New insulin types in type 1 diabetes mellitus

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Available online 29 January 2016. Keywords: Diabetes mellitus. Basal insulin. Insulin analogue. Insulin degludec. Insulin glargine. a b s t r a c t. Since its ...
Med Clin (Barc). 2015;145(2):70–75

www.elsevier.es/medicinaclinica

Review

New insulin types in type 1 diabetes mellitus夽 Jordi Mesa Servicio de Endocrinología y Nutrición, Hospital Universitari Vall d’Hebron, Barcelona, Spain

a r t i c l e

i n f o

Article history: Received 2 April 2014 Accepted 10 April 2014 Available online 29 January 2016 Keywords: Diabetes mellitus Basal insulin Insulin analogue Insulin degludec Insulin glargine

a b s t r a c t Since its discovery almost a century ago, insulin remains the mainstay of treatment of patients with type 1 diabetes mellitus. Although progress in the synthesis of new formulations has been remarkable, the physiological profile of insulin is still different from that observed with preparations available nowadays. In the last decade, the introduction into clinical practice of insulin analogues has allowed significantly improvement in glycemic control and has facilitated the spread of basal/bolus patterns, the most physiological ones until now. Despite the benefits of basal analogues, glycemia often varies considerably when used as a single daily injection and this is why new molecules have been further investigated. Improvement has been achieved especially in terms of duration and rate of hypoglycemia, the main limiting factor of intensive therapy. This article reviews the available data concerning the new basal insulin analogues, degludec, pegylated lispro and glargine U300, and new formulations currently under development. ˜ S.L.U. All rights reserved. © 2014 Elsevier Espana,

Nuevas insulinas en la diabetes tipo 1 r e s u m e n Palabras clave: Diabetes mellitus Insulina basal Análogo de insulina Insulina degludec Insulina glargina

Transcurrido casi un siglo desde el descubrimiento de la insulina, sigue siendo en la actualidad la base del tratamiento de los pacientes con diabetes mellitus de tipo 1. Aunque los progresos en la síntesis de nuevas formulaciones han sido notables, el perfil fisiológico de la insulina es aún distinto del que se obtiene con las preparaciones disponibles en la actualidad. En la última década, la incorporación a la práctica clínica de los análogos de insulina ha permitido mejorar de forma importante el control glucémico de los diabéticos y ha facilitado la generalización de las pautas bolo/basal, las más fisiológicas hasta estos momentos. A pesar de las ventajas de los análogos basales, en muchas ocasiones las glucemias oscilan considerablemente cuando se utilizan en forma de inyección única diaria, y es por ello que se han seguido investigando nuevas moléculas que mejoren las existentes, especialmente en cuanto a duración y para evitar la presencia de hipoglucemias, el factor limitante fundamental de las pautas intensificadas. En el presente artículo se revisan los datos disponibles referentes a los nuevos análogos de insulina basal, la insulina degludec, la insulina lispro pegilada y la insulina glargina U300, y de las nuevas formulaciones actualmente en fase de desarrollo. ˜ S.L.U. Todos los derechos reservados. © 2014 Elsevier Espana,

Introduction The subcutaneous administration of insulin is still the mainstay of treatment for patients with type 1 diabetes mellitus (DM1) and its main objective is to control glycaemia in the most physiological way possible.1

夽 Please cite this article as: Mesa J. Nuevas insulinas en la diabetes tipo 1. Med Clin (Barc). 2015;145:70–75. E-mail address: [email protected] ˜ S.L.U. All rights reserved. 2387-0206/© 2014 Elsevier Espana,

In the more than 90 years that insulin has been available, many advances have been made in its production, purification, formulation, and method of administration. The first baseline insulin to be produced, protamine-zinc, was developed in the 1930s, and was followed 20 years later by the long-acting, and NPH insulins. Both insulins were widely used for decades, while essential advances were made in reducing their immunogenicity. In the 1990s there was renewed interest in prolonging the action of basal insulin when deficient glycaemic control was associated with microvascular complications. The Diabetes Control and Complications Trial (DCCT)2,3 demonstrated that intensifying insulin treatment in order to normalise glycaemia as much as possible, evaluated by a

