**7. Treatment and management**

observed decline in lung function is less clear. Plausible theories include direct pulmonary damage or suppression of various components of the immune system in the setting of hyperglycaemia leading to an increased risk of pulmonary infections which might also be more severe in nature [14], as has been demonstrated in other types of diabetes [44]. Insulin therapy has been shown to reduce sputum pathogen levels in CF patients [45]. It has also been hypothesised that the predominant factor in the decline in both respiratory function and nutritional status is a direct consequence of the altered protein metabolism experienced by CF patients who become relatively deficient in insulin therefore losing its important anabolic effects [14]. CFRD has been considered to be a risk factor for the development of distal intestinal obstruction syndrome in cystic fibrosis patients [59]; however, it is unclear how strong the association really is between these two conditions [60] or what causal mechanism might be

Microvascular complications may develop in CFRD leading to the typical associated pathol‐ ogies (retinopathy, nephropathy and neuropathy), any of which may significantly impact the on-going management of the condition, particularly the development of visual impairment,

Where glucose control has deteriorated to the point that fasting hyperglycaemia is present (a relatively rare occurrence in the CFRD population), a significant proportion will also have developed retinopathy and microalbuminaemia (16% and 14%, respectively) [61]. Almost half of all CFRD patients will display some degree of neuropathy, in most cases where the dys‐

Examples of autonomic dysfunction and gastroparesis have been reported [61], although the latter condition may be difficult to differentiate from the delayed gastric emptying that occurs

Overall, the prevalence of microvascular complications is less in CFRD than in other forms of diabetes, possibly due to the partially preserved endogenous insulin production and sensi‐

Although there is nothing to suggest dysglycaemia is not a significant risk factor for the development of macrovascular complications in individuals with CF, as it is in other popula‐ tions, at present their occurrence very infrequently complicates the management of CFRD.

Although there are case reports of both coronary artery disease and strokes occurring in diabetic CF patients [62, 63], there is at present no evidence of excess mortality attributable to cardiovascular or cerebrovascular disease despite these patients often having co-existing

Currently, the consequences of significant dysglycaemia are likely to manifest earlier and more profoundly in other ways, e.g. deteriorating lung function, but as the life expectancy of the

in up to 50% of the CF population regardless of their glucose tolerance [43].

involved.

**6.1. Microvascular complications**

96 Cystic Fibrosis in the Light of New Research

gastroparesis and renal failure.

**6.2. Macrovascular complications**

dyslipidaemia.

glycaemia has been present for over a decade [43].

tivity leading to relatively short periods of hyperglycaemia.

Treatment of CFRD is currently exclusively limited to insulin therapy, since by the time CFRD is formally diagnosed the predominant issue is one of failure of insulin secretion. Evidence of improved outcomes with insulin therapy is established for those who have a positive OGTT with and without fasting hyperglycaemia [2, 39, 64]. It is also recommended that insulin is initiated in those patients that exhibit diabetic responses whilst suffering an infective exacer‐ bation [11], which presumably reflects a group with poor pancreatic reserve, meaning that they are unable to respond adequately when peripheral insulin resistance increases due to higher levels of inflammation or treatment with corticosteroids. The UK CF Trust (2004) guidelines for the management of CFRD [11] have produced recommendations for instigation of treatment, which are as follows; Treatment should be considered:


Definite indications for initiating treatment are:


Better awareness and more aggressive management of CFRD have led to a considerable improvement in outcomes over the last 5 years including mortality [2]. As discussed above, the concept of truly normal glucose tolerance in the majority of adult CF patients, especially if pancreatic-insufficient, is a fallacy and all such patients could be reasonably considered in a 'pre-diabetic' state; however, the role of early treatment to prevent CFRD is less clear. Small studies have previously suggested only a trend towards improvement in various outcomes when CF patients with impaired glucose tolerance (IGT) received long-acting insulins [65].

As total insulin secretion is often preserved or only marginally decreased in non-diabetic CF patients, the use of insulin therapy in such a group may not be as efficacious and any benefits must be weighed against the increased treatment burden (which is considerable for the vast majority of CF patients) and the risk of hypoglycaemia.

However, there is now increasing evidence to support initiation of treatment in non-diabetic groups with improvement in pulmonary and other clinical outcomes seen after insulin treatment was started [64, 66, 67], particularly those with positive CGM results [57], although it is currently too early to know if such benefits are sustained long-term or will impact upon mortality rates.

The treatment of CFRD can prove challenging with treatment strategies having to constantly be changed due to the variability and disease progression of CF. There are many different variables associated with CF that have to be taken into consideration when managing CFRD.

### **7.1. Pharmacological treatments of CFRD**

Whenever treatment for dysglycaemia in CF patients is initiated, the only modality with an established evidence base is insulin therapy. Biguinide therapy potentially offers antiinflammatory activity as well as anti-diabetic effects and was shown to improve glucose control in 4 patients without significant side effects over a 10-year period [68]. However, given that insulin resistance is not the predominant abnormality in stable CF patients [36], coupled with concerns about an increased risk of hepatitis, lactic acidosis, weight loss and pancreatitis [69], metformin has not been widely used in this cohort.

