Insulin Analog Preparations and Their Use in Children and Adolescents with Type 1 Diabetes Mellitus

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1 Approval for publication Signed ate Number of amended pages returned Pediatr rugs 2008; 10 (3): 1 REVIEW ARTICLE /08/ /$48.00/ Adis ata Information BV. All rights reserved. Insulin Analog Preparations and Their Use in Children and Adolescents with Type 1 iabetes Mellitus Harriet L. Miles and Carlo L. Acerini epartment of Paediatrics, University of Cambridge, Addenbrooke s Hospital, Cambridge, UK Contents Abstract Fast-Acting Insulin Analogs Structure and Pharmacokinetics Clinical Advantages Quality of Life Postprandial Blood Glucose Control Hypoglycemia Avoidance Glycemic Control and Glycosylated Hemoglobin (HbA1c) Exercise and Sport Continuous Subcutaneous Insulin Infusion Therapy iabetic Ketoacidosis Management isadvantages Postprandial Hypoglycemia Preprandial Hyperglycemia Altered/Anomalous Receptor Binding Characteristics Long-Acting Insulin Analogs Structure and Pharmacokinetics Clinical Advantages Basal Bolus Therapy Application Reduced Nocturnal Hypoglycemia Glycemic Control and HbA1c Reduced Weight Gain isadvantages Sub-Optimal Background Insulin Levels Mixing with Short-Acting Insulin Analogs Altered/Anomalous Receptor Binding Characteristics Conclusion...12 Abstract Standard or traditional human insulin preparations such as regular soluble insulin and neutral protamine Hagedorn (NPH) insulin have shortcomings in terms of their pharmacokinetic and pharmacodynamic properties that limit their clinical efficacy. Structurally modified insulin molecules or insulin analogs have been developed with the aim of delivering insulin replacement therapy in a more physiological manner. In the last 10 years, five insulin analog preparations have become commercially available for clinical use in patients with type 1 diabetes mellitus: three rapid or fast-acting analogs (insulin lispro, aspart, and glulisine) and two long-acting analogs (insulin glargine and detemir). This review highlights the specific pharmacokinetic properties of these

2 2 Miles & Acerini new insulin analog preparations and focuses on their potential clinical advantages and disadvantages when used in children and adolescents with type 1 diabetes mellitus. The fast-acting analogs specifically facilitate more flexible insulin injection timing with regard to meals and activities, whereas the long-acting analogs have a more predictable profile of action and lack a peak effect. To date, clinical trials in children and adolescents have been few in number, but the evidence available from these and from other studies carried out in adults with type 1 diabetes suggest that they offer significant benefits in terms of reduced frequency of nocturnal hypoglycemia, better postprandial blood glucose control, and improved quality of life when compared with traditional insulins. In addition, insulin detemir therapy is unique in that patients may benefit from reduced risk of excessive weight, particularly during adolescence. Evidence for sustained long-term improvements in glycosylated hemoglobin, on the other hand, is modest. Furthermore, alterations to insulin/insulin-like growth factor I receptor binding characteristics have also raised theoretical concerns that insulin analogs may have an increased mitogenic potential and risk of tumor development, although evidence from both in vitro and in vivo animal studies do not support this assertion. Long-term surveillance has been recommended and further carefully designed prospective studies are needed to evaluate the overall benefits and clinical efficacy of insulin analog therapy in children and adolescents with type 1 diabetes. tages and disadvantages of these insulin preparations with particu- lar reference to, and a specific focus on, their use in the treatment of children and adolescents with type 1 diabetes. A search of the medical literature was undertaken for publications relevant to this topic. Both PubMed and Google Scholar databases were searched, using the following keywords: insulin analog, lispro, aspart, glulisine, glargine, detemir, type 1 diabetes mellitus, chil- dren and adolescent, paediatric, pediatric, clinical trial(s), and pharmacokinetics. Where no data or information relevant to children and adolescents were available we referred to the appropriate literature in the adult setting. 1. Fast-Acting Insulin Analogs 1.1 Structure and Pharmacokinetics Fast-acting analogs were developed to enhance the rate of absorption and therefore speed of action of short-acting insulin. When regular insulin is injected subcutaneously, its absorption depends upon both the volume and the concentration of the inject- ed solution. [1] In solution, insulin molecules associate to form high molecular weight hexamers that do not penetrate the capillary walls and therefore diffuse more slowly into the circulation than smaller dimers or monomers, which are absorbed more quickly. Substitution of specific amino acids may create an insulin molecule with diminished capacity for self-association in solution. Reduced hexamer formation facilitates more rapid insulin absorp- tion and action as a result of reduced molecular size. The metabolic action and pharmacokinetic profiles of all three of the commer- cially available fast-acting insulin analogs are similar. [2,3] The Advances in recombinant NA technology have not only provided a safe, plentiful supply of synthetic human insulin for the treatment of diabetes mellitus but have also enabled scientists to create subtle changes to the amino acid sequence of the native insulin molecule which alter its pharmacological and pharmacodynamic characteristics. These genetically engineered insulins or insulin analogs have been designed to overcome some of the significant limitations of standard human recombinant and animalderived insulin preparations. When injected subcutaneously, the absorption of regular or soluble short-acting human insulin is delayed, necessitating injection 30 minutes prior to a meal. As a result, problems with early postprandial hyperglycemia and late postprandial hypoglycemia are commonly observed. The longer acting neutral protamine Hagedorn (NPH) and insulin zinc (lente) preparations are formed by the addition of protamine and zinc, respectively, to the native insulin molecule, resulting in prolonged action due to slower absorption. These preparations, which are used as background or basal insulin preparations, have a pronounced peak effect and can cause problems in the form of nocturnal hypoglycemia. Both regular short-acting and long-acting insulins also have problems arising from variable absorption from subcutaneous injection sites. Five recombinant insulin analogs designed to behave in a more physiological manner are currently available for clinical use. Three are ultra short-acting analogs: insulin aspart (Novorapid, Novo Nordisk) 1, insulin lispro (Humalog, Lilly) and insulin glulisine (Apidra, sanofi-aventis, currently licensed only for adults), and two are long-acting analogs: insulin detemir (Levemir, Novo Nordisk) and glargine (Lantus, sanofi-aventis). This review considers the pharmacokinetic and clinical advan- 1 The use of tradenames is for product identification purposes only and does not imply endorsement Adis ata Information BV. All rights reserved. Pediatr rugs 2008; 10 (3)