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Table 1 New insulins under trial or development phase. Insulin

Patent

Duration

Characteristics

Phase/status

New analogues Degludec LY2605541 Glargine U300

Novo Nordisk Eli Lilly Sanofi

Long-acting Long-acting Long-acting

Two modifications of insulin ␤ chain Pegylated lispro insulin Glargine insulin at greater concentration

EMA authorisation Phase III Phase III

New formulations Insulin PH20 Linjeta BIOD adjustable basal LY2963016 MK-1293 FT-105 BIOD-Smart Basal Glaritus

Halozyme Therapeutics Biodel Biodel Eli Lilly MSD Flame Tech Biodel Wockhardt

Fast-acting Fast-acting Long-acting Long-acting Long-acting Long-acting Long-acting Long-acting

Regular insulin with recombinant hyaluronidase Regular human insulin with EDTA and citric acid New formulation of glargine insulin Insulin glargine biosimilar Insulin glargine biosimilar Insulin attached to vitamin E and polyglutamate Insulin glargine, glucose oxidase and peroxidase New formulation of insulin glargine

Phase II Phase II. Halted Phase I Phase III Phase III Phase I Preclinical Phase I

EDTA: ethylenediaminetetraacetic acid; EMA: European Medicines Agency.

reduction in glycated haemoglobin levels (HbA1c ), reduced the risk of developing secondary complications, and delayed its progression in patients already presenting with the disease. Until that time, the guidelines were one or 2 daily injections of intermediate action insulin with pre-prandial supplements of fast-acting insulin. However, after the DCCT, the general guidelines were to use intensive therapy, which has been shown to be more effective in achieving optimal control. The basal insulins, which are characterised by slow and progressive absorption, and long duration of action, imitate the physiological secretion of the pancreas and provide better overall glycaemic control, reducing morning pre-prandial hyperglycaemia and hypoglycaemia episodes. The application of DNA recombination technology since the mid-eighties enabled the development of different insulin analogues, whose features provide them with additional benefits over the insulins used previously. The basal insulins that are currently available are the long-acting analogues glargine and detemir, and the traditional intermediateacting human insulin, NPH. Insulin glargine (IGla) was developed by bioengineering in order to achieve a molecule with better solubility at physiological pH which, when injected as an acid solution, forms a precipitate in the subcutaneous space, thus enabling a slower absorption rate.4 In 2003, the use of detemir was authorised; it has a similar action profile to lGla, but unlike insulin glargine achieves its prolonged effect by binding to albumin.5 Both basal analogues have been demonstrated not to be inferior to NPH insulin, and while the latter is administered as a precipitate, the analogues achieve delayed absorption by means of other mechanisms. With the analogues, the risk of incomplete resuspension of the formulation before it is injected is avoided, and therefore the pharmacodynamic effect of injection-to-injection variability is eliminated. The therapeutic benefit of both basal insulins has been well established, producing a more prolonged effect, with a lower peak and less variability than the traditional NPH, which are currently standard in the management of diabetic patients. Generally their profile allows them to be administered once a day, with a lower risk of hypoglycaemia episodes.6–8 Some cost–benefit analyses have not proved favourable to the current analogues, essentially because of their high cost, but nonetheless they currently represent 80% of the insulin market.9,10 Despite the advantages of these basal analogues, glycaemias often vary considerably when they are used in the form of a single daily injection, and this is why new molecules continue to be investigated. The objective of these latest-generation, basal insulin analogues is to achieve a treatment which provides insulin in a continuous, stable and predictable way over at least 24 hours, with less

variability, a low incidence of hypoglycaemic episodes, and which are possible to use in premixed preparations.11,12 In this article we review the available data on the new insulin preparations which are about to be marketed or are currently under development (Table 1), with the objective of improving on those already available by achieving a constant and predictable effect on glycaemia, as well as the new formulations of both rapid and longacting analogues.

