ravae aos om Recomena Muman haut teay ana Say ets Tarpy PMC joach BSSenNoLoGY 4 European Endocrinology Laken ur Endostna 2018 Marah: 12-7 pucio-pucseretse Pulened online 2016 Mar 15, dl £0.17 £.2016.12.01.12 Pun: 20632601 Recombinant Human Insulins ~ Clinical Efficacy and Safety in Diabetes Therapy WotoansLandora and Juargan Sandu Abstract Insulin replacement therapy isthe standard of care for patients with type 1. and advanced type 2 diabetes mellitus, Porcine and bovine pancreatic tissue was the source of the hormone for many years, followed by semisynthetic human insulin obtained by moi fication of animal insulin, With the development of recombinant DNA technology, recombinant (biosynthetic) human insulin became available in large amounts by biosynthesis in microorganisms (Escherichia colt, yeast) providing reliable supplies of the hormone ‘worldwide at affordable costs. The purity and pharmaceutical quality of recombinant human insulin was demonstrated to be supe- ror to animal and semisynthetic insulin and patients with diabetes could be safely and effectively transferred from animal or semisynthetic human insulin to recombinant human insulin with no change expected in insulin dose, The decision for change remains a clinical objective, follow-up after any change of Insulin product is recommended to confirm clinical efficacy This review provides a summary and retrospective assessment of early clinical studies with recombinant insulins (Insuman®, Humulin®, Novolin®). Keywords: Recombinant human insulin clinical studies, Insuman formulations, NPH insulin, premix insulins, review Insulin preparations extracted from bovine or porcine pancreatic tissue have served as the mainstay of diabetes therapy since 1923, ‘when commercial production was established in Europe and the US+ Animal insulin sources became a limiting factor to provide suff cient supply of insulin for the increasing clinical demand of insulin worldwide, When the molecular structure of human insulin was elucidated, attempts were made at total chemical synthesis but failed to provide a clinically relevant supply.2# A next step towards ob- taining clinically suftable human insulin was processing of animal insulin by exchange of amino acids and extensive purificatio ‘The modified material was addressed as ‘semisynthetic human insulin’ and all pharmaceutical formulations (regular, neutral pro- ste nhuhgovoclatlesPMCSE 1382) snravae aos om Recomena Muman haut teay ana Say ets Tarpy PMC tamine Hagedorn [NPH], premixed insulins) were manufactured from such semisynthetic insulin. At the time when semisynthetic hu- ‘man insulin was introduced to the market, there was an intensive and partly acrimonious discussion about this change in insulin source and about the clinical relevance of the need for "human insulin: When clinical studies confirmed the comparable efficacy of this new type of insulin, the discussion subsequently focused on the improvements related to further purification, in particular, in de creasing the formation of insulin-directed antibodies due to therapy, and reducing the risk of local and systemic allergic reactions, “Recombinant human insln’ became available in large amounts by recombinant DNA technology using fermentation in microorgan sms (bacteria or yeast) Recombinant insulin has a superior level of purity and consistent quality compared with semisynthetic in- sulin, The process of biosynthesis was intially developed by Genentech and rapidly applied on an industrial scale by Eli Lilly fol Jowed by pharmaceutical and clinical process development at Novo Nordisk and Sanofi formerly Hoechst AG/Iloechst Marion Roussel/ Aventis). These companies are the lead manufacturers of recombinant human insulin (See Table ),the human insulin pro- files and clinical aspects have been described and reviewed extensively introduction to clinical therapy in 1982, re combinant human insulin represents the standard of care*!~¥ even after the introduction of insulin analogues“ The standard of care in diabetes therapy is addressed by international treatment guidelines° Many clnial studies with recombinant human in- sulins submitted for regulatory approval have not been published in detail: Bioequivalence studies performed with recombinant Insuman® (Sanofi Paris, France) have been reported recent “Scientific Summaries and Public Assessment Reports" ofthe European Medicines Agency (EMA) for marketed human insulins including Insuman% are found at the EMA website, and approval information atthe website of the US Food and Drug Administration (FDA) = Since is firs ste nhuhgovoclatlesPMCSE 1382)raven ess em Recomena Muman haut teay ana Say ets Tarpy PMC Table 1 Manutscturer Sam ‘Nove Norn Approval 1997 Esinsuman (HRA799, HPA) 1991 US 198205 a Production (Host call) Bacteria (Fecheichia al) ‘east (Succhoronyees cereviiod) Batra (Escherichia) Led de mame ——_insomang Noveling (U5) Hunn (U5) Formulations Insumane Rapid Novoling R Hamlin & Regular Insane Basal Novoling 8 umn Basa Insuman@ Comb 15/25/80/50 _Novoling 70/80" Hamlin 70/30 “In Actaphaneo® 30/70; **1n BU Huminslin 30/70:*naonal approval, In this review, we report on unpublished pivotal clinical studies with recombinant Insuman documenting the efficacy and safety of semisynthetic and recombinant Insuman, and comparing recombinant Insuman with marketed formulations of Hursulin® (Eh Lill, Indianapolis, Indiana, US), Furthermore, the use of insulin formulations in clinical practice Is discussed to review the place of recom binant human insulin in routine clinical practice of today. Clinical Studies with Recombinant Human Insulin ‘The initial clinical studies with recombinant human insulins (Humulin, Novolin®, Insuman) explored the change from animal insulin to semisynthetic insulin and to recombinant human insulin formulations. Clinical studies in patients with type 1 or type 2 diabetes, cluded paediatric and pregnant subjects Clinical pharmacology studies using the euglycaemic clamp technique were performed to demonstrate bioguivalence between the insulin formulations The clinical studies of 6 to 12 months duration focused on clinical efficacy and safety. Safety aspects comprised the incidence of hypoglycaemia, the perception of decreasing glucose levels (hypogly- caemie awareness) and the evel of manifestations of antigenicity (hypersensitivity reactions) Special interest was directed atthe antigenicity response (insulindirected antibodies, and antibodies to Escherichia coli or Saccharomeyes cerevisiae proteins) remaining after extensive purification of the preproinsulins#+ Clinical study objectives were incidence and severity of hypoglycaemia 2“ in este govoclvtledP MCSE)ravae aos om Recomena Muman haut teay ana Say ets Tarpy PMC jection-site reactions and adverse events (AEs) profil. Glycaemic targets (glycated haemoglobin [HbA , fasting blood glucose [FBG]) were usually defined individually for each subject by the investigators, Insulin dose titration did not yet follow a fasting treat- to-target concept at that time27 Humulin and Novolin ‘The pharmaceutical formulations of recombinant human insulins provided by the key manufacturers include soluble regular insulin, crystalline NPH insulin and premixed formulations (soluble insulin and NPH insulin in fixed ratios). The formulations were found to bbe bioequivalent and similar in efficacy and safety to those of semisynthetic insulin“ Bioequivalence studies comparing porcine insulin with recombinant human insulin showed small differences in the time-action profile, but were comparable in clinical efficacy: Clinical studies with semisynthetic and recombinant insulin derived from baker's yeast (Novolin, Novo Nordisk, Copenhagen, Denmark) showed similar profiles inefficacy and safety and established that patients with diabetes can be safely and effectively ‘wansferved from semisynthetic human insulin to recombinant human insulin with no change expected inthe insulin dase 2° Clinical pharmacology studies with recombinant human insulin produced by fermentation in E.coli (Humulin, El Lily Indianapolis) established bioequivalence of semisynthetic and recombinant Humulin formulations #233 Extensive clinical studies were per- formed in patients with type 1 and type 2 diabetesl“*3* to confirm consistent clinical efficacy when transferring patients to the re combinant formulations. Insuman Recombinant Insuman was approved in Europe in 1997 and launched in 1999. The early clinical studies are summarised in the EMA, approval documents. The formulations comprise regular soluble insulin (Insuman Rapid), an intermediate-acting insulin suspen- sion that contains isophane insulin (Insuman Basal), and premixed combinations of regular insulin and intermediate-acting insulins (insuman Comb)222 During early studies, the bioequivalence of formulations based on semisynthetic insulin and recombinant Insuman was established (see Ligure 1)22 subsequently bioequivalence studies for comparison with marketed recombinant insulin formulations were performed! and followed by the clinical studies reviewed here. ste nhuhgovoclatlesPMCSE 1382)raven ess em Buel: ‘Comparison of Pharmacokinetic (A) and Pharmacodynamic (8) Prot Serum insulin (wim assess sas Recomena Muman haut teay ana Say ets Tarpy PMC Glucose infusion rate (mgiminute ag — Regular insulin (semisynthetic) Regular insulin (nsuman Rapid S2a0tr2s a5 67 8 9 0 WD Hours after injection Regular insulin (semisynthetioy Regular insulin (nsuman Rapid) 2-10 12 3 4 5 67 8 9 01 2 Hours after injection of Semisynthetic Regular Insulin and Recombinant Regul (Cnsuman Rapid after a