Advances in Insulin Therapy: A Review of Insulin Degludec

,

Medical Education Library

Advances in Insulin Therapy: A Review of Insulin Degludec

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

PDF Download

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.

The findings from these investigations demonstrate that insulin degludec has a long half-life, resulting in a prolonged duration of blood glucose lowering with low within-subject pharmacodynamic variability.

FIGURE 1

Mean 24-hour glucose infusion rates (GIR) of insulin degludec at steady state

Copyright 2011 American Diabetes Association. From Diabetes®, Vol. 60,
Suppl. 1; 2011. Reprinted by permission of the American Diabetes Association.

Efficacy, Safety, and Tolerability of Insulin Degludec

Type 2 Diabetes Mellitus

Insulin degludec has been compared with insulin glargine in combination with oral glucose-lowering agents or in combination with a prandial insulin analog; one study investigated insulin degludec and insulin aspart in basal-bolus therapy in T2DM. In the basal-bolus treat-to-target trial, 992 patients with T2DM (mean A1C 8.3%) were randomized to receive insulin degludec or insulin glargine, each in combination with prandial insulin aspart ± metformin ± pioglitazone.¹⁵ Basal insulin was titrated to achieve a fasting plasma glucose (FPG) <90 mg/dL. At 1 year, mean A1C values were reduced by 1.1% and 1.2% with insulin degludec and insulin glargine, respectively (estimated treatment difference [ETD], 0.08%; 95% confidence interval (CI), –0.05 to 0.21). FPG was reduced by 41 and 36 mg/dL, respectively (ETD, –5.2 mg/dL; 95% CI, –11.7 to 1.1; P = non significant [NS]). Overall, the rates of confirmed hypoglycemia (plasma glucose <56 mg/dL or severe episodes requiring assistance) were lower in the group treated with insulin degludec than in the group treated with insulin glargine (11.1 vs 13.6 episodes/patient-year; estimated rate ratio [ERR], 0.82; 95% CI, 0.69 to 0.99; P = .0359). Nocturnal confirmed hypoglycemia, defined as episodes occurring between midnight and 6 am, occurred significantly less frequently in the insulin degludec group compared with the insulin glargine group (1.4 vs 1.8 episodes/patient-year, respectively; ERR, 0.75; 95% CI, 0.58 to 0.99; P = .0399) (FIGURE 2). Rates of other adverse events were similar between the 2 groups. At 1 year, the total mean daily insulin doses were 1.46 and 1.42 U/kg in the insulin degludec and insulin glargine groups, respectively, with a ~50:50 basal:bolus ratio for both groups.

Based on these findings, insulin degludec was associated with glycemic control similar to insulin glargine when given as basal-bolus therapy. Overall, confirmed and nocturnal hypoglycemia occurred less frequently with insulin degludec than with insulin glargine.

FIGURE 2

Incidences of nocturnal hypoglycemia with insulin degludec and insulin glargine^15,16,18

Type 1 Diabetes Mellitus

Insulin degludec has been investigated in the treatment of patients with T1DM. Two randomized trials involved basal-bolus therapy in combination with insulin aspart. A 1-year treat-to-target trial in 629 adults with T1DM (mean A1C 7.7%) compared insulin degludec with insulin glargine, each given once daily in a basal-bolus regimen with mealtime insulin aspart.¹⁶ Both groups were reported to have improved glycemic control, with overall A1C decreased by 0.4%. Similar proportions of patients achieved A1C <7.0% with insulin degludec and insulin glargine (40% vs 43%; P = NS). Mean FPG values were reduced similarly (ETD, 5.9 mg/dL; P = .35). Compared with insulin glargine, rates of confirmed nocturnal hypoglycemia were 25% lower with insulin degludec (4.4 vs 5.9 episodes/patient-year; ERR, 0.75; 95% CI, 0.59 to 0.96; P = .021), whereas rates of overall confirmed hypoglycemia were similar between treatment groups (42.5 vs 40.2 episodes/patient-year; ERR, 1.07; 95% CI, 0.89 to 1.28; P = .48). Overall rates of other adverse events were similar between groups.

Insulin degludec in a fixed-ratio combined formulation with insulin aspart (IDegAsp) was compared with insulin detemir and insulin aspart in basal-bolus therapy in a 26-week, open-label, treat-to-target trial involving 548 patients with T1DM (mean A1C, 8.3%; mean FPG, 189 mg/dL at baseline).¹⁷ IDegAsp was given once daily at any meal, with insulin aspart at the remaining meals, whereas insulin detemir was administered according to approved labeling with mealtime insulin aspart at all meals. The mean decrease in A1C was similar for IDegAsp and insulin detemir/insulin aspart (0.73% vs 0.68%, respectively). The decrease in mean FPG was also similar between groups (P = .52). The mean total daily insulin doses were 69 U (0.86 U/kg) for IDegAsp and 79 U (1.00 U/kg) for insulin detemir and insulin aspart. Rates of severe hypoglycemia were 0.33 and 0.42 episodes/patient-year with IDegAsp and insulin detemir, respectively. Rates of overall confirmed hypoglycemia were similar (39 vs 44 episodes/patient-year; P = .27), whereas confirmed nocturnal hypoglycemia was reported significantly less frequently with IDegAsp (3.7 vs 5.7 episodes/patient-year, respectively; P = .0003). Weight increase was significantly greater (by 1.04 kg) with IDegAsp compared with insulin detemir (P = .0021). Overall rates of other adverse events were similar between treatment groups.