3 Insulin Analog Preparations in Pediatric Type 1 iabetes 3 Table I. Peak serum insulin level and time to peak level for regular human insulin and fast-acting insulin analogs a Subcutaneous insulin Time to peak serum concentration (min) Peak serum concentration Reference regular insulin insulin analog regular insulin insulin analog Regular insulin vs lispro (10 U) pmol/l 698 pmol/l 6 Regular insulin vs aspart (0.1 U/kg) 217 (30) 149 (26) 18 (4) mu/ml 41 (11) mu/ml 7 Regular insulin vs glulisine (0.15 U/kg) mu/ml 58 mu/ml 8 a ata shown as mean (S). U = unit. onset of action of these analogs occurs minutes after subcu- lin molecule by substitution of two amino acids. Asparagine is taneous injection with peak effects occurring at minutes. [2,4] replaced by lysine at position B3 and lysine is replaced by gluta- In adults, peak concentrations are approximately twice as high as mic acid at position B29 (figure 1). This results in reduced regular human insulin and are achieved in half the time [5] (table I). oligomer formation and more rapid absorption following subcutaneous The first fast-acting analog to become available for clinical use, injection. [8] Although there is currently no licence for use of in 1996, was insulin lispro. Lispro is formed by transposition of glulisine in younger children, studies of the pharmacokinetic pro- lysine at position B29 with proline at position B28 in the β chain of file of insulin glulisine suggest that it is similar in both pediatric human insulin (figure 1). This amino acid modification results in a and adolescent age groups. [8] In a study involving 10 fasting conformational change that alters the normal binding of the C- children and 10 fasting adolescents with type 1 diabetes, maxi- terminal portion of the β chain and reduces the formation of mum concentrations of insulin glulisine were approximately twice dimers and hexamers. This results in more rapid absorption folachieved those of regular insulin (58 vs 33 µiu/ml, respectively) and were lowing subcutaneous injection and an earlier peak in plasma within a shorter period (54 vs 66 minutes, respective- values. Clinical studies in non-diabetic adult males comparing a ly). [8] Mean duration of action was shorter with glulisine (glucose 10-unit subcutaneous dose of insulin lispro with a 10-unit subcuta- area under the concentration-time curve from 0 to 6 hours [AUC6] neous dose of human regular insulin showed that peak serum 641 vs 801 mg h/dl) and postprandial glucose excursions (88 vs insulin concentrations were twice as high following the administration 137 minutes) were lower than after regular human insulin. [8] of lispro (maximum serum level 698 vs 308 pmol/l) and Subcutaneous insulin absorption characteristics can be different peaked in less than half the time (42 vs 101 minutes). [6] at different injection sites, but such variability may be less of a Insulin aspart is another short-acting analog licensed for use in problem with the short-acting insulin analogs than with regular children with diabetes. Aspart is formed by substitution of the insulin. Ter Braak et al. [9] consecutively compared the subcutaneproline at position B28 with aspartic acid in the β chain of human ous administration of 0.2 U/kg of insulin in three injection areas insulin (figure 1). This alteration creates a negative charge that (abdomen, upper arm and thigh) in 12 healthy subjects using reduces the stability of the monomer-monomer interaction, de- euglycemic clamp techniques. The total amount of intravenous creasing the formation of dimers and hexamers and resulting in glucose infused to maintain euglycemia (Gtot) was nearly identical more rapid absorption following subcutaneous injection. Home between the injection sites with insulin lispro administration (Gtot and colleagues [7] compared the pharmacokinetics of insulin aspart abdomen 9.94 mmol/kg; arm 10.3 mmol/kg; thigh 10.7 mmol/kg), with regular human insulin in a double-blind crossover trial in whereas significant variation was observed when regular insulin which 25 healthy male volunteers were given a subcutaneous was given at these sites (Gtot abdomen 10.6 mmol/kg; arm 11.8 injection of either insulin aspart or regular human insulin. The mmol/kg; thigh 12.6 mmol/kg). [9] Similar findings have been absorption of insulin aspart was more than twice as high as human observed for insulin aspart. In a similarly designed study to that by insulin with a peak mean (S) value of 41 (11) vs 18 (4) mu/ml ter Braak and colleagues, [9] Mudaliar and colleagues [10] compared and a time to peak concentration of 149 (26) vs 217 (30) minutes. regular insulin with insulin aspart (0.2 U/kg per dose) and found The same study demonstrated no difference in the total bioavaila- that the maximal glucose infusion rates to maintain euglycemia bility between insulin preparations; however, insulin aspart had a (abdomen 813 [S 23] mg/min; arm 861 [28] mg/min; thigh 857 significantly shorter duration of action and, thus, a closer profile to [33] mg/min) and the times to peak glucose infusion rate [abdomeal-stimulated endogenous insulin than regular human insulin. men 94 (46) min; arm 111 (59) min; thigh 145 (122) min] did not Insulin glulisine, which is currently licensed for adults and differ statistically between the injection sites when insulin aspart adolescents, is formed following modification of the human insu- was administered. However, in this study, abdominal administra Adis ata Information BV. All rights reserved. Pediatr rugs 2008; 10 (3)

4 Phe Glu 4 Miles & Acerini d Gly c S S α-chain Gly Gln S Ila Gln S Cys 20 Ala a Asp d Arg Arg S S Pro Lys Thr 30 β-chain Phe His Phe Asn 1 5 His Leu Gly b Lys Pro c Lys e Pro Lys C14 - fatty acid chain (myristolyic acid) Fig. 1. Amino acid sequence of native human insulin and its adaptation in the formation of commercially available insulin analog preparations. a = Insulin aspart. Substitution Pro B28 to Asp B28; b = Insulin lispro. Sequence change Pro B28;Lys B29 to Lys B28;Pro B29; c = Insulin glulisine. Substitutions Asn B3 to Lys B3 and Lys B29 to Glu B29; d = Insulin glargine. Sequence addition Arg B31;Arg B32, plus substitution Ala A21 to Gly A21; e = Insulin detemir. Acylation of Lys B29 with C14 fatty acid chain, plus removal of Thr B30. similar pharmacokinetic profiles are seen in children and adoles- tion of insulin aspart was associated with a much shorter overall duration of action (by up to 34 minutes, p < 0.001) compared with injections at other sites, an observation that is likely to be relevant to clinical practice. cents. Using a randomized, double-blind, two-period, crossover study design, Mortensen and colleagues [12] tested the effects of a single subcutaneous dose of insulin aspart or human insulin (0.15 U/kg) in a group of children and adolescents (n = 18; ages 6 17 years) with type 1 diabetes. The pharmacokinetic profile of insulin aspart differed significantly from that of human regular Fast-acting insulin analogs also have a more consistent duration of action (4 6 hours) compared with regular human insulin (5 8 hours). Injection of 0.2 U/kg subcutaneous regular human insulin in the deltoid region, monitored with a euglycemic clamp tech- nique, has been shown to have a peak effect at hours and a duration of action of between 7.7 and 9.1 hours, depending upon the blood glucose level. [11] In contrast, insulin apart and insulin lispro administered subcutaneously have been observed to have peak effects on carbohydrate metabolism at 2 3 hours and a maximum duration of action of 5 6 hours. [2] Although most of the pharmacokinetic data available for fast-acting insulin analogs relate to adults, data specific to the pediatric age range suggest that insulin with both higher mean (S) maximum serum insulin concentrations (Cmax 881 [321] vs 422 [193] pmol/l, respectively; p < 0.001) and shorter median time to peak insulin concentrations (tmax 40.0 vs 75.0 minutes, respectively; p < 0.001) observed with insulin aspart. Intriguingly, a statistically significant age-related effect on Cmax was observed with higher values in adolescents than in children (mean [S] 1039 [328] vs 723 [234] pmol/l, respectively) with insulin aspart; this finding could not be ex Adis ata Information BV. All rights reserved. Pediatr rugs 2008; 10 (3)

