Insulin degludec/insulin aspart combination for the treatment of type 1 and type 2 diabetes

Figures & data

Table 1 Summary of main studies using IDeg in patients with type 1 and type 2 DM

Authors	Study design	Comparators	Type of patients
Birkeland KI et al^Citation40 Diabetes Care, 2011	16-week, randomized, controlled, open-label, three-arm, parallel group trial	IDeg (600 micromol/L); IDeg (900 micromol/L) versus IGlar	Type 1 DM
Heller S et al^Citation41 Lancet, 2012	Open-label, treat-to-target, noninferiority trial	IDeg versus IGlar	Type 1 DM
Heise T et al^Citation35 Diabetes Obes Metab, 2012	Randomized, single-center, parallel-group, double-blind trial	IDeg versus IGlar	Type 1 DM
Mathieu C et al^Citation42 J Clin Endocrinol Metab, 2013	26 + 26-week, randomized, controlled, open-label, multinational, parallel-design, treat-to-target, noninferiority trial	IDeg (once daily, varying injection timing day) versus IGlar	Type 1 DM
Bode BW et al^Citation43 Diabet Med, 2013	Open-label trial (1-year main trial + 1-year extension trial)	IDeg versus IGlar	Type 1 DM
Koehler G et al^Citation44 Diabetologia, 2014	Double-blind, randomized, two-period, crossover trial	IDeg versus IGlar	Type 1 DM
Korsatko S et al^Citation45 Drugs Aging, 2014	Single-center, randomized, multiple-dose, double-blind, two-period, crossover trial	IDeg (pharmacokinetics/pharmacodynamics)	Type 1 DM (including elderly patients)
Biester T et al^Citation46 Pediatr Diabetes, 2014	Single center, randomized, single dose, double-blind two-period, crossover trial	IDeg versus IGlar	Type 1 DM (children, adolescents, and adults)
Davies MJ et al^Citation47 Diabetes Obes Metab, 2014	Multinational, 26-week, controlled, open-label, parallel group randomized trial	IDeg versus IDet	Type 1 DM
Zinman B et al^Citation48 Lancet, 2011	16-week, randomized, open-label, parallel group, Phase II trial	IDeg versus IGlar	Type 2 DM
Garber AJ et al^Citation49 Lancet, 2012	52-week, Phase III, open-label, treat-to-target, noninferiority trial	IDeg versus IGlar	Type 2 DM
Heise T et al^Citation50 Diabetes Obes Metab, 2012	Randomized, single center, double-blind, two-period, incomplete block crossover, multiple dose trial	IDeg 100 U/mL (0.4 U/kg; 0.6 U/kg, 0.8 U/kg) IDeg 200 U/mL (0.6 U/Kg) (pharmacokinetics)	Type 2 DM
Zinman B et al^Citation51 Diabetes Care, 2012	52-week, randomized, controlled, 1 year, parallel group, open-label, multinational, treat-to-target, noninferiority trial	IDeg versus IGlar	Type 2 DM
Meneghini L et al^Citation52 Diabetes Care, 2013	Phase III, 26-week, randomized, controlled, open-label, three-arm, parallel group trial	Once-daily IDeg, in a prespecified dosing schedule; once-daily IDeg, at the main evening meal; once-daily IGlar, at the same time each day	Type 2 DM
Philis-Tsimikas A et al^Citation53 Diabetes Obes Metab, 2013	26-week, randomized, open-label, multicenter, multinational, controlled trial	IDeg versus sitagliptin	Type 2 DM
Gough SC et al^Citation54 Diabetes Care, 2013	26-week, open-label, treat-to-target trial	IDeg versus IGlar	Type 2 DM
Philis-Tsimikas A et al^Citation55 Adv Ther, 2013	26-week, multinational, Phase IIIb, multicenter, two-armed, parallel group, open-label, randomized, treat-to-target trial	IDeg simple algorithm versus IDeg stepwise algorithm	Type 2 DM
Rodbard HW et al^Citation56 Diabet Med, 2013	Randomized, controlled, parallel group, open-label, multinational, treat-to-target, noninferiority trial	IDeg versus IGlar	Type 2 DM
Zinman B et al^Citation57 Lancet Diabetes Endocrinol, 2013	Two Phase III, 26-week, randomized, open-label, treat-to-target, noninferiority trials	IDeg injected three times a week versus IGlar once daily	Type 2 DM
Kiss I et al^Citation58 Clin Pharmacokinet, 2014	Single center, single dose, open-label, parallel group trial	IDeg (pharmacokinetics)	Patients with normal or impaired renal function (11/30 with Type 2 DM)
Kupčová V et al^Citation59 Clin Drug Investig 2014	Single center, single dose, open-label, parallel group trial	IDeg (pharmacokinetics)	Patients with hepatic impairment (Child-Pugh grade A, B, or C) (3/24 with Type 2 DM)
Mathieu C et al^Citation60 Diabetes Obes Metab, 2014	Multinational, Phase IIIb, open-label, randomized, treat-to-target trial (52-week main trial BEGIN ONCE-Long + 52-week extension)	IDeg + liraglutide versus IDeg + IAsp	Type 2 DM
Rodbard HW et al^Citation61 Diabetes Obes Metab, 2014	52 week open-label, treat-to-target trial	IDeg versus IGlar	Type 2 DM
Hompesch M et al^Citation62 Clin Ther, 2014	Randomized, single center, double-blind, two period crossover trial	IDeg versus IDet	Type 2 DM (African American, Hispanic/Latino, white)
Bode BW et al^Citation63 Endocr Pract, 2014	22-week, treat-to-target trial	IDeg (200 U/mL) versus IDeg (100 U/mL)	Type 2 DM

