Advances in Insulin Therapy: A Review of Insulin Degludec

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Medical Education Library

Advances in Insulin Therapy: A Review of Insulin Degludec

May 2012 · Vol. 61, No. 05 Suppl: S28-S31

By

Allen King, MD

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References

1. Rodbard HW, Jellinger PS, Davidson JA, et al. Statement by an American Association of Clinical Endocrinologists/American College of Endocrinology consensus panel on type 2 diabetes mellitus: an algorithm for glycemic control [published correction appears in Endocr Pract. 2009;15(7):768-770]. Endocr Pract. 2009;15(6):540-559.

2. Bartley PC, Bogoev M, Larsen J, Philotheou A. Long-term efficacy and safety of insulin detemir compared to Neutral Protamine Hagedorn insulin in patients with type 1 diabetes using a treat-to-target basal-bolus regimen with insulin aspart at meals: a 2-year, randomized, controlled trial. Diabet Med. 2008;25(4):442-449.

3. Riddle MC, Rosenstock J, Gerich J. Insulin Glargine 4002 Study Investigators. The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care. 2003;26(11):3080—3086.

4. Hermansen K, Davies M, Derezinski T, Martinez Ravn G, Clauson P, Home P. A 26-week, randomized, parallel, treat-to-target trial comparing insulin detemir with NPH insulin as add-on therapy to oral glucose-lowering drugs in insulin-naive people with type 2 diabetes [published correction appears in Diabetes Care. 2007;30(4):1035] Diabetes Care. 2006;29(6):1269-1274.

5. Heise T, Nosek L, Rønn BB, et al. Lower within-subject variability of insulin detemir in comparison to NPH insulin and insulin glargine in people with type 1 diabetes. Diabetes. 2004;53(6):1614-1620.

6. Ashwell SG, Gebbie J, Home PD. Twice-daily compared with once-daily insulin glargine in people with type 1 diabetes using meal-time insulin aspart. Diabet Med. 2006;23(8):879-886.

7. Donnelly LA, Morris AD, Frier BM, et al. DARTS/MEMO Collaboration. Frequency and predictors of hypoglycaemia in type 1 and insulin-treated type 2 diabetes: a population-based study. Diabet Med. 2005;22(6):749-755.

8. 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. 2009;25(11):2601-2608.

9. Kalra S, Unnikrishnan AG, Baruah M, Kalra B. Degludec insulin: a novel basal insulin. Indian J Endocrinol Metab. 2011;15(suppl 1):S12-S16.

10. Jonassen I, Havelund S, Ribel U, et al. Insulin degludec: Multi-hexamer formation is the underlying basis for this new generation ultra-long acting basal insulin. Paper presented at: European Association for the Study of Diabetes Annual Meeting; September 20-24, 2010; Stockholm, Sweden.

11. Kurtzhals P, Heise T, Strauss HM, et al. Multi-hexamer formation is the underlying mechanism behind the ultra-long glucose-lowering effect of insulin degludec. Paper presented at: American Diabetes Association 71st Scientific Sessions; June 24-28, 2011; San Diego, CA.

12. Nosek L, Heise T, Bøttcher SG, Hastrup H, Haahr H. Ultra-long-acting insulin degludec has a flat and stable glucose-lowering effect. Paper presented at: American Diabetes Association 71st Scientific Sessions; June 24-28, 2011; San Diego, CA.

13. Heise T, Hövelmann U, Nosek L, Bøttcher SG, Granhall C, Haahr H. Insulin degludec has a two-fold longer half-life and a more consistent pharmacokinetic profile than insulin glargine. Paper presented at: American Diabetes Association 71st Scientific Sessions; June 24-28, 2011; San Diego, CA.

14. Heise T, Hermanski L, Nosek L, Feldmann A, Rasmussen S, Haahr H. The pharmacodynamic variability of insulin degludec is consistently lower than insulin glargine over 24 hours at steady state. Diabetes. 2011;60(suppl 1):A263.-Poster 960-P.

Garber AJ, King AB, Del Prato S, et al. 15.NN1250-3582 (BEGIN BB T2D) Trial Investigators. Insulin degludec, an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 2 diabetes (BEGIN Basal-Bolus Type 2): a phase 3, randomised, open-label, treat-to-target non-inferiority trial. Lancet. 2012;379(9825):1498-1507.

16. Heller S, Buse J, Fisher M, et al. BEGIN Basal-Bolus Type 1 Trial Investigators. Insulin degludec, an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 1 diabetes (BEGIN Basal-Blus Type 1): a phase 3, randomised, open-label, treat-to-target non-inferiority trial. Lancet. 2012;379(9825):1489-1497.

17. Hirsch IB, Franek E, Courreges JP, Mersebach H, Dykiel P, Bode BW. Efficacy and safety of a new basal insulin with a bolus boost (IDegAsp) used once daily in combination wtih insulin apart (IAsp) in people wth type 1 diabetes. Diabetes. 2011;60(suppl 1):A292.-Poster 1064-P.

