diaendoСахарный диабетDiabetes mellitus2072-03512072-0378Endocrinology research centre10.14341/DM12357diaendo-12357Research ArticleОбзорыReviewСверхбыстродействующий инсулин аспарт: фармакокинетические и фармакодинамические свойства и их влияние на клинические эффектыFast-acting insulin aspart: a review of its pharmacokinetic and pharmacodynamic properties and the clinical consequenceshttps://orcid.org/0000-0002-6980-8230ХаарХаннаHaahrHanne

Отдел клинической фармакологии

PhD

hhaa@novonordisk.comhttps://orcid.org/0000-0002-8346-2037ХайзеТимHeiseTim

MD, PhD

tim.heise@profil-research.deНово НордискДанияNovo Nordisk A/SDenmark«Профиль»ГерманияProfilGermany202026062020232140160Copyright © Хаар Х., Хайзе Т., 20202020Хаар Х., Хайзе Т.Haahr H., Heise T.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.dia-endojournals.ru/jour/article/view/12357

Сверхбыстродействующий инсулин аспарт представляет собой инсулин аспарт (иАсп) с добавлением двух вспомогательных веществ, никотинамида и L-аргинина, для обеспечения ускоренного всасывания и стабильности состава после подкожного введения по сравнению с ранее разработанными аналогами инсулина ультракороткого действия. Фармакокинетические/фармакодинамические свойства сверхбыстродействующего инсулина аспарт были охарактеризованы в клинико-фармакологических исследованиях с сопоставимой общей методологией. У пациентов с сахарным диабетом 1 типа (СД1) или 2 типа (СД2) профили сывороточной концентрации иАсп и снижение уровня глюкозы смещены по временной шкале влево у сверхбыстродействующего инсулина аспарт по сравнению с иАсп. Кроме того применение сверхбыстродействующего инсулина аспарт обеспечивает более раннее начало действия, в 2 раза большую концентрацию и увеличение в 2,5 раза сахароснижающего эффекта в течение 30 минут после подкожной инъекции, а также более раннее окончание действия. Аналогичные результаты были продемонстрированы при постоянной подкожной инфузии инсулина (ППИИ). Улучшенные фармакологические свойства сверхбыстродействующего инсулина аспарт по сравнению с иАсп одинаковы для всех групп населения, включая пожилых людей, детей*, подростков и японцев. Таким образом, фармакологические характеристики сверхбыстродействующего инсулина аспарт в большей степени соответствуют секреции инсулина у здоровых людей, что дает сверхбыстродействующему инсулину аспарт больший потенциал для улучшения постпрандиальной гликемии у пациентов с СД. Так, по сравнению с исходными значениями изменение концентрации глюкозы через 1 ч после приема пищи значимо лучше у сверхбыстродействующего инсулина аспарт по сравнению с иАсп при его использовании в базис-болюсной или помповой инсулинотерапии в исследованиях III фазы у пациентов с СД1 или СД2. В данном обзоре обобщены опубликованные в настоящее время результаты клинико-фармакологических исследований сверхбыстродействующего инсулина аспарт и обсуждаются его клинические преимущества по сравнению с уже существующими аналогами инсулина ультракороткого действия.

Fast-acting insulin aspart (faster aspart) is insulin aspart (IAsp) with two added excipients, L-arginine and niacinamide, to ensure formulation stability with accelerated initial absorption after subcutaneous administration compared with previously developed rapid-acting insulins. The pharmacokinetic/pharmacodynamic properties of faster aspart have been characterised in clinical pharmacology trials with comparable overall methodology. In subjects with type 1 (T1D) or type 2 (T2D) diabetes, the serum IAsp concentration-time and glucose-lowering effect profiles are left-shifted for faster aspart compared with IAsp. In addition, faster aspart provides earlier onset, doubling of initial exposure, and an up to 2.5-fold increase in initial glucose-lowering effect within 30 min of subcutaneous injection, as well as earlier offset of exposure and effect. Similar results have been shown using continuous subcutaneous insulin infusion (CSII). The improved pharmacological properties of faster aspart versus IAsp are consistent across populations, i.e. in the elderly, children, adolescents and the Japanese. Thus, the faster aspart pharmacological characteristics more closely resemble the mealtime insulin secretion in healthy individuals, giving faster aspart the potential to further improve postprandial glucose control in subjects with diabetes. Indeed, change from baseline in 1-h postprandial glucose increment is in favour of faster aspart versus IAsp when used as basal-bolus or CSII treatment in phase III trials in subjects with T1D or T2D. This review summarises the currently published results from clinical pharmacology trials with faster aspart and discusses the potential clinical benefits of faster aspart compared with previous rapid-acting insulin products.

