Key Points
-
Established rapid-acting and long-acting insulin analogues have enabled more patients with type 1 diabetes mellitus to reach better glucose targets, with lower hypoglycaemia rates and a better quality of life than was possible with short-acting and long-acting human insulin
-
In patients who are prone to severe hypoglycaemia, using a full analogue regimen is rapidly cost saving and should therefore be the standard of care in all patients with type 1 diabetes mellitus
-
The new long-acting insulin analogues insulin glargine U300 and insulin degludec have shown increased stability, which translates to a reduced risk of nocturnal hypoglycaemia and increased flexibility in timing of administration
-
Faster and shorter acting insulin analogues are needed for use in insulin pumps and future 'artificial pancreas' systems; fast-acting insulin aspart, a new formulation of aspart, is well advanced in clinical development
Abstract
The treatment of type 1 diabetes mellitus consists of external replacement of the functions of β cells in an attempt to achieve blood levels of glucose as close to the normal range as possible. This approach means that glucose sensing needs to be replaced and levels of insulin need to mimic physiological insulin-action profiles, including basal coverage and changes around meals. Training and educating patients are crucial for the achievement of good glycaemic control, but having insulin preparations with action profiles that provide stable basal insulin coverage and appropriate mealtime insulin peaks helps people with type 1 diabetes mellitus to live active lives without sacrificing tight glycaemic control. Insulin analogues enable patients to achieve this goal, as some have fast action profiles, and some have very slow action profiles, which gives people with type 1 diabetes mellitus the tools to achieve dynamic insulin-action profiles that enable tight glycaemic control with a risk of hypoglycaemia that is lower than that with human short-acting and long-acting insulins. This Review discusses the established and novel insulin analogues that are used to treat patients with type 1 diabetes mellitus and provides insights into the future development of insulin analogues.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Atkinson, M. A., Eisenbarth, G. S. & Michels, A. W. Type 1 diabetes. Lancet 383, 69–82 (2014).
Donner, T. Insulin – pharmacology, therapeutic regimens and principles of intensive insulin therapy. Endotext https://www.ncbi.nlm.nih.gov/books/NBK278938/ (2000).
The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N. Engl. J. Med. 329, 977–986 (1993).
Nathan, D. M. & DCCT/EDIC Research Group. The diabetes control and complications trial/epidemiology of diabetes interventions and complications study at 30 years: overview. Diabetes Care 37, 9–16 (2014).
Home, P. D. The pharmacokinetics and pharmacodynamics of rapid-acting insulin analogues and their clinical consequences. Diabetes Obes. Metab. 14, 780–788 (2012).
de la Pena, A. et al. Pharmacokinetics and pharmacodynamics of high-dose human regular U-500 insulin versus human regular U-100 insulin in healthy obese subjects. Diabetes Care 34, 2496–2501 (2011).
Heise, T. et al. Lower within-subject variability of insulin detemir in comparison to NPH insulin and insulin glargine in people with type 1 diabetes. Diabetes 53, 1614–1620 (2004).
Heise, T. & Pieber, T. R. Towards peakless, reproducible and long-acting insulins. An assessment of the basal analogues based on isoglycaemic clamp studies. Diabetes Obes. Metab. 9, 648–659 (2007).
Lucidi, P. et al. Pharmacokinetics and pharmacodynamics of therapeutic doses of basal insulins NPH, glargine, and detemir after 1 week of daily administration at bedtime in type 2 diabetic subjects: a randomized cross-over study. Diabetes Care 34, 1312–1314 (2011).
Brange, J., Owens, D. R., Kang, S. & Volund, A. Monomeric insulins and their experimental and clinical implications. Diabetes Care 13, 923–954 (1990).
Heinemann, L. et al. Prandial glycaemia after a carbohydrate-rich meal in type I diabetic patients: using the rapid acting insulin analogue [Lys(B28), Pro(B29)] human insulin. Diabet. Med. 13, 625–629 (1996).
ter Braak, E. W. et al. Injection site effects on the pharmacokinetics and glucodynamics of insulin lispro and regular insulin. Diabetes Care 19, 1437–1440 (1996).
Tamas, G. et al. Glycaemic control in type 1 diabetic patients using optimised insulin aspart or human insulin in a randomised multinational study. Diabetes Res. Clin. Pract. 54, 105–114 (2001).
Valle, D., Santoro, D., Bates, P., Scarpa, L. & Italian Multicentre Lispro Study Group. Italian multicentre study of intensive therapy with insulin lispro in 1184 patients with type 1 diabetes. Diabetes Nutr. Metab. 14, 126–132 (2001).
