The role of modulators in cystic fibrosis related diabetes

Abstract

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.

Efficacy and Safety of Elexacaftor-Tezacaftor-Ivacaftor in the Treatment of Cystic Fibrosis: A Systematic Review

“…On the other hand, improved calorie intake and intestinal absorption, due to CFTR modulator therapy, leads to weight gain and, as a result, increased insulin resistance. No clinical trials have evaluated the effect of ELX/TEZ/IVA on CFRD and glucose metabolism [ 36 ]. An observational study conducted by Scully et al noticed an improvement in measures of hyperglycemia and glycemic variability with CGM after ELX/TEZ/IVA initiation [ 25 ].…”

Safety of elexacaftor/tezacaftor/ivacaftor dose reduction: Mechanistic exploration through physiologically based pharmacokinetic modeling and a clinical case series

“…Although liver toxicities accounted for most cases of AEs in our study, we had one case of dose reduction due to the elevated blood glucose. ETI treatment is generally associated with either no change in glycemic control or improvement in CF‐related diabetes due to increase in insulin secretion and sensitivity; however, there have also been some documentations of worsened glycemic control 24 . This is potentially due to increased nutritional absorption and appetite, although more research is needed to determine whether there is a relationship between hyperglycemia and ETI therapy.…”

The features of carbohydrate metabolism in children with cystic fi brosis: a 30-year-long history

“…Если дефект секреции инсулина обратим, то возможно введение модуляторов МВТР в более молодом возрасте может помочь предотвратить МЗСД. Наблюдение за такими пациентами и изучение влияния таргентной терапии модуляторами на эндокринную функцию поджелудочной железы будут продолжаться [47].…”