CFRD Diagnosis: Clinical Guidelines for Cystic Fibrosis-Related Diabetes

Clinical Care Guidelines for Cystic Fibrosis-Related Diabetes: a position statement by the American Diabetes Association and a clinical practice guideline by the Cystic Fibrosis Foundation, endorsed by the Pediatric Endocrine Society. Diabetes Care. 2010;33(12):2697-2708.

Cystic fibrosis-related diabetes (CFRD) stands as the most prevalent comorbidity associated with cystic fibrosis (CF), affecting a significant portion of the CF population, with prevalence rates reaching up to 20% in adolescents and as high as 50% in adults. A confirmed Cfrd Diagnosis is known to have detrimental effects on lung function, nutritional status, and overall survival rates in individuals with CF. Notably, early stages of CFRD can often be clinically silent, underscoring the critical need for consistent and strategic screening across various clinical scenarios. The diagnosis of CFRD relies on established American Diabetes Association criteria, but it also accounts for the detection of intermittent hyperglycemia, particularly during periods of illness or in patients receiving gastrostomy feedings. Management strategies are primarily centered around insulin therapy, coupled with continuous, specialized care delivered by a multidisciplinary team proficient in both CF and diabetes management.

Methodology for CFRD Diagnosis Guidelines

The 2010 Clinical Care Guidelines for Cystic Fibrosis-Related Diabetes (CFRD) represent the culmination of a joint effort by the Cystic Fibrosis Foundation, the American Diabetes Association (ADA), and the Pediatric Endocrine Society. These guidelines provide a comprehensive overview of recommendations concerning screening, diagnosis, and management of CFRD. While referencing the ADA Standards of Medical Care, which are updated annually in Diabetes Care and applicable to all individuals with diabetes, these guidelines specifically emphasize aspects unique to the clinical care of CFRD. The development process adhered to a rigorous methodology, encompassing the formation of an expert committee, the formulation of specific clinical questions, a systematic review of existing literature, the drafting of preliminary recommendations, committee voting, finalization of recommendations, and grading according to both the US Preventive Services Task Force (USPSTF) and ADA schemes. For detailed information regarding the USPSTF grading definitions, please refer to the USPSTF grading definitions.

Recommendations for CFRD Diagnosis and Screening

Screening Recommendations for Patients Without a Confirmed CFRD Diagnosis |

|—|
| Recommendations | Evaluation of the Evidence |
| 1. The recommended screening test is a 2-hour 75g Oral Glucose Tolerance Test (OGTT). 1. Annual screening should commence by age ≥ 10 years. 2. For individuals planning pregnancy or confirmed pregnant, an OGTT is recommended if prior results were abnormal or not conducted within the last 6 months. 3. For patients undergoing organ transplantation and not screened within the last 6 months, a preoperative OGTT is advised. | ADA – E Consensus ADA – B USPSTF – B ADA – E Consensus ADA – E Consensus |
| 2. Hemoglobin A1c (HbA1c) is not recommended as a primary screening test for CFRD diagnosis. | ADA – B USPSTF – D |
| 3. Self-monitoring of blood glucose (SMBG) can be utilized, but elevated readings should be confirmed by central laboratory glucose measurements. 1. During pulmonary exacerbations: Monitor fasting and 2-hour postprandial glucose levels via SMBG for 48 hours upon admission for exacerbations, IV antibiotics, and/or systemic glucocorticoids. 2. In patients receiving gastrostomy feedings: Monitoring mid- and post-feeding glucose levels is recommended for those on continuous enteral feeds, at the initiation of gastrostomy feeding, and then on a monthly basis. | ADA – E Consensus ADA – E Consensus |
| 4. Gestational diabetes screening is recommended in pregnant women with CF at both 12-16 weeks and 24-48 weeks gestation, utilizing a 2-hour 75g-OGTT with 0, 1, and 2-hour glucose measurements. 1. If gestational diabetes mellitus (GDM) is diagnosed, a repeat OGTT is recommended 6-12 weeks postpartum. | ADA – E Consensus ADA – E Consensus |

Diagnostic Criteria for CFRD |

|—|
| Recommendations | Evaluation of the Evidence |
| 5. During a period of stable baseline health, a CFRD diagnosis can be established based on standard ADA criteria (outlined below). Diagnostic testing should ideally be conducted on two separate days to confirm the diagnosis, unless there are unequivocal symptoms of hyperglycemia (polyuria, polydipsia) or symptoms accompanied by random glucose levels ≥ 200 mg/dL. 1. 2-hour OGTT plasma glucose ≥ 200 mg/dL (11.1 mmol/L) 2. Fasting plasma glucose (FPG) ≥ 126 mg/dL (7.0 mmol/L) 3. Hemoglobin A1c ≥ 6.5% (note: HbA1c levels are often lower in CF patients, and a value | ADA – E Consensus |
| 6. A CFRD diagnosis can be made in acutely ill patients (hospitalized and receiving IV antibiotics or systemic glucocorticoids) when FPG ≥ 126 mg/dL or 2-hour postprandial glucose levels are ≥ 200 mg/dL, and these levels persist for more than 48 hours. | ADA – E Consensus |
| 7. In patients on continuous enteral drip feedings, a CFRD diagnosis can be established when mid- or post-feeding glucose levels ≥ 200 mg/dL are observed on 2 separate days. | ADA – E Consensus |
| 8. The diagnosis of gestational diabetes in women with CF should adhere to the International Association of Diabetes and Pregnancy Study Groups recommendations. Diabetes is diagnosed if any one of the following criteria is met during a 75-g OGTT with 0-, 1-, and 2-hour glucose levels: 1. FPG ≥ 92 mg/dL (5.1 mmol/L) 2. 1-hour plasma glucose ≥ 180 mg/dL (10.0 mmol/L) 3. 2-hour plasma glucose ≥ 153 mg/dL (8.5 mmol/L) | ADA – E Consensus |
| 9. The onset of CFRD is defined as the date an individual first meets the diagnostic criteria, even if hyperglycemia subsequently resolves. | ADA – E Consensus |

