Insulin treatment in children and adolescents with diabetes

Insulin therapy started in 1922 using regular insulin before each main meal and one injection in the night, usually at 1 a.m. With the development of intermediate- and long-acting insulin, most patients moved to one or two injections per day after 1935. Already in 1960 a study showed that patients who were diagnosed between 1935 and 1945 and using one or two injections/day had a much higher risk of retinopathy after 15 years of diabetes compared to those diagnosed before 1935 using multiple daily injections (61% vs. 9%) (1) [C]. There are no randomized controlled studies comparing the longer term outcomes of using older more traditional insulins with newer regimens when both groups receive equal educational input. But the fact that the traditional insulins have certain clinical limitations, has lead to the development of new analogs, rapid and long-acting. These insulins represent some improvement in the care of diabetes, but the extent in a clinical long-term setting is not fully established. Adult data is not readily transferable to pediatric patients of different age groups (2)“[A]”, but in children and adolescents, as in adults (3) [A], rapid acting insulin (aspart) is rapidly absorbed and eliminated (4) [C]. Higher maximum insulin concentrations in adolescents vs. children were reported both for insulin aspart and human regular insulin (5) [A], but not with glulisine (6) [A]. The results from reference (5) are in line with the relatively impaired insulin sensitivity and higher insulin concentrations reported in healthy adolescents (7, 8) [B]. Such findings highlight the necessity to study the effects of these new insulins in all age groups separately. The different rapid acting analogs have different chemical properties, but no significant difference in time of action and duration has been reported (9). Their advantages compared to regular (soluble) insulin are still under debate. The Cochrane review from 2006 stated that in patients with type 1 diabetes, the weighted mean difference (WMD) of HbA1c was −0.1% in favour of insulin analog (−0.2% when using CSII, continuous subcutaneous insulin infusion) (2) [A]. In children and adolescents, blood glucose control has not been shown to be significantly improved with these analogs (10–14) [A]. A reduction in hypoglycemia has been reported, both for lispro (11, 12, 15) [A] (16) [B] and aspart (17, 18) [A]. In the Cohrane review, the WMD of the overall mean hypoglycaemic episodes per patient per month was −0.2 (95% CI: −1.1 to 0.7) (2) in favor of rapid acting insulin analogs. In adolescents, a significantly reduced rate was found with analogs (14), but in prepubertal children, no difference was found (11, 13). The median incidence of severe hypoglycemia for adults was 26.8 episodes/100 patient years vs. 46.1 for regular insulin. In the included pediatric studies, there was no difference found in prepubertal children (10, 11) or adolescents (14). The basal insulin analogs have different modes of action. Insulin glargine is a clear insulin which precipitates in situ after injection whereas insulin detemir is acylated insulin bound to albumin. These analogs have reduced day-to-day variability in absorption compared to NPH-insulin, with detemir having the lowest within-subject variability (19, 20) [A]. So far the reduction in hypoglycemia and not in HbA1c is the most prominent feature (21) [A], both for glargine (22–25) [A] (26) [B] (27, 28) [C] and detemir (29,30) [A] (31) [B] (32) [C]. Parental fear of severe hypoglycemia, especially night time, is an impediment to achieving morning blood glucose control. Lower body mass index (z-score) has been reported for detemir (30) [C]. In randomized trials, better blood glucose control has been obtained using multiple daily injections (MDI) and pumps compared to a twice daily treatment (33, 34). The Diabetes Control and Complications Trial (DCCT) proved convincingly that intensive insulin therapy including a heavy multidisciplinary approach in adolescents with multiple injections or pumps, resulted in a lower rate of long-term complications (34) [A]. Cognitive impairment 18 years after the conclusion of the DCCT study was unrelated to the rate of hypoglycemia during intensive therapy (35–36) [B]. Also, in a cross-sectional clinical setting HbA1c, hypoglycemia and diabetic ketoacidosis were not associated with the number of injections per day in pediatric populations (37) [B]. Insulin pump therapy is at present the best way to imitate the physiological insulin profile. Insulin is infused subcutaneously at a pre-programmed basal rate and boluses are added to counterbalance the intake of carbohydrates. CSII has mostly been compared to MDI with NPH as the long-acting insulin (38–39) [A] (40–42) [B] (43–48) [C]. A reduction in hypoglycemia and improved blood glucose control has been reported. One randomized study has recently confirmed these findings when glargine was the basal