Degludec insulin This is the first ultra-long acting insulin analogue on which there is the most data available; it was authorised by the European Medicines Agency (EMA) in 2013, and is soon to be marketed in Spain. The degludec (lDag) insulin molecule preserves the aminoacid sequence of human insulin, except the elimination of threonine in position B30 (TrB30, and the addition of a chain of 16 carbons attached to lysine at position B29 (LisB29) of the insulin B chain through a glutamic acid bond.13,14 It contains phenol and zinc in its pharmaceutical formulation, forming a soluble and stable dihexamer, but after injection they start to associate together, forming long chains of multihexamers, and creating a subcutaneous deposit. As the zinc disperses, these structures slowly dissociate into smaller units, and result in a slow release of active monomers into the blood stream. The process is slow and progressive, with a flat profile and no peaks, producing a stable effect on glucose regulation.

Pharmacokinetics and pharmacodynamics Its half life is approximately 25 h and is not associated with the dose given. With a daily injection, a state of equilibrium is reached in approximately 3 days. The pharmacological properties of IDeg have been studied in healthy volunteers, and in patients with DM1, and type 2 diabetes mellitus (DM2). All the studies confirm an increase in the length of its action compared to IGla, and a significant reduction in the inter-day variation in response.7 Its half life was almost double that of IGla in patients with DM1 (25.4 h compared to 12.5 h). IDeg remained detectable in the circulation during the entire study period, up to 120 h, whereas IGla reached the lower limit of quantification within 48 h. Its glucoselowering effect can be maintained over a period above 42 h. In addition to its prolonged effect, with no peaks, IDeg was associated with a highly predictable effect in patients with DM1, with little day-to-day variability, to reduce glucose compared with IGla (variation coefficient of 20% compared to 82%)15 and maintaining stability at all times over 24 h.16

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Efficacy and safety The evaluation of IDeg in the BEGIN clinical trials is the largest and most complete phase III programme undertaken for an insulin product, with more than 5000 selected patients. For DM1 the basal bolus regime was evaluated, and for DM2 the basal regime associated with oral lipid-lowering agents, and basal-bolus treatment. In most of these studies IGla was the comparator drug, using an intention-to-treat protocol. In the BEGIN Basal-Bolus Type 1 study,17 including 629 participants, and of 52 weeks duration, IDeg was not inferior to IGla with regard to the degree of glycaemic control; the percentage of patients achieving a HbA1c of lower than 7% was similar with both insulins (40% with IDeg compared to 43% with IGla). The fundamental difference was the fewer nocturnal hypoglycaemia episodes occurring with IDeg. Due to the practical and real difficulty of some patients to follow regular hours, the effects of a flexible dosing regimen with IDeg were assessed.18 Two types of irregular schedules were considered: the first, termed ‘forced flexible’, to evaluate the effects of extreme time variation in a single daily dose, in which the patients alternated evening and morning insulin doses, so that the interval between doses varied between 8 and 40 h; and the second schedule, ‘free flexible’, in which the patients could take their dose once a day at intervals that varied from day to day, and which could be as short as 8 h, or as long as 40 h. At the end of the 26-week BEGIN study, Flex T1, neither HbA1c nor the number of nocturnal hypoglycaemia episodes differed significantly between the flexible doses of IDeg and lGla or the fixed dose of IDeg. Therefore, 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, with fewer hypoglycaemic episodes, especially at night.19 It was also observed that IDeg, given once a day and at any time, has little impact on glycaemic control. In this sense, this insulin can be regarded as more permissive, as adhering to a strict schedule is not necessary, because it continues to be safe and effective even when administered at irregular times. The iatrogenic weight gain associated with insulin treatment was also evaluated in the BEGIN Basal-Bolus Type1 study; it was 1.8 kg with IDeg compared to 1.6 kg with IGla over 52 weeks. Therefore no benefit was demonstrated in this regard. A meta-analysis by Ratner et al.,20 which included all the randomised, open phase III studies (of 26 or 52 weeks’ duration), which had compared IDeg with IGla in patients with DM1 and DM2, concluded that treatment with IDeg offered important clinical advantages, especially in reducing diurnal hypoglycaemic episodes, and nocturnal episodes in particular, which were significantly lower with similar levels of HbA1c , enabling insulin doses to be titrated in a safer and more intensive way.