5 Insulin Analog Preparations in Pediatric Type 1 iabetes 5 plained but may have been due to the relatively small numbers of impact of diabetes on QOL and fewer concerns about diabetes than patients studied. [12] controls who remained on regular insulin. Similar results were In summary, fast-acting insulin analogs display less variability seen in a study of 27 children aged between 2 and 8 years in whom in absorption between injection sites, more rapid absorption with insulin lispro replaced short-acting regular insulin and was asso- maximum insulin values seen at minutes, and higher peak ciated with a substantial improvement in QOL. [16] Finally, the concentrations when compared with regular insulin. effect of insulin aspart on QOL was assessed in a large 6-month open-label trial of 424 adults with type 1 diabetes who were 1.2 Clinical Advantages randomized to basal-bolus treatment with either insulin aspart or human insulin. After 6 months the insulin aspart group reported Quality of Life significantly greater improvement in treatment satisfaction, main- Fast-acting insulin analogs have the potential to improve life- ly as a result of increased dietary and leisure time flexibility (p < style and quality of life (QOL) in children and adolescents. Their 0.01) and in QOL with respect to dietary restrictions (p < 0.01). [17] rapid onset of action allows them to be given just before or immediately after meals, in contrast to regular insulin, which Postprandial Blood Glucose Control requires administration minutes before food is consumed. The fast-acting insulin analogs are thought to allow a more This may be particularly suited to the busy lives and variable physiological pattern of insulin delivery that is closer to the mealroutine of many older children and teenagers, who do not wish to stimulated insulin response. Both insulin lispro and insulin aspart be burdened with the inconvenience of the expected mealtime have been shown to be superior to regular insulin in the reduction regular insulin injection ritual. Furthermore, immediate postpran- of postprandial hyperglycemia. [7,18,19] Home et al. [7] compared the dial fast-acting analog administration offers patients and families effectiveness of insulin aspart with regular human insulin in reducthe opportunity to more effectively match the dose of insulin to the ing postprandial glucose levels by administering a standard subcuamount of carbohydrate consumed. This can be particularly impor- taneous dose to 25 healthy male volunteers and monitoring serum tant for younger children with diabetes, for whom judging the insulin and plasma glucose. Plasma glucose fell more than twice as amount of carbohydrate that will be consumed at any given meal rapidly with insulin aspart (mean [S] time to minimum plasma can be difficult and unpredictable. In a study by Rutledge and glucose [C min ] 94 [45] minutes vs 226 [120] minutes; p < ) colleagues [13] involving toddlers with type 1 diabetes, 2-hour and to a greater extent (Cmin 1.4 [0.4] mmol/l vs 2.1 [0.6] mmol/ glucose excursions were significantly lower when insulin lispro L; plasma glucose 2.1 mmol/l p < ) compared with regular was administered postprandially compared with preprandial regu- insulin. A large multicenter study involving 1008 patients randomlar insulin, but no different when insulin lispro was administered ized to pre-meal insulin lispro or regular insulin also found that the immediately before the meal. Calculation of the amount of carbo- postprandial rise in serum glucose was significantly lower in the hydrate consumed after the meal has been completed empowers lispro group with a mean reduction in serum glucose of 1.3 mmol/ parents and patients to more accurately titrate an appropriate L at 1 hour and 2.0 mmol/l at 2 hours (p < 0.001). [18] In a recent insulin dose, thus reducing the risk of postprandial hypoglycemia review of insulin analog clinical trials in patients with type 1 and the worry associated with this. diabetes, the rapid-acting analogs were found to have a greater Following their inclusion into clinical studies of fast-acting impact on lowering postprandial blood glucose levels (postprandiinsulin analogs, it has been reported that most patients choose to al glucose level between 0.6 and 2.0 mmol/l lower in the analog remain on the new insulin rather than returning to their regular subjects) when compared with regular human insulin. [20] Lower insulin. This could be interpreted as a perceived improvement in postprandial blood glucose excursions may be important in reduc- QOL as a result of switching to the new insulin analog. Formal, ing the development of diabetes-related complications. The Amerobjective assessments of QOL measures with insulin analog usage ican iabetes Association Consensus Statement on postprandial have been carried out in patients with type 1 diabetes. In a blood glucose states that, in general, postprandial glucose is highly prospective comparison between insulin lispro and regular human correlated with glycosylated hemoglobin (HbA 1c ) and that elevat- insulin in 16 adults receiving multiple daily injections, QOL ed postprandial blood glucose may contribute to suboptimal scores 3 months after switching to insulin lispro were significantly glycemic control, which is associated with progression of longhigher for activities of daily living but no different for other QOL term microvascular complications. [21] There is also epidemiologi- parameters. [14] A larger cohort of 35 adolescents was followed for cal evidence, particularly in adults with type 2 diabetes, that 12 months after changing from regular human insulin to insulin postprandial glucose is an independent risk factor for cardiolispro. [15] Adolescents who received lispro reported a less negative vascular disease. [22] Therefore, the improvements in postprandial 2008 Adis ata Information BV. All rights reserved. Pediatr rugs 2008; 10 (3)

6 6 Miles & Acerini glucose seen with fast-acting analogs may confer a significant long-term cardiovascular benefit. in HbA1c with fast-acting insulin analogs may emerge as more longer-term studies are published. The impact of insulin lispro therapy in children and adolescents with type 1 diabetes has been evaluated by Garcia and colleagues [31] over a 3-year period (n = 44). When compared with regular insulin therapy (given in the year prior to the switch to insulin lispro), a significant decrease in HbA1c at the 3-year endpoint was observed in those with initial poor control (p = 0.03). Given that the overall glycemic control for most patients in the study was already excellent at baseline (mean [S] HbA 1c 6.6% [1.1]), it is perhaps not surprising that there were no significant improvements in HbA1c observed in the re- mainder of the group. [31] Hypoglycemia Avoidance Hypoglycemia occurring both during the daytime and overnight is of particular concern for children and adolescents with type 1 diabetes and is a serious impediment to intensifying insulin therapy and achieving optimal blood glucose control in this age group. Asymptomatic nocturnal hypoglycemia in children is particularly common, occurring in up to 45 50% of prepubertal children using conventional insulin injection regimens involving regular human insulin. [23] Because of their rapid absorption profile and immediate effect on lowering blood glucose levels, fast-acting insulin analogs offer the theoretical advantage of decreasing the Exercise and Sport risk of late postprandial hypoglycemia when compared with regu- For children and teenagers using a basal bolus insulin injection lar human insulin. Furthermore, when fast-acting analogs are used regimen, altering the pre- or post-sport dose of fast-acting insulin to cover the evening meal, the risk of insulin action overlap appropriately would be expected to improve blood glucose control leading to inappropriate nocturnal hyperinsulinemia and hypogly- before, during, and after the planned sport or exercise sessions. cemia is also reduced. Although there have been no specific studies comparing fastacting insulin analogs in this setting in children and