сверхбыстродействующий инсулин аспартфармакокинетикафармакодинамикаклэмпfaster aspartpharmacokineticpharmacodynamicclampReferencesMonnier L, Lapinski H, Colette C. Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients. Variations with increasing levels of HbA(1c). Diabetes Care. 2003;26(3):881–885. doi: https://doi.org/10.2337/diacare.26.3.881Monnier L, Lapinski H, Colette C. Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients. Variations with increasing levels of HbA(1c). Diabetes Care. 2003;26(3):881–885. doi: https://doi.org/10.2337/diacare.26.3.881Woerle HJ, Neumann C, Zschau S, et al. Impact of fasting and postprandial glycemia on overall glycemic control in type 2 diabetes Importance of postprandial glycemia to achieve target HbA1c levels. Diabetes Res Clin Pract. 2007;77(2):280–285. doi: https://doi.org/10.1016/j.diabres.2006.11.011Woerle HJ, Neumann C, Zschau S, et al. Impact of fasting and postprandial glycemia on overall glycemic control in type 2 diabetes Importance of postprandial glycemia to achieve target HbA1c levels. Diabetes Res Clin Pract. 2007;77(2):280–285. doi: https://doi.org/10.1016/j.diabres.2006.11.011Saad A, Dalla Man C, Nandy DK, et al. Diurnal pattern to insulin secretion and insulin action in healthy individuals. Diabetes. 2012;61(11):2691–2700. doi: https://doi.org/10.2337/db11-1478Saad A, Dalla Man C, Nandy DK, et al. Diurnal pattern to insulin secretion and insulin action in healthy individuals. Diabetes. 2012;61(11):2691–2700. doi: https://doi.org/10.2337/db11-1478Heise T. Getting closer to physiologic insulin secretion. Clin Ther. 2007;29(Suppl D):S161–165. doi: https://doi.org/10.1016/j.clinthera.2007.12.012Heise T. Getting closer to physiologic insulin secretion. Clin Ther. 2007;29(Suppl D):S161–165. doi: https://doi.org/10.1016/j.clinthera.2007.12.012Heinemann L, Muchmore DB. Ultrafast-acting insulins: state of the art. J Diabetes Sci Technol. 2012;6(4):728–742. doi: https://doi.org/10.1177/193229681200600402Heinemann L, Muchmore DB. Ultrafast-acting insulins: state of the art. J Diabetes Sci Technol. 2012;6(4):728–742. doi: https://doi.org/10.1177/193229681200600402Home PD. Plasma insulin profiles after subcutaneous injection: how close can we get to physiology in people with diabetes? Diabetes Obes Metab. 2015;17(11):1011–1020. doi: https://doi.org/10.1111/dom.12501Home PD. Plasma insulin profiles after subcutaneous injection: how close can we get to physiology in people with diabetes? Diabetes Obes Metab. 2015;17(11):1011–1020. doi: https://doi.org/10.1111/dom.12501American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes-2019. Diabetes Care. 2019;42(Suppl 1):S90–102. doi: https://doi.org/10.2337/dc19-S009American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes-2019. Diabetes Care. 2019;42(Suppl 1):S90–102. doi: https://doi.org/10.2337/dc19-S009Sheldon B, Russell-Jones D, Wright J. Insulin analogues: an example of applied medical science. Diabetes Obes Metab. 2009;11(1):5–19. doi: https://doi.org/10.1111/j.1463-1326.2008.01015.xSheldon B, Russell-Jones D, Wright J. Insulin analogues: an example of applied medical science. Diabetes Obes Metab. 2009;11(1):5–19. doi: https://doi.org/10.1111/j.1463-1326.2008.01015.xHome PD. The pharmacokinetics and pharmacodynamics of rapid-acting insulin analogues and their clinical consequences. Diabetes Obes Metab. 2012;14(9):780–788. doi: https://doi.org/10.1111/j.1463-1326.2012.01580.xHome PD. The pharmacokinetics and pharmacodynamics of rapid-acting insulin analogues and their clinical consequences. Diabetes Obes Metab. 2012;14(9):780–788. doi: https://doi.org/10.1111/j.1463-1326.2012.01580.xLuijf YM, van Bon AC, Hoekstra JB, Devries JH. Premeal injection of rapid-acting insulin reduces postprandial glycemic excursions in type 1 diabetes. Diabetes Care. 2010;33(10):2152–2155. doi: https://doi.org/10.2337/dc10-0692Luijf YM, van Bon AC, Hoekstra JB, Devries JH. Premeal injection of rapid-acting insulin reduces postprandial glycemic excursions in type 1 diabetes. Diabetes Care. 2010;33(10):2152–2155. doi: https://doi.org/10.2337/dc10-0692Slattery D, Amiel SA, Choudhary P. Optimal prandial timing of bolus insulin in diabetes management: a review. Diabet Med. 2018;35(3):306–316. doi: https://doi.org/10.1111/dme.13525Slattery D, Amiel SA, Choudhary P. Optimal prandial timing of bolus insulin in diabetes management: a review. Diabet Med. 2018;35(3):306–316. doi: https://doi.org/10.1111/dme.13525Overmann H, Heinemann L. Injection-meal interval: recommendations of diabetologists and how patients handle it. Diabetes Res Clin Pract. 1999;43(2):137–142. doi: https://doi.org/10.1016/s0168-8227(98)00132-6Overmann H, Heinemann L. Injection-meal interval: recommendations of diabetologists and how patients handle it. Diabetes Res Clin Pract. 