Clinical Updates in Cystic Fibrosis-Related Diabetes
Clinical Updates in Cystic Fibrosis-Related Diabetes
The dietary management of CFRD is very different from that of type 1 and type 2 diabetes (Table 4). Unlike in type 1 and 2, calorie restriction is usually not appropriate in CFRD. Some, but not all, current dietary recommendations for diabetes mellitus advise the use of low glycemic index foods. However, as many people with CF rely on refined sugary foods as a source of energy, restriction of the use of these foods may impact nutritional status. Therefore, in CFRD, normalization of blood glucose should be achieved by balancing insulin requirements with sufficient calorie intake.
Dietary recommendations for people with diabetes mellitus encourage a reduction in saturated and polyunsaturated fat and a promotion of monounsaturated fat to reduce atherosclerosis. People with CFRD require a high fat intake to maintain body weight because of malabsorption secondary to exocrine pancreatic insufficiency. No specific recommendations have been made for the type of fat to be eaten by people with CFRD, although a mix would be prudent. However, in time, the recommendations on fat intake may need to be adjusted as a small proportion of people with CF have recently been shown to have hypertriglyceridemia and hypercholesterolemia, and a few case reports exist of CF patients with symptomatic ischemic heart disease, suggesting that macrovascular disease can develop as people live longer.
Insulin deficiency is the primary defect in people with CFRD, and therefore insulin therapy is currently the only recommended treatment for this condition. Patients with CFRD characteristically require very little basal insulin therapy, but need supplemental insulin for meal coverage. The CF Foundation recommends multiple daily injections of short-acting insulin before each meal with a small dose of long-acting insulin at night. Food intake in people with CF is often more uneven than in people with type 1 or type 2 diabetes, with higher proportions of food being eaten later in the day. In addition, people with CF are encouraged to eat snacks that are often high in kilocalories and may receive overnight supplemental feeding. The use of short-acting insulin provides flexibility required by this diet, allowing the insulin dose to be adjusted to the carbohydrate content of each meal and additional boluses to be given for snacks or night feeds.
In patients who are not controlled with multiple injections, they can move on to a continuous subcutaneous insulin infusion pump. This provides a continuous infusion of short-acting insulin over 24 hours with the ability to bolus at any point to either correspond with meal-times or snacks or to correct hyperglycemia. Patients with CF and NGT or IGT who develop hyperglycemia during infective exacerbations or courses of steroids may require insulin therapy temporarily to restore glycemic control, which can be withdrawn when the exacerbation is controlled.
The benefits of insulin therapy in CFRD are not well studied but the current literature would suggest that there is an improvement in HbA1c value, with the biggest improvement being the 2% (at 1 year) and 1% (at 5 years): an increase in weight or BMI, with studies reporting rises of 1 to 3 points in BMI; improvements in lung function, such as rises in FEV1 (6–35%), expressed as percent of expected normal; and reductions in lung infections.
Very few oral agents are used in CFRD and most of the newer agents coming onto the market (such as the sodium-glucose transporter inhibitors [SGLT2]) are designed to help with weight loss as well as improve the patients' glycemic and metabolic profile. For this reason, their use is likely to be limited in the CFRD population. Further research is needed particularly in the overweight CFRD group, and insulin therefore remains the recommended first line therapy with oral therapy only being considered when there are significant difficulties in taking insulin.
Agents That Augment Insulin Release. Repaglinide stimulates insulin secretion and has been shown to increase insulin release and reduce glucose concentrations in people with CFRD without fasting hypoglycemia. In addition, repaglinide has a plasma half-life of 1 hour, which reduces the risk of between-meal or nocturnal hypoglycemia. A recent Cochrane review found no significant conclusive evidence that long-acting and short-acting insulins with repaglinide have a distinct advantage over one another in controlling hyperglycemia or clinical outcomes associated with CFRD.
GLP-1 is an incretin hormone released as a bioactive peptide from intestinal L-cells in response to eating. It works by stimulating insulin and inhibiting glucagon. It is quickly deactivated by the serine protease dipeptidyl peptidase IV (DPP-IV). Incretin hormones actually account for 70% of the release of insulin from the pancreas in response to food. Reduced levels of GLP-1 are seen in CF with and without diabetes. Studies are underway to investigate this pathway in CF patients and explore its potential therapeutic potential (Walshaw, Liverpool). DDP-4 inhibitors and GLP-1 analogues are already used to treat patients with type 2 diabetes.
Agents That Reduce Insulin Resistance. As insulin resistance is not the major etiological factor in the development of CFRD, drugs which reduce insulin resistance are unlikely to control blood glucose in CFRD when used as a single agent and are not be recommended in the acute setting when insulin resistance is more prevalent due to the risk of lactic acidosis (metformin) and worsening fluid retention (thiazolidinediones). They are therefore not recommended in any treatment pathway for CFRD.
Others. Acarbose prevents the degradation of complex carbohydrates into glucose by inhibiting the glycoside hydrolases needed to digest carbohydrates. The side effects are commonly gastrointestinal (flatulence) and dose related. Its use is to reduce the hyperglycemia postprandially and can be beneficial in the early stages of diagnosis of CFRD before insulin is prescribed.
