Effect of CFTR Modulators on Anthropometric Parameters in Individuals with Cystic Fibrosis: An Evidence Analysis Center Systematic Review

Bailey, Julianna; Rozga, Mary; McDonald, Catherine M.; Bowser, Ellen K.; Farnham, Kristen; Mangus, Mark; Padula, Laura; Porco, Kathleen; Alvarez, Jessica A.

doi:10.1016/j.jand.2020.03.014

Cited by 67 publications

(55 citation statements)

References 43 publications

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“…Furthermore, it is important to consider the effects of modulator therapy on weight gain [33] . Despite the improvements in insulin secretion that CFTR correction might mediate, and the possible improvement in insulin sensitivity resulting from reduced inflammation, increased physical activity and better quality of life, other factors should be considered.…”

Section: Knowledge Gaps and Future Directionsmentioning

confidence: 99%

The role of modulators in cystic fibrosis related diabetes

Merjaneh

Hasan

Kasim

et al. 2022

Journal of Clinical & Translational Endocrinology

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The development and introduction of modulator therapies have completely shifted the paradigm for the treatment of cystic fibrosis (CF). Highly effective modulator therapies have driven marked improvements in lung function, exacerbation rate, weight and quality of life in CF patients. However, their effect on CF related diabetes (CFRD) is not well delineated. The role of CF transmembrane conductance regulator (CFTR) in CFRD pathogenesis is inadequately understood and research aimed at deciphering the underlying mechanisms of CFRD continues to evolve. In this review, we summarize what is known regarding the effect of CFTR modulators on CFRD. Small studies using ivacaftor monotherapy in gating mutations have revealed improvement in insulin secretion, glucose tolerance and/or decrease in insulin requirement. However, lumacaftor/ivacaftor studies (primarily in delta F 508 homozygous) have not revealed significant improvement in CFRD or glucose tolerance. No studies are yet available regarding the effect of the highly effective triple therapy (elexacaftor/tezacaftor/ivacaftor) on CFRD or insulin secretion. CFTR modulators might affect development or progression of CFRD through many mechanisms including improving insulin secretion by correcting the CFTR defect directly, improving ductal function, reducing islet inflammation, and improving incretin secretion or by enhancing insulin sensitivity via reduced systemic inflammation and increased physical activity driven by improved lung function and quality of life. On the other hand, they can stimulate appetite and improve gastrointestinal function resulting in increased caloric intake and absorption, driving excessive weight gain and potentially increased insulin resistance. If the defect in insulin secretion is reversible then it is possible that initiation of CFTR modulators at a younger age might help prevent CFRD. Despite the advances in CF management, CFRD remains a challenge and knowledge continues to evolve. Future studies will drive better understanding of the role of highly effective CFTR modulators in CFRD.

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Section: Knowledge Gaps and Future Directionsmentioning

confidence: 99%

The role of modulators in cystic fibrosis related diabetes

Merjaneh

Hasan

Kasim

et al. 2022

Journal of Clinical & Translational Endocrinology

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“…CFTR modulators are a revolutionary treatment advance, partially restoring function to the dysfunctional, disease-causing CFTR channel, and are, therefore, likely to ameliorate undernutrition in CF. In fact, many studies have demonstrated weight gain in modulator-treated patients [28] , [29] . A recent systematic review examining 13 CFTR modulator trials performed between 2012 and 2017 found strong evidence for weight gain in ivacaftor-treated patients with a G511D mutation, but weaker evidence for weight gain with liumacaftor/tvacaftor or tezacaftor/ivacaftor treatment [29] .…”

Section: Causes Of Overweight and Obesity In People With Cfmentioning

confidence: 99%

“…In fact, many studies have demonstrated weight gain in modulator-treated patients [28] , [29] . A recent systematic review examining 13 CFTR modulator trials performed between 2012 and 2017 found strong evidence for weight gain in ivacaftor-treated patients with a G511D mutation, but weaker evidence for weight gain with liumacaftor/tvacaftor or tezacaftor/ivacaftor treatment [29] . Elexacaftor/tezacaftor/ivacaftor (ETI), approved in late 2019, was not included in the systematic review.…”

Section: Causes Of Overweight and Obesity In People With Cfmentioning

confidence: 99%

Obesity in cystic fibrosis

Kutney

Sandouk

Desimone

et al. 2021

Journal of Clinical & Translational Endocrinology

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The prevalence of obesity in patients with cystic fibrosis (CF) is increasing and around one-third of adults with CF are now overweight or obese. The causes of excess weight gain in CF are likely multifactorial, including: adherence to the high-fat legacy diet, reduced exercise tolerance, therapeutic advances, and general population trends. Increased weight has generally been considered favorable in CF, correlating with improved pulmonary function and survival. While the optimal BMI for overall health in CF is unknown, most studies demonstrate minimal improvement in pulmonary function when BMI exceeds 30 kg/m 2 . Dyslipidemia and cardiovascular disease are important co-morbidities of obesity in the general population, but are uncommon in CF. In people with CF, obesity is associated with hypertension and higher cholesterol levels. With longer life expectancy and rising obesity rates, there may be an increase in cardiovascular disease among people with CF in coming years. Overweight CF patients are more likely to be insulin resistant, taking on features of type 2 diabetes. Treating obesity in people with CF requires carefully weighing the metabolic risks of overnutrition with the impact of low or falling BMI on lung function. This article describes current knowledge on the epidemiology, causes, consequence, and treatment of obesity in people with CF.

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“…With the introduction of highly effective modulators we expect differences in body composition between and within patients to become more prevalent [ 54 ].…”

Section: Pharmacokinetics Of Cftr Modulators and Cf Features That May Change Pharmacokinetic Propertiesmentioning

confidence: 99%

CFTR Modulators: Does One Dose Fit All?

Meer

Wilms

Heijerman

2021

JPM

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For many people with cystic fibrosis (pwCF), CFTR modulators will be the cornerstone of their treatment. These modulators show robust treatment effects at group level in pwCF with specific mutations. The individual effect however, is variable. In this review we will explain reasons for reconsideration of dosing regimens of CFTR modulating therapy in order to improve treatment response and prevent side effects. Since the effect of a drug depends on pharmacodynamics and pharmacokinetics, pharmacodynamics and pharmacokinetic properties of CFTR modulators will be discussed. Pharmacokinetic-pharmacodynamic relationships will be used to gain insight in dosage response and exposure response relationships. To understand the cause of variation in drug exposure, pharmacokinetic properties that may change due to CF disease will be explained. We show that with current insight, there are conceivable situations that give reason for reconsideration of dosing regimens, however many questions need to be unravelled.

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Effect of CFTR Modulators on Anthropometric Parameters in Individuals with Cystic Fibrosis: An Evidence Analysis Center Systematic Review

Cited by 67 publications

References 43 publications

The role of modulators in cystic fibrosis related diabetes

The role of modulators in cystic fibrosis related diabetes

Obesity in cystic fibrosis

CFTR Modulators: Does One Dose Fit All?

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