Expert Opinion on Biological Therapy

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An update on the pharmacotherapy options for pediatric diabetes M Loredana Marcovecchio MD PhD & Francesco Chiarelli MD PhD To cite this article: M Loredana Marcovecchio MD PhD & Francesco Chiarelli MD PhD (2014) An update on the pharmacotherapy options for pediatric diabetes, Expert Opinion on Biological Therapy, 14:3, 355-364, DOI: 10.1517/14712598.2014.874413 To link to this article: http://dx.doi.org/10.1517/14712598.2014.874413

Published online: 06 Jan 2014.

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Date: 13 September 2015, At: 00:09

Review

An update on the pharmacotherapy options for pediatric diabetes 1.

Introduction

2.

Management of diabetes in children and adolescents

3.

Treatment of T1D in children

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and adolescents 4.

Treatment of T2D in youth

5.

Expert opinion

M Loredana Marcovecchio & Francesco Chiarelli† †

University of Chieti, Department of Paediatrics, and Clinical Research Center, Center of Excellence on Aging, Chieti, Italy

Introduction: Diabetes mellitus is a frequent endocrine disease during childhood and adolescence. Achieving a good glycemic control is of paramount importance to avoid short- and long-term complications and to allow a normal growth and quality of life. Areas covered: This review offers an update on current available treatment strategies for type 1 and type 2 diabetes approved for use in children and adolescents. Expert opinion: Although many progresses have been made in the field of diabetes management in children and adolescents, there are still several problems to deal with. With regard to type 1 diabetes, insulin remains the main and essential therapeutic strategy. However, the main issue is to develop a system that allows more physiological insulin coverage and reduces the risk of hypoglycemia and weight gain. Adjunct therapies would be invaluable for patients struggling to achieve an acceptable glycemic control. Treatment of type 2 diabetes is based on lifestyle interventions and metformin is the firstline drug for children older than 10 years. As for type 1 diabetes, there is a strong need for developing new drugs to be used alone or in combination. Keywords: adolescents, children, glycemic control, insulin, type 1 diabetes, type 2 diabetes Expert Opin. Biol. Ther. (2014) 14(3):355-364

1.

Introduction

Diabetes mellitus is a common metabolic disorder characterized by chronic hyperglycemia along with alterations of the metabolism of carbohydrates, lipids and proteins [1]. Among the various forms of diabetes, the most frequent in the pediatric population is type 1 diabetes (T1D), characterized by an autoimmune destruction of pancreatic b-cells, and representing > 90% of all cases of childhood diabetes. Over the past decades there has been an alarming increase in cases of T1D in children and adolescents, with a steeper increase in children younger than 5 years [2]. Based on recent data from the International Diabetes Federation, there are around 497,000 children with T1D worldwide, with 79,000 newly diagnosed cases per year [3]. In recent years, concomitant with the growing epidemic of childhood obesity, there has also been the emergence of youth-onset type 2 diabetes (T2D), a disease long been regarded as exclusive of adulthood [4]. T2D is characterized by the presence of a state of insulin resistance associated with a progressive loss of b-cell function. According to data from the SEARCH study, T2D now accounts for 8 -- 87% of new cases of pediatric diabetes in the USA, with an overall prevalence of 0.24 per 1000 [5,6]. A higher prevalence of T2D has been reported among minority race/ ethnic groups (American-Indian/Alaskan-native: 0.69 per 1000, Black 0.56 per 1000; Hispanic 0.40 per 1000) compared with non-Hispanic youth (0.09 per 10.1517/14712598.2014.874413 © 2014 Informa UK, Ltd. ISSN 1471-2598, e-ISSN 1744-7682 All rights reserved: reproduction in whole or in part not permitted

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Article highlights. . . .

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Diabetes management is challenging during childhood and adolescence due to age-specific characteristics. Insulin therapy is the cornerstone of treatment of type 1 diabetes. Scant data are available for additional type 1 diabetes treatment, such as metformin or glucagon-like peptide-1 agonists, dipeptidyl peptidase-IV inhibitors. Treatment of type 2 diabetes is based on lifestyle interventions and metformin as the first-line drug. There is limited experience with other oral agents in youth with type 2 diabetes. Insulin should be implemented in youth with type 2 diabetes and metabolic decompensation or in cases of difficult controls with oral agents. Ongoing and future trials will hopefully help in developing more appropriate and individualized treatment strategies.