Single Dose Injection of0.3 U/kg in 12 Healthy Subjects Using the Euglyeaemlc Clamp Technique? este govoclvtledP MCSE) sieravae aos om Recomena Muman haut teay ana Say ets Tarpy PMC ‘Two pivotal clinical studies with recombinant Insuman were conducted in patients with type 1 and type 2 diabetes investigating the efficacy and safety ofthe change from semisynthetic insulin to recombinant Insuman" and in comparison with recombinant insulin formulations of Huminsulin® An overview of the patient characteristics and the key efficacy and safety results ofthe two studies are provided in Table 2 ste nhuhgovoclatlesPMCSE 1382)ravae aos om Recomena Muman haut teay ana Say ets Tarpy PMC Table 2 ste nhuhgovoclatlesPMCSE 1382) naava esse Recomea Muman hau ~ Cl tency ana San eas Terpy PMC Parameter Seay 2 study 22 Human nslin sod losumand Homan insulin Insuan® (Recombinant) Huminsulin (ecombinan) N88 (Semisyothese) N26 No 236 (ecombinan) N=234 Formulations ured "Number of patens in Monotherapy (NPH or regular) Free combination (bsal-blus) retained combination (eather [NP eesti, asl) noe combination with oF without olen rein (25/75, 30/70) nied combination 0 ° 213.7456) 212 (03%) 75,264) a7) [Ni (erystlin basal. in recombination with oF without relies a premied Premed (30/70) fied combination 67 (28%) 595) 29 (12%) 25.00%) 140 655%) 130 (6498) ns) Sy devin Randomised deublebind Randomised open abel Sty duran 2a weaks Sh weoks "Number of paints wit 392 67%) 196 (66%) Only insuln-nalve ype 2 diabetes patients were lobes 95 (3356) 93 (24) tncluded Type ‘ype ‘re (rs) 81155 21186 5934100 5a5t99 Body mass index (am!) 249236 w7237 29267 waste Duration ofdisbetes (year) 124289 ny=98 99263 wares Hc at baseline (38) asi 278 11572209 e728 39420 beat sty en (96) 1057240 reed noes aie MbA;cchangeliombaselinete 0042245 0852270 1762009) 180 £009 endpoint ‘Data are mean standard deviation (Sb) ules ntindcated elsewhere ln dhs study, te emphasis was placed wo cllet sting bled glucose (°8G) and ‘many cenzes, patents were generally seen nate morning or termoon In keeping routine lila practice, Therefore results for FBG only reflect 33% of nts in cach group. Hb, cated haemoglobia: NPA = neutal protamine Hagedorn este govoclvtledP MCSE)ravae aos om Recomena Muman haut teay ana Say ets Tarpy PMC Ina first multinational, randomised, double-blind 24-week study including 575 adult patients with diabetes (879% with type 1, 33% ‘ype 2), patients were stratified either to a free combination of NPH insulin (crystalline, basal), with or without regular insulin, or to a fixed combination of Insuman Comb 25/75 and randomised to either recombinant or semisynthetic insulin preparations in each group. Ofthe randomised patients, 96% had been treated with insulin prior to the study and 37% of patients had a history of dia- botic late complications, and 429% had frequent mild hypoglycaemic episodes during the year before start ofthe study, The glycaemic target was to achieve a FBG value of 140 mg/dl or lower, Both recombinant and semisynthetic human insulin achieved a similar decrease of HbA,. and FBG after 24 weeks, Subgroups analy ses by age, gender, type of diabetes, prior insulin treatment and presence of diabetic late complications demonstrated similar out ‘comes, There has been an intense discussion about perception of hypoglycaemia in patients previously treated with animal insulins after changing to semisynthetic or recombinant human insulins.“ In this study no difference in incidence of symptomatic hypogly- ‘aemia and in calculated episodes per patient-year were found, as well as no change in the perception of hypoglycaemia, ‘Antigenicity has always been a concern when using animal insulins. However, early studies showed that antigenicity decreased ‘markedly when changing from animal insulins to recombinant insulins. In this study, the level of insulin antibodies related to insulin exposure before treatment was very low, and there was no relevant increase after treatment with semisynthetic insulin or recombi nant Insuman, In addition, there was a very low level of antibodies detected to E.coli proteins in patients treated with recombinant insulin, The absence of such proteins is particularly relevant for the pharmaceutical quality of recombinant insulins after intensive purification, The number of patients with AEs, serious AEs and with local and systemic reactions to insulin injection also did not dit- for between the insulin treatments, Ina second multinational, randomised, open-label 54-week study in 473 insulin-naive subjects with type 2 diabetes the efficacy and safety of recombinant Insuman was compared with recombinant Huminsulin formulations, Huminsulin formulations were selected as ‘a comparator based on bioequivalence confirmed with Insuman.!! Treatments comprised regular insulin, crystalline NPH insulin and premixed insulins (Insuman Comb 25 and 50, Huminsulin 30/70), Selection of treatment regimen was at the discretion of the investi- gators and individual dose titration was applied to achieve the best possible glycaemic control for each subject ‘The primary study objective was an evaluation of antigenicity and measurement of antibodies to human insulin and E.coli proteins?!