Heralding a New Era in Cystic Fibrosis Care
December 7, 2020
Jagdeesh Ullal, MD, MS, FACE, FACP, ECNU
Clinical Associate Professor of Medicine
UPMC Division of Diabetes and Endocrinology
Kara S. Hughan, MD Assistant Professor of Pediatrics
Division of Endocrinology and Diabetes
UPMC Children’s Hospital of Pittsburgh
Cystic Fibrosis Endocrinopathies
Cystic fibrosis (CF) is a multisystem disorder that results from pathogenic variants of the CF transmembrane conductance regulator (CFTR) gene on chromosome 7. The most common endocrinopathies that result from CF are manyfold, including diabetes, bone disease, hypogonadism, infertility, growth disorders, and malnutrition, in addition to multiple fat-soluble vitamin deficiencies. While the most common pathology is a progressive lung disease, which is often the cause of death, poor glycemic control and malnutrition greatly contribute to the worsening of lung disease. Individuals with CF have been known to develop a distinct form of diabetes referred to as type 3c diabetes mellitus (DM), which is distinct from type 1 and type 2 DM.
Type 3c DM is characterized by exocrine pancreatic insufficiency and consequent beta-cell dysfunction in the absence of autoantibodies1. This CF-related diabetes (CFRD) was previously referred to as pancreatogenous diabetes; however, the American Diabetes Association and the World Health Organization changed the terminology to type 3c diabetes in 2012-2013. Individuals with CFRD are subject to the DM-related risks of microvascular disease such as retinopathy, nephropathy, and neuropathy, but have a relatively low risk of macrovascular disease2.
The Cystic Fibrosis Center at the University of Pittsburgh and UPMC
In 1955, a group of volunteers in Philadelphia established the Cystic Fibrosis Foundation (CFF). In 1961, the CFF subsequently created an accredited care center network beginning with the formation of two centers devoted to treating CF. Following the formation of the CFF, yet long before the concept of multidisciplinary care for CF was recognized, the Cystic Fibrosis (CF) Center at the University of Pittsburgh was established by pediatrician Dr. Joan B. Rodman and pediatric radiologist Dr. Murray Sachs. This CF Center became the second center to receive CFF accreditation in the nation.
Due in large part to the concerted efforts of the national network of CF centers and the CFF, the median predicted survival increased from 16 years in the 1970s, to 29 years, in the late 1980s. This generated the need to recruit an adult pulmonologist for adult CF care, leading to the hire of Dr. Joel Weinberg in 1983 to build the adult CF Center at the University of Pittsburgh and UPMC.
Pediatric pulmonologist Dr. David Orenstein was recruited in the mid-1980s to lead what became the Antonio J. and Janet Palumbo Cystic Fibrosis Center. Adult pulmonologist Dr. Joseph Pilewski was recruited in the mid-1990s and is currently the Co-Director of the CF Center and Director of the Adult CF Program in Pittsburgh.
At the program’s inception, adult patients with CF were scheduled in conjunction with the pediatric pulmonary clinic at UPMC Children’s Hospital of Pittsburgh. As the program evolved, adult patients with CF were cared for at the Comprehensive Lung Center at UPMC Presbyterian-Shadyside Hospital.
The Lung Transplant Program at UPMC draws patients regionally and nationally due to the expertise and excellent outcomes in lung transplants in CF patients with Burkholderia cepacia colonization, and other resistant pathogens or risk factors for poor outcomes. The program treats patients with CF not only from western Pennsylvania, but also from Ohio, West Virginia, upstate New York, northwestern Maryland, and across the country.
The CF Center at UPMC is a stellar example of multidisciplinary care that is offered through the combined efforts of pulmonologists, dieticians, nurses, social workers, respiratory therapists, and pharmacists who collectively have decades of CF care experience. In addition, other subspecialties with interest and experience in CF, such as Gastroenterology, Otolaryngology, Hepatology, and Endocrinology are routinely incorporated for longitudinal care ofextra-pulmonary manifestations of CF. The endocrinology efforts in CF care are spearheaded by Dr. Kara Hughan at the Pediatric CF Center and Dr. Jagdeesh Ullal at the Adult CF Center.