This box summarizes key points contained in the article.

Treatment of T1D in children and adolescents

3.

1000) [6]. An increase in T2D prevalence has also been reported in Europe, Japan and other countries, although the rates are lower than in the USA [4,7,8]. The aim of the present review is to offer an update on current available treatment strategies for T1D and T2D in the pediatric population.

Management of diabetes in children and adolescents 2.

Diabetes management can be challenging during childhood and adolescence when it is based on the integration of medical therapies and nutritional guidance as well as on psychological and behavioral support for the patients and their families [9,10]. The goals of diabetes therapy are to maintain near normal glycemia, avoid short-term complications, such as diabetic ketoacidosis (DKA) and hypoglycemia, as well as minimize long-term complications, including microvascular and macrovascular disease, while allowing a normal physical growth and pubertal development and a good quality of life [9]. The Diabetes Control and Complications Trial (DCCT) and its follow-up study, the Epidemiology of Diabetes Interventions and Complications (EDIC), have undoubtedly shown the beneficial effect of intensive insulin therapy in achieving a better glycemic control and in reducing the risk of developing vascular complications and delay their progression when compared to conventional treatment [11,12]. Interestingly, the EDIC study also highlighted the important phenomenon of ‘metabolic memory’, derived from the observation that, although after 2 years from the end of the DCCT, HbA1c levels were similar between the previously intensively and conventionally treated groups, the rate of progression of complications in the previously intensively treated group was still significantly lower [12]. This observation suggests that 356

patients who benefited in the past from a better metabolic control continued to have an advantage in terms of development of complications several years later, and underscores the need for implementing intensive management as soon as diabetes is diagnosed. However, the DCCT/EDIC have also shown some key differences between managing T1D in adults versus youth. The DCCT cohort included a group of 195 adolescents, aged 13 -- 17 years, with an HbA1c significantly higher by about 1% when compared to the adult cohort, even after intensive insulin therapy [13]. In addition, the frequency of hypoglycemia and weight gain was higher in the adolescent than in the adult cohort [13]. These data underscore the difficulties in achieving an optimal glycemic control in adolescents with T1D. Subsequent studies have confirmed the difficulties in obtaining good glycemic control while avoiding hypoglycemia and weight gain in children and adolescents [14].

Insulin therapy in T1D The cornerstone of T1D treatment is insulin therapy. The discovery of insulin by Banting and Best in 1921 marked a major milestone in the management of the disease [15]. Before insulin was discovered, every child with T1D died within weeks to years of its onset. Since the introduction of insulin therapy, several major achievements have been made with the major aim of allowing patients to live a normal life [16]. The development of short- and long-acting insulin analogs, with more physiological profiles when compared to regular insulin, together with the availability of different insulin regimens, newer devices for insulin administrations and alternative ways of insulin delivery, such as continuous subcutaneous insulin infusion (CSII), represent all major breakthroughs in the management of T1D during childhood and adolescence [10]. Of particular importance is also the implementation of new ways of monitoring glucose with continuous glucose sensors (CGS) as well as the ongoing research on the development of a closed-loop system combining CSII with CGS monitoring to try to generate an ‘artificial pancreas’ [16]. Insulin treatment is based on the availability of several insulin preparations, which can be implemented in different insulin regimens, the most commonly used is multiple daily insulin injections [10,17]. Insulin dosage in children and adolescents can widely vary between subjects and in the same individual based on several factors: age, weight, pubertal stage, duration and phase of diabetes, state of injection sites, amount and composition of food intake, exercise patterns, presence of any intercurrent illness, blood glucose levels and overall glycemic control [10]. 3.1

Insulin analogs Regular soluble human insulin has been for years the essential component of most daily replacement regimens combined 3.2