adolescents etailed overnight blood glucose monitoring of 14 adolescents using insulin NPH showed that administration of insulin lispro with type 1 diabetes, their rapid onset of action and shorter with the evening meal resulted in fewer episodes of late nocturnal duration of action should allow for optimization of insulin levels hypoglycemia than regular insulin. [24] Furthermore, in an open appropriate for the type, duration, and intensity of the exercise. crossover study comparing insulin lispro with regular insulin in Continuous Subcutaneous Insulin Infusion Therapy prepubertal children with type 1 diabetes taking insulin NPH in a It is has been established that fast-acting insulin analogs are basal bolus regimen, treatment with lispro for 4 months resulted in safe to use and can improve the effectiveness of insulin therapy a significant reduction in the prevalence of overnight low blood compared with regular insulin when delivered by an insulin pump glucose levels (8% vs 13%). [25] A large meta-analysis representing system. [32-34] Raskin and colleagues compared the glycemic conmore than 1400 patient years and including data for 460 adolestrol obtained with either insulin lispro or regular human insulin in cents with type 1 diabetes also reported a 25% reduction in the 58 adults who received continuous subcutaneous insulin infusion frequency of severe hypoglycemia with the use of insulin lispro (CSII) in a 12-week crossover study. [32] Insulin lispro therapy was compared with regular insulin. [26] Similar effects have also been associated with a significantly lower HbA 1c compared with reguobserved with use of insulin aspart in adults with type 1 diabelar human insulin (mean [S] 7.41% [0.97%] vs 7.65% [0.85%], tes, [27] although in other studies increased daytime hypoglycemia respectively, p = 0.004). uring this study, postprandial blood has been reported. [28,29] glucose concentrations 60 and 120 minutes after consumption of a Glycemic Control and Glycosylated Hemoglobin (HbA 1c) standard meal were significantly lower during treatment with Although increasing numbers of studies comparing glycemic insulin lispro (mean [S] at 60 minutes: [4.29] vs control in patients taking fast-acting insulin analogs with that in [4.68] mmol/l, respectively, p = 0.012; at 120 minutes: 9.64 [4.10] patients taking regular human insulin are available for the adult vs [4.64] mmol/l, respectively, p = 0.001). Furthermore, no population, well constructed randomized control trials are lacking differences in hypoglycemia frequency, weight gain, or pump in the pediatric age group. In adults, a recent meta-analysis found occlusion events were observed when insulin lispro was compared that the weighted mean difference in HbA1c for rapid-acting with regular insulin. [32] In a safety and efficacy study, head to head analogs versus human insulin was only 0.12% (95% CI 0.17, comparisons between insulin aspart, insulin lispro and regular 0.07). [30] It has been suggested that this very small overall effect insulin revealed no differences in the frequencies of pump blockof rapid-acting analogs on HbA 1c may be due to the fact that the age and diabetic ketoacidosis (KA) events between the three early phase III clinical trials were designed to demonstrate equivalence different types of insulin when used in the CSII setting. [33] to standard insulin therapy rather than any superiority of The safety and efficacy of insulin lispro compared with regular insulin analogs over regular insulin. Nevertheless, improvements human insulin have also been studied in children with type Adis ata Information BV. All rights reserved. Pediatr rugs 2008; 10 (3)

7 Insulin Analog Preparations in Pediatric Type 1 iabetes 7 diabetes (mean [S] age 4.6 years [2.2]) treated with insulin pump Preprandial Hyperglycemia therapy in a 16-week crossover trial. [34] In this study, there were no Tighter postprandial control may be achieved at the expense of significant differences in HbA1c, frequency of hypoglycemic higher preprandial blood glucose readings because fast-acting events, occurrence of cutaneous infections, or frequency of catheinsulin. insulin analogs are cleared more quickly than regular human ter occlusions between the two insulins. Encouragingly, postpraninjection Fast-acting analogs are therefore best suited to multiple dial glucose excursions were lower (evening meal, p = 0.01) and basal bolus regimens, where insulin is administered on QOL indicators were improved (p = 0.02) with insulin lispro each occasion that food (meal or snack) is consumed. therapy compared with regular insulin Altered/Anomalous Receptor Binding Characteristics The US FA has recommended that use of all insulin analogs iabetic Ketoacidosis Management should remain under long-term surveillance with respect to their Fast-acting insulin analogs, when given subcutaneously, can be safety and efficacy. Structural changes to the native insulin moleused to treat episodes of KA. In a study carried out in children cule result in alterations to the binding characteristics of both the with type 1 diabetes presenting with moderate to severe KA insulin and the insulin-like growth factor I (IGF-I) receptors. The (venous ph <7.3, plasma bicarbonate <15 mmol/l, ketonuria long-term consequences of such alterations are unknown. uring >2+), ella Manna and colleagues [35] randomized 60 episodes of the development of the insulin analog molecule B10Asp, in- KA to be treated with either repeated boluses of subcutaneous creased tumor potential was observed in rats and was postulated to insulin lispro (0.15 U/kg every 2 4 hours) or continuous intrave- be related to the increased binding affinity of the molecule for the nous regular insulin (0.1 U/kg/h). Although both treatment strate- type 1 IGF-I receptor and to prolonged occupancy time at the gies met KA recovery criteria without complications, bolus insulin receptor. [38,39] However, there is no evidence that any of the subcutaneous insulin lispro was associated with a longer time to currently available fast-acting insulin analogs have any increased resolution of metabolic acidosis and ketosis (6 12 hours) com- mitogenic potential compared with regular insulin. pared with intravenous insulin therapy (<6 hours). [35] Although a recent international consensus statement on KA in children and 2. Long-Acting Insulin Analogs adolescents [36] indicates that low-dose intravenous insulin administration should be the standard of care in the management of KA, treatment with bolus subcutaneous rapid-acting analogs 2.1 Structure and Pharmacokinetics may be an acceptable alternative in situations where intravenous The long-acting insulin analogs have been developed to more insulin cannot be provided for financial, technical or logistical closely mimic the constant basal release of insulin from the reasons. pancreas that regulates lipolysis and hepatic glucose output. Traditional insulin NPH preparations have well recognized limitations, 1.3 isadvantages which include a wide variability of action both within and between patients, and a pharmacokinetic profile that results in a peak of insulin action at around 4 8 hours Postprandial Hypoglycemia Insulin glargine was the first long-acting basal insulin analog Early postprandial hypoglycemia is a potential problem with licensed for once-daily subcutaneous administration in adults and fast-acting insulin analog therapy. In a study carried out in adolesinsulin for children aged 6 years. Insulin glargine differs from native cents with type 1 diabetes, early evening insulin lispro administramodification by three amino acids (figure 1). The resulting molecular tion resulted in significantly lower blood glucose levels between causes a shift of the isoelectric point from ph 5.4 to the evening meal and the bedtime snack (blood glucose nadir 7.8 ph 6.7, making the insulin less soluble at a neutral ph. [40] Insulin vs 10.9 mmol/l, respectively; p = 0.02) and an increased frequenthe glargine is administered in an acid suspension (ph 4) and, when in cy of hypoglycemic episodes compared with an identical dose of neutral environment of the subcutaneous tissue, forms a pre- regular insulin administered at the same time and under identical cipitate that acts as a depot from which insulin is slowly released. nutritional and basal insulin (NPH) conditions. [37] Postprandial This results in a delayed onset of action and a constant non- hypoglycemia corresponded with a higher (mean [S] 458 [48] vs peaking delivery of insulin lasting approximately 24 hours. [40] 305 [33] pmol/l, respectively; p = 0.02), earlier (64 [4.6] vs 103 Pharmacodynamic studies confirm that insulin glargine levels [12] min, respectively; p = 0.01) and shorter-lasting (245 [21] vs do not reach a peak and have a mean duration of action of between 365 [39] minutes, respectively; p = 0.01) insulin peak with insulin 22 and 30 hours following subcutaneous injection in healthy adult lispro compared with regular insulin. volunteers. [41] Subcutaneous insulin glargine also demonstrates 2008 Adis ata Information BV. All rights reserved. Pediatr rugs 2008; 10 (3)