1999;43(2):137–142. doi: https://doi.org/10.1016/s0168-8227(98)00132-6Kildegaard J, Buckley ST, Nielsen RH, et al. Elucidating the mechanism of absorption of fast-acting insulin aspart: the role of niacinamide. Pharm Res. 2019;36(3):49. doi: https://doi.org/10.1007/s11095-019-2578-7Kildegaard J, Buckley ST, Nielsen RH, et al. Elucidating the mechanism of absorption of fast-acting insulin aspart: the role of niacinamide. Pharm Res. 2019;36(3):49. doi: https://doi.org/10.1007/s11095-019-2578-7Biester T, Kordonouri O, Danne T. Pharmacological properties of faster-acting insulin aspart. Curr Diabetes Rep. 2017;17(11):101. doi: https://doi.org/10.1007/s11892-017-0931-yBiester T, Kordonouri O, Danne T. Pharmacological properties of faster-acting insulin aspart. Curr Diabetes Rep. 2017;17(11):101. doi: https://doi.org/10.1007/s11892-017-0931-ySenior P, Hramiak I. Fast-acting insulin aspart and the need for new mealtime insulin analogues in adults with type 1 and type 2 diabetes: a Canadian perspective. Can J Diabetes. 2019;43(7):515–523. doi: https://doi.org/10.1016/j.jcjd.2019.01.004Senior P, Hramiak I. Fast-acting insulin aspart and the need for new mealtime insulin analogues in adults with type 1 and type 2 diabetes: a Canadian perspective. Can J Diabetes. 2019;43(7):515–523. doi: https://doi.org/10.1016/j.jcjd.2019.01.004Heise T, Pieber TR, Danne T, et al. A pooled analysis of clinical pharmacology trials investigating the pharmacokinetic and pharmacodynamic characteristics of fast-acting insulin aspart in adults with type 1 diabetes. Clin Pharmacokinet. 2017;56(5):551–559. doi: https://doi.org/10.1007/s40262-017-0514-8Heise T, Pieber TR, Danne T, et al. A pooled analysis of clinical pharmacology trials investigating the pharmacokinetic and pharmacodynamic characteristics of fast-acting insulin aspart in adults with type 1 diabetes. Clin Pharmacokinet. 2017;56(5):551–559. doi: https://doi.org/10.1007/s40262-017-0514-8Pieber TR, Svehlikova E, Brunner M, et al. Fast-acting insulin aspart in subjects with type 2 diabetes: earlier onset and greater initial exposure and glucose-lowering effect compared with insulin aspart. Diabetes Obes Metab. 2019;21(9):2068–2075. doi: https://doi.org/10.1111/dom.13767Pieber TR, Svehlikova E, Brunner M, et al. Fast-acting insulin aspart in subjects with type 2 diabetes: earlier onset and greater initial exposure and glucose-lowering effect compared with insulin aspart. Diabetes Obes Metab. 2019;21(9):2068–2075. doi: https://doi.org/10.1111/dom.13767Heise T, Hövelmann U, Brøndsted L, et al. Faster-acting insulin aspart: earlier onset of appearance and greater early pharmacokinetic and pharmacodynamic effects than insulin aspart. Diabetes Obes Metab. 2015;17(7):682–688. doi: https://doi.org/10.1111/dom.12468Heise T, Hövelmann U, Brøndsted L, et al. Faster-acting insulin aspart: earlier onset of appearance and greater early pharmacokinetic and pharmacodynamic effects than insulin aspart. Diabetes Obes Metab. 2015;17(7):682–688. doi: https://doi.org/10.1111/dom.12468Heise T, Stender-Petersen K, Hövelmann U, et al. Pharmacokinetic and pharmacodynamic properties of faster-acting insulin aspart versus insulin aspart across a clinically relevant dose range in subjects with type 1 diabetes mellitus. Clin Pharmacokinet. 2017;56(6):649–660. doi: https://doi.org/10.1007/s40262-016-0473-5Heise T, Stender-Petersen K, Hövelmann U, et al. Pharmacokinetic and pharmacodynamic properties of faster-acting insulin aspart versus insulin aspart across a clinically relevant dose range in subjects with type 1 diabetes mellitus. Clin Pharmacokinet. 2017;56(6):649–660. doi: https://doi.org/10.1007/s40262-016-0473-5Heise T, Zijlstra E, Nosek L, et al. Pharmacological properties of faster-acting insulin aspart vs insulin aspart in patients with type 1 diabetes receiving continuous subcutaneous insulin infusion: a randomized, double-blind, crossover trial. Diabetes Obes Metab. 2017;19(2):208–215. doi: https://doi.org/10.1111/dom.12803Heise T, Zijlstra E, Nosek L, et al. Pharmacological properties of faster-acting insulin aspart vs insulin aspart in patients with type 1 diabetes receiving continuous subcutaneous insulin infusion: a randomized, double-blind, crossover trial. Diabetes Obes Metab. 2017;19(2):208–215. doi: https://doi.org/10.1111/dom.12803Haahr H, Pieber TR, Mathieu C, et al. Clinical pharmacology of fast-acting insulin aspart versus insulin aspart measured as free or total insulin aspart and the relation to anti-insulin aspart antibody levels in subjects with type 1 diabetes mellitus. Clin Pharmacokinet. 2019;58(5):639–649. doi: https://doi.org/10.1007/s40262-018-0718-6Haahr H, Pieber TR, Mathieu C, et al. Clinical pharmacology of fast-acting insulin aspart versus insulin aspart measured as free or total insulin aspart and the relation to anti-insulin aspart antibody levels in subjects with type 1 diabetes mellitus. Clin Pharmacokinet. 