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with intermediate or long-acting insulins [10]. At present, this type of insulin is still a main component of diabetes treatment, although it has largely been replaced by short-acting insulin analogs. Regular insulin presents some intrinsic limitations, represented by slow onset of activity, plasma peak concentrations about half as low compared to the short-acting analogs, inconvenient interval between the injection and food intake (30 -- 45 min), long duration of activity (up to 12 h), potential for late postprandial hypoglycemia (4 -- 6 h) and need for additional snack in between main meals [18]. At present, there are three marketed short-acting insulin analogs: lispro (Humalog), aspart (Novorapid) and glulisine (Apidra), which are all approved for use in children and adolescents and they are all very similar in their effects on glucose control [18,19]. Insulin lispro is an insulin analog in which the amino acid sequence proline-lysine at positions 28 and 29 on the B chain of human insulin has been reversed. Insulin aspart is obtained from the substitution of the amino acid proline at position B28 with an aspartic acid residue. Insulin glulisine is the result of the replacement of asparagine with lysine at position 3 and of lysine by glutamic acid at position 29 on the B chain of the human insulin molecule [20]. These single amino acid changes inhibit dimer and hexamer formation after subcutaneous injection, thus allowing a faster absorption with consequent faster onset of action (after around 20 min from the injection) and shorter duration of action (3 -- 4 h), when compared to regular human insulin (Table 1) [18,19]. Overall, insulin analogs are more flexible and, in the case of very young children, they can be injected even after the meal, when in doubt of the amount and timing of food intake [21]. There are studies which have compared glucose control with a short-acting insulin analog given soon after the meal compared to the same analog given before the meal and, interestingly, they have shown comparable results [19,22]. Pediatric studies have shown that these short-acting insulin analogs are generally associated with better postprandial glucose control, less postprandial hyperglycemia, and reduced episodes of hypoglycemia, mainly at night, when compared with regular insulin [19]. In contrast, overall, there are no significant differences when compared to regular insulin in terms of HbA1c [19]. In addition, they can overcome the problem of unwanted morning snacks, which are required when using regular insulin [19]. Insulin glargine (Lantus) and insulin detemir (Levemir), the two available long-acting insulin analogs, are nowadays the most common preparations used in basal-bolus insulin regimens to cover the daily basal insulin requirement [18]. These are generally considered as peakless insulins, with a more physiological profile when compared with neutral protaminated Hagedorn (NPH) insulin or Lente insulin, previously largely used. Their onset of action starts 1.5 -- 4 h after the subcutaneous injection and their duration of action can be up to 20 -- 24 h, for insulin glargine, thus requiring a single daily injection, whereas for insulin detemir the duration is around 12 h, thus generally requiring to be injected

twice daily. When compared to NPH insulin or Lente insulin, these long-acting insulin analogs also show a more predictable absorption and less intraindividual and interindividual variability [18]. Insulin glargine derives from the substitution of glycine for asparagine at position A21 and the addition of two arginines to the carboxy terminal of B chain of the insulin molecule. The arginine amino acids shift the isoelectric point from a pH of 5.4 to pH 6.7, making the molecule more soluble at an acidic pH. In the neutral subcutaneous environment, these characteristics lead to a formation of aggregates, resulting in a slow, peakless dissolution and absorption of insulin from the site of injection [23]. Randomized controlled trials (RCTs) have demonstrated that glycemic control associated with insulin glargine use is at least comparable to that with NPH insulin in adults and in children and adolescents [24]. However, insulin glargine is associated with a significantly lower risk of hypoglycemia compared with NPH insulin [24,25]. There have been issues about the potential increased risk of cancer associated with insulin glargine, although, at present, there is no clear and definitive evidence supporting that issue [26]. Insulin detemir is a long-acting, soluble acylated analog of human insulin with a protracted action profile attributable to increased self-association at the injection site and buffering of insulin concentration via albumin binding in both the subcutaneous tissue and the blood [27]. In adults, when compared with NPH, insulin detemir is able to induce a similar effect on HbA1c as effectively, to lower fasting plasma glucose more, produce a smoother nocturnal glucose profile and cause a lower incidence of hypoglycemia [25,27]. In addition, insulin detemir seems to have a specific liver effect and a more favorable profile in terms of weight gain. Several studies have confirmed similar results in children and adolescents with T1D [19,28,29]. A recent 52-week randomized clinical trial showed that insulin detemir was noninferior to NPH insulin in children and adolescents (aged 2 -- 16 years) with T1D and was associated with a decreased risk of hypoglycemia and a lower weight gain [30]. Similar beneficial results with insulin detemir have also been previously reported for younger children, aged 2 -- 5 years, where it was associated with a similar glycemic control, but a more marked decrease in fasting plasma glucose and a lower rate of hypoglycemia when compared with NPH insulin [31]. At present, there is growing interest around two new generation long-acting insulin analogs: insulin degludec and a PEGylated insulin lispro, which are being evaluated in patients with T1D and T2D [32,33]. Insulin degludec is a new basal insulin with an amino acid sequence identical to human insulin except for removal of threonine at B30. At B29, a glutamic acid spacer is attached, and it bridges to a 16-carbon diacid. This new insulin forms soluble multihexamer assemblies after subcutaneous injection,