insulin in use (49) [B]. Several studies have compared the use of analogs and regular insulin in pumps (50) [A] (12) [B]. Insulin pumps from the onset have been found to result in superior metabolic control when compared to 1–2 injections/day (33) [A] but not to MDI (51) [C]. However , in the study comparing MDI vs. CSII, diabetes treatment satisfaction was higher with CSII. Data from a large pediatric survey showed a low incidence of acute complications at a mean HbA1c-level of 8.0% (52) [C]. An international consensus on pediatric indications and instructions for use has been published (53) [E].The most recent metanalysis of six pediatric randomized controlled trials with 165 patients showed a reduction of HbA1c by 0,24 % with CSII compared to MDI (54) [A]. Unequivocal evidence for the benefit of MDI, the analogs and CSII-treatment in children is lacking. Carefully structured randomized studies are needed. The fact that these modalities are more expensive than conventional treatment has been an obstacle to the implementation of the use of them in many countries. This implies that ISPAD's new practical recommendations have to be applicable for the total diabetes community world wide. The DCCT study and its follow-up EDIC (Epidemiology of Diabetes Interventions and Complications) study confirmed that an improvement in long-term glucose control, as obtained with intensified insulin therapy including heavy support and education, can reduce the incidence of complications and delay the progression of existing complications in type 1 diabetes, also in pediatric patients (34, 55, 56) [A]. A rapidly increasing numbers of centres around the world are introducing the basal/bolus concept of intensive insulin treatment already from the onset of diabetes. Children and adolescents with type 1 diabetes are dependent on insulin for survival and should have access to adequate amounts of at least regular and NPH-insulin. ISPAD and IDF are working towards making insulin available for all children and adolescents with diabetes and promoting universal insulin labeling. Many formulations of insulin are available; most have some role in the management of type 1 diabetes (table 1). Currently, children are prescribed human insulins instead of porcine or bovine insulin because of low immunogenicity, but in many countries these are being superceded by analogs. Porcine or bovine preparations may be cheaper and more readily available in some parts of the world. They are not inferior in clinical efficacy to human insulins (57) [A]. Some locally manufactured preparations have immunogenicity, and may by acting as insulin This is when using older bovine insulins are being from the and are towards of analog insulins the time the of insulins is by the The time action of most insulins is in that a has a duration of and [C] and There is some evidence that lispro and aspart [C] have the time action of The results of these studies are obtained from a relatively number of and the results in children may result in different of action. insulin to human is still as an of most daily regimens in many parts of the world insulin in twice daily injections in regimens before with insulin twice daily or a basal analog or twice Several insulin analogs have been rapid acting are available for children They have a rapid onset and duration of action than regular insulin 1). The rapid acting can when be before because there is evidence that the rapid action not but hypoglycemia may also be reduced (11, 12, 15) [A] (16) [B]. the of being after when and who are to [B]. a than regular insulin when with or including are most as or boluses in with longer acting insulins basal are most in insulin insulin analogs are with compared to human insulin, have been to in in [C]. in human have not effects [C]. In studies were published using large diabetes and the risk of in patients with insulin A but significant risk of was in patients with insulin glargine a of mostly older adults with type diabetes [C]. A study was and not a between and glargine [C]. In there was no clear evidence of in type 1 diabetes or in patients insulin glargine in with insulin analogs. The of the studies and the of the data available to and that no can be there are not that the use of insulin analogs in the pediatric age insulins are best for therapy and are in the Control of diabetes during insulin can also be [C]. the is not superior to that of regular insulin and is more The action of these insulins them for twice daily regimens and for in regimens preparations NPH insulin or insulins are mostly in children, because of for with regular insulin in the or insulins are in many countries. regular insulin is with preparations with its acting [B]. The new basal insulin analogs are glargine and detemir They a more insulin with day to day compared to NPH insulin (30) [A] [B]. In most the two basal analogs have not been for children the age of there is a of use of glargine in children from 1 to years of age [C]. analogs