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New insulin types in type 1 diabetes mellitus
Nuevas insulinas en la diabetes tipo 1
Jordi Mesa
Servicio de Endocrinología y Nutrición, Hospital Universitari Vall d’Hebron, Barcelona, Spain
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">The subcutaneous administration of insulin is still the mainstay of treatment for patients with type 1 diabetes mellitus &#40;DM1&#41; and its main objective is to control glycaemia in the most physiological way possible&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">In the more than 90 years that insulin has been available&#44; many advances have been made in its production&#44; purification&#44; formulation&#44; and method of administration&#46; The first baseline insulin to be produced&#44; protamine-zinc&#44; was developed in the 1930s&#44; and was followed 20 years later by the long-acting&#44; and NPH insulins&#46; Both insulins were widely used for decades&#44; while essential advances were made in reducing their immunogenicity&#46; In the 1990s there was renewed interest in prolonging the action of basal insulin when deficient glycaemic control was associated with microvascular complications&#46; The Diabetes Control and Complications Trial &#40;DCCT&#41;<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">2&#44;3</span></a> demonstrated that intensifying insulin treatment in order to normalise glycaemia as much as possible&#44; evaluated by a reduction in glycated haemoglobin levels &#40;HbA<span class="elsevierStyleInf">1c</span>&#41;&#44; reduced the risk of developing secondary complications&#44; and delayed its progression in patients already presenting with the disease&#46; Until that time&#44; the guidelines were one or 2 daily injections of intermediate action insulin with pre-prandial supplements of fast-acting insulin&#46; However&#44; after the DCCT&#44; the general guidelines were to use intensive therapy&#44; which has been shown to be more effective in achieving optimal control&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">The basal insulins&#44; which are characterised by slow and progressive absorption&#44; and long duration of action&#44; imitate the physiological secretion of the pancreas and provide better overall glycaemic control&#44; reducing morning pre-prandial hyperglycaemia and hypoglycaemia episodes&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">The application of DNA recombination technology since the mid-eighties enabled the development of different insulin analogues&#44; whose features provide them with additional benefits over the insulins used previously&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">The basal insulins that are currently available are the long-acting analogues glargine and detemir&#44; and the traditional intermediate-acting human insulin&#44; NPH&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">Insulin glargine &#40;IGla&#41; was developed by bioengineering in order to achieve a molecule with better solubility at physiological pH which&#44; when injected as an acid solution&#44; forms a precipitate in the subcutaneous space&#44; thus enabling a slower absorption rate&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">4</span></a> In 2003&#44; the use of detemir was authorised&#59; it has a similar action profile to lGla&#44; but unlike insulin glargine achieves its prolonged effect by binding to albumin&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">5</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Both basal analogues have been demonstrated not to be inferior to NPH insulin&#44; and while the latter is administered as a precipitate&#44; the analogues achieve delayed absorption by means of other mechanisms&#46; With the analogues&#44; the risk of incomplete resuspension of the formulation before it is injected is avoided&#44; and therefore the pharmacodynamic effect of injection-to-injection variability is eliminated&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">The therapeutic benefit of both basal insulins has been well established&#44; producing a more prolonged effect&#44; with a lower peak and less variability than the traditional NPH&#44; which are currently standard in the management of diabetic patients&#46; Generally their profile allows them to be administered once a day&#44; with a lower risk of hypoglycaemia episodes&#46;<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">6&#8211;8</span></a> Some cost&#8211;benefit analyses have not proved favourable to the current analogues&#44; essentially because of their high cost&#44; but nonetheless they currently represent 80&#37; of the insulin market&#46;<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">9&#44;10</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Despite the advantages of these basal analogues&#44; glycaemias often vary considerably when they are used in the form of a single daily injection&#44; and this is why new molecules continue to be investigated&#46; The objective of these latest-generation&#44; basal insulin analogues is to achieve a treatment which provides insulin in a continuous&#44; stable and predictable way over at least 24<span class="elsevierStyleHsp" style=""></span>hours&#44; with less variability&#44; a low incidence of hypoglycaemic episodes&#44; and which are possible to use in premixed preparations&#46;<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">11&#44;12</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">In this article we review the available data on the new insulin preparations which are about to be marketed or are currently under development &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#44; with the objective of improving on those already available by achieving a constant and predictable effect on glycaemia&#44; as well as the new formulations of both rapid and long-acting