2019;58(5):639–649. doi: https://doi.org/10.1007/s40262-018-0718-6Basu A, Pieber TR, Hansen AK, et al. Greater early postprandial suppression of endogenous glucose production and higher initial glucose disappearance is achieved with fast-acting insulin aspart compared with insulin aspart. Diabetes Obes Metab. 2018;20(7):1615–1622. doi: https://doi.org/10.1111/dom.13270Basu A, Pieber TR, Hansen AK, et al. Greater early postprandial suppression of endogenous glucose production and higher initial glucose disappearance is achieved with fast-acting insulin aspart compared with insulin aspart. Diabetes Obes Metab. 2018;20(7):1615–1622. doi: https://doi.org/10.1111/dom.13270Fath M, Danne T, Biester T, et al. Faster-acting insulin aspart provides faster onset and greater early exposure vs insulin aspart in children and adolescents with type 1 diabetes mellitus. Pediatr Diabetes. 2017;18(8):903–910. doi: https://doi.org/10.1111/pedi.12506Fath M, Danne T, Biester T, et al. Faster-acting insulin aspart provides faster onset and greater early exposure vs insulin aspart in children and adolescents with type 1 diabetes mellitus. Pediatr Diabetes. 2017;18(8):903–910. doi: https://doi.org/10.1111/pedi.12506Heise T, Hövelmann U, Zijlstra E, et al. A comparison of pharmacokinetic and pharmacodynamic properties between faster-acting insulin aspart and insulin aspart in elderly subjects with type 1 diabetes mellitus. Drugs Aging. 2017;34(1):29–38. doi: https://doi.org/10.1007/s40266-016-0418-6Heise T, Hövelmann U, Zijlstra E, et al. A comparison of pharmacokinetic and pharmacodynamic properties between faster-acting insulin aspart and insulin aspart in elderly subjects with type 1 diabetes mellitus. Drugs Aging. 2017;34(1):29–38. doi: https://doi.org/10.1007/s40266-016-0418-6Shiramoto M, Nishida T, Hansen AK, Haahr H. Fast-acting insulin aspart in Japanese patients with type 1 diabetes: faster onset, higher early exposure and greater early glucose-lowering effect relative to insulin aspart. J Diabetes Investig. 2018;9(2):303–310. doi: https://doi.org/10.1111/jdi.12697Shiramoto M, Nishida T, Hansen AK, Haahr H. Fast-acting insulin aspart in Japanese patients with type 1 diabetes: faster onset, higher early exposure and greater early glucose-lowering effect relative to insulin aspart. J Diabetes Investig. 2018;9(2):303–310. doi: https://doi.org/10.1111/jdi.12697Hövelmann U, Heise T, Nosek L, et al. Pharmacokinetic properties of fast-acting insulin aspart administered in different subcutaneous injection regions. Clin Drug Investig. 2017;37(5):503–509. doi: https://doi.org/10.1007/s40261-017-0499-yHövelmann U, Heise T, Nosek L, et al. Pharmacokinetic properties of fast-acting insulin aspart administered in different subcutaneous injection regions. Clin Drug Investig. 2017;37(5):503–509. doi: https://doi.org/10.1007/s40261-017-0499-yClinicalTrials.gov. A trial investigating the pharmacokinetic properties of formulations of NN1218 in subjects with type 1 diabetes [cited 2012 January]. Available from: https://clinicaltrials.gov/ct2/show/NCT01469143ClinicalTrials.gov. A trial investigating the pharmacokinetic properties of formulations of NN1218 in subjects with type 1 diabetes [cited 2012 January]. Available from: https://clinicaltrials.gov/ct2/show/NCT01469143Mathieu C, Bode BW, Franek E, et al. Efficacy and safety of fast-acting insulin aspart in comparison with insulin aspart in type 1 diabetes (onset 1): a 52-week, randomized, treat-to-target, phase III trial. Diabetes Obes Metab. 2018;20(5):1148–1155. doi: https://doi.org/10.1111/dom.13205Mathieu C, Bode BW, Franek E, et al. Efficacy and safety of fast-acting insulin aspart in comparison with insulin aspart in type 1 diabetes (onset 1): a 52-week, randomized, treat-to-target, phase III trial. Diabetes Obes Metab. 2018;20(5):1148–1155. doi: https://doi.org/10.1111/dom.13205Klonoff DC, Evans ML, Lane W, et al. A randomized, multicentre trial evaluating the efficacy and safety of fast-acting insulin aspart in continuous subcutaneous insulin infusion in adults with type 1 diabetes (onset 5). Diabetes Obes Metab. 2019;21(4):961–967. doi: https://doi.org/10.1111/dom.13610Klonoff DC, Evans ML, Lane W, et al. A randomized, multicentre trial evaluating the efficacy and safety of fast-acting insulin aspart in continuous subcutaneous insulin infusion in adults with type 1 diabetes (onset 5). Diabetes Obes Metab. 