Lindholm, A., McEwen, J. & Riis, A. P. Improved postprandial glycemic control with insulin aspart. A randomized double-blind cross-over trial in type 1 diabetes. Diabetes Care 22, 801–805 (1999).
Home, P. D., Barriocanal, L. & Lindholm, A. Comparative pharmacokinetics and pharmacodynamics of the novel rapid-acting insulin analogue, insulin aspart, in healthy volunteers. Eur. J. Clin. Pharmacol. 55, 199–203 (1999).
Plank, J. et al. A direct comparison of insulin aspart and insulin lispro in patients with type 1 diabetes. Diabetes Care 25, 2053–2057 (2002).
Homko, C., Deluzio, A., Jimenez, C., Kolaczynski, J. W. & Boden, G. Comparison of insulin aspart and lispro: pharmacokinetic and metabolic effects. Diabetes Care 26, 2027–2031 (2003).
Bartolo, P. D. et al. Better postprandial glucose stability during continuous subcutaneous infusion with insulin aspart compared with insulin lispro in patients with type 1 diabetes. Diabetes Technol. Ther. 10, 495–498 (2008).
Bode, B. et al. Comparison of insulin aspart with buffered regular insulin and insulin lispro in continuous subcutaneous insulin infusion: a randomized study in type 1 diabetes. Diabetes Care 25, 439–444 (2002).
Dreyer, M. et al. Efficacy and safety of insulin glulisine in patients with type 1 diabetes. Horm. Metab. Res. 37, 702–707 (2005).
Home, P. D., Lindholm, A., Riis, A. & European Insulin Aspart Study Group. Insulin aspart versus human insulin in the management of long-term blood glucose control in type 1 diabetes mellitus: a randomized controlled trial. Diabet. Med. 17, 762–770 (2000).
Raskin, P., Guthrie, R. A., Leiter, L., Riis, A. & Jovanovic, L. Use of insulin aspart, a fast-acting insulin analog, as the mealtime insulin in the management of patients with type 1 diabetes. Diabetes Care 23, 583–588 (2000).
Becker, R. H., Frick, A. D., Burger, F., Potgieter, J. H. & Scholtz, H. Insulin glulisine, a new rapid-acting insulin analogue, displays a rapid time-action profile in obese non-diabetic subjects. Exp. Clin. Endocrinol. Diabetes 113, 435–443 (2005).
Kerr, D., Wizemann, E., Senstius, J., Zacho, M. & Ampudia-Blasco, F. J. Stability and performance of rapid-acting insulin analogs used for continuous subcutaneous insulin infusion: a systematic review. J. Diabetes Sci. Technol. 7, 1595–1606 (2013).
Heise, T. et al. Insulin glulisine: a faster onset of action compared with insulin lispro. Diabetes Obes. Metab. 9, 746–753 (2007).
Arnolds, S. et al. Insulin glulisine has a faster onset of action compared with insulin aspart in healthy volunteers. Exp. Clin. Endocrinol. Diabetes 118, 662–664 (2010).
Luzio, S., Peter, R., Dunseath, G. J., Mustafa, L. & Owens, D. R. A comparison of preprandial insulin glulisine versus insulin lispro in people with type 2 diabetes over a 12- h period. Diabetes Res. Clin. Pract. 79, 269–275 (2008).
Bolli, G. B. et al. Comparative pharmacodynamic and pharmacokinetic characteristics of subcutaneous insulin glulisine and insulin aspart prior to a standard meal in obese subjects with type 2 diabetes. Diabetes Obes. Metab. 13, 251–257 (2011).
Garg, S. K., Rosenstock, J. & Ways, K. Optimized basal-bolus insulin regimens in type 1 diabetes: insulin glulisine versus regular human insulin in combination with basal insulin glargine. Endocr. Pract. 11, 11–17 (2005).
Fullerton, B. et al. Short-acting insulin analogues versus regular human insulin for adults with type 1 diabetes mellitus. Cochrane Database Syst. Rev. 6, CD012161 (2016).
Russell-Jones, D. 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 http://dx.doi.org/10.2337/dc16-1771 (2017).
DeVries, J. H. et al. A randomized trial of insulin aspart with intensified basal NPH insulin supplementation in people with type 1 diabetes. Diabet. Med. 20, 312–318 (2003).
Shafie, A. A., Ng, C. H., Tan, Y. P. & Chaiyakunapruk, N. Systematic review of the cost effectiveness of insulin analogues in type 1 and type 2 diabetes mellitus. Pharmacoeconomics 35, 141–162 (2017).