18. Meneghini L, Atkin SL, Bain S, et al. Flexible once-daily dosing of insulin degludec does not compromise glycemic control or safety compared to insulin glargine given once daily at the same time each day in people with type 2 diabetes. Paper presented at: American Diabetes Association 71st Scientific Sessions; June 24-28, 2011; San Diego, CA.

Table of Contents

Introduction

The Evolution of Insulin Therapy in Diabetes Mellitus

Individualizing Insulin Therapy

Advances in Insulin Therapy: A Review of Insulin Degludec

Introduction

Basal insulin has been an important treatment option for patients with diabetes mellitus (DM) and, along with prandial insulin, has undergone major improvements in terms of purity and similarity to the action of physiologic human insulin. (see The Evolution of Insulin Therapy in Diabetes Mellitus in this supplement.) Lente and Ultralente formulations were used for decades but are no longer available. The use of neutral protamine Hagedorn (NPH) insulin is also being replaced with the basal insulin analogs detemir and glargine.¹ Basal insulin analogs generally cause less severe and nocturnal hypoglycemia compared with NPH insulin owing to their improved pharmacologic profiles.^2-4 In comparison to NPH insulin, insulin glargine causes similar weight gain, whereas insulin detemir causes less weight gain.^2-4 In addition, insulin detemir has been associated with a glucose-lowering effect that is more predictable than that of NPH insulin.⁵ Despite the improvements observed with basal insulin analogs, their time-action profiles are not completely flat and are shorter than 24 hours in many patients.^5,6 In addition, severe hypoglycemia remains a concern, particularly in patients with type 1 DM (T1DM).^7,8 Consequently, the search for a better basal insulin continues.

The ideal basal insulin should possess numerous attributes. While each of the attributes listed in the TABLE is important, an overarching difficulty with basal insulin therapy is the need for administration at the same time each day.⁹ This dosing limitation may be most difficult for those with busy or erratic schedules or who may forget to administer their insulin dose. This article will review the clinical experience with insulin degludec, an ultra–long-acting insulin under review by the US Food and Drug Administration (FDA).

TABLE

Attributes of the ideal basal insulin⁹

Delivers a steady, stable, peakless, continuous insulin concentration for at least 24 hours, in a predictable manner, with low intraindividual and interindividual variability
Does not cause side effects such as weight gain or hypoglycemia
Does not induce mitogenicity
Can be used as monotherapy, as part of basal-bolus therapy, or in combination with oral glucose-lowering therapy
Equally efficacious, safe, and well-tolerated in patients with type 1 or type 2 diabetes mellitus
Indian Journal of Endocrinology and Metabolism. Copyright 2011 by MEDKNOW PUBLICATIONS AND MEDIA PVT LTD. Reproduced with permission of MEDKNOW PUBLICATIONS AND MEDIA PVT LTD in the format Journal via Copyright Clearance Center.

Clinical Pharmacology of Insulin Degludec

Removal of threonine at position 30 of the B chain of human insulin and the addition of a 16-carbon fatty diacid attached to lysine at position 29 of the B chain of human insulin via a glutamic acid spacer result in the insulin degludec molecule, which has several differences from available basal insulin analogs. Experimental investigations indicated that conditions mimicking subcutaneous injection of insulin degludec resulted in a reorganization of the insulin degludec molecule from dihexamers to multihexamer assemblies that remain in solution at physiologic pH.¹⁰ Slow release of zinc ions from the multihexamers leads to the slow release of insulin degludec monomers, which are easily absorbed into the systemic circulation.¹¹ The result is a half-life of insulin degludec that is longer than 24 hours, with a level that is detectable in circulation for at least 96 hours after administration of the dose.^10,12 The pharmacodynamic result is a relatively flat and consistent blood glucose–lowering effect with insulin degludec (FIGURE 1) reported to be longer than 24 hours in patients with T1DM or type 2 DM (T2DM).^11,12

A randomized, double-blind, two-period, crossover comparison of insulin degludec and insulin glargine in patients with T1DM (N = 66) reported a half-life of 25.4 hours with insulin degludec compared with 12.5 hours with insulin glargine.¹³ The serum exposure of insulin degludec was similar between the first and second 12-hour period postdose. On the other hand, approximately 60% of the serum exposure to insulin glargine occurred over the first 12 hours following administration. These results highlight that insulin degludec is an ultra–long-acting insulin preparation with improved pharmacodynamic stability.

Analysis of data in 54 patients with T1DM reported that the within-subject pharmacodynamic variability was lower with insulin degludec compared with insulin glargine during a 24-hour euglycemic glucose clamp.¹⁴ Over 24 hours, the coefficient of variation (CV) with insulin degludec was lower for the area under the glucose infusion rate curve (AUC_GIR) for total AUC_GIR,0-24h (CV, 23% vs. 72%; P < .001), for GIR_max (CV, 21% vs. 53%; P < .0001), and for the fluctuation around the mean GIR value over 24 hours (CV, 31% vs. 62%; P < .001).