2019;21(4):961–967. doi: https://doi.org/10.1111/dom.13610Russell-Jones D, Bode BW, de Block C, et al. Fast-acting insulin aspart improves glycemic control in basal-bolus treatment for type 1 diabetes: Results of a 26-week multicenter, active-controlled, treat-to-target, randomized, parallel-group trial (onset 1). Diabetes Care. 2017;40(7):943–950. doi: https://doi.org/10.2337/dc16-1771Russell-Jones D, Bode BW, de Block C, et al. Fast-acting insulin aspart improves glycemic control in basal-bolus treatment for type 1 diabetes: Results of a 26-week multicenter, active-controlled, treat-to-target, randomized, parallel-group trial (onset 1). Diabetes Care. 2017;40(7):943–950. doi: https://doi.org/10.2337/dc16-1771Buse JB, Carlson AL, Komatsu M, et al. Fast-acting insulin aspart versus insulin aspart in the setting of insulin degludec-treated type 1 diabetes: efficacy and safety from a randomized double-blind trial. Diabetes Obes Metab. 2018;20(12):2885–2893. doi: https://doi.org/10.1111/dom.13545Buse JB, Carlson AL, Komatsu M, et al. Fast-acting insulin aspart versus insulin aspart in the setting of insulin degludec-treated type 1 diabetes: efficacy and safety from a randomized double-blind trial. Diabetes Obes Metab. 2018;20(12):2885–2893. doi: https://doi.org/10.1111/dom.13545Bowering K, Case C, Harvey J, et al. Faster aspart versus insulin aspart as part of a basal-bolus regimen in inadequately controlled type 2 diabetes: the onset 2 trial. Diabetes Care. 2017;40(7):951–957. doi: https://doi.org/10.2337/dc16-1770Bowering K, Case C, Harvey J, et al. Faster aspart versus insulin aspart as part of a basal-bolus regimen in inadequately controlled type 2 diabetes: the onset 2 trial. Diabetes Care. 2017;40(7):951–957. doi: https://doi.org/10.2337/dc16-1770Lane W, Bozkurt K, Favaro E, et al. Efficacy and safety of fast-acting insulin aspart compared with insulin aspart, both with insulin degludec with or without metformin, in adults with type 2 diabetes. Diabetologia. 2019;62(Suppl. 1):S10–11.Lane W, Bozkurt K, Favaro E, et al. Efficacy and safety of fast-acting insulin aspart compared with insulin aspart, both with insulin degludec with or without metformin, in adults with type 2 diabetes. Diabetologia. 2019;62(Suppl. 1):S10–11.Rodbard HW, Tripathy D, Vidrio Velázquez M, et al. Adding fast-acting insulin aspart to basal insulin significantly improved glycaemic control in patients with type 2 diabetes: a randomized, 18-week, open-label, phase 3 trial (onset 3). Diabetes Obes Metab. 2017;19(10):1389–1396. doi: https://doi.org/10.1111/dom.12955Rodbard HW, Tripathy D, Vidrio Velázquez M, et al. Adding fast-acting insulin aspart to basal insulin significantly improved glycaemic control in patients with type 2 diabetes: a randomized, 18-week, open-label, phase 3 trial (onset 3). Diabetes Obes Metab. 2017;19(10):1389–1396. doi: https://doi.org/10.1111/dom.12955Bode BW, Iotova V, Kovarenko M, et al. Efficacy and safety of fast-acting insulin aspart compared with insulin aspart, both in combination with insulin degludec, in children and adolescents with type 1 diabetes: the onset 7 trial. Diabetes Care. 2019;42(7):1255–1262. doi: https://doi.org/10.2337/dc19-0009Bode BW, Iotova V, Kovarenko M, et al. Efficacy and safety of fast-acting insulin aspart compared with insulin aspart, both in combination with insulin degludec, in children and adolescents with type 1 diabetes: the onset 7 trial. Diabetes Care. 2019;42(7):1255–1262. doi: https://doi.org/10.2337/dc19-0009US FDA. Inactive ingredient search for approved drug products [cited 2020 January 30]. Available from: https://www.accessdata.fda.gov/scripts/cder/iig/index.cfmUS FDA. Inactive ingredient search for approved drug products [cited 2020 January 30]. Available from: https://www.accessdata.fda.gov/scripts/cder/iig/index.cfmUS FDA. SCOGS (Select Committee on GRAS Substances) [cited 2019 April 29]. Available from: https://www.accessdata.fda.gov/scripts/fdcc/?set=SCOGSUS FDA. SCOGS (Select Committee on GRAS Substances) [cited 2019 April 29]. Available from: https://www.accessdata.fda.gov/scripts/fdcc/?set=SCOGSKnip M, Douek IF, Moore WP, et al. Safety of high-dose nicotinamide: a review. Diabetologia. 2000;43(11):1337–1345. doi: https://doi.org/10.1007/s001250051536Knip M, Douek IF, Moore WP, et al. Safety of high-dose nicotinamide: a review. Diabetologia. 2000;43(11):1337–1345. doi: https://doi.org/10.1007/s001250051536McNeal CJ, Meininger CJ, Reddy D, et al. Safety and effectiveness of arginine in adults. J Nutr. 2016;146(12):2587S–2593S. doi: https://doi.org/10.3945/jn.116.234740McNeal CJ, Meininger CJ, Reddy D, et al. Safety and effectiveness of arginine in adults. J Nutr. 2016;146(12):2587S–2593S. doi: https://doi.org/10.3945/jn.116.234740Brange J, Langkjaer L. Chemical stability of insulin. 3. Influence of excipients, formulation, and pH. Acta Pharm Nord. 1992;4(3):149–158.Brange J, Langkjaer L. Chemical stability of insulin. 