Pedersen-Bjergaard, U. et al. Short-term cost-effectiveness of insulin detemir and insulin aspart in people with type 1 diabetes who are prone to recurrent severe hypoglycemia. Curr. Med. Res. Opin. 32, 1719–1725 (2016).
American Diabetes Association. 8. Pharmacologic approaches to glycemic treatment. Diabetes Care 40, S64–S74 (2017).
Gonzalez Blanco, C., Chico Ballesteros, A., Gich Saladich, I. & Corcoy Pla, R. Glycemic control and pregnancy outcomes in women with type 1 diabetes mellitus using lispro versus regular insulin: a systematic review and meta-analysis. Diabetes Technol. Ther. 13, 907–911 (2011).
Mathiesen, E. R. et al. Maternal glycemic control and hypoglycemia in type 1 diabetic pregnancy: a randomized trial of insulin aspart versus human insulin in 322 pregnant women. Diabetes Care 30, 771–776 (2007).
Pozzilli, P. et al. Continuous subcutaneous insulin infusion in diabetes: patient populations, safety, efficacy, and pharmacoeconomics. Diabetes Metab. Res. Rev. 32, 21–39 (2016).
Kerr, D., Morton, J., Whately-Smith, C., Everett, J. & Begley, J. P. Laboratory-based non-clinical comparison of occlusion rates using three rapid-acting insulin analogs in continuous subcutaneous insulin infusion catheters using low flow rates. J. Diabetes Sci. Technol. 2, 450–455 (2008).
Brunner, G. A. et al. Pharmacokinetic and pharmacodynamic properties of long-acting insulin analogue NN304 in comparison to NPH insulin in humans. Exp. Clin. Endocrinol. Diabetes 108, 100–105 (2000).
Porcellati, F., Bolli, G. B. & Fanelli, C. G. Pharmacokinetics and pharmacodynamics of basal insulins. Diabetes Technol. Ther. 13 (Suppl. 1), S15–S24 (2011).
Rosenstock, J., Park, G., Zimmerman, J. & U.S. Insulin Glargine (HOE 901) Type 1 Diabetes Investigator Group. Basal insulin glargine (HOE 901) versus NPH insulin in patients with type 1 diabetes on multiple daily insulin regimens. Diabetes Care 23, 1137–1142 (2000).
Albright, E. S., Desmond, R. & Bell, D. S. Efficacy of conversion from bedtime NPH insulin injection to once- or twice-daily injections of insulin glargine in type 1 diabetic patients using basal/bolus therapy. Diabetes Care 27, 632–633 (2004).
Ratner, R. E. et al. Less hypoglycemia with insulin glargine in intensive insulin therapy for type 1 diabetes. U.S. study group of insulin glargine in type 1 diabetes. Diabetes Care 23, 639–643 (2000).
Dornhorst, A. et al. Safety and efficacy of insulin detemir in clinical practice: 14-week follow-up data from type 1 and type 2 diabetes patients in the PREDICTIVE European cohort. Int. J. Clin. Pract. 61, 523–528 (2007).
Hermansen, K., Dornhorst, A. & Sreenan, S. Observational, open-label study of type 1 and type 2 diabetes patients switching from human insulin to insulin analogue basal-bolus regimens: insights from the PREDICTIVE study. Curr. Med. Res. Opin. 25, 2601–2608 (2009).
[No authors listed.] Top 50 pharmaceutical products by global sales. PMLiVE http://www.pmlive.com/top_pharma_list/Top_50_pharmaceutical_products_by_global_sales (2017).
Lepore, M. et al. Pharmacokinetics and pharmacodynamics of subcutaneous injection of long-acting human insulin analog glargine, NPH insulin, and ultralente human insulin and continuous subcutaneous infusion of insulin lispro. Diabetes 49, 2142–2148 (2000).
Porcellati, F. et al. Pharmacokinetics and pharmacodynamics of the long-acting insulin analog glargine after 1 week of use compared with its first administration in subjects with type 1 diabetes. Diabetes Care 30, 1261–1263 (2007).
Hilgenfeld, R. et al. Controlling insulin bioavailability by crystal contact engineering. Diabetologia 35, A193 (1992).
Klein, O. et al. Albumin-bound basal insulin analogues (insulin detemir and NN344): comparable time-action profiles but less variability than insulin glargine in type 2 diabetes. Diabetes Obes. Metab. 9, 290–299 (2007).