8 8 Miles & Acerini has similar activity to 1 U of traditional intermediate (NPH) or long-acting insulin. [48] There is no evidence for bioaccumulation of insulin detemir. Under controlled, single-dose, steady-state conditions, repeated subcutaneous injections of insulin detemir given every 12 hours reach a steady state after the second injection and demonstrate a constant metabolic effect over time when assessed by glucose clamp techniques in adults with type 1 diabe- tes. [49] In contrast, NPH injections given under the same conditions show significant peaks in action and much greater fluctuation in metabolic effect compared with insulin detemir. Following subcutaneous injection, the onset of action of insulin detemir is between 2 and 4 hours and is similar to that of insulin glargine. [53] However, the duration of action of insulin detemir is dose-dependent. A dose of 0.4 U/kg/day is associated with a duration of action of 20 hours, with lower doses resulting in shorter durations of action. [53] Therefore, patients receiving smaller doses of insulin detemir may require twice daily (12-hourly interval) insulin injection sched- much less intra-subject variability compared with either NPH or extended zinc insulin (ultralente) preparations when assessed by euglycemic clamp techniques, both in healthy subjects and those with type 1 diabetes. [42,43] Compared with NPH, insulin glargine has also been shown to have very reproducible absorption profiles following injection at different sites [44] and has been shown not to accumulate after multiple injections. [45] aily subcutaneous injections of the same dose of insulin glargine in adults with type 1 diabetes (n = 15; mean age 36 years) did not result in any significant changes in plasma free insulin level profiles nor in any other pharmacokinetic parameters when monitored over a continu- ous 12-day period. [45] There have been no detailed pharmacokinetic studies of insulin glargine in children with type 1 diabetes to date, although in one observational study, mean nocturnal plasma free insulin levels were lower in children following a bedtime (2200 h) injection (0.6 U/kg/dose) compared with NPH (0.3 U/kg/ dose). [24] espite the higher dose of insulin glargine used in this study, no overnight peak in plasma insulin levels were observed; this finding is in contrast to that for NPH, for which peak concentrations were observed at around 0400 h. The long-acting analog insulin detemir was launched for clinical use in etemir differs from native human insulin in two ways: a C14 fatty acid chain (myristolyic acid) is attached to lysine at position B29 and a threonine molecule is omitted at position B30 (figure 1). These modifications facilitate albumin binding at position B29. Following subcutaneous injection, insulin detemir associates to form hexamers, which delay its absorption from the subcutaneous sites into the circulation. [46,47] Once absorbed, the fatty acid chain of insulin detemir results in enhanced binding to albumin in both the interstitial fluid and plasma. [48,49] Equilibrium is reached between the free and albumin-bound portions of detemir following injection. Only the free fraction of insulin detemir is able to enter the circulation as the capillary endothelial cells prevent the transfer of albumin-bound molecules. Once in the circulation, detemir equilibrium is again formed between the albumin-bound and free fractions, and detemir must cross the endothelium in its unbound form to reach the target tissues. [50,51] The liver is thought to be a major site of action for insulin detemir. The hepatic vasculature is unique in that hepatic sinusoids lack a basal lamina and large gaps between the highly fenestrated epithelial cells allow unrestricted passage of both the bound and unbound fractions of insulin detemir into the perisinusoidal space and to the hepatocytes [52] (figure 2). Theoretically, this property results in improved delivery of insulin to the liver and helps to redress the imbalance in portal/peripheral insulin levels which inevitably results from subcutaneous administration of insulin. As insulin detemir has a low bioavailability, commercially available preparations have been formulated so that 1 U of detemir a b c = albumin = detemir In subcutaneous tissues, insulin detemir forms hexamers, which delays its absorption into circulation In muscle/fat, detemir must cross the endothelium in its unbound form, delaying its action Hepatic sinusoids have no basal lamina and detemir freely passes through large gaps in highly fenestrated epithelial cells Fig. 2. Absorption and action of insulin detemir: (a) subcutaneous tissue; (b) muscle/fat; (c) hepatic sinusoid Adis ata Information BV. All rights reserved. Pediatr rugs 2008; 10 (3)

9 Insulin Analog Preparations in Pediatric Type 1 iabetes 9 Table II. Summary of recent clinical studies evaluating the impact of insulin glargine therapy on hypoglycemia frequency a esign Patients Study duration Hypoglycemia outcome Reference (glargine vs NPH) P, R, C n = 28, age 14.8 y (12 18), 16 wk 43% reduction in nocturnal hypoglycemia 58 HbA1c 9.3% Ret, C-A n = 37, age 11.9 y (3.9), 6 mo 3 vs 0 severe episodes 62 HbA1c 10.5% (2.0) Ret, C-A n = 114, age 12.2 y (2 18), 9 mo Mean non-severe episodes/wk: 1.3 vs 2.0; 60 HbA1c 9.6% total number of severe episodes: 9 vs 22 Ret, C-A n = 71, age 11.5 y (4.9), 6 mo 65% reduction in nocturnal hypoglycemia 59 HbA1c 8.9% (1.6) Ret, C-A n = 64 pairs, age 5.1 y (SEM 0.2), 6 mo Total number of severe nocturnal episodes: 63 HbA1c 8.8% 1 vs 12; total number of episodes: 6 vs 16 P n = 80, age y (4.4), 6 mo Mean events per patient 0.11 vs HbA1c 7.63% (0.81) a ata shown are mean (S) or mean (range) unless otherwise stated. C = crossover; C-A = chart analysis; HbA 1c = glycosylated hemoglobin; NPH = neutral protamine Hagedorn; P = prospective; R = randomized; Ret = retrospective; SEM = standard error of the mean. ules. This observation is of particular importance because pharmacokinetic Reduced Nocturnal Hypoglycemia data in children and adolescents with type 1 diabetes also Nocturnal hypoglycemia is common in the pediatric population suggest that the half-life (t 1 /2) of insulin detemir may be shorter in and is usually asymptomatic. [57] For most children, an earlier these age groups. In an open-label, randomized, crossover study, bedtime routine means that the late evening snack is usually injection of 0.5 U/kg/dose of insulin detemir was associated with a consumed early in relation to peak NPH action, which occurs 4 8 significantly shorter t 1 /2 in children and adolescents (n = 23; age hours after the evening injection. Use of longer-acting basal insu years; mean [S] t 1 /2 302 [100] minutes) compared with lins with a flat, non-peaking