~2 Further safety aspects included hypoglycaemia assessment, local or general manifestations of insulin allergy and clin cal AES during treatment, 4s expected for insulin-naive type 2 subjects, the insulin antibody binding increased in both treatment groups while on insulin treat- ‘ment, with no relevant difference between groups. In both groups, increased insulin antibody binding was not associated with deteri- oration of metabolic control or a marked increase on the insulin dose or hypoglycaemia incidence. At study endpoint, 52% and 49% ste nhuhgovoclatlesPMCSE 1382) aneravae aos om Recomena Muman haut teay ana Say ets Tarpy PMC ‘of Insuuman- and Huminsulin-treated subjects, respectively, had detectable insulin antibody binding, Similar results were found for E coli antibody binding status, Only two Insuman and eight Huminsulin subjects had an increase in their E.coli protein antibody titre from baseline to endpoint. Randomised patients had a poor glycaemic control at baseline, As 2 result of insulin treatment, a clinically relevant decrease from baseline to endpoint was observed in HbA. and FBG in both treatment groups, with no statistically significant difference (see Table 2 }. Throughout the entire treatment phase, 40% and 496 of Insuman and Huminsulin patients reported at least one episode of symp- tomatic hypoglycaemia, respectively, and only a few subjects in both treatment groups reported moderate or severe hypoglycaemia during the study. The frequency and spectrum of non-serious and serious AES were comparable in both treatment groups. Hypersensitivity events of mild or moderate intensity were reported in 12 Insuman and in one Huminsulin subject, respectively, ‘These events were associated with pre-existing skin disorders, allergic reactions to concomitant medication or allergic diathesis None of the 12 Insuman subjects discontinued treatment because of a hypersensitivity event. Injection-site haemorrhage occurred ‘occasionally and was attributed to poor injection technique Injection-site reactions*? were reduced dramatically when educational ‘raining for regular changes in injection sites along with improved injection techniques were initiated during the study. None of the subjects in either treatment group discontinued treatment because of injection site reactions. In summary, both studies demonstrated improvements in glycaemic control and good tolerability with Insuman in type 1 and type 2 diabetes patients comparable to comparator treatment, In addition,no difference in immunogenicity between Insuman and Huminsulin or semisynthetic insulin was found, an important characteristic of recombinant insulin formulations" Clinical Use of Recombinant Human Insulin Formulations ‘The change from semisynthetic synthesis to recombinant rDNA technology! has enabled a worldwide human insulin supply of con- sistent high quality. The range of different insulin formulations derived from recombinant human insulin allows for an individual patient@s tallored treatment using different regimens that have been proved effective and safe in the long term (see Table 3). Hypoglycaemia associated with insulin treatment remains one of the major challenges during therapy; to minimise the risk, close ‘monitoring and guidance for the patient is recommended, particularly during initial and any later dose titration, Seli-monitoring of fasting and post-prandial blood glucose are helpful tools to avoid or reduce hypoglycaemia and to maintain blood glucose values in the target range. Therefore, patient education and guidance is a general task of insulin therapy to ensure a continued adherence to therapy and good metabolic control ste nhuhgovoclatlesPMCSE 1382) toeravae aos om Recomena Muman haut teay ana Say ets Tarpy PMC Table 3: Tsun Type ‘Onset ofAction Peak Efe Duration of Action” Injection to Meal Tnterval (otinte) ours) (tours) (inte) Regular (apace) Wid 30 255 e 130 [NPH (inermediat-acing) 60-90 ~20 None compound) wishin 30 st ~18 15:0 25/75 00 30/70 Regular Human I nsulin In this review, the use of formulations of recombinant insulin, in particular that of Insuman, is considered with references to dally clinical practice, in diabetes therapy of today. The clinical evid 1 injection-to-meal interval of about 30 minutes (prandial sulin) is based on the time-action profile of regular insulin + to match subcutaneous insulin absorption