Patient safety and minimizing risk with insulin administration – role of insulin degludec

Figures & data

Figure 1 Schematic representation of insulin degludec. DesB30 human insulin is acylated at the ε-amino group of Lysine^B29 with hexadecanoic acid via a γ-L-glutamic acid linker.

Note: Reproduced from Jonassen I, Havelund S, Hoeg-Jensen T, Steensgaard DB, Wahlund PO, Ribel U. Design of the novel protraction mechanism of insulin degludec, an ultra-long-acting basal insulin. Pharm Res. 2012;29(8):2104–2114. Copyright © 2012, the authors.¹

Figure 2 Schematic representation of the hypothesis for the mode of retarded absorption of insulin degludec.¹ Insulin degludec is injected subcutaneously as a zinc phenol formulation containing insulin degludec dihexamers in the T₃R₃ conformation. Rapid loss of phenol changes the degludec hexamers to T₆ configuration and multihexamer chains form. With slow diffusion of zinc, these chains break down into dimers, which quickly dissociate into readily absorbed monomers.

Note: Reproduced from Jonassen I, Havelund S, Hoeg-Jensen T, Steensgaard DB, Wahlund PO, Ribel U. Design of the novel protraction mechanism of insulin degludec, an ultra-long-acting basal insulin. Pharm Res. 2012;29(8): 2104–2114. Copyright © 2012, the authors.¹

Figure 3 Hypothetical examples of profiles of insulins with various half-lives.⁵²

Notes: (A) Accumulation from first dose to steady state and (B) perturbations following various types of common dosing errors as indicated by arrows, when introduced at steady-state. When interpreting the effects of double-dosing (bottom row), it is important to note that different pharmacokinetic scales have been used for the rapid-acting and basal insulin curves. Fluctuations in insulin concentration (and therefore glucose-lowering action) are greatest, and dosing errors have the most acute effects, with basal insulin having a shorter half-life (eg, 6 hours) and duration of action. Fluctuations are dampened and dosing errors have less acute effects with insulin formulations having a longer half-life/duration of action. The half-lives for basal insulin shown in the figure correspond approximately to those of neutral protamine Hagedorn insulin (6 hours), insulin glargine (12.5 hours), and insulin degludec (25 hours). Reprinted from Endocrine Practice. Heise T, Meneghini LF. Insulin stacking versus therapeutic accumulation: understanding the differences. Endocr Pract. 2013;20(1):75–83. Copyright 2013, with permission from the American Association of Clinical Endocrinologists.⁵²