analogues&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Degludec insulin</span><p id="par0055" class="elsevierStylePara elsevierViewall">This is the first ultra-long acting insulin analogue on which there is the most data available&#59; it was authorised by the European Medicines Agency &#40;EMA&#41; in 2013&#44; and is soon to be marketed in Spain&#46; The degludec &#40;lDag&#41; insulin molecule preserves the amino-acid sequence of human insulin&#44; except the elimination of threonine in position B30 &#40;TrB30&#44; and the addition of a chain of 16 carbons attached to lysine at position B29 &#40;LisB29&#41; of the insulin B chain through a glutamic acid bond&#46;<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">13&#44;14</span></a> It contains phenol and zinc in its pharmaceutical formulation&#44; forming a soluble and stable dihexamer&#44; but after injection they start to associate together&#44; forming long chains of multihexamers&#44; and creating a subcutaneous deposit&#46; As the zinc disperses&#44; these structures slowly dissociate into smaller units&#44; and result in a slow release of active monomers into the blood stream&#46; The process is slow and progressive&#44; with a flat profile and no peaks&#44; producing a stable effect on glucose regulation&#46;</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Pharmacokinetics and pharmacodynamics</span><p id="par0060" class="elsevierStylePara elsevierViewall">Its half life is approximately 25<span class="elsevierStyleHsp" style=""></span>h and is not associated with the dose given&#46; With a daily injection&#44; a state of equilibrium is reached in approximately 3 days&#46; The pharmacological properties of IDeg have been studied in healthy volunteers&#44; and in patients with DM1&#44; and type 2 diabetes mellitus &#40;DM2&#41;&#46; All the studies confirm an increase in the length of its action compared to IGla&#44; and a significant reduction in the inter-day variation in response&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">7</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">Its half life was almost double that of IGla in patients with DM1 &#40;25&#46;4<span class="elsevierStyleHsp" style=""></span>h compared to 12&#46;5<span class="elsevierStyleHsp" style=""></span>h&#41;&#46; IDeg remained detectable in the circulation during the entire study period&#44; up to 120<span class="elsevierStyleHsp" style=""></span>h&#44; whereas IGla reached the lower limit of quantification within 48<span class="elsevierStyleHsp" style=""></span>h&#46; Its glucose-lowering effect can be maintained over a period above 42<span class="elsevierStyleHsp" style=""></span>h&#46; In addition to its prolonged effect&#44; with no peaks&#44; IDeg was associated with a highly predictable effect in patients with DM1&#44; with little day-to-day variability&#44; to reduce glucose compared with IGla &#40;variation coefficient of 20&#37; compared to 82&#37;&#41;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">15</span></a> and maintaining stability at all times over 24<span class="elsevierStyleHsp" style=""></span>h&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">16</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Efficacy and safety</span><p id="par0070" class="elsevierStylePara elsevierViewall">The evaluation of IDeg in the BEGIN clinical trials is the largest and most complete phase III programme undertaken for an insulin product&#44; with more than 5000 selected patients&#46; For DM1 the basal bolus regime was evaluated&#44; and for DM2 the basal regime associated with oral lipid-lowering agents&#44; and basal-bolus treatment&#46; In most of these studies IGla was the comparator drug&#44; using an intention-to-treat protocol&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">In the BEGIN Basal-Bolus Type 1 study&#44;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">17</span></a> including 629 participants&#44; and of 52 weeks duration&#44; IDeg was not inferior to IGla with regard to the degree of glycaemic control&#59; the percentage of patients achieving a HbA<span class="elsevierStyleInf">1c</span> of lower than 7&#37; was similar with both insulins &#40;40&#37; with IDeg compared to 43&#37; with IGla&#41;&#46; The fundamental difference was the fewer nocturnal hypoglycaemia episodes occurring with IDeg&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">Due to the practical and real difficulty of some patients to follow regular hours&#44; the effects of a flexible dosing regimen with IDeg were assessed&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">18</span></a> Two types of irregular schedules were considered&#58; the first&#44; termed &#8216;forced flexible&#8217;&#44; to evaluate the effects of extreme time variation in a single daily dose&#44; in which the patients alternated evening and morning insulin doses&#44; so that the interval between doses varied between 8 and 40<span class="elsevierStyleHsp" style=""></span>h&#59; and the second schedule&#44; &#8216;free flexible&#8217;&#44; in which the patients could take their dose once a day at intervals that varied from day to day&#44; and which could be as short as 8<span class="elsevierStyleHsp" style=""></span>h&#44; or as long as 40<span class="elsevierStyleHsp" style=""></span>h&#46; At the end of the 26-week BEGIN study&#44; Flex T1&#44; neither HbA<span class="elsevierStyleInf">1c</span> nor the number of nocturnal hypoglycaemia episodes differed significantly between the flexible doses of IDeg and lGla or the fixed dose of IDeg&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">Therefore&#44; the numerous clinical trials with patients with DM1 and DM2 have demonstrated that this ultra-long-acting insulin analogue is capable of reducing plasma glucose levels&#44; with fewer hypoglycaemic episodes&#44; especially at