with ingestion of carbohy- drates (see Figure 2)*344 This ensures efficacy, albeit at the disadvantage of having to follow a more restrictive lifestyle. Subsequent. studies have shown some advantage for insulin analogues in reducing the injection-to-mesl interval, at the expense of increasing the cost of therapy. ce fi ste nhuhgovoclatlesPMCSE 1382) sieravae aos om Recomena Muman haut teay ana Say ets Tarpy PMC —insuman Rapid se Insuman Basal sc lin concentration uu/ml (median) serum in Tres e567 BWM 1S Hours ‘Comparison of Serum Insulin Concentrations ater Subeutaneous Singledose Injection (0-3 U/kg) of Two tnsuman Formulations in 24 Healthy ests In clinical emergency, Insuman Rapid may be injected or infused intravenously under strict glucose control. When using continuous subcutaneous insulis infusion (insulin pumps), there isa clear clinical preference for fast-acting insulin analogues in the paediatric population. Studies with a specific formulation (Insuman Infusat) in external portable insulin pumps have shown improved stability to minimise loss of efficacy which may result from mechanical and thermal stress. limited number of studies have been performed for the use of Insuman Infusat in external insulin pumps, and with Insuman Implantable in intraperitoneal insulin pumps 242 Neutral Protamine Hagedorn Insulin iis ah govclalesPMCSETS 2 saeravae eos om Recomenam Human hau = Cl teay ana Say ets Tarpy PMC Intermediate-acting NPH insulin has been used extensively for basal insulin supply the clinical efficacy has been well documented*2#? and the associated quality of life has not been found to be worse when compared with long-acting insulin largine#? There has been a discussion about once- or twice-daily injections, in the morning and at dinner time /bedtime == Limitations of clinical utility when using NPH insulin are the duration of aetion and more frequent hypoglycaemia episodes than with suspension immediately before each injection, Tong-acting insulin analogues. Another limitation isthe need for r In several clinical trials, where human NPH insulin was used as the comparator for insulin glargine!2435122 comparable glycaemic control was found, whereas the incidence of nocturnal hypoglycaemia was reduced with insulin glargine, Decreased incidence of hy- poglycaemia was also described with other long-acting analogue insulins (detemir, degludec). NPH insulin in vials or insulin pens needs to be re-suspended immediately before the injection. This requires patient guidance and instruction to ensure consistent ad- herence to this procedure. Twice-daiy injections of NPI insulin, in the morning and at dinner time/bedtime, are recommended by some clinicians because the time-action profile of NPH insulin does not adequately cover the 24-hour period (see Figure 2). The rec- ‘ommendiation for twice-daily injection is valid for premixed insulins, which contain a 70-75% fraction of NPH insulin, Premixed Insulins In the early clinical period of using semisynthetic insulins from vials, patients used to perform the mixing themselves using two sepa- rate vials of regular insulin and NPH insulin, In several studies, premixed insulins were compared with self-mixed insulins, and for~ :mulations were developed for the use in cartridges containing a ratio of soluble to NPH insulin over a range which varied from 15/85 to 50/50. ‘Today, the ratio of 30/70 is most frequently used both in pens with cartridges and disposable insulin pens# Premixed insulins are recommended for patients with a regular lifestyle and consistent insulin requirement. When compared with premixed insulin ana- Jogues, they retain the advantages of low cost and established efficacy. The availabilty of reliable and affordable insulin pens has contributed markedly to patient convenience in countries with limited resources. Use in Pregnancy and Gestational Diabetes ‘uman insulins the standard of care in pregnant womens Inthe early elinical studies in pregnancy, the change from ania in sulins to recombinant insulin was addressed and subsequently implemented. Consistent glicose monitoring and dose adaptation is {important throughout pregnancy and counseling needs to be established within the programme of pregnaney care for mothers with diabetes. Gestational diabetes develops during pregnancy and may disappear after parturition, The condition of gestational diabetes ste nhuhgovoclatlesPMCSE 1382) saeravae aos om Recomena Muman haut teay ana Say ets Tarpy PMC hhas received much attention, because there are established treatment options with insulin during pregnancy, which have consider: able efficacy in preventing foetal macrosomia in a similar manner as for women with established diabetes prior to pregnancy, The use of human insulin and Insuman formulations during pregnancy