Degludec plus This is the coformulation of 70% IDeg and 30% of the fast-acting analogue aspart. Its efficacy in adults with DM1 was examined in a 26-week, phase III study and was compared with insulin detemir.21 General glycaemic control was similar with both insulins (reductions inHbA1c of 0.73% and 0.68%, respectively), and the number of hypoglycaemia episodes was also similar (39 compared to 44 episodes per patient-year of exposure). However, nocturnal hypoglycaemia was 37% lower with insulin degludec plus (IDegPlus) (3.7 compared to 5.7 episodes per patient-year of exposure); the rates of general adverse events were similar with both. At the end of the study, both the basal insulin doses and the daily total were significantly lower with IDeg than with insulin detemir,

although there was no significant difference between the groups with regard to daily insulin bolus dose. Weight gain was significantly higher in the patients treated with IDegPlus than those treated with insulin detemir. Cardiovascular safety Analysis of 16 phase 3 clinical trials shows a similar incidence of major cardiovascular episodes, comprising cardiovascular death, stroke and coronary syndrome, in patients treated with IDeg or IDegPlus compared to the comparator drugs (1.48 compared to 1.44 episodes/100 patient-years). Patients with pre-existing cardiovascular disease presented a greater risk of an episode in both groups than patients with no previous disease.22 A post hoc analysis which also included additional trials (including extension trials), but which excluded unstable angina as a combined variable, found an incidence of major adverse cardiovascular events (MACE) of 1.41 events/100 patient-years for patients treated with IDeg or IDegPlus, and of 0.90 events/100 patient years for those treated with the comparator drugs, resulting in a hazard ratio (HR) of 1.614. However, the data from the extension trials only represented 35% of the original population, and provided 2 years of data on cardiovascular events in approximately 12% of the population with IDeg. Because these data were considered less consistent than those of the original trials, a subsequent post hoc analysis excluded the data from the extension trials. This analysis resulted in MACE rates of 1.51 events/100 patient-years (HR 1.125). Because these analyses neither confirm nor exclude an increased cardiovascular risk with IDeg, further studies are currently in progress. The Food and Drug Administration (FDA) requested a additional study specifically for cardiovascular results before reviewing the drug’s application for approval in the U.S.A.23 Its use has been approved in the European Union and Japan without a requirement for additional cardiovascular data. Pegylated lispro insulin Lispro insulin is a fast-acting analogue which has been used for the control of post-prandial glucose levels for more than 15 years. Ly26045541 is a new insulin, formed by attaching a lispro insulin to a polyethylene glycol chain (PEG) to extend its duration of action.24 The molecule of pegylated insulin lispro (PEGlispro) is 4 times larger than that of insulin lispro, therefore its absorption from the subcutaneous space is slowed and, in turn, its glomerular filtration is reduced, thus prolonging its action time. The available pharmacokinetic data for single doses reveal a flat action profile, compared to the available analogues. Efficacy and safety Various studies have evaluated peglispro in patients with DM1 as well as patients with DM2. In Rosenstock et al.’s study,25 137 patients with DM1 were treated, it was compared with lGla in combination with mealtime insulin over 8 weeks. HbA1c was more reduced in the patients with peglispro (−0.63% compared to −0.48%), with similar fasting blood sugars and a lower inter-day variability (−13.1 compared to −4.8 mg/dl). With the known data, it can be confirmed that the glycaemic control obtained is comparable or superior to that achieved with the available basal analogues; some weight loss is also achieved in both DM1 and DM2 patients. Weight loss was 1.19 kg compared to a weight gain of 0.68 kg in the lGla group, due to a mechanism that has not yet been clarified. The overall risk of presenting hypoglycaemic episodes is rather higher than with IGla (8.7 compared to 7.4 monthly episodes) but curiously, the risk of presenting nocturnal hypoglycaemic episodes