night&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">19</span></a> It was also observed that IDeg&#44; given once a day and at any time&#44; has little impact on glycaemic control&#46; In this sense&#44; this insulin can be regarded as more permissive&#44; as adhering to a strict schedule is not necessary&#44; because it continues to be safe and effective even when administered at irregular times&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">The iatrogenic weight gain associated with insulin treatment was also evaluated in the BEGIN Basal-Bolus Type1 study&#59; it was 1&#46;8<span class="elsevierStyleHsp" style=""></span>kg with IDeg compared to 1&#46;6<span class="elsevierStyleHsp" style=""></span>kg with IGla over 52 weeks&#46; Therefore no benefit was demonstrated in this regard&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">A meta-analysis by Ratner et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">20</span></a> which included all the randomised&#44; open phase III studies &#40;of 26 or 52 weeks&#8217; duration&#41;&#44; which had compared IDeg with IGla in patients with DM1 and DM2&#44; concluded that treatment with IDeg offered important clinical advantages&#44; especially in reducing diurnal hypoglycaemic episodes&#44; and nocturnal episodes in particular&#44; which were significantly lower with similar levels of HbA<span class="elsevierStyleInf">1c</span>&#44; enabling insulin doses to be titrated in a safer and more intensive way&#46;</p></span></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Degludec plus</span><p id="par0100" class="elsevierStylePara elsevierViewall">This is the coformulation of 70&#37; IDeg and 30&#37; of the fast-acting analogue aspart&#46; Its efficacy in adults with DM1 was examined in a 26-week&#44; phase III study and was compared with insulin detemir&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">21</span></a> General glycaemic control was similar with both insulins &#40;reductions inHbA<span class="elsevierStyleInf">1c</span> of 0&#46;73&#37; and 0&#46;68&#37;&#44; respectively&#41;&#44; and the number of hypoglycaemia episodes was also similar &#40;39 compared to 44 episodes per patient-year of exposure&#41;&#46; However&#44; nocturnal hypoglycaemia was 37&#37; lower with insulin degludec plus &#40;IDegPlus&#41; &#40;3&#46;7 compared to 5&#46;7 episodes per patient-year of exposure&#41;&#59; the rates of general adverse events were similar with both&#46; At the end of the study&#44; both the basal insulin doses and the daily total were significantly lower with IDeg than with insulin detemir&#44; although there was no significant difference between the groups with regard to daily insulin bolus dose&#46; Weight gain was significantly higher in the patients treated with IDegPlus than those treated with insulin detemir&#46;</p><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Cardiovascular safety</span><p id="par0105" class="elsevierStylePara elsevierViewall">Analysis of 16 phase 3 clinical trials shows a similar incidence of major cardiovascular episodes&#44; comprising cardiovascular death&#44; stroke and coronary syndrome&#44; in patients treated with IDeg or IDegPlus compared to the comparator drugs &#40;1&#46;48 compared to 1&#46;44 episodes&#47;100 patient-years&#41;&#46; Patients with pre-existing cardiovascular disease presented a greater risk of an episode in both groups than patients with no previous disease&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">22</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">A post hoc analysis which also included additional trials &#40;including extension trials&#41;&#44; but which excluded unstable angina as a combined variable&#44; found an incidence of major adverse cardiovascular events &#40;MACE&#41; of 1&#46;41 events&#47;100 patient-years for patients treated with IDeg or IDegPlus&#44; and of 0&#46;90 events&#47;100 patient years for those treated with the comparator drugs&#44; resulting in a hazard ratio &#40;HR&#41; of 1&#46;614&#46; However&#44; the data from the extension trials only represented 35&#37; of the original population&#44; and provided 2 years of data on cardiovascular events in approximately 12&#37; of the population with IDeg&#46; Because these data were considered less consistent than those of the original trials&#44; a subsequent post hoc analysis excluded the data from the extension trials&#46; This analysis resulted in MACE rates of 1&#46;51 events&#47;100 patient-years &#40;HR 1&#46;125&#41;&#46; Because these analyses neither confirm nor exclude an increased cardiovascular risk with IDeg&#44; further studies are currently in progress&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">The Food and Drug Administration &#40;FDA&#41; requested a additional study specifically for cardiovascular results before reviewing the drug&#39;s application for approval in the U&#46;S&#46;A&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">23</span></a> Its use has been approved in the European Union and Japan without a requirement for additional cardiovascular data&#46;</p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Pegylated lispro insulin</span><p id="par0120" class="elsevierStylePara elsevierViewall">Lispro insulin is a fast-acting analogue which has been used for the control of post-prandial glucose levels for more than 15 years&#46; Ly26045541 is a new insulin&#44; formed by attaching a lispro insulin to a polyethylene glycol chain &#40;PEG&#41; to extend its duration of action&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">24</span></a> The molecule of pegylated insulin lispro &#40;PEGlispro&#41; is 4 times larger than that of insulin lispro&#44; therefore its absorption from the subcutaneous space is slowed and&#44; in turn&#44; its glomerular filtration is reduced&#44; thus prolonging its action time&#46; The available pharmacokinetic data for single doses reveal