are more expensive of an of glargine on has been shown in one study [C]. The of glargine for to in a can be after injection [A]. Some children a when glargine to the [C]. A review of pediatric studies in the six years of daily insulin glargine found a or improvement in HbA1c but a reduced rate of hypoglycemia, and a treatment satisfaction in adolescents compared to conventional basal insulins [C]. A study with detemir in adults found the time of action to be between and when between and were [A]. In a pediatric of the patients detemir twice daily (30) [A]. In studies with detemir have shown reduction or (32) [A], which has been also in children and adolescents (30) [C]. is by a more than glargine in children and adolescents with type 1 diabetes [A]. and insulins were to have a duration of more than to basal insulin and be in injection Their action in children to be with basal insulin analogs are superior to traditional long-acting insulins insulins of and basal are in some countries for prepubertal children on twice daily reduce in insulin, the by of the two Such is especially for children with insulins have also available with rapid acting analogs. insulin aspart aspart and aspart bound to for main with NPH at was as human insulin for morning and with regular insulin for and [B]. There is no clear evidence that insulins in children are but some evidence of metabolic control when in adolescents insulins with regular rapid in different are available in countries from different insulins are for use in insulins may be to reduce the number of injections when to the is a This new of insulin therapy has been in children years of age as of a study in adults but was not for clinical use in The of insulin was in The most available insulin is with or concentrations as is also to and be to that the is each time new are children insulin with obtained from the but care is in and the insulin the insulin can be to or with NPH and for 1 month [C] for use in pumps for or children from to insulin, may practical in insulin but has not shown a in control in a large pediatric [C]. that the insulin at least of its at insulin of its In insulin in a of its [C]. recommendations are more on than of The recommendations and be These usually Insulin be or insulin. should not use insulins that have in or insulin should be in a an insulin should be after at or at for some insulin of use in In is not [C] or a around the insulin to insulin In children on of insulin, instead of should be to of insulin. The injection when absorption is and may be by or of for absorption of longer acting be in of children with subcutaneous injection is more and may or of is not is a at injection is [C]. to insulin injections are but when of the insulin more may be with from the A of an insulin may the is can be using available from the a of to the insulin may [C]. with the of in the are in children is the of but has been also with the newer analogs [C]. injections are a in of the and of injection to injections are not being and that the is can more [A]. can injection [A]. of insulin is and be of from of the after the is or with the injection and are more after injection or of the of have shown significantly at the injection [B]. in insulin should be the is not to the of insulin should not using insulin in the can of insulin on the of the [C]. Insulin variability both day to day in the and between children The and duration of action many which significantly the and of and care should the which insulin absorption children, subcutaneous mass subcutaneous also with analogs [B] of injection [C]. and of injection than no data on absorption from vs. injection injection absorption in [B]. injections can glucose control [B]. Insulin type and [B]. and body [B]. In the absorption of analogs is by the There is no significant difference in the absorption of glargine from or [B]. not glargine absorption [A]. There is a risk of hypoglycemia glargine in and [C]. absorption usually results in duration of action with are to are available in a of in different but is to have with per available for are for many with diabetes them significant in risk of [B]. should be there is or injection as when [A]. Insulin have a with the insulin be with because of the risk of is that all children and adolescents with diabetes should to insulin by because injection may are and may be available from and diabetes may be available to the and a with may be and of in or for insulin in have been to injections and more They the for from an insulin the is on a and may be for insulin from at or on injection of and are available and may on injection [B]. of and are available from the Some can be to is a in some countries and may and are a more expensive of insulin. are in children on multiple injection regimens or of insulin but are when of insulins is in a or The traditional of has been by that are A is for all of injections to a subcutaneous injection [C]. With the injections can be a there is subcutaneous which