Elucidating the Impact of Elexacaftor/Tezacaftor/Ivacaftor on Glucose Intolerance in People With Cystic Fibrosis

Commentary

Cystic fibrosis-related diabetes (CFRD) is the most common comorbidity in cystic fibrosis (CF). In people with CF and pancreatic exocrine insufficiency, pancreatic β-cell function becomes increasingly abnormal over time. Insulin secretory rate is significantly reduced in those who progress to CFRD (around 50% of adults) (1). Worsening glucose tolerance in CF is also associated with incrementally decreasing peripheral insulin sensitivity (1).

The development and recent implementation of highly effective cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy with elexacaftor/tezacaftor/ivacaftor (ETI) have had a transformative impact on pulmonary function and overall life expectancy in CF. The effect of ETI on insulin secretion and overall glycaemic control remains unclear, however.

In the PROMISE-ENDO study, Chan et al prospectively investigated the impact of ETI on glucose tolerance in 79 people with CF aged ≥12 years with at least 1 F508del mutation using frequently sampled extended oral glucose tolerance tests (OGTTs) enabling mathematical modeling of insulin secretory rate and insulin sensitivity (2). A modest but significant [4 mg/dL (0.2 mmol/)] reduction in fasting glucose was seen after 2 to 2.5 years of ETI treatment without any changes in overall OGTT glucose excursions, despite a partial improvement in insulin secretory dynamics. In parallel, a significant decrease in insulin sensitivity was seen at the end of the study with a trend toward an increase in body mass index. These bidirectional effects could explain the overall stable glycemic status found in the study. Whether any improvement in islet function results from a compensatory response to changes in peripheral insulin sensitivity, a direct impact of CFTR modulator therapy on the pancreas, or a response to reduced systemic inflammation relieving “β-cell toxicity” remains unclear.

Findings in the smaller previous studies that have been undertaken have been inconsistent. Korten et al reported improvements in glucose values during an OGTT in 16 adolescents after 4 to 6 weeks of ETI treatment (3). At a median of 10.5 months of ETI in adolescents and young adults within the EnVision study, insulin sensitivity worsened without significant changes in OGTT glucose levels or continuous glucose monitoring metrics. Reductions [18-36 mg/dL (1-2 mmol/L)] in OGTT-stimulated glucose levels were reported in 33 adults with CF after 6 months of ETI but without evidence of significantly enhanced insulin secretion (4). In line with the PROMISE-ENDO study, these divergent findings support an overall conclusion that ETI has limited restorative effect on β-cell function in adults with CF.

Studies have been hampered by the absence of a control group given the ethical imperative to ensure access to ETI for proven pulmonary benefits. Thus, most of the current literature does not examine potential stabilizing effects of ETI on β-cell deterioration. However, a single case-control longitudinal study compared 9 adults receiving ETI over a median 5-year period with 8 controls using the gold standard glucose potentiation of arginine secretion test of β-cell functional mass. The results showed deterioration in the insulin response among controls but not in the ETI group (5). This small study suggests that ETI may attenuate loss of β-cell function, which could imply a lower incidence of CFRD in the future. However, with increasing long-term survival in CF, CFRD may develop at an older age, leaving overall CFRD burden unchanged.

In contrast to the lack of definitive positive impact of ETI on glucose parameters, small but significant improvements in hemoglobin A1c (HbA1c) have been consistently reported (4, 6, 7) with a 0.3% reduction in HbA1c to 5.5% in PROMISE-ENDO (2). The ETI-associated effects on hemoglobin glycosylation therefore seem to be unrelated to the changes in glucose levels in these studies. The decline in HbA1c has been shown to be independent of hemoglobin concentration with possible relationships to reduced serum ferritin or increased bilirubin proposed (7). This further suggests that a modest reduction in HbA1c does not necessarily signify an improvement in glucose tolerance after ETI.

The PROMISE-ENDO investigators are to be congratulated on the rigor with which they have undertaken this study, including 10 US centres providing high-quality long-term data in a meaningfully large prospectively studied cohort. They have demonstrated the feasibility of undertaking frequently sampled OGTTs within future well-powered studies to determine the therapeutic impact of a novel therapeutic approach to CFRD prevention, treatment, and remission. The adoption of this approach will provide detailed evaluation of β-cell function and insulin sensitivity without more invasive and less scalable/participant-acceptable metabolic tests.

With completion of the PROMISE-ENDO trial, it can be safely concluded that, even if it can prevent the natural history of declining β-cell function in CF, ETI cannot deliver the glucose-lowering benefit necessary to prevent the burden of diabetes in those ≥12 years old at commencement. It provides support also for an alternative paradigm that weight gain and changes in body composition in parallel with the benefits of highly effective modulator therapy may ultimately lead to a net worsening of metabolic status and increased cardiovascular risk.

Pancreatic imaging and postmortem studies have shown that the exocrine pancreas is almost entirely replaced by fat in early childhood, with islets remaining remarkably intact. In the normal human pancreas, CFTR is expressed most highly in duct cells (8). Accruing evidence that highly effective modulator therapy if commenced early enough in life may improve pancreatic exocrine function supports carefully designed trials to assess the potential for preventing progressive dysglycaemia now that ETI has been licensed for infants as young as 2 years old.

While it appears clear that response to ETI in pancreatic β-cells in older individuals is at best limited, the persistence of insulin-containing islet cells even in established CFRD supports alternative non-CFTR approaches to enhance functional mass. Possibilities include potentially disease-modifying glucose-lowering agents, repurposing established antifibrotic therapies, and novel therapeutics targeting restoration of normal islet blood flow.

PROMISE-ENDO has set a benchmark for optimal study outcomes incorporated within adequately scaled studies to accelerate progress toward a future without diabetes for those with CF.

Disclosures

The authors have nothing to disclose.

References