absorption profile has the potential to adults (n = 11; age >18 years; t 1 /2 425 [78] minutes). [54] Therefore, reduce the frequency of nocturnal hypoglycemic events. Clinical the need for twice-daily insulin administration schedules with trials in adults with type 1 diabetes confirm a reduction in the insulin detemir may be greater in young patients with type 1 frequency of nocturnal hypoglycemia with insulin glargine comdiabetes. In all age groups with type 1 diabetes, insulin detemir has pared with traditional NPH insulin. A recent meta-analysis of also been associated with less intra-subject variability in insulin these clinical trials found that basal long-acting analog administralevels compared with NPH and other traditional longer-acting tion reduces hypoglycemic risk, particularly at night, whether used insulins. [54,55] Furthermore, detemir has not shown any clinically in combination with regular insulin or with a short-acting anarelevant interactions with other albumin-bound drugs, despite its log. [20] This finding has also been observed in clinical trials carried high affinity for albumin. [56] out in children and adolescents with type 1 diabetes (table II). In a randomized, crossover study of 28 adolescents with type 1 diabe- 2.2 Clinical Advantages tes, Murphy et al. [58] reported a 43% decrease in nocturnal hypoglycemic episodes with insulin glargine and preprandial insulin Basal Bolus Therapy Application lispro therapy compared with standard therapy with NPH and Reduced variability of absorption and the lack of a peak insulin regular insulin. In another study carried out in children with type 1 level effect make the long-acting insulin analogs particularly well diabetes (n = 71; mean age 11.5 years) who had been experiencing suited for basal bolus regimens. The use of basal bolus insulin problems with nocturnal hypoglycemia, a 65% decrease in the regimens, whereby multiple bolus injections of fast-acting insulin total number of night-time blood glucose readings with a value of are administered with food, are increasingly becoming the mainglargine. 50 mg/dl was observed after switching from NPH to insulin stay of insulin therapy in children of all ages. In addition to the [59] However, the switch from NPH to insulin glargine in lack of peak action, the reduced variability in basal insulin levels this study was also associated with three episodes of severe also has the advantage of a more predictable effect on blood hypoglycemia resulting in seizures during the first week following glucose from day to day, thus aiding insulin dose adjustment. initiation of glargine therapy, leading the authors to recommend a 2008 Adis ata Information BV. All rights reserved. Pediatr rugs 2008; 10 (3)

10 10 Miles & Acerini this large (n = 347; ages 6 17 years) open-label, randomized, parallel-group trial, once- or twice-daily insulin detemir therapy, given with pre-meal insulin aspart, was compared with NPH and insulin aspart over a 26-week period. Patients receiving insulin detemir had a 26% lower risk of nocturnal hypoglycemia com- pared with the group who received NPH, although the frequency of overall 24-hour reported hypoglycemia events was not different between the two groups. This lower risk of nocturnal hypoglycemia was achieved without compromising either fasting blood glucose levels, which were significantly better compared with the NPH group (8.4 mmol/l vs 9.6 mmol/l, respectively), or overall glycemic control (HbA1c mean: detemir 8.0% vs NPH 7.9%). [65] These results are supported by data from adult studies. [55,66,67] In two, similarly designed, multicenter, open-label, parallel-group trials comparing twice-daily insulin detemir therapy with insulin NPH therapy (with insulin aspart at mealtimes), the reductions in nocturnal hypoglycemia frequency were of the order of 32% and 53%, respectively, in those receiving insulin detemir. [66,67] degree of caution when performing this conversion process. Furthermore, in a prospective, randomized, controlled, 9-month study from the US, which included 114 patients with type 1 diabetes aged between 2 and 18 years, non-severe hypoglycemic events significantly decreased following initiation of insulin glargine therapy (pre-glargine/nph therapy mean [standard error of the mean (SEM)] 2.0 [0.1]/wk vs glargine 1.3 [0.1]/wk; p < 0.001). [60] Severe hypoglycemic episodes were also reduced from a total of 22 in the 9 months before insulin glargine initiation to 9 in the 9 months after glargine therapy was commenced in this study. Finally, Colino and colleagues [61] reported similar observations in a study of 80 patients with type 1 diabetes (ages 2 19 years), in whom hypoglycemic events decreased from an average of 0.18 events per patient in the 6 months before insulin glargine therapy to 0.11 events per patient in the 6 months after glargine onset. Given that young children have the highest incidence of severe hypoglycemia and are at the greatest risk of adverse neurocognitive sequelae as a consequence of this, [64] long-acting insulin in a basal bolus regimen may be particularly advantageous in this age group. This is supported by the results of a large (n = 128) retrospective study of young children (aged 6 years) with type 1 diabetes in whom the frequency of severe hypoglycemic events was significantly reduced in those children changed from NPH to insulin glargine. [63] Comparisons of the 6-month periods before and after the introduction of insulin glargine therapy revealed significant reductions in the frequency of night-time hypoglycemia with insulin glargine (12 episodes pre-glargine vs 1 episode with glargine). To date, there has been only one published study that has evaluated the benefits of insulin detemir in terms of reduced hypoglycemia frequency in children with type 1 diabetes. [65] In Glycemic Control and HbA 1c Studies in children and adolescents that have evaluated the effects of long-acting insulin analogs have been limited to small numbers of participants over relatively short time periods (table III). The evidence to date suggesting that use of the new long- acting insulin analogs facilitates a reduction in HbA1c in this age group is mixed and far from conclusive. The two largest studies carried out so far have both showed modest decreases in HbA 1c after a period of 6 9 months. [60,61] In a prospective, randomized, controlled study, 114 children with type 1 diabetes were commenced on insulin glargine. [60] Baseline mean HbA1c fell from 9.6% to 9.3% (p = 0.01) after 9 months. Similar small, but statistically significant, reductions in HbA1c were also observed in Table III. Summary of recent clinical studies evaluating the impact of long-acting insulin analog therapy on glycosylated hemoglobin (HbA1c) a esign Patients uration Insulin HbA 1c (analog vs regular insulin/nph) Reference P n = 44, age 15.6 y (2.7) 3 y Lispro vs regular At 1 year: 6.3% (1.1) vs 6.6% 31 (1.1),p = 0.03; at 3 years: 6.3% (0.9) vs 6.6% (1.1), p = 0.03 Ret, C-A n = 114, age 12.2 y (2 18) 9 mo Glargine vs NPH At 9 months: 9.3% (0.1) vs 9.6% (0.1), p = Ret, C-A n = 71, age 11.5 y (4.9) 6 mo Glargine vs NPH At 6 months: 8.9% (1.5) vs 8.9% (1.6), 59 p = NS P n = 80, age 11.1 y (4.4) 6 mo Glargine vs NPH Whole cohort: 7.1% (0.7) vs 7.6% (0.81), 61 p < 0.001; preschool (n = 14): 6.96% (0.57) vs 7.54% (0.6), p < 0.05 P, R n = 347, age 11.8 y (2.7) 6 mo etemir vs NPH At 6 months: 8.0% (0.1) vs 7.9% (0.1), 65 p = NS a ata shown are mean (S) or mean (range) unless otherwise stated. C-A = chart analysis; NPH = neutral protamine Hagedorn; NS = not significant; P = prospective; R = randomized; Ret = retrospective Adis ata Information BV. All rights reserved. Pediatr rugs 2008; 10 (3)