The CF center also supports basic and clinical research in CF. Via its role as a longstanding site in the CF Therapeutics Development Network, the UPMC CF Center has contributed to pre-clinical development and Phase 2 and 3 clinical trials of modulators of the CF transmembrane conductance regulator (CFTR). CFTR modulator treatment is a new class of small molecular therapies that represent a major development in the therapeutics of CF. With the approval and use of CFTR modulators and other pulmonary therapies over the last three decades, the median predicted survival for CF patients now approaches 50 years.
Both Drs. Hughan and Ullal are funded through the CFF “EnVision CF: Emerging Leaders in CF Endocrinology II Program” as mentor and mentee, respectively. This award program provides training in developing expertise in the endocrinologic care of patients with CF by developing and maintaining a CF Endocrine clinic, a series of monthly webinars, and lectures and participation in local and national meetings. The program encourages the development of a research track in CF and promotes scholarly activity in CF Endocrine care. Drs. Hughan and Ullal have CF-dedicated Endocrine clinics that are conducted in conjunction with CF Pulmonary clinics and are actively engaged in their own clinical research projects. Continuity of care is established through a smooth transition from the pediatric CF Endocrine clinic to the adult CF Endocrine clinic. This multidisciplinary care model, along with ongoing research projects and the continuously growing literature on clinical care for patients with CF, enables the team at the CF Center to provide the most up-to-date evidenced-based care for our patients.
A Groundbreaking Change in Cystic Fibrosis Care
The CFTR gene regulates the chloride channel, and the lack of function of the chloride channels causes decreased transport of chloride and sodium. This leads to dehydration and desiccation of epithelial cells and mucous membranes. CFTR is highly expressed in the pancreatic ducts and is essential for proper duct function. Its loss from ductal epithelium may contribute to islet dysfunction in CF via paracrine mechanisms3. It is also possible that CFTR may have direct actions in β-cells, although this issue remains controversial4.
CFTR modulators are a class of drugs that improve synthesis and intracellular processing of CFTR protein resulting in expression of chloride channels, thus addressing the primary defect in CF5. CF gating mutations are characterized by a defect in the passage of chloride ions through the CFTR. Ivacaftor is a medication that potentiates the chloride flux by activating CFTR protein without ATP. This drug was FDA approved in 2012. Ivacaftor and Lumacaftor are drugs that act as chaperones during protein folding and increase the number of CFTR channels that are trafficked to the plasma membrane. This combination was FDA-approved in 2015. Elexacaftor is a CFTR corrector that substantially increases the amount of mature CFTR protein and CFTR activity when added to the combination of tezacaftor plus ivacaftor.
This triple drug combination, when given to individuals with at least one CF F508del mutation, has been shown to cause a profound improvement in lung function (FEV1), sweat chloride concentration, and quality of life6. The combination medication elexacaftor-tezacaftor-ivacaftor (Trikafta®) with respective ratios of 100:50:75 mg with doses delivered in two tablets taken in the morning and ivacaftor 150 mg tablet taken in the evening. Trikafta® received FDA approval in October 2019 for patients with at least one F508del mutation. This represents a significant milestone in the development of therapeutics for CF7.
CFTR modulator drugs may help to treat and/or prevent CFRD by recovering CFTR-dependent islet-associated ductal function, by improving gut incretin function, and reducing the inflammation and insulin resistance of systemic illness8. The therapeutic effects of this drug class on endocrine pancreatic function and other organs remain to be ascertained. A two-year observational study, in which UPMC Children’s Hospital of Pittsburgh is participating, (PROMISE; ClinicalTrials.gov: NCT04038047) has been designed to address longer-term, multi-system outcomes.
Case Reports of Individuals with CF Treated with Triple Combination Therapy
Case 1: A 48-year-old female with pancreatic insufficient CF (delF508/delF508) was diagnosed with CFRD at age 19 while hospitalized for pneumonia and on glucocorticoid treatment when her blood glucose concentrations were as high as 600mg/dl. She had been treated with insulin over the subsequent three decades. In 2012, insulin pump therapy was initiated with a basal rate of 0.4 units/hour (9.6 units/day), carbohydrate ratio of 1:20, and correction factor of 1 unit for every 60 above 120mg/dl. Her HbA1c was estimated at 6.7% while her post-prandial glucoses were reported to be as high as 300mg/dl. The patient was seen by the CF pulmonary nutritionist to optimize calorie intake and the endocrinology diabetes educator to estimate carbohydrate ratios for mealtime insulin and to educate the patient on pump and continuous glucose monitor (CGM) use.