3. Influence of excipients, formulation, and pH. Acta Pharm Nord. 1992;4(3):149–158.Březina K, Duboué-Dijon E, Palivec V, et al. Can arginine inhibit insulin aggregation? A combined protein crystallography, capillary electrophoresis, and molecular simulation study. J Phys Chem B. 2018;122(44):10069–10076. doi: https://doi.org/10.1021/acs.jpcb.8b06557Březina K, Duboué-Dijon E, Palivec V, et al. Can arginine inhibit insulin aggregation? A combined protein crystallography, capillary electrophoresis, and molecular simulation study. J Phys Chem B. 2018;122(44):10069–10076. doi: https://doi.org/10.1021/acs.jpcb.8b06557Zijlstra E, Demissie M, Graungaard T, et al. Investigation of pump compatibility of fast-acting insulin aspart in subjects with type 1 diabetes. J Diabetes Sci Technol. 2018;12(1):145–151. doi: https://doi.org/10.1177/1932296817730375Zijlstra E, Demissie M, Graungaard T, et al. Investigation of pump compatibility of fast-acting insulin aspart in subjects with type 1 diabetes. J Diabetes Sci Technol. 2018;12(1):145–151. doi: https://doi.org/10.1177/1932296817730375Bode BW, Johnson JA, Hyveled L, et al. Improved postprandial glycemic control with faster-acting insulin aspart in patients with type 1 diabetes using continuous subcutaneous insulin infusion. Diabetes Technol Ther. 2017;19(1):25–33. doi: https://doi.org/10.1089/dia.2016.0350Bode BW, Johnson JA, Hyveled L, et al. Improved postprandial glycemic control with faster-acting insulin aspart in patients with type 1 diabetes using continuous subcutaneous insulin infusion. Diabetes Technol Ther. 2017;19(1):25–33. doi: https://doi.org/10.1089/dia.2016.0350Heise T, Zijlstra E, Nosek L, et al. Euglycaemic glucose clamp: what it can and cannot do, and how to do it. Diabetes Obes Metab. 2016;18(10):962–972. doi: https://doi.org/10.1111/dom.12703Heise T, Zijlstra E, Nosek L, et al. Euglycaemic glucose clamp: what it can and cannot do, and how to do it. Diabetes Obes Metab. 2016;18(10):962–972. doi: https://doi.org/10.1111/dom.12703Jain L, Parks MH, Sahajwalla C. Determination of time to onset and rate of action of insulin products: importance and new approaches. J Pharm Sci. 2013;102(1):271–279. doi: https://doi.org/10.1002/jps.23355Jain L, Parks MH, Sahajwalla C. Determination of time to onset and rate of action of insulin products: importance and new approaches. J Pharm Sci. 2013;102(1):271–279. doi: https://doi.org/10.1002/jps.23355Steiner S, Hompesch M, Pohl R, et al. A novel insulin formulation with a more rapid onset of action. Diabetologia. 2008;51(9):1602–1606. doi: https://doi.org/10.1007/s00125-008-1095-8Steiner S, Hompesch M, Pohl R, et al. A novel insulin formulation with a more rapid onset of action. Diabetologia. 2008;51(9):1602–1606. doi: https://doi.org/10.1007/s00125-008-1095-8Lindholm A, Jacobsen LV. Clinical pharmacokinetics and pharmacodynamics of insulin aspart. Clin Pharmacokinet. 2001;40(9):641–659. doi: https://doi.org/10.2165/00003088-200140090-00002Lindholm A, Jacobsen LV. Clinical pharmacokinetics and pharmacodynamics of insulin aspart. Clin Pharmacokinet. 2001;40(9):641–659. doi: https://doi.org/10.2165/00003088-200140090-00002Becker RH, Frick AD. Clinical pharmacokinetics and pharmacodynamics of insulin glulisine. Clin Pharmacokinet. 2008;47(1):7–20. doi: https://doi.org/10.2165/00003088-200847010-00002Becker RH, Frick AD. Clinical pharmacokinetics and pharmacodynamics of insulin glulisine. Clin Pharmacokinet. 2008;47(1):7–20. doi: https://doi.org/10.2165/00003088-200847010-00002Morrow L, Muchmore DB, Hompesch M, et al. Comparative pharmacokinetics and insulin action for three rapid-acting insulin analogs injected subcutaneously with and without hyaluronidase. Diabetes Care. 2013;36(2):273–275. doi: https://doi.org/10.2337/dc12-0808Morrow L, Muchmore DB, Hompesch M, et al. Comparative pharmacokinetics and insulin action for three rapid-acting insulin analogs injected subcutaneously with and without hyaluronidase. Diabetes Care. 2013;36(2):273–275. doi: https://doi.org/10.2337/dc12-0808Arnqvist H, Olsson PO, von Schenck H. Free and total insulin as determined after precipitation with polyethylene glycol: analytical characteristics and effects of sample handling and storage. Clin Chem. 1987;33(1):93–96. doi: https://doi.org/10.1093/clinchem/33.1.93Arnqvist H, Olsson PO, von Schenck H. Free and total insulin as determined after precipitation with polyethylene glycol: analytical characteristics and effects of sample handling and storage. Clin Chem. 1987;33(1):93–96. doi: https://doi.org/10.1093/clinchem/33.1.93Sapin R. Anti-insulin antibodies in insulin immunometric assays: a still possible pitfall. Eur J Clin Chem Clin Biochem. 1997;35(5):365–367. doi: https://doi.org/10.1515/cclm.1997.35.5.365Sapin R. Anti-insulin antibodies in insulin immunometric assays: a still possible pitfall. Eur J Clin Chem Clin Biochem. 1997;35(5):365–367. doi: https://doi.org/10.1515/cclm.1997.35.5.365Heise T, Nosek L, Spitzer H, et al. Insulin glulisine: a faster onset of action compared with insulin lispro. Diabetes Obes Metab. 2007;9(5):746–753. doi: https://doi.org/10.1111/j.1463-1326.2007.00746.xHeise T, Nosek L, Spitzer H, et al. Insulin glulisine: a faster onset of action compared with insulin lispro. Diabetes Obes Metab. 