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Table 1. Pharmacokinetics of available insulin preparations approved for use in youth. Insulin Short-acting Regular insulin Insulin lispro Insulin aspart Insulin glulisine Intermediate/long-acting Human NPH insulin Insulin glargine Insulin detemir

Onset of action

Peak effect

Duration of action

30 -- 60 min 5 -- 15 min 5 -- 15 min 5 -- 15 min

2 -- 4 h 30 -- 90 min 30 -- 90 min 30 -- 90 min

5 4 4 4

2 -- 4 h 2 -- 4 h 2 -- 4 h

4 -- 10 h Lack of peak Lack of peak

2 -- 18 h 20 -- 24 h 12 -- 20 h

-----

8 6 6 6

h h h h

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NPH: Neutral protaminated Hagedorn.

resulting in an ultra-long action profile, with reported half-life longer than 25 h and activity lasting over 40 h [32]. These characteristics reduce plasma concentration and variability and create a flat steady-state profile following once-daily injection. Phase II trials have already shown promising results for insulin degludec. In a recent Phase III, 52-week randomized, controlled, open-label trial in adult patients with T1D, insulin degludec, associated to prandial insulin aspart, led to similar glycemic control than insulin glargine, and this was also associated with a 25% reduction in nocturnal hypoglycemia in the degludec group [34]. Insulin degludec has been approved and marketed in Europe, whereas the FDA has asked for more cardiovascular safety data before approval of this new insulin analog [35]. In addition, currently, there are no available data on the efficacy of insulin degludec in the pediatric population [36]. Another long-acting insulin analog currently under investigation is LY2605541 or PEGylated insulin lispro [33]. This analog consists of insulin lispro modified with a 20-kDa polyethylene glycol moiety having a large hydrodynamic size which delays insulin absorption and reduces clearance, resulting in prolonged duration of action. The increase in functional molecular size appears to alter the distribution of this insulin to tissues, with a preferential transport to the liver relative to peripheral tissues [33]. This analog is now moving toward Phase III studies. Alternative ways for insulin administration: continuous subcutaneous insulin infusion

3.3

CSII or insulin pump therapy was introduced in the late 1970s. This system allows the continuous subcutaneous administration of regular insulin or a short-acting insulin analog, through a catheter inserted in the subcutaneous tissue [37]. CSII represents the most physiological method of insulin delivery currently available, simulating the pattern of insulin secretion with a continuous adjustable ‘basal’ delivery and superimposed mealtime ‘boluses’. CSII offers greater flexibility and more precise insulin delivery compared with multiple daily injections. There is no age limit for the application of CSII, but this requires specific training of the patients and the parents and a strong compliance [37,38]. 358

Specific indications for the use of CSII are: recurrent severe hypoglycemia, wide fluctuations in blood glucose levels regardless of HbA1c, suboptimal diabetes control, microvascular complications and/or risk factors for macrovascular complications and good metabolic control but insulin regimen that compromises lifestyle [38]. Other circumstances in which CSII may be beneficial include: young children and especially infants and neonates, adolescents with eating disorders, children and adolescents with a pronounced dawn phenomenon, children with needle phobia, pregnant adolescents, ideally preconception, ketosis-prone individuals and competitive athletes [38]. Recently, the results of the largest and with longest followup study on use of insulin pump in youth with T1D from a single pediatric center in Australia showed that CSII is associated with an improved glycemic control up to 7-year follow up. This improvement was achieved together with a decreased rate of hypoglycemia and DKA and without any relevant increase in body mass index (BMI) [39]. During the past years, there has been a further step in the pump therapy field: the introduction of sensor-augmented insulin pump (SAP) therapy, which integrates CSII and CGS monitoring into one system and allows patients and clinicians to monitor treatment and response through Internet-based software. A recent study showed a significant improvement in glycemic control, as assessed by HbA1c levels, in children and adults with T1D and poor glycemic control on insulin pump therapy, after the addition of a continuous glucose monitoring (CGM). The improvement in HbA1c was also associated with increased time spent in normoglycemia [40]. Artificial pancreas The artificial pancreas or closed-loop insulin delivery is an emerging therapeutic approach for people with diabetes. It is a medical device consisting of a CGM and an insulin pump [41,42]. These two components are linked through a wireless system allowing from transmission of data from the glucose sensor to a controller algorithm, which will adjust the insulin dose and this message will be transmitted to the pump. The adjustments are based on the interstitial glucose levels detected by the glucose sensor [41,42]. 3.4