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is lower (0.9 compared to 1.1 monthly episodes). Some mild gastrointestinal side effects have been reported, such as a feeling of fullness or abdominal bloating, which have not resulted in stopping the treatment. Studies in DM2 have not shown differences with IGla in reducing levels of HbA1c , fasting blood glucose levels or inter-day variability, but the intra-day glycaemic variability was lower with PEGlispro.26 Recently, Bergenstal et al.27 evaluated the impact of peglispro on glycaemic variability, and hypoglycaemic episodes in 51 patients with DM2 using continuous glucose monitoring. The authors found that fewer patients presented hypoglycaemic episodes, and that this represented less time recorded in that situation compared with lGla. In sum, the pharmacokinetic and pharmacodynamic profiles of peglispro insulin demonstrate a lasting effect of more than 24 h, with greater glycaemic control in DM1, and similar to lGla in DM2. Phase III clinical trials are currently still in progress, of which there are as yet no available results.

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to the new insulin U300 was good, with no differences in other adverse events observed for IGla. In the EDITION II32 study, the efficacy and safety of the new insulin U300 were evaluated in a population with DM2 (811 patients) treated with basal insulin plus oral anti-diabetics. The main results of EDITION II are similar to the findings of EDITION I, achieving similar glycaemic control, and fewer nocturnal hypoglycaemic episodes. EDITION III trials are currently underway in insulin-naïve DM2 patients, EDITION IV in DM1 patients, EDITION JP I in Japanese patients with DM1 (basal + bolus insulin) and EDITION JP II in Japanese patients with DM2 (basal insulin + oral treatment). The principal benefit of high-concentration basal insulin is that patients who require high doses do not need to divide them into separate injections. 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. In these types of patients there are often doubts as to their adherence in completing the dose in a second injection. The analysts are expecting regulatory approval for U300 in the U.S.A., and the European Union this year.

Insulin glargine U300 Subcutaneous injection of glargine insulin provides insulinaemia levels which enable it to be administered once a day, and because of its efficacy and safety, in the past decade it has become a standard treatment for diabetes, and is currently the most-prescribed insulin in the world. As mentioned earlier, in many diabetics it is not possible to achieve the established glycaemic control objectives with the currently-available analogues, and therefore different molecules are still being investigated. In the case of lGla, the patent protection of which expires in 2015, Sanofi have provided a new approach for the development of better basal insulins, and the use of high-concentration formulations, such as insulin glargine U300 (Gla-300) (300 U/ml), currently in clinical trial phase. The new Gla-300, which contains triple concentration per millilitre, improves the profile of this insulin, giving it more stability with reduced peak-trough fluctuations. Its reduced subcutaneous precipitation rate results in even flatter and prolonged pharmacokinetics and pharmacodynamics, in order to achieve better glycaemic control than the original IGla.28 In patients with DM1 the pharmacokinetic and pharmacodynamic profile is dose-dependent, and blood sugar control is evident up to 36 h after injection.29,30 The clinical evaluation of this new insulin was undertaken through the EDITION programme, 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. As a first study of the phase III EDITION programme, EDITION I31 evaluated the efficacy of the new insulin compared with conventional IGla in people with DM2 who used basal insulin plus mealtime insulin. Eight hundred and seven diabetics were randomised to receive a single daily nocturnal injection of the new insulin U300 (n = 404) or IGla (n = 403), while they continued to receive mealtime insulin. The principal evaluation criterion was a change in HbA1c from inclusion up to the sixth month, and the second criterion was the percentage of people with at least one serious or confirmed episode of nocturnal hypoglycaemia. EDITION I showed similar reductions in HbA1c with the new insulin U300, and with IGla at 6 months. Moreover, approximately 40% of the trial participants with uncontrolled glycaemia levels, despite receiving combined treatment (oral anti-diabetic agents plus basal and mealtime insulins), achieved an HbA1c < 7% both in the new insulin U300 group (39.6%), and in the IGla group (40.9%). U300 was associated with a 21% reduction in serious or confirmed, nocturnal hypoglycaemic episodes, between months 3 and 6. In this study, tolerance

