group of researchers from the Lucerne Cantonal Hospital, the University Hospital of Lausanne, and the University Hospital of Geneva sought to identify such parameters (measured within 7 to 14 days of starting treatment with a CFTR modulator) that could potentially predict the long-term efficacy of CFTR modulators.
In their prospective observational study, they included a total of 67 CF patients (mean age 11.6 years) at the hospitals in Lucerne, Lausanne, and Geneva who were scheduled to start treatment with a CFTR modulator or to switch from one modulator to another. Fifty patients started therapy with the triple ELX/TEZ/IVA, 9 received the combination lumacaftor/ivacaftor, 5 tezacaftor/ivacaftor, and 3 ivacaftor mono. There were 14 patients in the triple group who switched from LUM/IVA (n=9) or TEZ/IVA (n=5) to ELX/TEZ/IVA.
The researchers found significant early changes in body mass index, sweat chloride concentration and lung function, ASAT and ALAT, total bilirubin, and gamma-GT. In the nasal potential difference test, basal potential, Δ amiloride, Δ lowchloride, Δ isoprotenerol, Sermet score, and Wilschanski index also changed significantly. Improvement was also observed in inflammatory parameters (white blood cells, neutrophils, fecal calprotectin). In contrast, no early significant changes were observed in blood pressure, SpO2, respiratory rate, erythrocyte sedimentation rate erythrocyte sedimentation rate, CRP, immunoglobulin G, or fecal elastase.
The positive parameters would be further investigated in their ongoing work as potential predictors of long-term response to treatment with CFTR modulators, the authors concluded.
Congress: SGP Annual Meeting 2023
Sources:
- Steinack C, Matthias E, Beuschlein F, et al.: Improved Glucose Tolerance after Initiation of Elexacaftor/Tezacaftor/Ivacaftor in Adults with Cystic Fibrosis. SSC/SSCS – SSP/SSTS Joint Annual Meeting 2023; Abstract 043.
- Walter AL, Schmiedeberg K, Joos L, et al: CFTR Modulator Treatment Duration is Associated with a Decreased Burden of Cystic Fibrosis-Associated Arthropathy. SSC/SSCS – SSP/SSTS Joint Annual Meeting 2023; Abstract 044.
- Heer P, Fernandez C, Rochat I, et al.: Early Parameters to Predict Long-Term Efficacy of CFTR Modulators in Patients with Cystic Fibrosis. SSC/SSCS – SSP/SSTS Joint Annual Meeting 2023; Abstract 070.
InFo PNEUMOLOGIE & ALLERGOLOGIE 2023; 5(3): 30