has been monitored in pharmacovigilance programmes (periodic safety updates, riskemanagement plan) and found to be safe. Use in Paediatrics ‘The change from animal insulins to recombinant human insulin is well documented in the paediatric population"! and is found to bbe an advantage because the decrease in manifestations of antigenicity is particulary relevant in children. The preference for use in children has been included in guidelines.? Consistent glucose monitoring is required because of the widely varying dose require ‘ment and distinct changes in insulin requirement during the growth period of children. The Place of Recombinant Human Insulin in Diabetes Therapy When considering efficacy, there is clearly an established place for human insulin formulations inthe therapy of type 1 (multiple daly injections) and type 2 diabetes. This clearly addressed in current gudelines2"2 The need for action s particulary urgent in ‘ype 2 diabetes 2 When comparing cst of therapies, recombinant human insulin formulations are the choice for countries in pa- tients with limited resources. In countries with more ample resources, combination therapy is now extensWvely investigated, eg aadingeacagorte pepe 1 ‘agonists or dpeptdy peptidase # inhibtors=== and by once-daty injection of prandial insulin Convenience of using insulins analogue is well established, and there is a certain advantage in reducing hypoglycaemic episodes #42542 The established regiments of basal, premixed and basal-bolus therapy can be implemented with the available range cof human insulin formulations when access to insulin analogues and reimbursement are not available. The essential conditions for improving therapy are ghicose monitoring, its frequent implementation, continuing patient education about insulin injection technique! and how to re-suspend NPH premixed insulins before each injection. Although adherence to rec ‘ommendations for storage conditions is helpful, there is, however, no difference from the analogue insulins in this respect. In light of ‘worldwide awareness that early implementation of insulin therapy can prevent or delay diabetes complications, access to affordable insulin therapy is the predominant factor when considering recombinant human insulin formulations. Conclusions stm uh govoclaleuPMCSE 1382)rave esse Recomenam Human hau = Cl teay ana Say ets Tarpy PMC As the burden of diabetes is predicted to increase dramatically inthe next decades, the demand of insulin in sufficient amounts and at affordable costs remains a challenge, particularly in developing countries. For that reason, recombinant human insulin formula tlons are considered to be effective alternatives to insulin analogues in countries with limited healthcare systems and limited re sources. Continuing patient education support programmes on disease management and correct use of human insulins are essential (eg, resuspension of NPH and premixed formulations, injection technique, adequate storage) for a key role of recombinant human insulins in diabetes treatment. In developing countries, improving access to human insulin can support initiates for earlier insulin therapy, to improve glycaemic control in the communities, and finally to delay or reduce diabetes complications in the long term. Acknowledgments ‘Medical writing assistance for this manuscript was provided by Catherine Amey at Touch Medical Media and was funded by Sanofi US. The contents of this paper and opinions expressed within are those of the authors, and it was the decision of the authors to sub- mitthe manuscript for publication, The authors were responsible for the conception of the article and contributed to the writing i cluding critical review and editing of each draft, and approval of the submitted version. Funding Statement Support: The publication of this article was supported by Sanofi US References 1. Walsh 6. Therapeti insulins and ther large-scale manufacture ppl Microbiol Biotechnol 2005;67181-9, Pub} [Sage hala} 2, Chance RE, Frank BH. Research, development production and safeyoflosynthetc man insulin, Diabetes Care. 1998 t6(Suppl. 9) 133-42, [ubMad Henle scholar] {3 Mayer IF Zhang Marchi RD. Insulin structure and function. Bopoymers 200788:687-713, EubMed [Gane Scholar} 44 Ruttenberg MA, Human insulin: file synthesis by modification of porcine insulin, Since 1972:177'623-6 [EubMad) [Goose Scholar} 5 ObermeierR, Geiger R Anew semisynthesis of human insulin. Hoppe Seyler Z Physiol Chem, 1976:387:759-67 (EubM} [Googe Scholar} 6 Ladisch Mf, Kohlmann KL, Recombinant hunan insula, Blowchea ro, 199238-469-78,[Pubbed) [Googe Scholar 7 Brogden RN Hel RC. Human insulin. eview ofits ological actly, phamacoknetes and therapeutic use. Drags 1987;34:350-71, (PubMed) [Goode Sehol este govoclvtledP MCSE) ssi8raven ess em Recomena Muman haut teay ana Say ets Tarpy PMC 8, Home PD, Thow C, Tunbridge Fk. Insulin trstment a decade of change fr Med Bul 1989;4592-110, [PubMed (ole Shela] 9 vor) Kee , Changing fom porcine to human insulin. Drags 199447285-96 (EubMad) [Gaus Scholae} 10, 1D (2032) ternational Diabetes ederaon Cina Guidelines Task Force: Global Gudeline for Type 2 Diabetes 2012, vaale a used /etes/deay es IDF dlie fo Type 2-D betes pt (acessed 9 uly 2015). 