New insulin formulations Various second generation insulin formulations are being investigated which include new formulations of both fast-acting and long-acting analogues. Amongst the former, in order to improve post-prandial glycaemia values and meet the objectives as closely as possible, 2 ultra-fast-acting insulin analogues are being developed, insulin-PH20 and Linjeta. The molecule of insulin-PH2024,25 comprises a mealtime insulin and recombinant hyaluronidase. In phase I and II trials faster absorption has been observed, with accelerated pharmacokinetic and glycodynamic effect and lower inter- and intra-patient variability. Linjeta is a new formulation based on regular insulin combined with EDTA and citric acid, which acts as a zinc chelater, and thus prevents self-aggregation of the insulin molecules to form hexamers after subcutaneous injection, maintaining their momomeric status.33,34 In phase I and II clinical trials it showed a faster onset of action, and maximum peak compared with regular insulin or with the fast-acting analogue lispro, in both healthy volunteers and patients with DM1. The last phase II clinical trial undertaken with DM1 patients who were pump users, comparing with insulin lispro, was halted 2 years ago officially due to the drug’s lack of availability, the studies have not been resumed to date. The new formulations of slow-acting analogues are 2 modifications of IGla, BIOD-Adjustable basal and LY2963016. BIODAdjustable 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.35 LY2963016 is a new molecule investigated by Eli Lilly and Boehringer Ingelheim, which constitutes a new IGla product developed for treating both DM1 and DM2 patients.36 In July 2013, the EMA accepted the marketing authorisation application for revision, and in December the FDA did the same. The presentations were made through a regulatory route which allowed reference to be made to previous findings on safety, and the efficacy data which had already been approved for IGla, in addition to the trials of LY2963016 itself. Apart from compared pharmacokinetics and pharmacodynamic studies, the presentation included the results of phase III studies which were completed in patients with DM1, and DM2, using IGla as the active comparator drug.26,37