11 Insulin Analog Preparations in Pediatric Type 1 iabetes 11 a prospective 6-month study of 80 children with type 1 diabetes amongst females. [68] The mechanism for this weight-sparing effect (ages 2 19 years) commenced on insulin glargine (mean change in of detemir is unknown but may be due to the relative hepato HbA1c 0.49%; p < 0.001). [61] For a subgroup of 14 preschool selectivity of insulin detemir action or to suppression of food and aged children in this study, the reductions in HbA 1c were greater calorie intake through reduced hypoglycemia occurrence or altera- (mean change in HbA1c 0.58; p < 0.05). In contrast, a retrospective tions in central appetite regulation. [71] study comparing the 6-month periods immediately before and after initiation of insulin glargine therapy in 71 children with type 1 diabetes (mean age 11.5 years) failed to show any significant 2.3 isadvantages changes in HbA1c (mean HbA1c 8.9% vs 8.9%, respectively). [59] The greatest improvements in HbA1c following initiation of longacting Sub-Optimal Background Insulin Levels insulin analog therapy are invariably observed in those with As with any long-acting insulin preparation administered sub- the worst glycemic control. In a retrospective case series analysis cutaneously, sub-optimal therapeutic insulin levels may occur of 37 patients with poorly controlled type 1 diabetes (HbA1c >8%), when the subcutaneous insulin depot begins to deplete well before glycemic control was significantly improved in 80% of patients the next dose is due to be given. Neither insulin glargine nor following a change from NPH to insulin glargine, with the most insulin detemir have a pharmacokinetic profile that ideally suits a impressive results being observed in those with HbA1c values 24-hour interval between each injection. In clinical practice, wan- >12%. [62] Although it is likely that improvements in glycemic ing of basal insulin background cover a few hours before the next control in this subgroup may have also been a result of better dose is due is often observed and may necessitate a change in overall diabetes care, improvements in HbA1c were significant for insulin therapy strategy. The t 1 /2 of insulin detemir, in particular, is the whole group after 6 months of insulin glargine therapy irresitates shorter in children and adolescents than in adults and often neces- spective of baseline HbA1c (mean change in HbA1c 1.2%; p = a twice-daily administration schedule ) Mixing with Short-Acting Insulin Analogs Current manufacturers recommendations state that the long Reduced Weight Gain acting insulin analogs should not be mixed with any other insulin Intensification of subcutaneous insulin therapy is usually asso- preparation in the same injection device or delivery system. In the ciated with increased risk of excessive weight gain. This is partic- case of insulin glargine there are concerns that mixing with anularly true for females with type 1 diabetes, especially during other insulin will alter the unique ph and solubility properties of puberty and adolescence, and can largely be attributed to the the glargine formulation and thus adversely affect its pharmacoincreased insulin resistance typically seen at this time. [68,69] When kinetic profile. long-acting analogs are used in combination with fast-acting ana- The long-acting insulin analogs therefore seem to be suited logs, a reduction in hypoglycemia in conjunction with lower only for basal bolus, multiple insulin injection regimens where weight gain has been observed in adults with type 1 diabetes. [20] In mixing of short- and long-acting insulin components is not necesadults, insulin detemir appears to have a weight gain-sparing effect sary. Such injection regimens, while ideal in terms of achieving as evidenced from recent clinical trials in which either a reduced optimal insulin delivery, are far from acceptable for many children rate of weight gain or weight loss was observed in comparison to and families, who may struggle to increase the number of daily human NPH insulin, despite maintenance of equivalent glycemic injections either for personal (e.g. injection phobia) or logistical control and insulin dose requirements. [62,70] Robertson and col- (e.g. unsupervised at school) reasons. Long-acting insulin analogs leagues [65] have also recently corroborated this observation in therefore seem to have no place in either twice- daily or threechildren and adolescents with type 1 diabetes. In their study, mean times-daily insulin injection regimens. Nevertheless, one study has body mass index (BMI) standard deviation score (SS) after 26 explored the effects of mixing insulin glargine with a rapid-acting weeks of therapy with insulin detemir was significantly lower analog in the same syringe in children (n = 55; age 13.4 ± 3.8 compared with a parallel NPH-treated group (BMI SS 0.08 vs years) with type 1 diabetes. [72] After 6 months of treatment, no 0.26, respectively) and was slightly lower compared with baseline. significant differences in glycemic control (HbA1c), hypoglyce- This effect of insulin detemir may offer an important advantage for mia frequency, hospitalization rate for KA, or any other adverse the adolescent population with type 1 diabetes, in whom excessive events were observed in children who received mixed insulin weight gain, aberrant eating habits, and insulin omission for compared with a matched control group for whom insulin was not weight control purposes are common occurrences, especially mixed Adis ata Information BV. All rights reserved. Pediatr rugs 2008; 10 (3)

12 12 Miles & Acerini Altered/Anomalous Receptor Binding Characteristics requires further careful long-term follow-up studies to evaluate Changes to the structure of the insulin molecule can potentially their benefits in children and adolescents with type 1 diabetes, alter both its metabolic and its mitogenic activity and as a result initial reports in this age group are promising. some concerns have been raised about the long-term safety of long-acting insulin analogs. The evidence for this is at best limited Acknowledgements at present and mainly concerns the activity of insulin glargine. In vitro studies have established that insulin glargine has a 6- to No sources of funding were used to assist in the preparation of this review. Carlo Acerini has received speaking/lecture honoraria and educational and 8-fold increase in binding affinity for the type 1 IGF-I receptor, research grant support for independent investigator-led research from Novo and is eight times more potent at stimulating NA synthesis in Nordisk. Harriet Miles has no conflicts of interest that are directly relevant to human osteosarcoma cell lines than the native insulin molecule. [73] the content of this review. This increased mitogenic potential has not, however, been observed in other human and animal cell lines, [74] and in vivo studies References using a murine animal model have not reported any increase in 1. Mosekilde E, Jensen KS, Binder C, et al. Modeling absorption kinetics of subcutaneous tumor development after long-term insulin glargine administration. injected soluble insulin. J Pharmacokinet Biopharm 1989 Feb; 17 (1): [75] Furthermore, the in vivo significance of increased IGF-I Homko C, eluzio A, Jimenez C, et al. Comparison of insulin aspart and lispro: receptor affinity and its impact on the growth hormone/igf-i axis pharmacokinetic and metabolic effects. iabetes Care 2003 Jul; 26 (7): Becker RH, Frick A, Burger F, et al. Insulin glulisine, a new rapid-acting insulin in humans with type 1 diabetes have been evaluated and have analogue, displays a rapid time-action profile in obese non-diabetic subjects. failed to show any relevant IGF-I-like activity of insulin glargine. Exp Clin Endocrinol iabetes 2005 Sep; 113 (8): In a crossover study comparing insulin glargine with NPH therapy, 4. Plank J, Wutte A, Brunner G, et al. A direct comparison of insulin aspart and insulin lispro in patients with type 1 diabetes. iabetes Care 2002 Nov; 25 (11): serum IGF-I levels were paradoxically, and unexpectedly, higher after 3 weeks of insulin glargine treatment; such