a flat action profile&#44; compared to the available analogues&#46;</p><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Efficacy and safety</span><p id="par0125" class="elsevierStylePara elsevierViewall">Various studies have evaluated peglispro in patients with DM1 as well as patients with DM2&#46; In Rosenstock et al&#46;&#8217;s study&#44;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">25</span></a> 137 patients with DM1 were treated&#44; it was compared with lGla in combination with mealtime insulin over 8 weeks&#46; HbA<span class="elsevierStyleInf">1c</span> was more reduced in the patients with peglispro &#40;&#8722;0&#46;63&#37; compared to &#8722;0&#46;48&#37;&#41;&#44; with similar fasting blood sugars and a lower inter-day variability &#40;&#8722;13&#46;1 compared to &#8722;4&#46;8<span class="elsevierStyleHsp" style=""></span>mg&#47;dl&#41;&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">With the known data&#44; it can be confirmed that the glycaemic control obtained is comparable or superior to that achieved with the available basal analogues&#59; some weight loss is also achieved in both DM1 and DM2 patients&#46; Weight loss was 1&#46;19<span class="elsevierStyleHsp" style=""></span>kg compared to a weight gain of 0&#46;68<span class="elsevierStyleHsp" style=""></span>kg in the lGla group&#44; due to a mechanism that has not yet been clarified&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">The overall risk of presenting hypoglycaemic episodes is rather higher than with IGla &#40;8&#46;7 compared to 7&#46;4 monthly episodes&#41; but curiously&#44; the risk of presenting nocturnal hypoglycaemic episodes is lower &#40;0&#46;9 compared to 1&#46;1 monthly episodes&#41;&#46; Some mild gastrointestinal side effects have been reported&#44; such as a feeling of fullness or abdominal bloating&#44; which have not resulted in stopping the treatment&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">Studies in DM2 have not shown differences with IGla in reducing levels of HbA<span class="elsevierStyleInf">1c</span>&#44; fasting blood glucose levels or inter-day variability&#44; but the intra-day glycaemic variability was lower with PEGlispro&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">26</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">Recently&#44; Bergenstal et al&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">27</span></a> evaluated the impact of peglispro on glycaemic variability&#44; and hypoglycaemic episodes in 51 patients with DM2 using continuous glucose monitoring&#46; The authors found that fewer patients presented hypoglycaemic episodes&#44; and that this represented less time recorded in that situation compared with lGla&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">In sum&#44; the pharmacokinetic and pharmacodynamic profiles of peglispro insulin demonstrate a lasting effect of more than 24<span class="elsevierStyleHsp" style=""></span>h&#44; with greater glycaemic control in DM1&#44; and similar to lGla in DM2&#46; Phase III clinical trials are currently still in progress&#44; of which there are as yet no available results&#46;</p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Insulin glargine U300</span><p id="par0155" class="elsevierStylePara elsevierViewall">Subcutaneous injection of glargine insulin provides insulinaemia levels which enable it to be administered once a day&#44; and because of its efficacy and safety&#44; in the past decade it has become a standard treatment for diabetes&#44; and is currently the most-prescribed insulin in the world&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">As mentioned earlier&#44; in many diabetics it is not possible to achieve the established glycaemic control objectives with the currently-available analogues&#44; and therefore different molecules are still being investigated&#46; In the case of lGla&#44; the patent protection of which expires in 2015&#44; Sanofi have provided a new approach for the development of better basal insulins&#44; and the use of high-concentration formulations&#44; such as insulin glargine U300 &#40;Gla-300&#41; &#40;300<span class="elsevierStyleHsp" style=""></span>U&#47;ml&#41;&#44; currently in clinical trial phase&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">The new Gla-300&#44; which contains triple concentration per millilitre&#44; improves the profile of this insulin&#44; giving it more stability with reduced peak-trough fluctuations&#46; Its reduced subcutaneous precipitation rate results in even flatter and prolonged pharmacokinetics and pharmacodynamics&#44; in order to achieve better glycaemic control than the original IGla&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">28</span></a> In patients with DM1 the pharmacokinetic and pharmacodynamic profile is dose-dependent&#44; and blood sugar control is evident up to 36<span class="elsevierStyleHsp" style=""></span>h after injection&#46;<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">29&#44;30</span></a></p><p id="par0170" class="elsevierStylePara elsevierViewall">The clinical evaluation of this new insulin was undertaken through the EDITION programme&#44; which comprised a complete series of phase III studies which evaluated the efficacy and safety of the new U300 insulin in broad and diverse diabetic populations&#46; As a first study of the phase III EDITION programme&#44; EDITION I<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">31</span></a> evaluated the efficacy of the new insulin compared with conventional IGla in people with DM2 who used basal insulin plus mealtime insulin&#46; Eight hundred and seven diabetics were randomised to receive a single daily nocturnal injection of the new insulin U300 &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>404&#41; or IGla &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>403&#41;&#44; while they continued to