Cystic fibrosis-related diabetes: An interdisciplinary diagnostic and therapeutic challenge

Cystic fibrosis (CF) is the most common autosomal recessive hereditary disease in Caucasian people, with an incidence of one in 3000 live births, and is caused by mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene.

Abnormal lung function is the main factor responsible for the high mortality rate in patients with CF. However, advances in respiratory therapy and specialised treatment of CF over the last few decades have significantly increased these patients’ life expectancy,¹ achieving current mean survival of more than 30 years. This increase in survival has led to an increase in extrapulmonary complications, with cystic fibrosis-related diabetes (CFRD) being the most common comorbidity. CFRD is a comorbidity caused by impairment of the endocrine pancreas and constitutes a determining factor in lung function as well as a marker of a worse prognosis and a higher mortality rate.^2,3 Its prevalence increases with age and its onset is usually preceded even years ahead by carbohydrate metabolism abnormalities, respiratory worsening and weight loss.⁴ CFRD may be chronic or intermittent, and it is of multifactorial aetiology. CFRD treatment with insulin appears to improve these patients’ respiratory and nutritional status.⁵

Lung transplantation is the only treatment available in end-stage lung disease. The incidence of CFRD in patients who require lung transplantation is 28.6%.⁶

The objectives of the study were to assess the diagnostic possibilities that might be offered by continuous glucose monitoring (CGM) added to oral glucose tolerance testing (OGTT) in isolation and to analyse respiratory and metabolic improvement brought about by early insulin therapy in these patients.

We report a case series of six patients aged eight to 16 years followed up at our hospital’s CF Unit and Diabetes Unit, who received insulin therapy after exhibiting abnormal carbohydrate metabolism by the usual methods (OGTT and glycated haemoglobin [HbA1c]) and CGM, accompanied by nutritional decline and respiratory worsening, in whom improvement following insulin therapy was observed.

All patients had elevated HbA1c levels (≥5.7%); 83.3% of them also had abnormal OGTT (blood glucose >200 mg/dl after two hours). A CGM system was placed and fasting and/or postprandial hyperglycaemia was observed in all cases; postprandial hyperglycaemia alone was seen in the female patient who had had normal OGTT.

Once abnormal carbohydrate metabolism had been confirmed in all patients, insulin therapy was started with multiple doses of subcutaneous rapid-acting insulin in all of them, while two patients were also administered insulin glargine. Personalised diabetes education regarding insulin therapy, self-management, portion control and decompensation was provided. In one case, insulin therapy was stopped after three months due to clinical and spirometric respiratory improvement and suitable weight gain. Currently, the other five cases are still on insulin therapy.

Follow-up was scheduled one month after starting insulin therapy, then after three months, after six months and after a year, in order to monitor changes in nutrition and weight (weight percentile), metabolism (HbA1c) and respiratory function (spirometry). All patients showed respiratory and nutritional improvement in follow-up appointments, with weight gain and an increase in weight percentile (see Table 1). A mean drop in HbA1c levels by 7.3% compared to baseline was seen six months after starting insulin therapy. Follow-up spirometry at six months also showed improvements in the three parameters recorded (forced vital capacity [FVC], forced expiratory volume in one second [FEV1] and FEV1/FVC ratio) in all patients, with mean increases in FVC of 33.38%, in FEV1 of 42.19% and in FEV1/FVC of 19.76%.

Table 1.

Summary of patients’ parameters when starting insulin therapy and changes observed at their six-month follow-up appointment (values specified as “post” in the table).

	1	2	3	4	5	6
Gender	♂	♀	♀	♀	♂	♂
Weight percentile	p < 3	p < 3	p37	p26	p31	p29
HbA1c (%)	6.1	6.2	5.9	5.8	5.7	5.7
OGTT	Abnormal	Abnormal	Normal	Abnormal	Abnormal	Abnormal
CGM	Abnormal	Abnormal	Abnormal	Abnormal	Abnormal	Abnormal
Rapid-acting insulin	Yes	Yes	Yes	Yes	Yes	Yes
Insulin glargine	Yes	Yes	No	No	No	No
FVC (%)	67	55	60	55	93	91
FEV1 (%)	56	48	44	43	82	65
FEV1/FVC (%)	70	76	64	66	78	57
Post weight percentile	p3	p9	p61	p37	p46	p41
Post HbA1c (%)	5.6	5.9	5.4	5.4	5.3	5.2
Post FVC (%)	68	100	71.8	91	102	103
Post FEV1 (%)	59	82.4	61.3	69.3	100	100
Post FEV1/FVC (%)	72	82.4	72.6	65	96	97

Other publications have reported results similar to those seen in our patients, with follow-up showing good metabolic management in CFRD to have documented rapid, prolonged beneficial effects on respiratory decline in CF.⁷

There are case reports of patients with an indication for lung transplantation in whom insulin therapy achieved sufficient improvement to reverse this indication and ward off a need for transplantation for at least another eight years.⁷

The latest guidelines recommend systematic annual OGTT as of 10 years, or earlier in the event of clinical symptoms such as worsening of lung function or nutritional status with no other explanatory cause,⁸ in order to detect any abnormality in carbohydrate metabolism as early as possible. In addition, the usefulness of CGM in detecting postprandial hyperglycaemia, which would otherwise go undetected with OGTT, has gained some attention.⁸

Therefore, we believe that CGM could be a useful tool for the early detection of carbohydrate metabolism abnormalities in patients with CF, as well as in cases with normal OGTT but with respiratory and nutritional worsening with no other apparent cause, and patients who require treatment with systemic corticosteroid therapy due to its hyperglycaemia-inducing effects. CGM would therefore enable earlier detection of carbohydrate abnormalities in patients with CF, thereby facilitating earlier initiation of insulin therapy and consequently preventing greater respiratory and metabolic decline.

Conflicts of interest

None.