Ashwell, S. G., Gebbie, J. & Home, P. D. Optimal timing of injection of once-daily insulin glargine in people with type 1 diabetes using insulin lispro at meal-times. Diabet. Med. 23, 46–52 (2006).
Havelund, S. et al. The mechanism of protraction of insulin detemir, a long-acting, acylated analog of human insulin. Pharm. Res. 21, 1498–1504 (2004).
Pieber, T. R. et al. Duration of action, pharmacodynamic profile and between-subject variability of insulin detemir in subjects with type 1 diabetes. Diabetes 51, A53 (2002).
Pieber, T. R. et al. Comparison of insulin detemir and insulin glargine in subjects with type 1 diabetes using intensive insulin therapy. Diabet. Med. 24, 635–642 (2007).
Heller, S., Koenen, C. & Bode, B. Comparison of insulin detemir and insulin glargine in a basal-bolus regimen, with insulin aspart as the mealtime insulin, in patients with type 1 diabetes: a 52-week, multinational, randomized, open-label, parallel-group, treat-to-target noninferiority trial. Clin. Ther. 31, 2086–2097 (2009).
Plank, J. et al. A double-blind, randomized, dose-response study investigating the pharmacodynamic and pharmacokinetic properties of the long-acting insulin analog detemir. Diabetes Care 28, 1107–1112 (2005).
Koehler, G. et al. Pharmacodynamics of the long-acting insulin analogues detemir and glargine following single-doses and under steady-state conditions in patients with type 1 diabetes. Diabetes Obes. Metab. 16, 57–62 (2014).
Danne, T. et al. Insulin detemir is characterized by a more reproducible pharmacokinetic profile than insulin glargine in children and adolescents with type 1 diabetes: results from a randomized, double-blind, controlled trial. Pediatr. Diabetes 9, 554–560 (2008).
De Leeuw, I. et al. Insulin detemir used in basal-bolus therapy in people with type 1 diabetes is associated with a lower risk of nocturnal hypoglycaemia and less weight gain over 12 months in comparison to NPH insulin. Diabetes Obes. Metab. 7, 73–82 (2005).
Tricco, A. C. et al. Safety, effectiveness, and cost effectiveness of long acting versus intermediate acting insulin for patients with type 1 diabetes: systematic review and network meta-analysis. BMJ 349, g5459 (2014).
Frier, B. M., Russell-Jones, D. & Heise, T. A comparison of insulin detemir and neutral protamine Hagedorn (isophane) insulin in the treatment of diabetes: a systematic review. Diabetes Obes. Metab. 15, 978–986 (2013).
Rosenstock, J. et al. A randomised, 52-week, treat-to-target trial comparing insulin detemir with insulin glargine when administered as add-on to glucose-lowering drugs in insulin-naive people with type 2 diabetes. Diabetologia 51, 408–416 (2008).
Hordern, S. V. & Russell-Jones, D. L. Insulin detemir, does a new century bring a better basal insulin? Int. J. Clin. Pract. 59, 730–739 (2005).
Herring, R. et al. Effect of subcutaneous insulin detemir on glucose flux, lipolysis and electroencephalography in type 1 diabetes. Diabetes Obes. Metab. 17, 1100–1103 (2015).
Pollex, E., Moretti, M. E., Koren, G. & Feig, D. S. Safety of insulin glargine use in pregnancy: a systematic review and meta-analysis. Ann. Pharmacother. 45, 9–16 (2011).
Blumer, I. et al. Diabetes and pregnancy: an endocrine society clinical practice guideline. J. Clin. Endocrinol. Metab. 98, 4227–4249 (2013).
Mathiesen, E. R. et al. Maternal efficacy and safety outcomes in a randomized, controlled trial comparing insulin detemir with NPH insulin in 310 pregnant women with type 1 diabetes. Diabetes Care 35, 2012–2017 (2012).
Tan, C. Y., Wilson, D. M. & Buckingham, B. Initiation of insulin glargine in children and adolescents with type 1 diabetes. Pediatr. Diabetes 5, 80–86 (2004).
Thalange, N., Bereket, A., Larsen, J., Hiort, L. C. & Peterkova, V. Treatment with insulin detemir or NPH insulin in children aged 2–5 yr with type 1 diabetes mellitus. Pediatr. Diabetes 12, 632–641 (2011).
National Institute for Health and Care Excellence. Type 1 diabetes in adults: diagnosis and management. NICE https://www.nice.org.uk/guidance/ng17 (2015).