receive mealtime insulin&#46; The principal evaluation criterion was a change in HbA<span class="elsevierStyleInf">1c</span> from inclusion up to the sixth month&#44; and the second criterion was the percentage of people with at least one serious or confirmed episode of nocturnal hypoglycaemia&#46; EDITION I showed similar reductions in HbA<span class="elsevierStyleInf">1c</span> with the new insulin U300&#44; and with IGla at 6 months&#46; Moreover&#44; approximately 40&#37; of the trial participants with uncontrolled glycaemia levels&#44; despite receiving combined treatment &#40;oral anti-diabetic agents plus basal and mealtime insulins&#41;&#44; achieved an HbA<span class="elsevierStyleInf">1c</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>7&#37; both in the new insulin U300 group &#40;39&#46;6&#37;&#41;&#44; and in the IGla group &#40;40&#46;9&#37;&#41;&#46; U300 was associated with a 21&#37; reduction in serious or confirmed&#44; nocturnal hypoglycaemic episodes&#44; between months 3 and 6&#46; In this study&#44; tolerance to the new insulin U300 was good&#44; with no differences in other adverse events observed for IGla&#46;</p><p id="par0175" class="elsevierStylePara elsevierViewall">In the EDITION II<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">32</span></a> study&#44; the efficacy and safety of the new insulin U300 were evaluated in a population with DM2 &#40;811 patients&#41; treated with basal insulin plus oral anti-diabetics&#46; The main results of EDITION II are similar to the findings of EDITION I&#44; achieving similar glycaemic control&#44; and fewer nocturnal hypoglycaemic episodes&#46; EDITION III trials are currently underway in insulin-na&#239;ve DM2 patients&#44; EDITION IV in DM1 patients&#44; EDITION JP <span class="elsevierStyleSmallCaps">I</span> in Japanese patients with DM1 &#40;basal<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>bolus insulin&#41; and EDITION JP II in Japanese patients with DM2 &#40;basal insulin<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>oral treatment&#41;&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">The principal benefit of high-concentration basal insulin is that patients who require high doses do not need to divide them into separate injections&#46; The high prevalence of obesity means that many patients require doses that exceed the capacity of their injection pen for them to administer it in a single dose&#46; In these types of patients there are often doubts as to their adherence in completing the dose in a second injection&#46; The analysts are expecting regulatory approval for U300 in the U&#46;S&#46;A&#46;&#44; and the European Union this year&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">New insulin formulations</span><p id="par0185" class="elsevierStylePara elsevierViewall">Various second generation insulin formulations are being investigated which include new formulations of both fast-acting and long-acting analogues&#46; Amongst the former&#44; in order to improve post-prandial glycaemia values and meet the objectives as closely as possible&#44; 2 ultra-fast-acting insulin analogues are being developed&#44; insulin-PH20 and Linjeta&#46;</p><p id="par0190" class="elsevierStylePara elsevierViewall">The molecule of insulin-PH20<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">24&#44;25</span></a> comprises a mealtime insulin and recombinant hyaluronidase&#46; In phase I and II trials faster absorption has been observed&#44; with accelerated pharmacokinetic and glycodynamic effect and lower inter- and intra-patient variability&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">Linjeta is a new formulation based on regular insulin combined with EDTA and citric acid&#44; which acts as a zinc chelater&#44; and thus prevents self-aggregation of the insulin molecules to form hexamers after subcutaneous injection&#44; maintaining their momomeric status&#46;<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">33&#44;34</span></a> In phase I and II clinical trials it showed a faster onset of action&#44; and maximum peak compared with regular insulin or with the fast-acting analogue lispro&#44; in both healthy volunteers and patients with DM1&#46; The last phase II clinical trial undertaken with DM1 patients who were pump users&#44; comparing with insulin lispro&#44; was halted 2 years ago officially due to the drug&#39;s lack of availability&#44; the studies have not been resumed to date&#46;</p><p id="par0200" class="elsevierStylePara elsevierViewall">The new formulations of slow-acting analogues are 2 modifications of IGla&#44; BIOD-Adjustable basal and LY2963016&#46; BIOD-Adjustable basal insulin is obtained by a modification in the production of IGla with the theoretical advantage of having a more prolonged duration of action and that it can be mixed with other types of insulin&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">35</span></a></p><p id="par0205" class="elsevierStylePara elsevierViewall">LY2963016 is a new molecule investigated by Eli Lilly and Boehringer Ingelheim&#44; which constitutes a new IGla product developed for treating both DM1 and DM2 patients&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">36</span></a> In July 2013&#44; the EMA accepted the marketing authorisation application for revision&#44; and in December the FDA did the same&#46; The presentations were made through a regulatory route which allowed reference to be made to previous findings on safety&#44; and the efficacy data which had already been approved for IGla&#44; in addition to the trials of LY2963016 itself&#46; Apart from compared pharmacokinetics and pharmacodynamic studies&#44; the presentation included the results of phase III studies which were completed in patients with DM1&#44; and DM2&#44; using IGla as the active comparator drug&#46;<a class="elsevierStyleCrossRefs" href="#bib0320"><span