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Over the past years, several studies have proven that the artificial pancreas system is a valuable means to control nocturnal glucose levels and allow a good glycemic control both in adults and children with T1D [43]. This represents a key conclusion given that nocturnal hypoglycemia is a common complication in youth with T1D, in whom a high rate of severe episodes occur at night and some of them can be even undetected (hypoglycemia unawareness) [44]. Recently, similar results have also been achieved in a diabetic camp setting. In a crossover study performed at three diabetes camps, one in Slovenia, one in Israel and one in Germany, 56 children with T1D, aged between 10 and 18 years, were randomized to an overnight treatment with an MD-Logic artificial pancreas or with a SAP system. The artificial pancreas system was associated with a significantly reduced number of hypoglycemic episodes at night and with an overall more stable glycemic control [45]. In the coming months/years results on the validity and applicability of the artificial pancreas systems in home settings should be available. Adjunct therapies for T1D Although there is a wide range of available insulin preparations and insulin regimens, achieving an optimal glycemic control still remains elusive for many children and adolescents with T1D [10]. This is due to several factors, including the yet nonperfect profile of the insulin formulations in use, the subcutaneous administration, which does not mimic the physiological higher concentration of insulin in the portal circulation. In contrast, after subcutaneous injections, there is a non-physiological peripheral hyperinsulinemia, which can have negative effects on tissues generally not exposed to high insulin levels [46]. In healthy subjects, glucose homeostasis derives from the interplay of several hormones, including insulin, glucagon, glucagon-like peptide-1 (GLP-1) and amylin [47]. Therefore, in people with diabetes, not only is there a lack of endogenous insulin production but also the secretion and/or the action of these other hormones may be impaired and contribute to the overall metabolic imbalance. Adjunct therapies to improve glycemic control are, therefore, particularly warranted in children and adolescents [48]. In this context, over the past years, there has been increasing interest in the potential use of metformin in patients with T1D. Metformin is an oral biguanide insulin sensitizer, and its main effect is exerted on the liver, by blocking glucose production and release [49]. In addition, it can increase glucose uptake by peripheral tissues, such as the muscle and the adipose tissues [49]. Insulin resistance is a typical feature in adolescents with T1D and it is one of the main determinants of the encountered difficulties in managing T1D in this age group [50]. A recent systematic review of RCTs with metformin in T1D concluded that this drug was associated with a significant reduction of daily insulin dose but there was no significant effect on HbA1c along with inconsistent effects on body weight and cholesterol and an increased risk of hypoglycemia [51]. A Cochrane review 3.5