Ashwell, S. G. et al. Improved glycaemic control with insulin glargine plus insulin lispro: a multicentre, randomized, cross-over trial in people with type 1 diabetes. Diabet. Med. 23, 285–292 (2006).
Pedersen-Bjergaard, U. et al. Effect of insulin analogues on risk of severe hypoglycaemia in patients with type 1 diabetes prone to recurrent severe hypoglycaemia (HypoAna trial): a prospective, randomised, open-label, blinded-endpoint crossover trial. Lancet Diabetes Endocrinol. 2, 553–561 (2014).
Taki, K. et al. Analysis of 24-hour glycemic excursions in patients with type 1 diabetes by using continuous glucose monitoring. Diabetes Technol. Ther. 12, 523–528 (2010).
Maia, F. F. & Araujo, L. R. Efficacy of continuous glucose monitoring system (CGMS) to detect postprandial hyperglycemia and unrecognized hypoglycemia in type 1 diabetic patients. Diabetes Res. Clin. Pract. 75, 30–34 (2007).
European Medicines Agency. Abasaglar (previously Abasria). EMA http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002835/human_med_001790.jsp&mid=WC0b01ac058001d124 (2014).
US Food and Drug Administration. FDA approves Basaglar, the first “follow-on” insulin glargine product to treat diabetes. FDA https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm477734.htm (2015).
Linnebjerg, H. et al. Comparison of the pharmacokinetics and pharmacodynamics of LY2963016 insulin glargine and EU- and US-approved versions of lantus insulin glargine in healthy subjects: three randomized euglycemic clamp studies. Diabetes Care 38, 2226–2233 (2015).
Linnebjerg, H. et al. Pharmacokinetics of the long-acting basal insulin LY2605541 in subjects with varying degrees of renal function. Clin. Pharmacol. Drug Dev. 5, 216–224 (2016).
Ilag, L. L. et al. Evaluation of immunogenicity of LY2963016 insulin glargine compared with Lantus® insulin glargine in patients with type 1 or type 2 diabetes mellitus. Diabetes Obes. Metab. 18, 159–168 (2016).
Hadjiyianni, I. et al. Efficacy and safety of LY2963016 insulin glargine in patients with type 1 and type 2 diabetes previously treated with insulin glargine. Diabetes Obes. Metab. 18, 425–429 (2016).
Linnebjerg, H. et al. Duration of action of two insulin glargine products, LY2963016 insulin glargine and Lantus insulin glargine, in subjects with type 1 diabetes mellitus. Diabetes Obes. Metab. 19, 33–39 (2016).
Sindelka, G., Heinemann, L., Berger, M., Frenck, W. & Chantelau, E. Effect of insulin concentration, subcutaneous fat thickness and skin temperature on subcutaneous insulin absorption in healthy subjects. Diabetologia 37, 377–380 (1994).
Becker, R. H., Nowotny, I., Teichert, L., Bergmann, K. & Kapitza, C. Low within- and between-day variability in exposure to new insulin glargine 300 U/ml. Diabetes Obes. Metab. 17, 261–267 (2015).
Becker, R. H. et al. New insulin glargine 300 Units·mL−1 provides a more even activity profile and prolonged glycemic control at steady state compared with insulin glargine 100 Units·mL−1. Diabetes Care 38, 637–643 (2015).
Bergenstal, R. M. et al. Comparison of insulin glargine 300 U/mL and 100 U/mL in adults with type 1 diabetes: continuous glucose monitoring profiles and variability using morning or evening injections. Diabetes Care 40, 554–560 (2017).
Matsuhisa, M. et al. Sustained glycaemic control and less nocturnal hypoglycaemia with insulin glargine 300U/mL compared with glargine 100U/mL in Japanese adults with type 1 diabetes (EDITION JP 1 randomised 12-month trial including 6-month extension). Diabetes Res. Clin. Pract. 122, 133–140 (2016).
Home, P. D. et al. New insulin glargine 300 Units/mL versus glargine 100 Units/mL in people with type 1 diabetes: a randomized, phase 3a, open-label clinical trial (EDITION 4). Diabetes Care 38, 2217–2225 (2015).
Heller, S., Mathieu, C., Kapur, R., Wolden, M. L. & Zinman, B. A meta-analysis of rate ratios for nocturnal confirmed hypoglycaemia with insulin degludec versus insulin glargine using different definitions for hypoglycaemia. Diabet. Med. 33, 478–487 (2016).
Mathieu, C. et al. Efficacy and safety of insulin degludec in a flexible dosing regimen versus 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. 98, 1154–1162 (2013).