2007;9(5):746–753. doi: https://doi.org/10.1111/j.1463-1326.2007.00746.xArnolds S, Rave K, Hövelmann U, et al. Insulin glulisine has a faster onset of action compared with insulin aspart in healthy volunteers. Exp Clin Endocrinol Diabetes. 2010;118(9):662–664. doi: https://doi.org/10.1055/s-0030-1252067Arnolds S, Rave K, Hövelmann U, et al. Insulin glulisine has a faster onset of action compared with insulin aspart in healthy volunteers. Exp Clin Endocrinol Diabetes. 2010;118(9):662–664. doi: https://doi.org/10.1055/s-0030-1252067Swinnen SG, Holleman F, deVries JH. The interpretation of glucose clamp studies of long-acting insulin analogues: from physiology to marketing and back. Diabetologia. 2008;51(10):1790–1795. doi: https://doi.org/10.1007/s00125-008-1098-5Swinnen SG, Holleman F, deVries JH. The interpretation of glucose clamp studies of long-acting insulin analogues: from physiology to marketing and back. Diabetologia. 2008;51(10):1790–1795. doi: https://doi.org/10.1007/s00125-008-1098-5Becker RH, Frick AD, Nosek L, et al. Dose-response relationship of insulin glulisine in subjects with type 1 diabetes. Diabetes Care. 2007;30(10):2506–2507. doi: https://doi.org/10.2337/dc06-2114Becker RH, Frick AD, Nosek L, et al. Dose-response relationship of insulin glulisine in subjects with type 1 diabetes. Diabetes Care. 2007;30(10):2506–2507. doi: https://doi.org/10.2337/dc06-2114Freidenberg GR, Suter SL, Henry RR, et al. In vivo stimulation of the insulin receptor kinase in human skeletal muscle. Correlation with insulin-stimulated glucose disposal during euglycemic clamp studies. J Clin Invest. 1991;87(6):2222–2229. doi: https://doi.org/10.1172/JCI115257Freidenberg GR, Suter SL, Henry RR, et al. In vivo stimulation of the insulin receptor kinase in human skeletal muscle. Correlation with insulin-stimulated glucose disposal during euglycemic clamp studies. J Clin Invest. 1991;87(6):2222–2229. doi: https://doi.org/10.1172/JCI115257Heinemann L. Variability of insulin action: does it matter? Insulin. 2008;3(1):37–45. doi: https://doi.org/10.1016/s1557-0843(08)80010-3Heinemann L. Variability of insulin action: does it matter? Insulin. 2008;3(1):37–45. doi: https://doi.org/10.1016/s1557-0843(08)80010-3Herring R, Jones RH, Russell-Jones DL. Hepatoselectivity and the evolution of insulin. Diabetes Obes Metab. 2014;16(1):1–8. doi: https://doi.org/10.1111/dom.12117Herring R, Jones RH, Russell-Jones DL. Hepatoselectivity and the evolution of insulin. Diabetes Obes Metab. 2014;16(1):1–8. doi: https://doi.org/10.1111/dom.12117Heise T, Linnebjerg H, Cao D, et al. Ultra rapid lispro (URLi) lowers postprandial glucose (PPG) and more closely matches normal physiological glucose response compared with other rapid insulin analogs. In: American Diabetes association 79th scientific sessions. Diabetes. 2019;68(Suppl 1):1112. doi: https://doi.org/10.2337/db19-1112-pHeise T, Linnebjerg H, Cao D, et al. Ultra rapid lispro (URLi) lowers postprandial glucose (PPG) and more closely matches normal physiological glucose response compared with other rapid insulin analogs. In: American Diabetes association 79th scientific sessions. Diabetes. 2019;68(Suppl 1):1112. doi: https://doi.org/10.2337/db19-1112-pPozzilli P, Battelino T, Danne T, et al. Continuous subcutaneous insulin infusion in diabetes: patient populations, safety, efficacy, and pharmacoeconomics. Diabetes Metab Res Rev. 2016;32(1):21–39. doi: https://doi.org/10.1002/dmrr.2653Pozzilli P, Battelino T, Danne T, et al. Continuous subcutaneous insulin infusion in diabetes: patient populations, safety, efficacy, and pharmacoeconomics. Diabetes Metab Res Rev. 2016;32(1):21–39. doi: https://doi.org/10.1002/dmrr.2653Paglialunga S, Offman E, Ichhpurani N, et al. Update and trends on pharmacokinetic studies in patients with impaired renal function: practical insight into application of the FDA and EMA guidelines. Expert Rev Clin Pharmacol. 2017;10(3):273–283. doi: https://doi.org/10.1080/17512433.2017.1274651Paglialunga S, Offman E, Ichhpurani N, et al. Update and trends on pharmacokinetic studies in patients with impaired renal function: practical insight into application of the FDA and EMA guidelines. Expert Rev Clin Pharmacol. 2017;10(3):273–283. doi: https://doi.org/10.1080/17512433.2017.1274651Verbeeck RK. Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction. Eur J Clin Pharmacol. 2008;64(12):1147–1161. doi: https://doi.org/10.1007/s00228-008-0553-zVerbeeck RK. Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction. Eur J Clin Pharmacol. 2008;64(12):1147–1161. doi: https://doi.org/10.1007/s00228-008-0553-zHolmes G, Galitz L, Hu P, Lyness W. Pharmacokinetics of insulin aspart in obesity, renal impairment, or hepatic impairment. Br J Clin Pharmacol. 