is the in least as the are when [C]. have a subcutaneous especially on the [C]. the the subcutaneous is usually to a There is a risk of injections are not fully the Such using may be to with injection at the onset of diabetes [A]. is in an increasing number of for of The use of not metabolic control [B]. In children with injection HbA1c has been by using [B]. The use of a basal analog and a or rapid acting insulin at the injection time in an is not in of of the two insulins with should be to and a on insulin absorption [C]. injection are for children who have a fear of a is the and the by a The of these are that the is from and the is the injection for insulin are available [B]. injection of insulin the has been to the use of may have a role in of The use of has resulted in metabolic control both to conventional injections and CSII but with have included a of and [B]. The use of pumps is increasing and is to be and [A] [C] in [C] [C]. studies in the have to better control [A]. The effects on control and hypoglycemia in studies have been by the patient in these studies, as metabolic control. therapy has also been found in ketoacidosis [C]. This the of the of the of therapy for An insulin pump is an to treatment with MDI basal HbA1c is the hypoglycemia is a or of be improved [C] therapy is an for many patients to treatment In a review of pediatric studies comparing CSII vs. MDI, a of the patients and to with CSII after the of the studies, in studies insulin pumps showed no benefit A randomized study of CSII vs. MDI from the onset of diabetes in also found a significant improvement in treatment satisfaction in of no difference in HbA1c (49) [A]. Insulin pump use is increasing in the age as more with CSII as a more physiological insulin therapy The newer of pumps that meal or boluses on and insulin sensitivity have as and to in diabetes management Insulin pump treatment may be when and to therapy is because of the of subcutaneous insulin and the in when insulin is for in patients resulted in of but not [B]. in children and adolescents to be [C]. The risk of when using pumps comparing with MDI is in studies [C]. A review found an risk of in pediatric pump patients in some studies [C]. Data on have shown both an [C] and an risk of [C]. using insulin pumps, especially children, benefit from being to patients using insulin pumps, and are to may to a of basal insulin before be on treatment of insulin with a or in of pump and acting analog insulins are in most pumps and a has shown a lower HbA1c when comparing with human regular insulin [A]. insulin is in pumps but rapid acting insulin is not age of the may a of insulin of and a duration of insulin [B]. There is no difference in action [A], pump or when using insulin lispro or aspart in pumps [C]. Lower of basal insulin and more than daily boluses are an for better metabolic control when using pumps (52) [C]. to be a for the long-term of of therapy [C]. The of for continuous glucose not a benefit for control in children and adolescents [A]. with were associated with a significant improvement of HbA1c compared to blood glucose when This was shown in studies of including both pediatric and patients [A]. with should be for therapy in the Diabetes a significant improvement of HbA1c was in adults in the [A]. Many children and adolescents to the which may have a on metabolic control in the In randomized an improvement was when the was for more than of the time [A]. patients are to from therapy to be An of the pump when the has hypoglycemia has been in children [C]. in adolescents with a the glucose the insulin in the pump have been published [C]. by are usually the subcutaneous a of at a A can be the is including the to that no or in the A of 15 after in the to of insulin the [B]. should be that a of with diabetes have a severe of injections which may control these an injection [B] or insulin pump therapy may There is in the age for children to [B]. The age to than children the age of years injections or with them [B]. children injection with a or care may to the or the and under be to the is by an as with a or diabetes or care should not that and should of with the for from children on multiple injection regimens may to in to to a of two insulins is regular with is most that there is no of one insulin with the in the the There is no of but most is that regular is the before insulin or of insulin be at least to the insulin before the clear insulin. the insulin is of type the be the regular with which the action [C]. from different should be with as there may be between the NPH and insulins should be acting insulin analogs may be in the as NPH before injections [B] [C]. injection of a of and has been found not to the [C]. The that glargine should not be with insulin before but there is some evidence that can be with insulin lispro and aspart the blood glucose [B] or HbA1c [C]. The that detemir should not be with insulin before There are no available studies on The of insulin on many