Ratner, R. E. et al. Hypoglycaemia risk with insulin degludec compared with insulin glargine in type 2 and type 1 diabetes: a pre-planned meta-analysis of phase 3 trials. Diabetes Obes. Metab. 15, 175–184 (2013).
Heise, T. et al. Comparison of the pharmacokinetic and pharmacodynamic profiles of insulin degludec and insulin glargine. Expert Opin. Drug Metab. Toxicol. 11, 1193–1201 (2015).
Heise, T. et al. A new-generation ultra-long-acting basal insulin with a bolus boost compared with insulin glargine in insulin-naive people with type 2 diabetes: a randomized, controlled trial. Diabetes Care 34, 669–674 (2011).
Heise, T., Nosek, L., Bottcher, S. G., Hastrup, H. & Haahr, H. Ultra-long-acting insulin degludec has a flat and stable glucose-lowering effect in type 2 diabetes. Diabetes Obes. Metab. 14, 944–950 (2012).
Heise, T. & Meneghini, L. F. Insulin stacking versus therapeutic accumulation: understanding the differences. Endocr. Pract. 20, 75–83 (2014).
Heller, S. 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 379, 1489–1497 (2012).
Lane, W. S. et al. Switch1: reduced hypoglycaemia with insulin degludec (IDeg) vs. insulin glargine (IGlar), both U100, in patients with T1D at high risk of hypoglycaemia: a randomized, double-blind, crossover trial [abstract LB-87]. American Diabetes Association (2016).
Galasso, S. et al. Switching from twice-daily glargine or detemir to once-daily degludec improves glucose control in type 1 diabetes. An observational study. Nutr. Metab. Cardiovasc. Dis. 26, 1112–1119 (2016).
Korsatko, S. et al. A comparison of the steady-state pharmacokinetic and pharmacodynamic profiles of 100 and 200 U/mL formulations of ultra-long-acting insulin degludec. Clin. Drug Investig. 33, 515–521 (2013).
Jonassen, I. et al. Design of the novel protraction mechanism of insulin degludec, an ultra-long-acting basal insulin. Pharm. Res. 29, 2104–2114 (2012).
Haahr, H. & Heise, T. A review of the pharmacological properties of insulin degludec and their clinical relevance. Clin. Pharmacokinet. 53, 787–800 (2014).
Thalange, N. et al. Insulin degludec in combination with bolus insulin aspart is safe and effective in children and adolescents with type 1 diabetes. Pediatr. Diabetes 16, 164–176 (2015).
Evans, M., Chubb, B. & Gundgaard, J. Cost-effectiveness of insulin degludec versus insulin glargine in adults with type 1 and type 2 diabetes mellitus. Diabetes Ther. http:dx.doi.org/10.1007/s13300-017-0236-9 (2017).
Landstedt-Hallin, L., Gundgaard, J., Ericsson, A. & Ellfors-Zetterlund, S. Cost-effectiveness of switching to insulin degludec from other basal insulins: evidence from Swedish real-world data. Curr. Med. Res. Opin. http://dx.doi.org/10.1080/03007995.2016.1277194 (2017).
Henry, R. R. et al. Basal insulin peglispro demonstrates preferential hepatic versus peripheral action relative to insulin glargine in healthy subjects. Diabetes Care 37, 2609–2615 (2014).
Sinha, V. P. et al. Single-dose pharmacokinetics and glucodynamics of the novel, long-acting basal insulin LY2605541 in healthy subjects. J. Clin. Pharmacol. 54, 792–799 (2014).
Caparrotta, T. M. & Evans, M. PEGylated insulin lispro, (LY2605541) — a new basal insulin analogue. Diabetes Obes. Metab. 16, 388–395 (2014).
Buse, J. B. et al. Randomized clinical trial comparing basal insulin peglispro and insulin glargine in patients with type 2 diabetes previously treated with basal insulin: IMAGINE 5. Diabetes Care 39, 92–100 (2016).
Garg, S. et al. A randomized clinical trial comparing basal insulin peglispro and insulin glargine, in combination with prandial insulin lispro, in patients with type 1 diabetes: IMAGINE 1. Diabetes Obes. Metab. 18 (Suppl. 2), 25–33 (2016).
Garg, S. et al. Greater HbA1c reduction with basal insulin peglispro (BIL) versus insulin glargine (GL) in an open-label, randomised study in type 1 diabetic patients: IMAGINE 1 [abstract 3]. Diabetologia 58 (Suppl. 1), S2 (2015).