Management Recommendations Post-CFRD Diagnosis |

|—|
| Recommendations | Evaluation of the Evidence |
| 10. Optimal care involves quarterly consultations with a specialized multidisciplinary team possessing expertise in both diabetes and CF. | ADA – E Consensus |
| 11. Patients should participate in ongoing diabetes self-management education programs that meet established national standards. | ADA – E Consensus |
| 12. Insulin therapy is the recommended treatment modality for CFRD management. | ADA – A USPSTF – B |
| 13. Oral diabetes agents are not considered as effective as insulin in improving nutritional and metabolic outcomes in CFRD and are generally not recommended outside of clinical research trial settings. | ADA – A USPSTF – D |
| 14. Patients on insulin therapy should perform SMBG at least 3 times daily. | ADA – E Consensus |
| 15. Patients should aim to achieve plasma glucose goals as recommended by the ADA for all individuals with diabetes. | ADA – E Consensus |
| 16. Quarterly HbA1c measurements are recommended to monitor glycemic control. | ADA – E Consensus |
| 17. The target HbA1c treatment goal is generally | ADA – E Consensus |
| 18. Adherence to CF Foundation evidence-based guidelines for nutritional management is essential. | ADA – E Consensus |
| 19. Regular moderate aerobic exercise for a minimum of 150 minutes per week is advised. | |
| 20. Monitoring for complications: 1. Education on hypoglycemia, including glucagon administration, is crucial. 2. Blood pressure should be monitored at routine diabetes visits, adhering to ADA guidelines. Elevated readings should be confirmed on a separate day to diagnose hypertension. 3. Annual monitoring for microvascular complications is recommended, commencing 5 years post-CFRD diagnosis. 4. Patients with hypertension or microvascular complications should receive treatment as per ADA recommendations for all people with diabetes, with specific exceptions regarding sodium and protein restriction. 5. An annual lipid profile is recommended for patients exhibiting risk factors such as obesity, family history of coronary artery disease, or undergoing immunosuppressive therapy post-transplantation. | ADA – E Consensus ADA – E Consensus ADA – E Consensus ADA – E Consensus ADA – E Consensus |

Emerging Issues in CFRD Diagnosis

Since the publication of these guidelines in 2010, further research has indicated a higher incidence of glucose abnormalities in children with CF younger than 10 years of age than previously recognized. Contemporary insights into CFRD pathophysiology suggest a potential role of CFTR mutations in beta-cell dysfunction, which may contribute to early impairments in insulin secretion detectable even in young children. These findings suggest that screening protocols for high-risk children under the age of 10 may be warranted to ensure early CFRD diagnosis.

Unresolved Questions in CFRD Diagnosis and Management

Several questions remain unanswered and are areas of ongoing research and discussion within the CFRD clinical and research community:

Should the recommended age for initiating CFRD screening be lowered to include patients younger than 10 years?
What is the potential role of alternative CFRD screening methods, such as glucose challenge tests or continuous glucose monitoring (CGM)?
How will CFTR modulator therapies impact the natural progression of CFRD development and its subsequent course?
Is there a role for newer classes of anti-diabetic agents in the management of CFRD, including GLP-1 agonists, DPP-4 inhibitors, and SGLT2 inhibitors?
What is the appropriate role for insulin therapy in individuals with CF-related prediabetes?
What is the impact of treatment burden on patients’ self-management practices and overall outcomes?

Application of These CFRD Diagnosis Guidelines

The Cystic Fibrosis Foundation provides this executive summary to offer a concise overview of the comprehensive published guideline. This guideline synthesizes available evidence and presents clinically sound recommendations for healthcare professionals, patients, and other stakeholders. Decisions regarding the care of individual patients should be made through a collaborative process, integrating these guidelines with a thorough assessment of the benefits and risks of treatment options by the clinical team, consideration of the patient’s unique circumstances, and alignment with the patient’s and their family’s goals and preferences. This shared decision-making approach between the patient and clinician is paramount in delivering patient-centered care.

This executive summary was prepared by: Christine L. Chan, MD (University of Colorado) and Antoinette Moran, MD (University of Minnesota)

It is important to note that while these guidelines were initially published in December 2010 and reviewed in July 2021, it was determined at that time that no update was necessary. Clinicians should always consider the most current research and evolving best practices in CFRD diagnosis and management in their clinical decision-making.