1. zucehi SE, Bepenstal RM, Buse JB tal. Management of typerpycemlain ype 2 dabeesspaen-centred approach: postion statement ofthe American Diabers Assocation (ADA) andthe European Association forthe Study of Diabetss(EASD) Diabetes Cave 201235:1364-79, [PCs rica [ble] [Goals schol 12, Canadian Diabetes Assocation 2008 Clinical Practice Guldelines forthe Prevention and Management of Diabetes n Canada Con iobtes 2008;321-20, (Gaoalesehola) 15 Sandow J LandgafW, Becker, Sipe G Equivalent recombinant human nsuln preparations and thee plac in tharpy Bur Endocrinology 2015;1110-6,(oosle schol 14 Delawter DE, Moss. Mumman insulin: a double-blind clinical sud ofits fecvenes. South Med 1985,78634-5, [PubMed (Gaus Scala 15, Drages#PDA: FDA Approved Drug Product: Search insulin, Avallable st hi: ne sccecst fa g/cc /ade Mugen? fuseacuonSarch SorchActionkSearehType=BasicSarchdsearhTorm=insli accessed 7 September 2015), 16, Mann NF Johnstor DI, Reeves WG, Murphy MA Human insulin and porcine insulins the teatnent of abel cildren comparison of meubalic contol and Insulin antibody production Br Med) 1983:267-1580-2 [PMC ie article) [PubMed [Goole Sols] 17. Jovanovic Peterson tml ls Peterson CM, Randomized rl of human versus animal species nslin in dabei pregnant women: improved lycere canta, not ewer antibodies tosis iuerces birth wight Am Obstet Gynecol 1997; 167:1325-30 (Publi (Gaol Seba 1, Markassen J Damgaar Pigs M. tal Human asin (Novo): chemistry and characteristics. Dieter Cae, 19835(Supp- 1) 4-8. (Publ Goth Sola] 19, Padersea 6 Hoctholes AA comparison of semisynthetic human NP insulin and porcine NP insulin inthe tetment of nsll-dapendent abet lis Diabet Med 198743046, [Publed [Goope Scholar 20, Deckert. The immunogenicity of new insulins, Diabetes 1985;24(Supp.2}94-6, PubMed) [Google shale] 21. Van Haein TW. nial signsicance of insulin antbodes in insulin-treated diabee patiens Diabetes Care. 198%;124641-B, [Pubed] [Googe Scala 22 Laustano AA, laments RSJ: Bel D. nel antibodies in nominali-dependen diabetes melts of treatment with semsyaic human insulin Ci Ther 1989;11268-77. [PubMed (Goose Schole 23. Scheraner . Immunogenicity ad allenic potential of animal an human insulins. Disheter Care 1993:16(Suppl. 3155-65 [PubMed [Geo este govoclvtledP MCSE) toi8raven ess em Recomena Muman haut teay ana Say ets Tarpy PMC 24, yer P, Davis SN, Sbamoon Hypoglycemia in dsbetes, Diets Care, 2003,261902~12, (PubMed (aale Sela] 25, Cyer PE Hypoglycemia type 1 diabetes melts. Endocrinol Mtab Cl North, 2010;3%641-54, [MC fee ail] (PubMed) (Google hols} 26, Seagust BR, Anerson, Childs B etal. Hypoglycemia and diabetes: a report ofa workgroup ofthe American Diabetes Assocation an the Endocrine Society Diabetes are 2013865138495 [PMC fee article) [PubMed] [Goose Sela 27. Owens DR. Stepwise Intensifteason of inslln therapy Intype diabetes managementexploring the concep ofthe basal pus approach in clinical practice Diabet ‘Med, 2013:30276-88, PMC fse ail] (PubMed [Google hola} 28. Fletcher A, Barnett AM, Pyke DA etl, Transfer fom animal ins (abet (Google hola) inst semisyahetic human insulin a tay n four contre. Diabetes Res 1990;4:151-8 29, bavidson A, Ramer LG Ras Seam Jl Transfer of patents with dlabets fom semisymeic human nel ty human insulin prepare by recombinant DNA ‘wchnology using’ yeast a double lind, randomized study. Clin Ther. 1991;13587-68, [Pte] (Gogle Scola 30, Raskin sola Clements RS e-The use of human insulin derive rom baker's yeasty eecombinant DNA techno Cn Ther 19911356978 (PubMed) [Goole 51 AronoffS Goldberg, Kumar D etl, Use ofa premixed insulin regimen (Novoln 70/30) replace selsmined insulin regimens. ln Ther. 1994:1641-8 PubMed] (Google Sobol 52, Beyer), zmana FLauerbach Mel. Treatment wth human insulin (Feombinant DNA) in dlabetc subjects retreated with ork ox Beef ns: stress af a ‘multicenter study. Diabetes Care, 19825(Suppl.2}340-8, [PubMed [Goose Scholar 35. Galloway JA, Root MA Berputrora Reta. nical pharmacologe studies with human insulin recombinant DNA) Diabetes Care 1982:5(Suppl 2):13-22 (PubMed (Gaotle Sohal} 24. Garber Al, Davidson J, Krosick Atl. Impact of anser from aimal-saurce insulins to biosynthetic human insulin (DNA Ecol) inpatients with dibetes melts ln Ther 1991:13:627-36, (PubMed) [Soop Seba 35. ll DS, Cuter GR Laustano AA. lea ofa premixed semisynthetc human insulin regimen Ther: 198911-795-801,(Pub¥ed)[Goope eho 36. trodowe K Chetsor RA comparison of prmbied insulin preparaions in aldely patents iliac of 70/30 and 50/50 human insula matures, Diabetes Care 1995A8855-7,(DubMed [GoogleScholar 137. W500022779 Insuman selene discussion, updated 2005 Available a in. /wwnemseurona.ey/does/en GB /Socument ary /EPAR -Ssiniic Discusion /humsn/000201/AVC500033779.d (acess 9 uly 2015). 