duration of diabetes, of metabolic control and The concept a pump or acting insulin analog or twice daily and or regular boluses with and has the best of the physiological insulin profile. least two injections of insulin per day and basal are in most regimens a of or rapid acting insulin and insulin, acting or basal but some children may during the metabolic control on or acting insulins an HbA1c to the injections daily of a of or rapid and acting insulins and the main injections daily using a of or rapid and acting insulins before rapid or regular insulin before or the main acting insulin before or of of the total daily insulin should be basal insulin, the or regular insulin. injection of regular insulin before each main meal and the main insulin or acting analog at or twice daily injection of rapid acting insulin analog before (11, [A] each main meal and main analogs may to be 15 before the meal to have especially at insulin or analog at before and at or twice daily Insulin pump are with a or basal and with glucose with CSII or MDI is in children with diabetes, but the time in studies [A]. of these regimens can be by blood glucose on many as of and of diabetes. of injection intake and of blood glucose on the the total daily insulin is children the usually may 1 and to The of insulin is that which the best control for an or hypoglycemia and the to and Children on twice daily regimens more of total daily insulin in the morning and in the of the insulin may be insulin and two may be insulin these with age and of the regimens the insulin may represent between for regular and for of total daily insulin. as or as regular insulin is between using insulin for the of basal insulin is usually as insulin also some basal is a but many children may to be twice a day or with NPH to basal insulin [C]. can be before before or at with equal but hypoglycemia significantly after injection to glargine as basal insulin, the total of basal insulin to be reduced by to hypoglycemia [C]. the should be is most twice daily in children (30) [A] and to detemir from the can be to with by of the diabetes care on to of insulin at is of educational Insulin should be and HbA1c are is not are especially in the of control. twice daily insulin insulin are usually on of daily of blood glucose the or a number of or in of to intake or regimens or of insulin are before and in to In the daily blood glucose should be The rapid acting analogs may after to insulin is on and on from a have the of the in different in to reduce the blood glucose [C]. Many newer insulin pumps for these for blood glucose and before or or acting insulin. during the night are to that not result in in after a meal insulin. before meal basal insulin or of acting insulin on using rapid acting insulin for the or type of basal insulin may to be in using of may in for to can be to the by total daily insulin to the that 1 of insulin lower the blood use the by total daily insulin regular insulin, a can be for results in and a for results in should be before on insulin in after meal meal acting insulin. hypoglycemia of insulin or hypoglycemia in the of a of day to day insulin may be for in especially or of of diabetes may be when there are of educational or which may of insulin of regular in of the total of insulin should not be reduced but to the and of total intake is reduced during the daily of insulin for usually to be for to or of the glucose to in the of the morning after to This is the In the to insulin action and glucose These are more in studies [B] [C] have shown that children more basal insulin before than after With a basal analog can be by regular instead of rapid acting insulin for the of the day time blood glucose to be In with type 1 diabetes, is by insulin the can in some be by hypoglycemia, being in pump therapy compared to MDI [B]. of is to an of the insulin to insulin the night and the morning by the use of acting insulin in the or at a longer acting insulin to insulin pump Insulin treatment be started as as after is to metabolic and diabetic In all age as to physiological insulin as and control be the which should the of an intensive insulin no insulin injection insulin is be by for the and of the and for insulin the to basal and higher of insulin in an to the of insulin between and regular review and The of insulin the day of of insulin should be on the daily of blood in control, when by intensive insulin treatment with MDI or pump the of There is no to that is not the also in children should have or regular insulin available for is that a of insulin should be readily available to all children and adolescents that the is Children and adolescents should be to the at a time in the but the to to be by insulin injection to the of insulin being of injection injection and a of care and The use of pumps for but not to be to with access to pump The pump or the should be to to multiple injections with or in of care have the to care and on insulin therapy and This regular review, and