results contrasted 5. Lindholm A, Jacobsen LV. Clinical pharmacokinetics and pharmacodynamics of with the expected decrease in IGF-I levels hypothesized on the insulin aspart. Clin Pharmacokinet 2001; 40 (9): basis of negative feedback regulation of the growth hormone/igf- 6. Howey C, Bowsher RR, Brunelle RL, et al. [Lys(B28), Pro(B29)]-human insulin: a rapidly absorbed analogue of human insulin. iabetes 1994 Mar; 43 (3): I axis. [76] Home P, Barriocanal L, Lindholm A. Comparative pharmacokinetics and The affinity of insulin detemir for the IGF-I receptor is 15 times pharmacodynamics of the novel rapid-acting insulin analogue, insulin aspart, in lower than that of native insulin molecule. Therefore, it is not healthy volunteers. Eur J Clin Pharmacol 1999 May; 55 (3): surprising that the mitogenic effects of insulin detemir have been 8. anne T, Becker RH, Heise T, et al. Pharmacokinetics, prandial glucose control, found to be more than 250-fold lower than those of human insulin and safety of insulin glulisine in children and adolescents with type 1 diabetes. iabetes Care 2005 Sep; 28 (9): when assessed in human in vitro cell lines. [73] 9. ter Braak EW, Woodworth JR, Bianchi R, et al. Injection site effects on the 3. Conclusion pharmacokinetics and glucodynamics of insulin lispro and regular insulin. iabetes Care 1996 ec; 19 (12): Mudaliar SR, Lindberg FA, Joyce M, et al. Insulin aspart (B28 Asp-insulin): a fastacting analog of human insulin: absorption kinetics and action profile compared The new generation of insulin analog preparations has in- with regular human insulin in healthy nondiabetic subjects. iabetes Care 1999 creased the therapy options for children and adolescents with type Sep; 22 (9): Gardner F, Arakaki RF, Podet EJ, et al. The pharmacokinetics of subcutaneous 1 diabetes and their families. As a result of their specific pharmaregular insulin in type I diabetic patients: assessment using a glucose clamp cokinetic and pharmacodynamic characteristics, both the fast- and technique. J Clin Endocrinol Metab 1986; 63 (3): long-acting insulin analogs provide a number of physiological and 12. Mortensen HB, Lindholm A, Olsen BS, et al. Rapid appearance and onset of action clinical advantages that offer the potential for improved glycemic of insulin aspart in paediatric subjects with type 1 diabetes. Eur J Pediatr 2000 Jul; 159 (7): control and increased flexibility of lifestyle. Fast-acting analogs 13. Rutledge KS, Chase HP, Klingensmith GJ, et al. Effectiveness of postprandial Humalog in toddlers with diabetes. Pediatrics 1997 ec; 100 (6): specifically facilitate more flexible insulin injection timing with 14. Kamoi K, Miyakoshi M, Maruyama R. A quality-of-life assessment of intensive regard to meals and exercise, and result in decreased postprandial insulin therapy using insulin lispro switched from short-acting insulin and glucose excursions together with fewer hypoglycemic episodes. measured by an ITR-QOL questionnaire: a prospective comparison of multiple The long-acting analogs have a more predictable profile of action daily insulin injections and continuous subcutaneous insulin infusion. iabetes Res Clin Pract 2004 Apr; 64 (1): and their lack of peak effect contributes to a decrease in the 15. Grey M, Boland EA, Tamborlane WV. Use of lispro insulin and quality of life in adolescents on intensive therapy. iabetes Educ 1999 Nov-ec; 25 (6): frequency of nocturnal hypoglycemia. Although long-term bene- 16. eja G, Jarosz-Chobot P, Muchacka-Bianga M, et al. Insulin lispro in treatment of fits in terms of HbA1c are modest, it is clear that the slightly lower children and adolescents with type 1 diabetes and its effect on quality of life. HbA1c observed with the insulin analogs is associated with the iabetologia Polska 2002; 9 (2): Bott U, Ebrahim S, Hirschberger S, et al. Effect of the rapid-acting insulin analogue benefit of fewer hypoglycemic episodes. Finally, while the poteninsulin aspart on quality of life and treatment satisfaction in patients with type 1 tial for improved overall glycemic control with insulin analogs diabetes. iabet Med 2003 Aug; 20 (8): Adis ata Information BV. All rights reserved. Pediatr rugs 2008; 10 (3)

13 Insulin Analog Preparations in Pediatric Type 1 iabetes Anderson Jr JH, Brunelle RL, Koivisto VA, et al. Reduction of postprandial 39. Slieker LJ, Brooke GS, imarchi R, et al. Modifications in the B10 and B26-30 hyperglycemia and frequency of hypoglycemia in IM patients on insulin- regions of the B chain of human insulin alter affinity for the human IGF-I analog treatment. Multicenter Insulin Lispro Study Group. iabetes 1997 Feb; receptor more than for the insulin receptor. iabetologia 1997 Jul; 40 Suppl. 2: 46 (2): S Home P, Lindholm A, Hylleberg B, et al. Improved glycemic control with insulin 40. Bolli GB, i Marchi R, Park G, Insulin analogues and their potential in the aspart: a multicenter randomized double-blind crossover trial in type 1 diabetic management of diabetes mellitus. iabetologia 1999 Oct; 42 (10): patients. UK Insulin Aspart Study Group. iabetes Care 1998 Nov; 21 (11): 41. Heinemann L, Linkeschova R, Rave K, et al. Time-action profile of the long-acting insulin analog insulin glargine (HOE901) in comparison with those of NPH 20. Gough SC. A review of human and analogue insulin trials. iabetes Res Clin Pract insulin and placebo. iabetes Care 2000 May; 23 (5): ; 77 (1): Lepore M, Pampanelli S, Fanelli C, et al. Pharmacokinetics and pharmaco- 21. American iabetes Association. Postprandial blood glucose. iabetes Care 2001 dynamics of subcutaneous injection of long-acting human insulin analog Apr; 24 (4): glargine, NPH insulin, and ultralente human insulin and continuous subcutane- 22. Ceriello A, avidson J, Hanefeld M, et al. Postprandial hyperglycaemia and ous infusion of insulin lispro. iabetes 2000 ec; 49 (12): cardiovascular complications of diabetes: an update. Nutr Metab Cardiovasc 43. Pieber TR, Eugene-Jolchine I, erobert E. Efficacy and safety of HOE 901 versus is 2006 Oct; 16 (7): NPH insulin in patients with type 1 diabetes. The European Study Group of 23. Amin R, Ross K, Acerini CL, et al. Hypoglycemia prevalence in prepubertal HOE 901 in type 1 diabetes. iabetes Care 2000 Feb; 23 (2): children with type 1 diabetes on standard insulin regimen: use of continuous 44. Owens R, Coates PA, Luzio S, et al. Pharmacokinetics of 125I-labeled insulin glucose monitoring system. iabetes Care 2003 Mar; 26 (3): glargine (HOE 901) in healthy men: comparison with NPH insulin and the 24. Mohn A, Strang S, Wernicke-Panten K, et al. Nocturnal glucose control and free influence of different subcutaneous injection sites. iabetes Care 2000 Jun; 23 insulin levels in children with type 1 diabetes by use of the long-acting insulin (6): HOE 901 as part of a three-injection regimen. iabetes Care 2000 Apr; 23 (4): 45. Heise T, Bott S, Rave K, et al. No evidence for accumulation of insulin glargine (LANTUS): a multiple injection study in patients with type 1 diabetes. iabet 25. Ford-Adams ME, Murphy NP, Moore EJ, et al. Insulin lispro: a potential role in Med 2002 Jun; 19 (6): preventing nocturnal hypoglycaemia in young children with diabetes mellitus. 46. Kurtzhals P, Havelund S, Jonassen I, et al. Albumin binding of insulins acylated iabet Med 2003 Aug; 20 (8): with fatty acids: characterization of the ligand-protein interaction and correla- 26. Brunelle BL, Llewelyn J, Anderson Jr JH, et al. Meta-analysis of the effect of tion between binding affinity and timing of the insulin effect in vivo. Biochem J insulin lispro on severe hypoglycemia in patients with type 1 diabetes. iabetes 1995 ec 15; 312 (Pt 3): Care 1998 Oct; 21 (10): Whittingham JL, Havelund S, Jonassen I. Crystal structure of a prolonged-acting 27. Hermansen K, Fontaine P, Kukolja KK, et al. Insulin analogues (insulin detemir insulin with albumin-binding properties. 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