CFDB - Cystic Fibrosis DataBase

Abnormal glucose metabolism -CFRD- IGT therapy-

Abnormal glucose metabolism therapy

Background

  

Cystic Fibrosis-related diabetes (CFRD) is the most frequent complication of  Cystic Fibrosis (Kayani K, 2018). It is  age-dependent (Kelly A, 2014),  even if glucose metabolism abnormalities may begin also very early ( Haliloglu B,2016) and  a deficiency in beta-cell number, already during  childwood, has been  speculated (Bogdani M,2017), (Banavath TN, 2018).  

It is a uniquely complex entity  with clear differences from T1DM and T2DM (Konrad K, 2013 ). Thought  pancreatic insufficiency is a major CFRD risk (Soave D, 2014), it has been affirmed (Wooldridge JL, 2015)  that CFRD screening guidelines should be followed also by  patients with pancreatic sufficiency.

Emerging evidence (Kayani K, 2018) shows that CFTR  impairment  itself has an important role in the release of insulin and glucagon and in the protection of β cells from oxidative stress and that intra-islet inflammation is another important cause of β cells demage.(Hart NJ, 2018), (Norris AW,2019)  Among contributors to the development of CFRD, in addition to CFTR genotype,  other genetic factors related or not related to type 2 diabetes have been speculated  (Iafusco F, 2021)  

 

Anyway, reduced insulin secretion is  the key factor to explain high prevalence of glucose intolerance in patients with cystic fibrosis, even if, variations of insulin sensitivity are also associated (Boudreau V, 2016) (Colomba J, 2019)

According to CF Foundation, criteria for CFRD diagnosis are based on elevated fasting blood glucose level greater than 6.94 mmol/liter (125 mg/deciliter) or OGTT value  greater than 11.11 mmol/liter (200 mg/deciliter) at two hours  or symptomatic diabetes  with random glucose levels greater than 11.11 mmol/liter (200 mg/deciliter) and glycated hemoglobin levels >6.5%.

Oral glucose tolerance test (OGTT) is commonly used to screen an  abnormal glucose metaboliosm and in CF patients with pancreatic insufficiency it has been speculated that a  1-hour OGTT glucose level  ≥155 mg/dL, already could manifest impaired β-cell secretory capacity with associated early-phase insulin secretion defects (Nyiriesy SC.2018)  (Bonhoure A, 2021). Continuous glucose monitoring could be a more useful tool for evaluating early abnormalities (Taylor-Cousar JL, 2016). HbA1c value does not possess the characteristics of a  sensitive screening test for pre-CFRD condition (DarukhanavalaA, 2021)  It has been  speculated that both serum fructosamine  (Lam GY, 2017) and homeostasis model assessment index of β-cell function (HOMA-%B), may be effective( Mainguy C, 2017) , (Toin T, 2021)

The relationship between abnormal glucose metabolism and increased  morbidity and mortality in CF patients, mostly in females, is well known ( Kerem E, 2013), (Lewis C, 2015), (Bilodeau C, 2016) and also earlier stages of glucose metabolism impairment have been recognized, far back (Rolon MA, 2001), as relevant risk factors in the long-term prognosis (Lavie M, 2015), (Terliesner N, 2017)., also in children (Mozzillo E, 2021)

Diabetic microvascular complications may occur in CFRD (Schwarzenberg SJ, 2007) and, although the prevalence of retinopathy and nephropathy appears to be lower than that found in other forms of diabetes, annual complication screening should be performed at 5 years from diagnosis of CFRD with fasting hyperglycemia.

Even if the use of oral agents may prove beneficial in treating CFRD, insulin remains the mainstay of treatment (Brennan AL, 2015) ( Moheet A, 2018) and, probably, it  has to be started already in the first stages of glucose abnormal condition (Pu MZ,2016). It has been postulated  ( Hayes D Jr, 2014), ( Games H, 2021)   that Ivacaftor, the CFTR modulator for patients with gating mutations, might be not only a mean to potentially delay or prevent the development of CFRD, but also a mean to correct well established CFRD.  On the contrary, Lumacaftor/Ivacaftor, CFTR modulator for patients with two F508del mutations, did not demonstrate a consistent impact on glucose tolerance and insulin secretion ( Thomassen JC, 2018).   (Moheet A, 2021). In CFRD patients, a free diet is recommended, but it has been postulated that a low glycemic index diet may improve glucose tolerance status (Balzer B. 2012) (Birch L, 2018)

In the last years, regarding glucose abnormal metabolism in CF, hypoglycaemia, in the absence of diabetes or glucose lowering therapies,  is receiving growing attention in the literature (Armaghanian N, 2016) ( Kayani K,2018). It may be caused by delayed and abnormal insuline release and ineffective counter-regulation of glucagone, as extension of an OGTT to 3 h, may be able to demonstrate (Armaghanian N, 2020)

 

Issues

Modalities of glucose tolerance screening.

Timing and protocols of treatment of abnormal glucose metabolism.

Role of oral hypoglycemic agents.

Role of insulin pump.

Optimal glycemic control to reduce the impact of CFRD on long-term prognosis.