published in 2009 assessed the results of the only two available RCTs in adolescents with poorly controlled T1D treated with metformin as an adjunct therapy to insulin for 3 months [52]. Both studies suggested that metformin treatment lowered HbA1c by around 0.6 -- 0.9%. However, there were no reported improvements in insulin sensitivity, body composition or serum lipids. Risk of hypoglycemia increased in one study but not in the other. Adverse effects were mainly gastrointestinal in both studies and hypoglycemia in one study [52]. Overall, the available information on metformin in pediatric populations is still limited to make firm conclusions. In addition, another aspect which deserves investigation is whether metformin treatment could exert beneficial cardiovascular effects as reported for adult patients with T2D. In this context, there are some ongoing investigations also in youth with T1D [53]. In adults with diabetes, pramlintide, a synthetic analog of the pancreatic hormone amylin that suppresses glucagon secretion in an insulin-independent manner, has been shown to decrease HbA1c and postprandial glucose excursions as well as to reduce weight gain and gastric emptying [54]. Preliminary data regarding adolescents with T1D have shown that this molecule can delay gastric emptying, inhibit glucagon secretion and improve postprandial glucose excursions and has shown similar pharmacokinetics and safety profile in adults [47,55,56]. These results seem encouraging but they are still limited and further studies are required. During the past years, there has been growing interest on the potential application of analogs of the incretin hormone GLP-1 and dipeptidyl peptidase-IV (DPP-IV) inhibitors as adjunct therapies in patients with T1D [57] -- drugs already approved for the treatment of T2D in adults. GLP-1 is a gastrointestinal hormone, which reduces glucagon levels, increases satiety and delays gastric emptying [58,59]. There is also evidence from animal models that the same hormone can have a beneficial effect on b-cells, by promoting their replication and neogenesis [60-62]. GLP-1 levels can be manipulated by inhibiting DPP-IV, the enzyme which clears GLP-1 from the circulation, and extends its very short half-life of around 2 min. In T1D subjects, DPPIV inhibitors have been shown to reduce HbA1c and total insulin requirements in a short double-blind crossover study [63]. The long-acting GLP-1 receptor agonist exenatide was recently assessed in eight adolescents with T1D, where two doses of exenatide (1.25 and 2.5 µg) were compared with insulin monotherapy [64]. Treatment with both doses of exenatide was associated with a significant reduction of postprandial glucose excursions. This reduction in glucose excursions occurred despite reduction in insulin dose. These results are encouraging, although these need to be confirmed in larger studies. The DPP-IV inhibitors, sitagliptin, saxagliptin, vildagliptin and linagliptin, have recently been found to improve the overall glycemic control in studies performed in adult patients

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with T1D [15,16]. However, there is a need of studies in children and adolescents with T1D to assess whether similar effects are seen also in this age group. Overall, the available information on adjunct therapies in children and adolescents with T1D is still scant and further studies in this field are required before drawing firm conclusions.

pre-diabetes phase; better knowledge of the mechanisms implicated in the pathogenesis of T1D to develop more effective treatment strategies. In addition, the lack of success of single immunotherapy suggests that, like in other complex disease, more than one intervention directed toward different targets might be combined [66]. 4.

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3.6

Treatment of T2D in youth

Immunotherapy

In the context of diabetes, immunotherapy aims at targeting autoimmunity against pancreatic b-cells. Immunotherapy can be applied during early stages of the progressive process leading to clinical manifestation of T1D, before the appearance of autoantibody in high-risk subjects (primary prevention) or after the development of autoimmunity as a secondary prevention. In subjects with an established diagnosis of T1D, immunotherapy could still play a role soon after the onset of the disease to preserve residual b-cell function [65,66]. Disappointing results have emerged from the first Phase III immune intervention trials in T1D, which have been partly unexpected, given that Phase II trials showed promising results [67]. A recent randomized double-blind trial, where 334 patients with recent onset T1D were randomized to receive glutamic acid decarboxylase (GAD)-alum or placebo, was unable to show any difference between the two groups in stimulated C-peptide between baseline and 15 months as well as in HbA1c, insulin dose and hypoglycemic episodes. These results differ from those of a previous Phase II study, where treatment with GAD-alum was associated with a preserved C-peptide at 30 months and preserved stimulated C-peptide at 15 months [67]. This could be due to differences in characteristics of the studied populations or differences in the time of year (seasonal effect) when treatment was implemented. Recently, there has been increasing interest in the role of the innate immune system in the pathogenesis of T1D. Special attention has been focused on IL-1b, a proinflammatory molecule, with a b-cell proapoptotic effect and mediating b-cell glucotoxicity [68]. These observations and the results of a preliminary small trial led the way to two recent trials with canakinumab and anakinra [69]. A total of 69 patients were randomly assigned to canakinumab or placebo monthly for 12 months and 69 patients were randomly assigned to anakinra or placebo daily for 9 months. The study results were disappointing, given that there was no significant difference in C-peptide area under curve between the canakinumab and placebo groups at 12 months or between the anakinra and the placebo groups at 9 months, indicating that canakinumab and anakinra were not effective as single immunomodulatory drugs in recent-onset T1D. Overall, the negative results of studies based on immunotherapies suggest that there are aspects which should be more carefully considered in future studies, such as a better patient stratification; longer treatment periods; earlier implementation of these therapies, for example, during the 360