Bergenstal, R. M. et al. Randomized, double-blind clinical trial comparing basal insulin peglispro and insulin glargine, in combination with prandial insulin lispro, in patients with type 1 diabetes: IMAGINE 3. Diabetes Obes. Metab. 18, 1081–1088 (2016).
Cusi, K. et al. Different effects of basal insulin peglispro and insulin glargine on liver enzymes and liver fat content in patients with type 1 and type 2 diabetes. Diabetes Obes. Metab. 18 (Suppl. 2), 50–58 (2016).
Munoz-Garach, A., Molina-Vega, M. & Tinahones, F. J. How can a good idea fail? Basal insulin peglispro [LY2605541] for the treatment of type 2 diabetes. Diabetes Ther. 8, 9–22 (2017).
Atkin, S., Javed, Z. & Fulcher, G. Insulin degludec and insulin aspart: novel insulins for the management of diabetes mellitus. Ther. Adv. Chronic Dis. 6, 375–388 (2015).
Heise, T. et al. Distinct prandial and basal glucose-lowering effects of insulin degludec/insulin aspart (IDegAsp) at steady state in subjects with type 1 diabetes mellitus. Diabetes Ther. 5, 255–265 (2014).
Hirsch, I. B., Franek, E., Mersebach, H., Bardtrum, L. & Hermansen, K. Safety and efficacy of insulin degludec/insulin aspart with bolus mealtime insulin aspart compared with standard basal-bolus treatment in people with type 1 diabetes: 1-year results from a randomized clinical trial (BOOST(R) T1). Diabet. Med. 34, 167–173 (2017).
Heise, T. et al. Faster-acting insulin aspart: earlier onset of appearance and greater early pharmacokinetic and pharmacodynamic effects than insulin aspart. Diabetes Obes. Metab. 17, 682–688 (2015).
de la Pena, A. et al. Bioequivalence and comparative pharmacodynamics of insulin lispro 200 U/mL relative to insulin lispro (Humalog®) 100 U/mL. Clin. Pharmacol. Drug Dev. 5, 69–75 (2016).
Muchmore, D. B. & Vaughn, D. E. Review of the mechanism of action and clinical efficacy of recombinant human hyaluronidase coadministration with current prandial insulin formulations. J. Diabetes Sci. Technol. 4, 419–428 (2010).
Muchmore, D. B. & Vaughn, D. E. Accelerating and improving the consistency of rapid-acting analog insulin absorption and action for both subcutaneous injection and continuous subcutaneous infusion using recombinant human hyaluronidase. J. Diabetes Sci. Technol. 6, 764–772 (2012).
Krasner, A. et al. A review of a family of ultra-rapid-acting insulins: formulation development. J. Diabetes Sci. Technol. 6, 786–796 (2012).
Pandyarajan, V. & Weiss, M. A. Design of non-standard insulin analogs for the treatment of diabetes mellitus. Curr. Diab. Rep. 12, 697–704 (2012).
Heise, T., Pieber, R. R., Danne, T., Erlichsen, L. & Haahr, H. Faster onset and greater early exposure and glucose-lowering effect with faster-acting insulin aspart versus insulin aspart: a pooled analysis in subjects with type 1 diabetes [abstract 929-P]. American Diabetes Association (2016).
Heise, T. 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 34, 29–38 (2017).
Fath, M. et al. Faster-acting insulin aspart provides faster onset and greater early exposure versus insulin aspart in children and adolescents with type 1 diabetes mellitus. Pediatr. Diabetes http://dx.doi.org/10.1111/pedi.12506 (2017).
Heise, T., Zijlstra, E., Nosek, L., Rikte, T. & Haahr, H. Pharmacological properties of faster-acting insulin aspart versus insulin aspart in patients with type 1 diabetes using continuous subcutaneous insulin infusion: a randomised, double-blind, crossover trial. Diabetes Obes. Metab. 19, 208–215 (2017).
Bode, B. W., Johnson, J. A., Hyveled, L., Tamer, S. C. & Demissie, M. Improved postprandial glycemic control with faster-acting insulin aspart in patients with type 1 diabetes using continuous subcutaneous insulin infusion. Diabetes Technol. Ther. 19, 25–33 (2017).
European Medicines Agency. Fiasp. EMA http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/004046/human_med_002063.jsp&mid=WC0b01ac058001d124 (2017).
Cengiz, E., Bode, B., Van Name, M. & Tamborlane, W. V. Moving toward the ideal insulin for insulin pumps. Expert Rev. Med. Devices 13, 57–69 (2016).