Type of Treatment
Nutrition
The dietary management of CFRD is very different from that of type 1 and type 2 diabetes (Table 4). Unlike in type 1 and 2, calorie restriction is usually not appropriate in CFRD. Some, but not all, current dietary recommendations for diabetes mellitus advise the use of low glycemic index foods. However, as many people with CF rely on refined sugary foods as a source of energy, restriction of the use of these foods may impact nutritional status. Therefore, in CFRD, normalization of blood glucose should be achieved by balancing insulin requirements with sufficient calorie intake.
Dietary recommendations for people with diabetes mellitus encourage a reduction in saturated and polyunsaturated fat and a promotion of monounsaturated fat to reduce atherosclerosis. People with CFRD require a high fat intake to maintain body weight because of malabsorption secondary to exocrine pancreatic insufficiency. No specific recommendations have been made for the type of fat to be eaten by people with CFRD, although a mix would be prudent. However, in time, the recommendations on fat intake may need to be adjusted as a small proportion of people with CF have recently been shown to have hypertriglyceridemia and hypercholesterolemia, and a few case reports exist of CF patients with symptomatic ischemic heart disease, suggesting that macrovascular disease can develop as people live longer.
Insulin Therapy
Insulin deficiency is the primary defect in people with CFRD, and therefore insulin therapy is currently the only recommended treatment for this condition. Patients with CFRD characteristically require very little basal insulin therapy, but need supplemental insulin for meal coverage. The CF Foundation recommends multiple daily injections of short-acting insulin before each meal with a small dose of long-acting insulin at night. Food intake in people with CF is often more uneven than in people with type 1 or type 2 diabetes, with higher proportions of food being eaten later in the day. In addition, people with CF are encouraged to eat snacks that are often high in kilocalories and may receive overnight supplemental feeding. The use of short-acting insulin provides flexibility required by this diet, allowing the insulin dose to be adjusted to the carbohydrate content of each meal and additional boluses to be given for snacks or night feeds.
In patients who are not controlled with multiple injections, they can move on to a continuous subcutaneous insulin infusion pump. This provides a continuous infusion of short-acting insulin over 24 hours with the ability to bolus at any point to either correspond with meal-times or snacks or to correct hyperglycemia. Patients with CF and NGT or IGT who develop hyperglycemia during infective exacerbations or courses of steroids may require insulin therapy temporarily to restore glycemic control, which can be withdrawn when the exacerbation is controlled.
The benefits of insulin therapy in CFRD are not well studied but the current literature would suggest that there is an improvement in HbA1c value, with the biggest improvement being the 2% (at 1 year) and 1% (at 5 years): an increase in weight or BMI, with studies reporting rises of 1 to 3 points in BMI; improvements in lung function, such as rises in FEV1 (6–35%), expressed as percent of expected normal; and reductions in lung infections.
Oral Hypoglycemic Agents
Very few oral agents are used in CFRD and most of the newer agents coming onto the market (such as the sodium-glucose transporter inhibitors [SGLT2]) are designed to help with weight loss as well as improve the patients' glycemic and metabolic profile. For this reason, their use is likely to be limited in the CFRD population. Further research is needed particularly in the overweight CFRD group, and insulin therefore remains the recommended first line therapy with oral therapy only being considered when there are significant difficulties in taking insulin.
Agents That Augment Insulin Release. Repaglinide stimulates insulin secretion and has been shown to increase insulin release and reduce glucose concentrations in people with CFRD without fasting hypoglycemia. In addition, repaglinide has a plasma half-life of 1 hour, which reduces the risk of between-meal or nocturnal hypoglycemia. A recent Cochrane review found no significant conclusive evidence that long-acting and short-acting insulins with repaglinide have a distinct advantage over one another in controlling hyperglycemia or clinical outcomes associated with CFRD.
GLP-1 is an incretin hormone released as a bioactive peptide from intestinal L-cells in response to eating. It works by stimulating insulin and inhibiting glucagon. It is quickly deactivated by the serine protease dipeptidyl peptidase IV (DPP-IV). Incretin hormones actually account for 70% of the release of insulin from the pancreas in response to food. Reduced levels of GLP-1 are seen in CF with and without diabetes. Studies are underway to investigate this pathway in CF patients and explore its potential therapeutic potential (Walshaw, Liverpool). DDP-4 inhibitors and GLP-1 analogues are already used to treat patients with type 2 diabetes.
Agents That Reduce Insulin Resistance. As insulin resistance is not the major etiological factor in the development of CFRD, drugs which reduce insulin resistance are unlikely to control blood glucose in CFRD when used as a single agent and are not be recommended in the acute setting when insulin resistance is more prevalent due to the risk of lactic acidosis (metformin) and worsening fluid retention (thiazolidinediones). They are therefore not recommended in any treatment pathway for CFRD.
Others. Acarbose prevents the degradation of complex carbohydrates into glucose by inhibiting the glycoside hydrolases needed to digest carbohydrates. The side effects are commonly gastrointestinal (flatulence) and dose related. Its use is to reduce the hyperglycemia postprandially and can be beneficial in the early stages of diagnosis of CFRD before insulin is prescribed.