Although T2D is a growing condition among youth, and there is evidence that complication rate is higher when compared to adult-onset T2D as well as to childhood-onset T1D [70], up to now there have been limited trials assessing specific treatment strategies in the pediatric age group. Most of the treatment approaches for T2D in youth are based on data from adult populations [7,71]. Treatment should target the two main pathological features of T2D, such as insulin resistance and decreased insulin secretion [72]. As for T1D, treatment of the adolescent with T2D can be challenging due to specific psychological issues typical of this age of life. Adolescents should be directly involved in the daily management of their diabetes, although parental involvement is also of paramount importance. In order to assist physicians in managing T2D in youth, the American Academy of Pediatrics (AAP) has recently issued specific guidelines [73]. Lifestyle interventions The first-line therapy for youth with T2D is based on lifestyle interventions, including promotion of a healthy diet and exercise combined with behavioral therapy, with the aim of stopping weight gain or even obtaining weight loss [73]. Dietary interventions are based on reducing excess caloric intake, intake of sugar beverages and high fat food, while promoting increasing fruit and vegetable consumption. Regular physical activity is also strongly recommended and this should be based on reducing sedentary activity and promoting moderate-to-vigorous exercise for at least 60 min/day [73]. However, recent data indicate that only around 17% of youth treated with lifestyle modification have a reduction in BMI during a 1-year period, and only 23% do not require specific pharmacotherapy over a 2-year period [74]. Due to this low success rate with lifestyle interventions alone, the AAP recommends to start metformin in youth diagnosed with T2D as the first-line therapy together with diet and excise recommendations. 4.1

Oral hypoglycemic agents Up to now, metformin is the only oral hypoglycemic agent approved for youth with T2D, older than 10 years. Metformin should be initiated at 500 mg orally daily or twice daily with meals and slowly titrated to 1000 mg orally twice daily over 3 -- 4 weeks [7,71,73]. The safety and the efficacy of metformin in adolescents with T2D was originally evaluated in a randomized, 4.2

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double-blind, placebo-controlled trial [75], where 82 patients aged 10 -- 16 years of age, received metformin at a dosage up to 1000 mg twice daily for up to 16 weeks. Metformin significantly improved glycemic control in these subjects when compared with the control group receiving placebo, obtaining a significant reduction in both glycemia and HbA1c values. However, this first trial has already highlighted several difficulties encountered in performing interventional studies in youth with T2D, as indicated by the low recruitment rate, being around 10% of the screened population. In addition, the trial was affected by a high dropout rate, equal to 55% in the metformin arm and 93% in the placebo arm, and this was primarily due to need for glycemic rescue therapy. In terms of adverse effects, this trial highlighted that gastrointestinal symptoms and headache were the main complains and these symptoms improved over time and with the formulation of appropriate dosing schedules. Subsequent studies confirmed a beneficial effect of metformin in adolescents with T2D [49]. The main contraindications for the use of metformin in youth with T2D are: impaired renal function, hepatic disease, cardiac or respiratory insufficiency, hypoxemic conditions, severe infections or when a patient undergoes testing with radiographic contrast materials or when the risk of lactic acidosis is increased with dehydration. If monotherapy with metformin is not successful, inclusion of additional drugs should be considered: sulfonylureas, glitazones, or newer drugs such as GLP-1 agonists or DPP-IV inhibitors, although there is limited evidence for their use based on pediatric studies [7,73]. In adults with T2D, sulfonylureas are often used in order to improve insulin secretion. In fact, sulfonylureas are insulin secretagogues, which bind to the sulfonylurea receptor on the b-cells, leading to closure of the KATP channel, depolarization of the cell membrane and calcium influx through the calcium channels, which results in insulin release. Side effects associated with sulfonylureas use are hypoglycemia and weight gain. There is limited experience with use of sulfonylureas in youth with T2D. A randomized trial performed in 285 subjects comparing glimepiride (1 -- 8 mg/day) with metformin (500 -- 1000 mg twice daily) for 24 weeks showed similar reductions from baseline in HbA1c in the two groups: glimepiride -0.54 versus -0.71% in the metformin group. However, treatment with glimepiride was associated with greater weight gain [76]. Thiazolidinediones (TZDs), such a rosiglitazone and pioglitazone, are peroxisome proliferator-activated receptor-g agonists, which act by promoting glucose uptake by skeletal muscles, liver and adipocytes [77]. Adult studies have shown a beneficial effect of rosiglitazone on HbA1c, with reduction of 0.5 -- 3% [78]. TZDs are not approved for use in youth with T2D and use of rosiglitazone has been restricted in adults with T2D due to potential association with adverse cardiovascular outcomes, in particular, increased risk of myocardial infarction [79,80]. Recently, there were also issues related to the potential association between pioglitazone use and bladder cancer [81].