Zaykov, A. N., Mayer, J. P. & DiMarchi, R. D. Pursuit of a perfect insulin. Nat. Rev. Drug Discov. 15, 425–439 (2016).
Wang, Y., Shao, J., Zaro, J. L. & Shen, W. C. Proinsulin-transferrin fusion protein as a novel long-acting insulin analog for the inhibition of hepatic glucose production. Diabetes 63, 1779–1788 (2014).
Phillips, N. B., Whittaker, J., Ismail-Beigi, F. & Weiss, M. A. Insulin fibrillation and protein design: topological resistance of single-chain analogs to thermal degradation with application to a pump reservoir. J. Diabetes Sci. Technol. 6, 277–288 (2012).
Chou, D. H. et al. Glucose-responsive insulin activity by covalent modification with aliphatic phenylboronic acid conjugates. Proc. Natl Acad. Sci. USA 112, 2401–2406 (2015).
Baeshen, N. A. et al. Cell factories for insulin production. Microb. Cell Fact. 13, 141 (2014).
Santos Cavaiola, T. & Edelman, S. Inhaled insulin: a breath of fresh air? A review of inhaled insulin. Clin. Ther. 36, 1275–1289 (2014).
Heinemann, L. Insulin pens and new ways of insulin delivery. Diabetes Technol. Ther. 16 (Suppl. 1), S44–S55 (2014).
Fonte, P., Araujo, F., Reis, S. & Sarmento, B. Oral insulin delivery: how far are we? J. Diabetes Sci. Technol. 7, 520–531 (2013).
Author information
Authors and Affiliations
Contributions
C.M. and K.B. researched data for the article, contributed to discussion of the content, wrote the article and reviewed and/or edited the manuscript before submission. P.G. contributed to discussion of the content and reviewed and/or edited the manuscript before submission.
Corresponding author
Ethics declarations
Competing interests
C.M. serves or has served on the advisory panel for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly and Company, Intrexon, Janssen Pharmaceuticals, Hanmi Pharmaceuticals, Mannkind, Medtronic, Merck Sharp and Dohme Ltd., Novartis, Novo Nordisk, Pfizer, Sanofi, Roche Diagnostics and UCB. KU Leuven has received research support for C.M. from Abbott, Eli Lilly and Company, Intrexon, Merck Sharp and Dohme Ltd., Novartis, Novo Nordisk, Roche Diagnostics and Sanofi. C.M. serves or has served on the speakers bureau for AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Merck Sharp and Dohme, Novartis, Novo Nordisk and Sanofi. P.G. has served on the advisory panel for AstraZeneca, Lilly, Merck Sharp and Dohme Ltd., Novo Nordisk and Sanofi. P.G. has served on the speakers bureau for AstraZeneca, Bristol-Meyers Squibb, Boehringer Ingelheim, Janssen Pharmaceuticals, Lilly, Novartis, Novo Nordisk and Sanofi. K.B. has served on the advisory panel for AstraZeneca, Merck Sharp and Dohme Ltd. and Novo Nordisk. K.B. has served on the speakers bureau for AstraZeneca, Bristol-Meyers Squibb, Boehringer Ingelheim, Janssen Pharmaceuticals, Lilly, Novartis and Novo Nordisk. KU Leuven has received research grants for K.B. from AstraZeneca, Janssen Pharmaceuticals, Merck Sharp and Dohme Ltd., Novartis, Novo Nordisk and Sanofi.
Rights and permissions
About this article
Cite this article
Mathieu, C., Gillard, P. & Benhalima, K. Insulin analogues in type 1 diabetes mellitus: getting better all the time. Nat Rev Endocrinol 13, 385–399 (2017). https://doi.org/10.1038/nrendo.2017.39
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrendo.2017.39
This article is cited by
-
Association of glucose-lowering drug target and risk of gastrointestinal cancer: a mendelian randomization study
Cell & Bioscience (2024)
-
Safety and glycemic control with insulin degludec use in clinical practice: results from a 3-year Japanese post-marketing surveillance study
Diabetology International (2024)
-
Enhanced hexamerization of insulin via assembly pathway rerouting revealed by single particle studies
Communications Biology (2023)
-
Development and Characterization of Guinea Pig Anti-Insulin Polyclonal Antibody
Applied Biochemistry and Biotechnology (2023)
-
Diagnostik und Therapie des Typ 1 Diabetes mellitus (Update 2023)
Wiener klinische Wochenschrift (2023)