Table 1 Hypoglycemia rates in clinical trials of insulin degludec

ClinicalTrials.gov registration number	Study design	Patient population	Randomized trial treatment (full analysis set)	Initial insulin dose	Overall confirmed hypoglycemia (IDeg vs IGlar) episodes/PYE (rate ratio [95% CI])	Nocturnal confirmed hypoglycemia (IDeg vs IGlar) episodes/PYE (rate ratio [95% CI])
NCT00982644 (BEGIN ONCE LONG)^Citation41,Citation57	52-week, open-label, randomized, treat-to-target, non-inferiority trial	Insulin-naïve adults with type 2 diabetes inadequately controlled with oral antidiabetic drugs	3:1 randomization ratio IDeg OD (n=773) IGlar OD (n=257)	Ten units	1.52 vs 1.85 episodes/PYE (0.82 [0.64–1.04], NS)	0.25 vs 0.39 episodes/PYE (0.64 [0.42–0.98], P=0.038)
NCT00972283 (BEGIN BB)^Citation38,Citation58	52-week, open-label, randomized, treat-to-target, non-inferiority trial	Adults with uncontrolled type 2 diabetes treated with any insulin regimen for ≥3 months	3:1 randomization ratio IDeg OD (n=744) IGlar OD (n=248)	Starting dose in insulin-naïve patients: ten units Patients receiving prior OD basal insulin switched on a 1:1 basis, whereas patients on a pre-study BID basal insulin regimen were switched to lower starting doses of IGlar and IDeg. For IGlar, the starting dose was 20%–30% lower than the pre-study total daily insulin dose according to approved product labeling; for IDeg, the starting dose was determined by the investigator on an individual patient basis	11.09 vs 13.63 episodes/PYE (0.82 [0.69–0.99], P=0.036)	1.39 vs 1.84 episodes/PYE (0.75 [0.58–0.99], P=0.040)
NCT00982228 (BEGIN BB T1 LONG)^Citation39,Citation59	52-week, open-label, randomized, treat-to-target, non-inferiority trial	Adults with uncontrolled type 1 diabetes treated with basal–bolus insulin for ≥1 year	3:1 randomization ratio IDeg OD + IAsp (n=472) IGlar OD + IAsp (n=157)	Patients receiving prior OD basal insulin switched on a 1:1 basis, whereas patients on a pre-study BID basal insulin regimen were switched to lower starting doses of IGlar and 1:1 for IDeg. For IGlar, the starting dose was 20%–30% lower than the pre-study total daily insulin dose according to approved product labeling	42.54 vs 40.18 episodes/PYE (1.07 [0.89–1.28], NS)	4.41 vs 5.86 episodes/PYE (0.75 [0.59–0.96], P=0.021)
NCT01006291 (BEGIN FLEX)^Citation53,Citation60	26-week, open-label, randomized, treat-to-target, non-inferiority trial	Insulin-naïve adults with type 2 diabetes inadequately controlled with oral antidiabetic drugs Adults with uncontrolled type 2 diabetes treated with any insulin regimen for ≥3 months	1:1:1 randomization ratio IDeg flexible OD (n=229) IDeg fixed OD (n=228) IGlar OD (n=230)	Starting dose in insulin-naïve patients: 10 units Patients receiving prior OD basal insulin switched on a 1:1 basis, whereas patients on a pre-study BID basal insulin regimen were switched to lower starting doses of IGlar and IDeg. For IGlar, the starting dose was 20%–30% lower than the pre-study total daily insulin dose according to approved product labeling; for IDeg, the starting dose was determined by the investigator on an individual patient basis	3.6 (IDeg Flex) vs 3.6 (IDeg Fixed) vs 3.5 (IGlar) episodes/PYE (IDeg Flex vs IGlar: 1.03 [0.75–1.40], NS; IDeg Flex vs IDeg Fixed: 1.10 [0.79–1.52], NS)	0.6 (IDeg Flex) vs 0.6 (IDeg Fixed) vs 0.8 (IGlar) episodes/PYE (IDeg Flex vs IGlar: 0.77 [0.44–1.35], NS; IDeg Flex vs IDeg Fixed: 1.18 [0.66–2.12], NS)
NCT01079234 (BEGIN FLEX T1)^Citation54,Citation61	26-week, open-label, randomized, treat-to-target, non-inferiority trial	Adults with uncontrolled type 1 diabetes treated with basal-bolus insulin for ≥1 year	1:1:1 randomization ratio IDeg flexible OD (n=164) IDeg fixed OD (n=165) IGlar OD (n=164)	Patients receiving prior OD basal insulin switched on a 1:1 basis, whereas patients on a pre-study BID basal insulin regimen were switched to lower starting doses of IGlar and IDeg. For IGlar, the starting dose was 20%–30% lower than the pre- study total daily insulin dose according to approved product labeling; for IDeg, the starting dose was determined by the investigator on an individual patient basis	82.4 (IDeg Flex) vs 88.3 (IDeg Fixed) vs 79.7 (IGlar) episodes/PYE (IDeg Flex vs IGlar: 1.03 [0.85–1.26], NS; IDeg Flex vs IDeg Fixed: 0.92 [0.76–1.12], NS)	6.2 (IDeg Flex) vs 9.6 (IDeg Fixed) vs 10.0 (IGlar) episodes/PYE (IDeg Flex vs IGlar: 0.60 [0.44–0.82], P=0.001; IDeg Flex vs IDeg Fixed: 0.63 [0.46–0.86], P=0.003)
NCT01059799 (BEGIN ONCE ASIA)^Citation55,Citation62	26-week, open-label, randomized, Pan-Asian, treat-to-target, non-inferiority trial	Insulin-naïve adults with type 2 diabetes inadequately controlled with oral antidiabetic drugs	2:1 randomization ratio IDeg OD (n=289) IGlar OD (n=146)	Ten units	3.0 vs 3.7 episodes/PYE (0.82 [0.60–1.11], P=0.20)	0.8 vs 1.2 episodes/PYE (0.62 [0.38–1.04], P=0.07)
NCT01068665 (BEGIN LOW VOLUME)^Citation56,Citation63	26-week, open-label, randomized, treat-to-target, non-inferiority trial	Insulin-naïve adults with type 2 diabetes inadequately controlled with oral antidiabetic drugs	1:1 randomization ratio IDeg U200 OD (n=228) IGlar U100 OD (n=229)	Ten units	1.22 vs 1.42 episodes/PYE (0.86 [0.58–1.28], NS)	0.18 vs 0.28 episodes/PYE (0.64 [0.30–1.37], NS)

Notes: In the BEGIN studies, “confirmed hypoglycemia” was defined as episodes in which the plasma glucose value was <3.1 mmol/L (irrespective of symptoms) or severe (requiring assistance). “Nocturnal hypoglycemia” was defined as episodes occurring between 0001 and 0559 hours (inclusive).

Abbreviations: BID, twice daily; CI, confidence interval; IAsp, insulin aspart; IDeg, insulin degludec; IDeg Flex, insulin degludec administered at varying times day to day; IDeg fixed, insulin degludec administered at a fixed time every day; IGlar, insulin glargine; NS, nonsignificant; OD, once daily; PYE, patient years of exposure; U200, 200 units/mL formulation; U100, 100 units/mL formulation; vs, versus.

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