Abbreviations: IDeg, insulin degludec; IGlar, insulin glargine; IDet, insulin detemir; type 1 DM, type 1 diabetes mellitus; type 2 DM, type 2 diabetes mellitus; IAsp, insulin aspart.

Table 2 Chemical structure and pharmacokinetic/pharmacodynamic profiles of IAsp, IGlar, IDet, and IDeg

	IAsp	IGlar	IDet	IDeg
Molecular formula	C256H381N65O79S6	C267H404N72O78S6	C267H402O76N64S6	C274H411N65O81S6
Molecular weight	5,825.8 Da	6,063.0 Da	5,916.9 Da	6,103.97 Da
Formulation properties	Rapid-acting analog	Formation of microprecipitates, or stabilized aggregates; slow dissolution of free hexamers	Dihexamerization and albumin binding	Multihexamer formation
Onset	15 minutes	30–60 minutes	30–60 minutes	30–90 minutes
Peak	1–3 hours	Relatively flat	Relatively flat	Flat
Duration	3–5 hours	24 hours	Up to 24 hours	>24 hours
Dosing	Premeal	Same time every day	Same time every day (once-daily or twice-daily)	Any time of day

Abbreviations: IAsp, insulin aspart; IGlar, insulin glargine; IDet, insulin detemir; IDeg, insulin degludec; Da, dalton.

Table 3 Summary of main studies using IDeg/IAsp in patients with type 1 and type 2 DM

Authors	Study design	Comparators	HbA1c change %	Hypo (PYE)	Nocturnal hypo (PYE)	Type of DM (number of patients)
Hirsch IB et al^Citation20 Diabetes Care, 2012	26-week, multinational, multicenter, open-label, two-arm, parallel, randomized, treat-to-target trial	IDegAsp versus IDet	IDegAsp, −0.75; IDet, −0.70	IDegAsp, 39.17; IDet, 44.34	IDegAsp, 3.71; IDet, 5.72; (P<0.05)	T1DM (n=548)
Heise T et al^Citation74 Diabetes Care, 2011	Phase II, open-label, randomized, controlled, 16-week trial	IDegAsp versus IGlar	IDegAsp, −1.3; IGlar, −1.3	IDegAsp, 1.2; IGlar, 0.7	IDegAsp, 1; IGlar, 3	T2DM (n=119)
Niskanen L et al^Citation75 Eur J Endocrinol, 2012	Phase II, open-label, three-arm, parallel-group, randomized, controlled, 16-week trial	IDegAsp versus BIAsp 30	IDegAsp, −1.8; BIAsp, −1.8	IDegAsp, 2.9; BIAsp 30, 7.3	IDegAsp, 0.4; BIAsp 30, 1.1	T2DM (n=122)
Onishi Y et al^Citation77 Diabetes Obes Metab, 2013	Phase III, 26-week, open-label, randomized, stratified, parallel-group, multicenter, treat-to-target trial	IDegAsp versus Iglar	IDegAsp, −1.4; IGlar, −1.2; (P<0.01)	IDegAsp, 1.91; IGlar, 2.71	IDegAsp, 0.39; IGlar, 0.53	T2DM (n=296)

Abbreviations: IDegAsp, insulin degludec/insulin aspart; IDet, insulin detemir; DM, diabetes mellitus; IGlar, insulin glargine; BIAsp 30, biphasic insulin aspart 30; hypo, hypoglycemia; PYE, episodes per patient/years of exposure; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus; HbA_1c, glycated hemoglobin.

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