A small study (n=12) using acarbose in a group of CF patients with IGT receiving inpatient antibiotics for a pulmonary exacerbation showed an improvement in glucose profile compared to placebo but also a very high incidence of GI side effects [70].

Secretagogues, such as the sulphonylureas, have been shown to be of little benefit in a CF setting whilst increasing the risk of symptomatic hypoglycaemia in this group [71].

Dietary modification can play a role in decreasing very high post-prandial glucose excursions in CF patients and Balzer et al. have suggested that adopting a low glycaemic index diet could be advantageous in CFRD [72]. As such, insulin remains the only recommended treatment for CFRD [11]; however, even the use of short-acting insulin in a bolus regime, attempting to control post-prandial glucose excursions, still risks symptomatic hypoglycaemia developing as endogenous hormone levels belatedly rise.

The incretin system is particularly important in the post-prandial handling of carbohydrate; therefore, agents that enhance its effects are of considerable interest in the management of CFRD, particularly as theoretically at least they have a much lower propensity to cause hypoglycaemia. However, the widespread use of these agents has not yet been investigated in a CF-specific setting, although initial small-scale use seems to have been well tolerated [73].

### **7.2. Insulin regimes for insulin therapy**

Different types of insulin are available for use to treat CFRD. Their different modes of action need to be correlated with glucose profiles and individual requirements of the patient in order to manage glucose levels effectively.

The main categories of insulin are:

**•** Long-acting insulin analogues – Normally administered once daily with a duration of 18-24 hours, achieving a steady state after 2-3 days (e.g. insulin glargine; detemir or degludec).


Typically, either a basal/bolus or a combination of both is used to treat CFRD [74].

Short acting rapid insulin before meals remains the insulin of choice for those without fasting hyperglycaemia.

Taking into account treatment burden, long lasting basal insulin needs to be considered and is frequently given [74].

Pre-mix insulin is used in some cases although with the variability in eating patterns this may prove detrimental.

### **7.3. Multidisciplinary approach to management**

it is currently too early to know if such benefits are sustained long-term or will impact upon

The treatment of CFRD can prove challenging with treatment strategies having to constantly be changed due to the variability and disease progression of CF. There are many different variables associated with CF that have to be taken into consideration when managing CFRD.

Whenever treatment for dysglycaemia in CF patients is initiated, the only modality with an established evidence base is insulin therapy. Biguinide therapy potentially offers antiinflammatory activity as well as anti-diabetic effects and was shown to improve glucose control in 4 patients without significant side effects over a 10-year period [68]. However, given that insulin resistance is not the predominant abnormality in stable CF patients [36], coupled with concerns about an increased risk of hepatitis, lactic acidosis, weight loss and pancreatitis

A small study (n=12) using acarbose in a group of CF patients with IGT receiving inpatient antibiotics for a pulmonary exacerbation showed an improvement in glucose profile compared

Secretagogues, such as the sulphonylureas, have been shown to be of little benefit in a CF

Dietary modification can play a role in decreasing very high post-prandial glucose excursions in CF patients and Balzer et al. have suggested that adopting a low glycaemic index diet could be advantageous in CFRD [72]. As such, insulin remains the only recommended treatment for CFRD [11]; however, even the use of short-acting insulin in a bolus regime, attempting to control post-prandial glucose excursions, still risks symptomatic hypoglycaemia developing

The incretin system is particularly important in the post-prandial handling of carbohydrate; therefore, agents that enhance its effects are of considerable interest in the management of CFRD, particularly as theoretically at least they have a much lower propensity to cause hypoglycaemia. However, the widespread use of these agents has not yet been investigated in a CF-specific setting, although initial small-scale use seems to have been well tolerated [73].

Different types of insulin are available for use to treat CFRD. Their different modes of action need to be correlated with glucose profiles and individual requirements of the patient in order

**•** Long-acting insulin analogues – Normally administered once daily with a duration of 18-24 hours, achieving a steady state after 2-3 days (e.g. insulin glargine; detemir or degludec).

setting whilst increasing the risk of symptomatic hypoglycaemia in this group [71].

mortality rates.

98 Cystic Fibrosis in the Light of New Research

**7.1. Pharmacological treatments of CFRD**

[69], metformin has not been widely used in this cohort.

as endogenous hormone levels belatedly rise.

**7.2. Insulin regimes for insulin therapy**

to manage glucose levels effectively.

The main categories of insulin are:

to placebo but also a very high incidence of GI side effects [70].

When diagnosing and managing patients with CFRD, it is of paramount importance that the multidisciplinary team have excellent knowledge relating to this complication. In ideal circumstances an endocrinologist with experience of CF will form part of the regular multidisciplinary team caring for patients, but in many centres the task of coordinating diabetic care will be delegated to a specialist nurse.

Communication is crucial to ensure patients are fully informed about the condition, particu‐ larly the differences between CFRD and other types of diabetes as patients may come with pre-conceived notions that could impact their engagement with treatment and on-going management, e.g. undertake wholly inappropriate calorie restriction.

Wherever possible, both the specialist CF dietician and clinical psychologist should be involved at the earliest opportunity to ensure the best possible expert care and management for the patient.