class="elsevierStyleSup">26&#44;37</span></a></p><p id="par0210" class="elsevierStylePara elsevierViewall">Insulin glargine biosimilar MK-1293 is following the same regulatory route and 2 studies are underway in DM1&#46; A phase I study is currently evaluating the safety&#44; tolerability&#44; pharmacokinetics and pharmacodynamics of MK-1293 compared with a basal insulin &#40;IGla&#41; in DM1&#44; and another phase III trial &#40;ClinicalTrials&#46;gov&#58; <a id="intr0010" class="elsevierStyleInterRef" href="https://clinicaltrials.gov/NCT02059161">NCT02059161</a>&#41; started selection a month ago&#44; it will be of 52 weeks&#8217; duration&#44; and include 500 patients&#44; in order to evaluate the drug&#39;s effectiveness and safety compared with IGla&#46; A phase III study with the same molecule is underway simultaneously in DM2 &#40;ClinicalTrials&#46;gov&#58; <a id="intr0015" class="elsevierStyleInterRef" href="https://clinicaltrials.gov/NCT02059187">NCT02059187</a>&#41; with similar objectives&#44; and the same number of cases and duration&#46;</p><p id="par0215" class="elsevierStylePara elsevierViewall">A unique type of ultra-long acting basal insulin&#44; FT-105&#44;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">38</span></a> is under development&#44; and consists of a formulation combined with vitamin E&#44; and a polyglutamate peptide in a hydrogel&#44; which gives rise to the formation of dense macroparticles&#44; causing slow release of the insulin into the blood stream&#46; Phase I studies indicate that its duration of action is longer than 48<span class="elsevierStyleHsp" style=""></span>h&#44; with low intra-patient variability and a reduction in hypoglycaemic episodes&#46;</p><p id="par0220" class="elsevierStylePara elsevierViewall">A new approach in injectable treatment&#44; currently in the preclinical investigation phase&#44; is a formulation of insulin which is sensitive to glucose&#46; BIOD-Smart Basal insulin is a formulation which contains glargine&#44; glucose oxidase and peroxidase&#46; This smart insulin is released in proportion to the glucose levels in its environment&#44; which can reduce the risk of hypoglycaemia and hyperglycaemia&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">11</span></a></p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Conclusions</span><p id="par0225" class="elsevierStylePara elsevierViewall">The second-generation insulin analogues which are currently under development&#44; some of which will soon be available clinically&#44; constitute an advance in the treatment of diabetes&#46; With their improved pharmacokinetic and pharmacodynamic profiles&#44; they have demonstrated a capacity to improve the glycaemic control achieved with the first-generation basal analogues&#44; in reducing the risk of one of the major obstacles to achieving adequate control&#44; hypoglycaemia&#44; particularly nocturnal hypoglycaemia&#46; The numerous clinical trials have demonstrated that they are not inferior&#44; and that they are even superior in terms of level of glycaemic control evaluated through fasting glucose and HbA<span class="elsevierStyleInf">1c</span> levels&#46; They also present lower intra- and inter-daily glycaemic variability&#44; with fewer hypoglycaemias&#44; especially nocturnal&#44; and a more physiological profile&#46; The greater flexibility of the new insulin analogues have the potential to improve patients&#8217; compliance with treatment regimens&#44; in that they enable an administration schedule to fit patients&#8217; different needs and lifestyles&#46;</p><p id="par0230" class="elsevierStylePara elsevierViewall">The clinical availability of these new analogues will help us to continue improving diabetic care&#44; providing greater flexibility in treatment&#44; while reducing the adverse effects of insulin treatment&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Conflict of interests</span><p id="par0235" class="elsevierStylePara elsevierViewall">The author has participated as an investigator in clinical trials for the development of insulins glargine and degludec&#46;</p></span></span>"
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      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Since its discovery almost a century ago&#44; insulin remains the mainstay of treatment of patients with type 1 diabetes mellitus&#46; Although progress in the synthesis of new formulations has been remarkable&#44; the physiological profile of insulin is still different from that observed with preparations available nowadays&#46; In the last decade&#44; the introduction into clinical practice of insulin analogues has allowed significantly improvement in glycemic control and has facilitated the spread of basal&#47;bolus patterns&#44; the most physiological ones until now&#46; Despite the benefits of basal analogues&#44; glycemia often varies considerably when used as a single daily injection and this is why new molecules have been further investigated&#46; Improvement has been achieved especially in terms of duration and rate of hypoglycemia&#44; the main limiting factor of intensive therapy&#46; This article reviews the available data concerning the new basal insulin analogues&#44; degludec&#44; pegylated lispro and glargine U300&#44; and new formulations currently under development&#46;</p></span>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Transcurrido casi un siglo desde el descubrimiento de la insulina&#44; sigue siendo en la actualidad la base del tratamiento de los pacientes con diabetes mellitus de tipo 1&#46; Aunque los progresos en la s&#237;ntesis de nuevas formulaciones han sido notables&#44; el perfil fisiol&#243;gico de la insulina es a&#250;n distinto del que se obtiene con las preparaciones disponibles en la actualidad&#46; En la &#250;ltima d&#233;cada&#44; la incorporaci&#243;n a la pr&#225;ctica cl&#237;nica de los