As for T1D, also in the context of T2D, there is growing interest in the use of GLP-1 analogs and DPP-IV inhibitors, although there are no available data yet on the efficacy and safety of these drugs in the pediatric population [82]. However, there are ongoing pediatric studies on these drugs. Recently, the results of the TODAY study, a large multicenter study performed in 699 adolescents with T2D (10 -- 17 years), comparing the efficacy of three treatment strategies (metformin alone, metformin plus lifestyle, metformin plus rosiglitazone) to achieve durable glycemic control, have been reported [83]. Single-drug monotherapy with metformin was ineffective in maintaining glycemic control for around 50% of the cohort within 1 year of treatment. Better results were obtained with the combination metformin plus rosiglitazone, whereas no significant improvement was seen with the combination metformin/lifestyle intervention. Overall, this big trial reiterates the limited rate of success of lifestyle interventions and also underlines the point that metabolic deterioration with metformin alone can be common and, therefore, a more aggressive drug approach might be required for youth with T2D. The trial highlights the potential beneficial effect of combining rosiglitazone to metformin, although, at present, this treatment option is not applicable, due to the safety concern on TZDs. Insulin therapy Insulin has a role in the management of youth with T2D when patients present with marked hyperglycemia, as indicated by blood glucose levels > 250 mg/dl or an HbA1c > 9%. In addition, insulin therapy is required for youth presenting with ketosis or DKA or in those in whom the distinction between T1D and T2D is not clear [73]. Switching to an oral agent is recommended once metabolic control is more stable. Long- and short-acting analogs may be applicable in the long-term management of patients who cannot be managed adequately with other treatment options [71,73]. A daily administration of long-acting insulin analog is often the first insulin regimen to be used in adolescents with a difficult control of T2D, combined with an oral hypoglycemic drug. If there are also difficulties in managing postprandial hyperglycemia, a short-acting insulin analog can be added [73]. 4.3

5.

Expert opinion

Over the past decades, there has been an increasing incidence of both T1D and T2D in the pediatric population. Although there have been many considerable progresses in the field of diabetes management in children and adolescents, there are still several problems to deal with. With regard to T1D, insulin remains the main and essential therapeutic strategy. However, as already stated, the main issue is to develop a system allowing more physiological basal and meal insulin coverage and reducing the risk of hypoglycemia and weight gain. Although many insulin preparations are

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available, together with several new devices for their injection and alternative ways of insulin delivery, glycemic control is still suboptimal in many young patients, particularly during adolescence. Therefore, achieving an optimal glycemic control in children and adolescents with T1D remains a major challenge. In this context, there is a great hope in ongoing and future studies assessing adjunct therapies, mainly incretin analogs, new immunomodulatory drugs as well as alternative ways of insulin delivery. Similarly, in the context of T2D, there is a strong need of developing new drugs to be used alone or in combination, particularly in cases difficult to manage. Individualizing treatment is a key point in the management of both T1D and T2D and this approach should take into account the specific characteristic of each patient. Future advances in terms of understanding of the pathogenesis of both forms of diabetes as well as the development Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.

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Declaration of interest The authors state no conflict of interest and have received no payment in preparation of this manuscript.

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Affiliation M Loredana Marcovecchio1,2 MD PhD & Francesco Chiarelli†1,2 MD PhD † Author for correspondence 1 University of Chieti, Department of Paediatrics, Via dei Vestini 5, 66100 Chieti, Italy Tel: +0039 0871 358015; Fax: +0039 0871 574538; E-mail: [email protected] 2 University of Chieti, Clinical Research Center, Center of Excellence on Aging, Chieti, Italy