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Insulin glargine biosimilar MK-1293 is following the same regulatory route and 2 studies are underway in DM1. A phase I study is currently evaluating the safety, tolerability, pharmacokinetics and pharmacodynamics of MK-1293 compared with a basal insulin (IGla) in DM1, and another phase III trial (ClinicalTrials.gov: NCT02059161) started selection a month ago, it will be of 52 weeks’ duration, and include 500 patients, in order to evaluate the drug’s effectiveness and safety compared with IGla. A phase III study with the same molecule is underway simultaneously in DM2 (ClinicalTrials.gov: NCT02059187) with similar objectives, and the same number of cases and duration. A unique type of ultra-long acting basal insulin, FT-105,38 is under development, and consists of a formulation combined with vitamin E, and a polyglutamate peptide in a hydrogel, which gives rise to the formation of dense macroparticles, causing slow release of the insulin into the blood stream. Phase I studies indicate that its duration of action is longer than 48 h, with low intra-patient variability and a reduction in hypoglycaemic episodes. A new approach in injectable treatment, currently in the preclinical investigation phase, is a formulation of insulin which is sensitive to glucose. BIOD-Smart Basal insulin is a formulation which contains glargine, glucose oxidase and peroxidase. This smart insulin is released in proportion to the glucose levels in its environment, which can reduce the risk of hypoglycaemia and hyperglycaemia.11 Conclusions The second-generation insulin analogues which are currently under development, some of which will soon be available clinically, constitute an advance in the treatment of diabetes. With their improved pharmacokinetic and pharmacodynamic profiles, they have demonstrated a capacity to improve the glycaemic control achieved with the first-generation basal analogues, in reducing the risk of one of the major obstacles to achieving adequate control, hypoglycaemia, particularly nocturnal hypoglycaemia. The numerous clinical trials have demonstrated that they are not inferior, and that they are even superior in terms of level of glycaemic control evaluated through fasting glucose and HbA1c levels. They also present lower intra- and inter-daily glycaemic variability, with fewer hypoglycaemias, especially nocturnal, and a more physiological profile. The greater flexibility of the new insulin analogues have the potential to improve patients’ compliance with treatment regimens, in that they enable an administration schedule to fit patients’ different needs and lifestyles. The clinical availability of these new analogues will help us to continue improving diabetic care, providing greater flexibility in treatment, while reducing the adverse effects of insulin treatment. Conflict of interests The author has participated as an investigator in clinical trials for the development of insulins glargine and degludec. References ˜ CA, Zinman B. Insulins: past, present, and future. Endocrinol Metab Clin 1. Borgono North Am. 2012;41:1–24. 2. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of longterm complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329:977–86. 3. Nathan DM, Cleary PA, Backlund JY, Genuth SM, Lachin JM, Orchard TJ, et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005;353:2643–53. 4. Ashwell SG, Home PD. Insulin glargine: the first clinically useful extended-action insulin analogue. Exp Opin Pharmacother. 2001;2:1891–902.

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Owens DR. Insulin preparations with prolonged effect. Diabetes Technol Ther. 2011;13 Suppl. 1:S5–14. 12. Meneghini L. Demonstrating strategies for initiation of insulin therapy: matching the right insulin to the right patient. Int J Clin Pract. 2008;62:1255–64. 13. Wang F, Surh J, Kaur M. Insulin degludec as an ultralong-acting basal insulin once a day: a systematic review. Diabetes Metab Syndr Obes. 2012;5:191–204. 14. Jonassen I, Havelund S, Hoeg-Jensen T, Steensgaard DB, Wahlund P-O, Ribel U. Design of the novel protraction mechanism of insulin degludec, an ultra-longacting basal insulin. Pharm Res. 2012;29:2104–14. 15. Heise T, Hermanski L, Nosek L, Feldman A, Rasmussen S, Haahr H. Insulin degludec: four times lower pharmacodynamic variability than insulin glargine under steady-state conditions in type 1 diabetes. Diabetes Obes Metab. 2012;14:859–64. 16. Birkeland KI, Home PD, Wendisch U, Ratner RE, Johansen T, Endahl LA, et al. Insulin degludec in type 1 diabetes: a randomized controlled trial of a newgeneration ultra-long-acting insulin compared with insulin glargine. Diabetes Care. 2011;34:661–5. 17. Heller S, Buse J, Fisher M, Garg S, Marre M, Merker L, et al. Insulin degludec, an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 1 diabetes (BEGIN Basal-Bolus Type 1): a phase 3, randomised, open-label, treat-to-target non-inferiority trial. Lancet. 2012;379:1489–97. 18. Mathieu C, Hollander P, Miranda-Palma B, Cooper J, Franek E, Russell-Jones D, et al. Efficacy and safety of insulin degludec in a flexible dosing regimen vs insulin glargine in patients with type 1 diabetes (BEGIN: Flex T1): a 26-week randomized, treat-to-target trial with a 26-week extension. J Clin Endocrinol Metab. 2013;98:1154–62. 19. Bode BW, Buse JB, Fisher M, Garg SK, Marre M, Merker L, et al. 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