an&#225;logos de insulina ha permitido mejorar de forma importante el control gluc&#233;mico de los diab&#233;ticos y ha facilitado la generalizaci&#243;n de las pautas bolo&#47;basal&#44; las m&#225;s fisiol&#243;gicas hasta estos momentos&#46; A pesar de las ventajas de los an&#225;logos basales&#44; en muchas ocasiones las glucemias oscilan considerablemente cuando se utilizan en forma de inyecci&#243;n &#250;nica diaria&#44; y es por ello que se han seguido investigando nuevas mol&#233;culas que mejoren las existentes&#44; especialmente en cuanto a duraci&#243;n y para evitar la presencia de hipoglucemias&#44; el factor limitante fundamental de las pautas intensificadas&#46; En el presente art&#237;culo se revisan los datos disponibles referentes a los nuevos an&#225;logos de insulina basal&#44; la insulina degludec&#44; la insulina lispro pegilada y la insulina glargina U300&#44; y de las nuevas formulaciones actualmente en fase de desarrollo&#46;</p></span>"
      ]
    ]
    "NotaPie" => array:1 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Mesa J&#46; Nuevas insulinas en la diabetes tipo 1&#46; Med Clin &#40;Barc&#41;&#46; 2015&#59;145&#58;70&#8211;75&#46;</p>"
      ]
    ]
    "multimedia" => array:1 [
      0 => array:7 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">EDTA&#58; ethylenediaminetetraacetic acid&#59; EMA&#58; European Medicines Agency&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Insulin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Patent&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Duration&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Characteristics&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Phase&#47;status&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleItalic">New analogues</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Degludec&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Novo Nordisk&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Long-acting&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Two modifications of insulin &#946; chain&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">EMA authorisation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>LY2605541&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Eli Lilly&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Long-acting&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pegylated lispro insulin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Phase III&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Glargine U300&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Sanofi&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Long-acting&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Glargine insulin at greater concentration&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Phase III&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleItalic">New formulations</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Insulin PH20&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Halozyme Therapeutics&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Fast-acting&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Regular insulin with recombinant hyaluronidase&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Phase II&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Linjeta&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Biodel&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Fast-acting&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Regular human insulin with EDTA and citric acid&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Phase II&#46; Halted&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span> BIOD adjustable basal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Biodel&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Long-acting&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">New formulation of glargine insulin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Phase I&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>LY2963016&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Eli Lilly&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Long-acting&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Insulin glargine biosimilar&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Phase III&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>MK-1293&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MSD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Long-acting&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Insulin glargine biosimilar&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Phase III&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>FT-105&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Flame Tech&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Long-acting&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Insulin attached to vitamin E and polyglutamate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Phase I&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>BIOD-Smart Basal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Biodel&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Long-acting&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Insulin glargine&#44; glucose oxidase and peroxidase&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Preclinical&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Glaritus&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Wockhardt&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Long-acting&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">New formulation of insulin glargine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Phase I&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab996549.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">New insulins under trial or development phase&#46;</p>"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