2005;60(5):469–476. doi: https://doi.org/10.1111/j.1365-2125.2005.02476.xHolmes G, Galitz L, Hu P, Lyness W. Pharmacokinetics of insulin aspart in obesity, renal impairment, or hepatic impairment. Br J Clin Pharmacol. 2005;60(5):469–476. doi: https://doi.org/10.1111/j.1365-2125.2005.02476.xMorello CM. Pharmacokinetics and pharmacodynamics of insulin analogs in special populations with type 2 diabetes mellitus. Int J Gen Med. 2011;4:827–835. doi: https://doi.org/10.2147/IJGM.S26889Morello CM. Pharmacokinetics and pharmacodynamics of insulin analogs in special populations with type 2 diabetes mellitus. Int J Gen Med. 2011;4:827–835. doi: https://doi.org/10.2147/IJGM.S26889Frid AH, Kreugel G, Grassi G, et al. New insulin delivery recommendations. Mayo Clin Proc. 2016;91(9):1231–1255. doi: https://doi.org/10.1016/j.mayocp.2016.06.010Frid AH, Kreugel G, Grassi G, et al. New insulin delivery recommendations. Mayo Clin Proc. 2016;91(9):1231–1255. doi: https://doi.org/10.1016/j.mayocp.2016.06.010Ter Braak EW, Woodworth JR, Bianchi R, et al. Injection site effects on the pharmacokinetics and glucodynamics of insulin lispro and regular insulin. Diabetes Care. 1996;19(12):1437–1440. doi: https://doi.org/10.2337/diacare.19.12.1437Ter Braak EW, Woodworth JR, Bianchi R, et al. Injection site effects on the pharmacokinetics and glucodynamics of insulin lispro and regular insulin. Diabetes Care. 1996;19(12):1437–1440. doi: https://doi.org/10.2337/diacare.19.12.1437Mudaliar SR, Lindberg FA, Joyce M, et al. Insulin aspart (B28 asp-insulin): a fast-acting analog of human insulin: absorption kinetics and action profile compared with regular human insulin in healthy nondiabetic subjects. Diabetes Care. 1999;22(9):1501–1506. doi: https://doi.org/10.2337/diacare.22.9.1501Mudaliar SR, Lindberg FA, Joyce M, et al. Insulin aspart (B28 asp-insulin): a fast-acting analog of human insulin: absorption kinetics and action profile compared with regular human insulin in healthy nondiabetic subjects. Diabetes Care. 1999;22(9):1501–1506. doi: https://doi.org/10.2337/diacare.22.9.1501Heise T, Bott S, Tusek C, et al. The effect of insulin antibodies on the metabolic action of inhaled and subcutaneous insulin: a prospective randomized pharmacodynamic study. Diabetes Care. 2005;28(9):2161–2169. doi: https://doi.org/10.2337/diacare.28.9.2161Heise T, Bott S, Tusek C, et al. The effect of insulin antibodies on the metabolic action of inhaled and subcutaneous insulin: a prospective randomized pharmacodynamic study. Diabetes Care. 2005;28(9):2161–2169. doi: https://doi.org/10.2337/diacare.28.9.2161Chen JW, Frystyk J, Lauritzen T, Christiansen JS. Impact of insulin antibodies on insulin aspart pharmacokinetics and pharmacodynamics after 12-week treatment with multiple daily injections of biphasic insulin aspart 30 in patients with type 1 diabetes. Eur J Endocrinol. 2005;153(6):907–913. doi: https://doi.org/10.1530/eje.1.02021Chen JW, Frystyk J, Lauritzen T, Christiansen JS. Impact of insulin antibodies on insulin aspart pharmacokinetics and pharmacodynamics after 12-week treatment with multiple daily injections of biphasic insulin aspart 30 in patients with type 1 diabetes. Eur J Endocrinol. 2005;153(6):907–913. doi: https://doi.org/10.1530/eje.1.02021Lindholm A, Jensen LB, Home PD, et al. Immune responses to insulin aspart and biphasic insulin aspart in people with type 1 and type 2 diabetes. Diabetes Care. 2002;25(5):876–882. doi: https://doi.org/10.2337/diacare.25.5.876Lindholm A, Jensen LB, Home PD, et al. Immune responses to insulin aspart and biphasic insulin aspart in people with type 1 and type 2 diabetes. Diabetes Care. 2002;25(5):876–882. doi: https://doi.org/10.2337/diacare.25.5.876Cengiz E, Bode B, van Name M, Tamborlane WV. Moving toward the ideal insulin for insulin pumps. Expert Rev Med Devices. 2016;13(1):57–69. doi: https://doi.org/10.1586/17434440.2016.1109442Cengiz E, Bode B, van Name M, Tamborlane WV. Moving toward the ideal insulin for insulin pumps. Expert Rev Med Devices. 2016;13(1):57–69. doi: https://doi.org/10.1586/17434440.2016.1109442Majeed W, Thabit H. Closed-loop insulin delivery: current status of diabetes technologies and future prospects. Expert Rev Med Devices. 2018;15(8):579–590. doi: https://doi.org/10.1080/17434440.2018.1503530Majeed W, Thabit H. Closed-loop insulin delivery: current status of diabetes technologies and future prospects. Expert Rev Med Devices. 2018;15(8):579–590. doi: https://doi.org/10.1080/17434440.2018.1503530Evans M, Ceriello A, Danne T. Use of fast-acting insulin aspart in insulin pump therapy in clinical practice. Diabetes Obes Metab. 2019;21(9):2039–2047. doi: https://doi.org/10.1111/dom.13798Evans M, Ceriello A, Danne T. Use of fast-acting insulin aspart in insulin pump therapy in clinical practice. Diabetes Obes Metab. 2019;21(9):2039–2047. doi: https://doi.org/10.1111/dom.13798

The authors declare that there are no conflicts of interest present.