EXPERT ANALYSIS FROM THE PAS ANNUAL MEETING
SAN DIEGO (FRONTLINE MEDICAL NEWS) – Promising developments in the treatment and perhaps even prevention of cystic fibrosis–related diabetes are on the horizon – and they’re coming none too soon.
This is a field in need of a kick start, Dr. Antoinette Moran said at the annual meeting of the Pediatric Academic Societies.
She cited her recent review of 664 cystic fibrosis patients treated at the University of Minnesota during 2008-2012. Overall mortality in those with cystic fibrosis–related diabetes (CFRD) was unchanged from the high rates seen in a similar review covering 2003-2008, despite adoption of an institutional policy of aggressive screening for diabetes and early initiation of insulin therapy upon diagnosis of CFRD ( Am. J. Respir. Crit. Care Med. 2015;191:194-200 ).
“Certainly screening and early institution of insulin are critical, but we seem to have come up against a wall. Honestly, at the University of Minnesota there is no way that we can be more aggressive than we already are with screening and with insulin. We have done as much as we can. So we need to think of something different to move this to the next stage,” said Dr. Moran, professor of pediatrics and chief of the division of pediatric endocrinology and diabetes at the University of Minnesota, Minneapolis.
She highlighted what she considers two of the most promising novel areas of CFRD research. One involves high-priority studies laying the groundwork for possible initiation of insulin therapy in cystic fibrosis (CF) patients even before they are diagnosed with CFRD, possibly starting in infancy.
The other major event is the anticipated Food and Drug Administration approval of a fixed-dose combination of ivacaftor and lumacaftor, a combined potentiator and corrector of the CF transmembrane conductance regulator (CFTR). Mutations in this chloride conduction channel are the most common cause of CF. Marketing approval for the new combination agent, which has breakthrough drug designation, is believed to be imminent.
“This is absolutely fascinating and a real game changer in the world of CF: the ability to fix CFTR, the abnormal CF chloride channel,” Dr. Moran said. “It’s expected that virtually every CF patient in the country is going to be on these drugs once the combination is approved.”
A large multicenter postmarketing study known as PROSPECT is in place and ready to start once the ivacaftor/lumacaftor combination receives approval. It will capture patients right before they start the agent and then follow them longitudinally. Dr. Moran is principal investigator for the GIFT (Gastrointestinal/Glucose and Insulin Functional Testing) substudy of PROSPECT. This 75-patient study will entail oral glucose tolerance testing with insulin, glucose, and C-peptide levels obtained at baseline and 1, 6, and 12 months.
The rationale for GIFT comes from the fact that CFTR mutations are present in the pancreatic beta cells of CF patients. An earlier five-patient pilot study conducted by Dr. Moran suggested ivacaftor might improve insulin secretion in patients with CF. This observation raises the question: “If we could start the drugs in very young children, might it prevent the development of diabetes? If the basic CFTR defect impacts beta cell function, it suggests this is going to be the way to get around that impasse – that treatment other than insulin will prevent or at least partially treat CFRD,” she said.
Another approach to preventing CFRD is being pursued by her colleague, Dr. Katie Larson Ode, a pediatric diabetologist at the University of Iowa, Iowa City. She showed that abnormal glucose tolerance was already present in 41% of 6- to 9-year-olds with CF, and among that subgroup, 42% developed early-onset CFRD at an average age of 11 years in girls and 12 years in boys, in contrast to the general Minnesota CF population, where the average age of onset of CFRD is age 23 years.
Moreover, the 59% of 6- to 9-year-olds with normal glucose tolerance had impaired insulin secretion. Their insulin secretion on oral glucose tolerance testing was half that of controls without CF.
This raises a question: Were these CF children born with these defects, or do the abnormalities evolve slowly during childhood? Dr. Ode is attempting to find out by performing annual oral glucose tolerance tests starting in infancy at the time of CF diagnosis. She is looking prospectively at the relationships between glucose and insulin levels and exocrine function, growth, inflammation, and pulmonary function, with the subjects’ unaffected siblings serving as controls.
“If those infants and toddlers with CF have abnormal insulin secretion and if it correlates with worse clinical parameters, we’re really going to have to consider whether we should be starting insulin right away in these babies. After all, we don’t wait to start vitamin D in CF infants until they develop rickets. We treat everything else preventively – we may need to think about doing that with insulin,” said Dr. Moran.
In her 664-patient review of the University of Minnesota experience with CF during 2008-2012, overall mortality in those with CFRD was 1.8 per 100 person-years ,compared with 0.5 per 100 person-years in CF patients without diabetes. In patients with mild CF genotypes, the risk of mortality was 20% in those with CFRD compared with 2% without diabetes. In patients with severe genotypes, overall mortality was 12% in those with CFRD, threefold higher than in those without diabetes.
Dr. Moran reported having financial relationships with Novo Nordisk and Vertex, which is developing ivacaftor/lumacaftor.