          "bibliografiaReferencia" => array:38 [
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              "identificador" => "bib0195"
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Insulins&#58; past&#44; present&#44; and future"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "C&#46;A&#46; Borgo&#241;o"
                            1 => "B&#46; Zinman"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
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                        "tituloSerie" => "Endocrinol Metab Clin North Am"
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                        "volumen" => "41"
                        "paginaInicial" => "1"
                        "paginaFinal" => "24"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22575404"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus"
                      "autores" => array:1 [
                        0 => array:2 [
                          "colaboracion" => "The Diabetes Control and Complications Trial Research Group"
                          "etal" => false
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJM199309303291401"
                      "Revista" => array:6 [
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                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0205"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "D&#46;M&#46; Nathan"
                            1 => "P&#46;A&#46; Cleary"
                            2 => "J&#46;Y&#46; Backlund"
                            3 => "S&#46;M&#46; Genuth"
                            4 => "J&#46;M&#46; Lachin"
                            5 => "T&#46;J&#46; Orchard"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJMoa052187"
                      "Revista" => array:6 [
                        "tituloSerie" => "N Engl J Med"
                        "fecha" => "2005"
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                        ]
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                    ]
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                ]
              ]
            ]
            3 => array:3 [
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              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Insulin glargine&#58; the first clinically useful extended-action insulin analogue"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "S&#46;G&#46; Ashwell"
                            1 => "P&#46;D&#46; Home"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
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                        "fecha" => "2001"
                        "volumen" => "2"
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                    ]
                  ]
                ]
              ]
            ]
            4 => array:3 [
              "identificador" => "bib0215"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pharmacology of insulin detemir"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "P&#46; Kurtzhals"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:7 [
                        "tituloSerie" => "Endocrinol Metab Clin North Am"
                        "fecha" => "2007"
                        "volumen" => "36"
                        "numero" => "Suppl&#46; 1"
                        "paginaInicial" => "14"
                        "paginaFinal" => "20"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17881328"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            5 => array:3 [
              "identificador" => "bib0220"
              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A review of human and analogue insulin trials"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "S&#46;C&#46; Gough"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.diabres.2006.10.015"
                      "Revista" => array:6 [
                        "tituloSerie" => "Diabetes Res Clin Pract"
                        "fecha" => "2007"
                        "volumen" => "77"
                        "paginaInicial" => "1"
                        "paginaFinal" => "15"
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                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            6 => array:3 [
              "identificador" => "bib0225"
              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Lower within-subject variability of insulin detemir in comparison to NPH insulin and insulin glargine in people with type 1 diabetes"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "T&#46; Heise"
                            1 => "L&#46; Nosek"
                            2 => "B&#46;B&#46; R&#248;nn"
                            3 => "L&#46; Endahl"
                            4 => "L&#46; Heinemann"
                            5 => "C&#46; Kapitza"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Diabetes"
                        "fecha" => "2004"
                        "volumen" => "53"
                        "paginaInicial" => "1614"
                        "paginaFinal" => "1620"
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                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15161770"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            7 => array:3 [
              "identificador" => "bib0230"
              "etiqueta" => "8"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Less hypoglycemia with insulin glargine in intensive insulin therapy for type 1 diabetes&#46; U&#46; S&#46; Study Group of Insulin Glargine in Type 1 Diabetes"
                      "autores" => array:1 [
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                          "etal" => false
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ISSN: 23870206
Original language: English
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