Over the following six years, the same basal rate was maintained, but her carbohydrate ratios varied from meal to meal: Breakfast 1:16; Lunch 1:20, and Dinner 1:25. While her HbA1c remained below 7% in 2018, her average sensor glucose reading, as recorded on a professional CGM, was 191±105mg/dl. In May 2019, she was changed to a personal CGM that helped her to improve her average glucose to 150±58 mg/dl, with only three episodes of hypoglycemia every two weeks. Two weeks after initiating Trikafta® (January 2020), hypoglycemia became more frequent (up to six episodes every two weeks). The rapid, uncontrolled descent of her blood glucose levels required her to suspend her pump insulin delivery several times a day to minimize hypoglycemia.
Subsequent reduction of total basal insulin doses from 7.8 to 3.9 units/day and relaxation of carbohydrate ratios to 1:25 were recommended to address the recurrent hypoglycemia. No other medications had been introduced to explain the drastic decline in insulin requirements. Kidney function remained stable and no signs of adrenal insufficiency (hypotension or anorexia) were present. The patient felt drastically better on Trikafta® and her glucoses remain reasonably controlled at this time with a HbA1c of 5.7%.
Case 2: A 24-year-old male with homozygous delta F508 mutation deletion CF was first identified to have CFRD in 2011 and was started on insulin therapy in early 2013. His HbA1c was 6.2% with insulin therapy. His CFRD had progressed to uncontrolled CFRD by mid-2015 with worsening glycemic control, an HbA1c of 9.2%, and a 4.7 kg weight loss noted.
The worsening control of his blood glucose levels accompanied increased CF exacerbations. This required the use of steroids, which further worsened blood glucose control. Eventually, mealtime Lispro insulin was added with a carbohydrate ratio of 1:10 grams and correction factor of 1 unit for every 25 mg/dl above 150 mg/dl.
The patient had a fear of needles, which may have contributed to his poor adherence to the prescribed insulin regimen. A team-based approach helped to identify his fear of needles. The problem was ameliorated by introducing him to Autoshield Duo needles that keep the needle shaft hidden from view at the time of the injection. The patient worked closely with his psychologist and the social worker from his CF team to help overcome his anxiety and improve his willingness to take his injections, which yielded in improved weight gain. Unfortunately, the patient was unable to maintain self-management tasks, self-monitoring, and insulin adherence, which resulted in a subsequent rise of HbA1c levels to the 10-11% range. Insulin Degludec was prescribed to support basal coverage, which helped to lower his HbA1c to 8.7%. His total daily Lispro doses remained constant at 60 units in divided doses. A professional CGM revealed an average sensor glucose of 220 +/- 108 mg/dl.
In 2019, the patient’s HbA1c again increased to 11.8%. Following this the patient was placed on the triple combination CFTR modulator, which led to rapid improvement in his HbA1c to 7.9%. His weight improved from 73 kg to 81 kg. Insulin doses were reduced by 20% in order to prevent low blood glucose.
While both patients above demonstrated a change in their insulin requirements and improvements in glycemic control, these are not universal results with triple combination therapy. Many of our CF endocrine colleagues, both adult and pediatric, across the country have reported varying effects of triple combination therapy on glycemic control. Until data from long-term studies are available, we recommend close monitoring of patients’ glycemic control in the weeks and months following initiation of modulator therapy. The care of CF is entering a new age where drug therapy is dramatically improving the pathophysiologic defect caused by the delF508 genetic mutation. This advance has been due to a concerted effort by the CFF, basic scientists, clinicians, industry, patients, and their families. The future holds great promise for bettering the lives of individuals with cystic fibrosis.
Conclusion
CF is a complex disease that requires a team of professionals to deliver specialized and comprehensive care. Over the years, the natural evolution of CF care and best practices have grown and developed into one that is best delivered through the combined effort of a multidisciplinary team. A group of trained and experienced CF specialist health care professionals can offer care that improves morbidity and mortality and face the challenge of addressing complex issues such as treatment of CFRD, pregnancy, renal disease, metabolic bone disease, malnutrition, and transplantation. Indeed, at CF centers, we embody a slogan from the Cystic Fibrosis Foundation – “Together is the way forward.”
References
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