38. Guan Sqnorin AM, Gon Inslin formations ~ review. Bur ev Med Pharmacol Sl 20015:73-A3|2ubMed)(Gaople Scholae} este govoclvtledP MCSE) amieraven ess em Recomena Muman haut teay ana Say ets Tarpy PMC 38, study 1006 (1995), Comparison ofthe pharmacodynamics and pharmacokineses of HOES: HGT (biosynthetic humar insulin) and HOBSLK (semisymthetc hun insulin using the eulycamic clamp tchniqu. linia Sudy report At HOE 31 HGT/2/D/11 [data one 40, Study 302 (1995) Comparison ofthe eflacy and safety of diferent blosyathec and semisynthtic humas nslls formulations in a 24wook therapeutic tsa Cnc Study report #1 HOE 36 HCT/2/MN/302/DM [data i) 44, study 3002 (2000), comparison of safety and efficacy of recombinant human insulin of Hoechst Marion Roussel and of Lil requiring insulin eatment(HR1799A/3002), Cina study repore No, F2000CL.NO624; 200, [ata on fe. tn ype2 Diet patents 42. Kalra Sahara¥, Sarah MP ctal-The est Indln recommendations forbes practices in nsll Injection technique. ndlan J Endor Metab 2012:16876-86, (eo fee anil) (Eubbed (Goope Scholar] 45, study H117994-1001 (1997. Comparisons of the pharmacodynamics and pharmacokinetics ofblosyatatc regular buman insula (Meechst Marion Rousse!) and bosynetic regular human insulin (Lill) by using he euglycemic clamp technlgue. nical study repr [data one}. 44 study 17994-1003 (1997. Comparisons ofthe pharmacodynamics and pharmacokinetics of blosyntatic basal human insulin (Hoechst Marion Rousse!) and bosyatetic basal uaa insulin (Lil) by sing the euglycemic clamp technlgue, Cina study repr [dats one), 45 Jeandiler Slam J, Renard etal. Dacreasd severe hypoglycemia fequency during inuaperttncl sulin infusion using programmable eplanable pumps ‘valine udy Group Diets Care, 199519780 (PubMed) [Gaol Seba 46, Seam J itera nd implantable ineulin pumps: current plac inthe treatment of abet, xp Clin Endoriol Diabetes, 200;109(Suppl.2)}S223-40, [PubMed (angle Sobol} 47. Duckworth W, Davis SN, Comparzon of insulin large and NP insulin nthe treatment of ype 2 dabetesa review of lineal studles,j Dab Complications 2007.21:196-204[Pubsed [Gouge Seda 48, Yljurvinen Ry hkdlaK etal, Comprisn of bedume insula regimens in patients with pe 2 dlabetes melts. A randomized, contol ial. Ane Ice Med 1999;150389-96, [bed] [gle Sola 49. Merman N, Keleer 8, Kehimann Teal, Treatment sassfiction and qualiy-a-ifebetwean ype 2 diabetes patents inating long vs. intermetiteacting baal Inulin therapy in combination with rl hypoyiycemic spent ~ randomized, respective crossover open clinical tl leah ond Quality of Life Outcome 2015;1377-90, (MC real] (PubMed) [Google Sohal 50, Csi K Cunningham GR, Comstock Safety and eicaey of normalising fasting glucose wit bedtime NP insulin alone NIDDM. Diabetes Care 195: 18:63-51 (abst [Ganj Seholar 5. Rosenstock J Sehwarts St Carle CM J eal. taal nsln therapy in type? dlabetes: 28-week comparison of insulin large (10% 901) and NP nsuln Diabet are, 200124681-6, [PubMed [Goole Sol este govoclvtledP MCSE) seraven ess em Recomena Muman haut teay ana Say ets Tarpy PMC 52, Massi Benedetti M,Murnburg Dressler A Ziemen M.A one-year randomised, multicentre tal comparing insulin largine with NPH insulin in combination with coral agents in pation wth spe 2 dlabetes. Horm Metab Res, 2003'35:289-96, [bubMed Goal Sola ‘53. Techledel 8 lmlda 0, Redfeur|, lack Ifa expertence and evalatlon of eusble Insulin pen devices among patients with dlaberes in emerging counties, Diabetes Therapy. 20145545-SS, [EMCseae arcs) [PubMed inate Scola] 5¢, itil, Block]M, Brown FM, etal Managing preasting diabetes for pregnancy: summary of evidence and consensus recommendatons for care, Diets (ore 2008311060-79, (EMC xe rac) [2ubMed} (Ganse Scala 55, Aga MM, Punnose |. Recent advances nthe mestment of gsttonal diabetes, Expert Opin Investig Drugs 2004;13:1102-11, PubMed} [angle Shalt} 56, Hare, egg A Dyson Petal, Insulin for ype 2 dlabetes: choosing secondin Insulin regimen Int) Cn Pract 2008,62:1647-S9 EMC fe ait] (Pub (Google Sebati) 57 ollu WT alley Crete RG. eal Insulin therapy in people with type? dlbets: opportunities and challenges, Diebetes Cave, 201437-1499-508 [PMC ae ule (bub) (Songle Schalan} 58. RaccahD, Bree! RG, Owens D, Riddle M. When basal Insulin therapy Intype 2 dabetes mellitus isnot encugh—what nex? Diabetes Metab Res Rev 2007:28257— 4, aba) (Gaogle schol este govoclvtledP MCSE)