What is known

 

In 2012, a Systematic Review by Health Technology Assessment (Waugh N,2012) reviewed the methods for CFRD screening and suggested that continuous glucose monitoring is the best screening test and that blood glucose level excursions > 8 mmol/l (= 144 mg/l) must be considered potentially harmful to the lung by promoting colonisation and infection.

 

The most recent Cochrane review (Onady GM, 2020)  studied insulin and oral agents efficacy for managing CFRD. Twenty nine studies studies have been considered and four RCTs (200 participants) have been included in the analysis This review has not found any conclusive evidence that any agent has a distinct advantage over another in controlling hyperglycemia or the clinical outcomes associated with CFRD. However, given the treatment burden already experienced by people with cystic fibrosis, oral therapy may be a viable treatment option to consider.

 

About the therapy in earlier stages of impared glucose tolerance (IGT), one RCT (Moran A, 2009) showed that insulin therapy safely reversed chronic weight loss in patients with CFRD without fasting hyperglycemia and another RCT (Minicucci L, 2012) showed that glargine treatment, in patients with glucose intolerance,  was well accepted and tolerated, even if its efficacy in improving clinical and glycometabolic conditions was not demonstrated.

In a RCT (Beaudoin N, 2016) combined exercise training has proven to be effective to improve glycemic control in CF patients and, perhaps, to offer a possibility that could delay the onset of CFRD.

One multicentric european RCT (Ballmann M, 2018) compared efficacy and safety of a 24 months treatment with insulin (n=41) and repaglinide (n=34) in CFRD patients aged 10 years and older. The primary outcome was HbA1C. Boths treatments resulted equally efficacious and safe.

In 2019 a RCT (Geyer MC, 2019) has speculated  that  exanetide (a glucagon-like peptide-1 receptor agonist, used to treat diabetes mellitus type 2, that works by increasing insulin release from the pancreas and decreases excessive glucagon release) could correct post-prandial hyperglicemia in young people with CF and IG and that could be a candidate treatment in CFRD.

In 2021 ( Colombo C, 2021) a retrospective case–control study on 13 patients homozygous for Phe508del CFTR mutation, who received LUMA/IVA for one year and on 13 patients with identical genotype who did not receive this treatment,  did not find any evidence of improvements in glucose tolerance associated with LUMA/IVA treatment.

In 2021 (Kelly A, 2021) a RCT about 26 adult with abnormal glucose tolence  showed that sitagliptin intervention augmented meal-related incretin responses with improved early insulin secretion and glucagon suppression, even if  no improvements in glucose tolerance or β-cell sensitivity to glucose, including for second-phase insulin response, were found.

Unresolved questions

 

  • Timing and protocols of treatment of abnormal glucose metabolism 
  • Role of oral hypoglycemic agents
  • Role of insulin pump

 Several studies are ongoing on this issue:

A study  is ongoing about the feasibility of outpatient automated blood glucose control with the bionic pancreas (NCT03258853)

A research is ongoing to find the genes and other factors that are responsible for the development of CFRD (NCT01113216)

A study is ongoing about the feasibility of methylated insulin DNA, as a a biomarker of beta cell death, in determining the development of diabetes.  (NCT03713437)

A pilot study is ongoing about the combination of continuous glucose monitor (CGM) and insulin pump therapy, also known as sensor augmented pump (SAP) therapy, for cystic fibrosis related diabetes (CFRD) management in the inpatient setting, with the aim of improving glycemic control. (NCT03939065)

A phase 4 study is ongoing about the effect of postprandial insulin administration of faster-acting insulin analogue versus pre-prandial administration of acting-insulin analogue (NCT04381429)

An EnVision CF multicenter  observational study is ongoing about glucose tolerance in Cystic Fibrosis (NCT03650712)

An observational study about the Characterization of β-cell Function and Insulin Sensitivity in Pre-transplant Patients With Cystic Fibrosis  (NCT04379726)

An observational study about the effects of cystic fibrosis and cystic fibrosis related diabetes on brain structure and cognitive function  (NCT03820349)

 

Study of the Effectiveness of Chronic Incretin-based therapy using the DPP-4 inhibitor sitagliptin  on insulin secretion in Cystic Fibrosis ( NCT01879228)

An observational  study about Glycemic Characterization and Pancreatic Imaging Correlates in Cystic Fibrosis (NCT03961516)

An observational study about the characterization of glucose variability by continuous glucose monitoring in non-diabetic youth with and without Cystic Fibrosis (NCT02211235)

A study about Beta-cell Responsiveness to the Incretin Hormones GLP-1 and GIP in Cystic Fibrosis (NCT01851694)

An observational study about Diet, Physical Activity and Glucose Tolerance in Cystic Fibrosis. (NCT04249466)

A phase 2/3 study about the impact of insulin therapy on protein turnover in pre-diabetic Cystic Fibrosis patients (NCT02496780)

An open label, randomized, interventional study about efficacy of a weekly administration of the of the long-acting glucagon-like peptide-1 (GLP-1) agonist dulaglutide, in order to  improve defective early-phase insulin secretion and improve glucose tolerance  ( NCT04731272)

Keywords: Diabetes Mellitus; Glucose Intolerance; Hypoglycemic Agents; Insulin;