Insulin degludec as an ultralong-acting basal insulin once a day: a systematic review

Figures & data

Table 1 Summary of clinical trials in patients with type 1 diabetes

Study	N	Duration (weeks)	Mean baseline values Age (years); BMI (kg/m^2); HbA1c (%); FPG (mg/dL)	Comparators	Basal insulin target goals FPG (mg/dL)	HbA1c, %		FPG, mg/dL (laboratory measured)
						Change (±SD) from baseline to end of study	ETD (95% CI)	Change (±SD) from baseline to end of study	ETD (95% CI)
Birkeland et al*,^Citation29 Phase II M, R, C, O	178	16	Age: 45.8; BMI: 26.9; HbA1c: 8.4; FPG: 178.2	IDeg§ vs IGlar	72–108	IDeg (A): −0.57 (±0.76) IDeg (B): −0.54 (±0.78) IGlar: −0.62 (±0.68)	IDeg (A) – IGlar: −0.10 (−0.1–0.3) IDeg (B) – IGlar: −0.18 (−0.06–0.4)	IDeg (A): −28.8 (±83.88) IDeg (B): −37.08 (±93.06) IGlar: −9.72 (±78.48)	IDeg (A) vs IGlar: −10.08 (−33.1–13.1) IDeg (B) vs IGlar: −13.68 (−36.7–9.4)
Hirsch et al†,^Citation36,Citation37 Phase III O, R, treat-to-target	548	26	Age: 41; HbA1c: 8.3; FPG: 189	IDegAsp (70/30) vs detemir	Not reported	IDegAsp: −0.73 Detemir: −0.68	IDegAsp – detemir: −0.05 (−0.2–0.08)	IDegAsp: −28.8 Detemir: −43.2	IDegAsp vs detemir: 4.1 (−8.3–16.4)
Russell-Jones et al and Heller et al†,^Citation26,Citation28 Phase III O, R, treat-to-target	629	52	Age: 43; HbA1c: 7.7; FPG: not reported	IDeg vs IGlar	<90	IDeg: −0.4 IGlar: −0.4	IDeg – IGlar: −0.01 (−0.14–0.11)	IDeg: −23 IGlar: −25	IDeg vs IGlar: −5.94 (−18.6–6.5)

Notes:

§ Trials using two formulations of insulin degludec (IDeg (A), 600 μmol/L, 1 unit/6 nmol; IDeg (B), 900 μmol/L, 1 unit/9 nmol); IDeg (B) was discontinued following study (mean dose was decreased over the trial suggesting the starting dose for this higher strength was too high);

† Abstract;

* Full publication.

Abbreviations: M, multicenter; R, randomized; C, controlled; P, parallel-group; O, open-label; BMI, body-mass index; HbA_1c, glycosylated hemoglobin; FPG, fasting plasma glucose; IDeg, insulin degludec; IGlar, insulin glargine; IDegAsp is a soluble co-formulation of IDeg (70%) and insulin aspart (IAsp; 30%); ETD, estimated mean treatment difference.

Table 2 Summary of clinical trials in patients with type 2 diabetes

Study	N	Duration (weeks)	Mean baseline values Age (years); BMI (kg/m^2); HbA1c (%); FPG (mg/dL)	Comparators	Basal insulin target goals FPG (mg/dL)	HbA1c, %		FPG, mg/dL (laboratory measured)
						Change (±SD) from baseline to end of study	ETD (95% CI)	Change (±SD) from baseline to end of study	ETD (95% CI)
Zinman et al*,^Citation34 Phase II M, R, O, P	245	16	Age: 54; BMI: 29.5; HbA1c: 8.7; FPG: 184	IDeg 3TW vs IDegOD§ vs IGlarOD	72–108	IDeg 3TW: −1.5 (1.1) IDegOD (A): −1.3 (1.1) IDegOD (B): −1.3 (1.1) IGlarOD: −1.5 (1.1)	IDeg 3TW vs IGlar: −0.08 (−0.23–0.40) IDegOD (A) vs IGlar: −0.17 (−0.15–0.48) IDegOD (B) vs IGlar: −0.28 (−0.04–0.59)	IDeg 3TW: −75.6 (63) IDegOD (A): −64.8 (59.4) IDegOD (B): −75.6 (77.4) IGlarOD: −61.2 (52.2)	IDeg 3TW vs IGlar: 0.72 (−15.12–16.56) IDegOD (A) vs IGlar: −1.62 (−17.46–14.22) IDegOD (B) vs IGlar: −3.6 (−19.44–12.24)
Heise et al‐,^Citation38 Phase II M, R, O, C	178	16	Age: 59.1; BMI 30.3; HbA1c: 8.5; FPG: 208	IDegAsp (70/30) vs IDegAsp AF (55/45) vs IGlar	72–108	IDegAsp: −1.3 (1) AF: −1.5 (1.4) IGlar: −1.3 (1.1)	IDegAsp vs IGlar: −0.11 (−0.41–0.19) AF vs IGlar: −0.08 (−0.22–0.38)	IDegAsp: −77.4 (±63) AF: −73.8 (±55.8) IGlar: −91.8 (±70.2)	IDegAsp vs IGlar: −2.34 (−18.54–13.86) IDegAsp vs AF: −11.52 (−4.5–27.54)
Vaag et al†,^Citation41,Citation49,Citation51 Phase II O, R, treat-to-target	182	16	Age: 60; BMI: 31.4; HbA1c: 8.5; FPG: 209	IDegAsp (70/30) vs IDegAsp AF (55/45) vs BIAsp 30	72–108	IDegAsp: −1.8‡ AF: −1.9‡ BIAsp 30: −1.8‡	IDegAsp vs BIAsp 30: −0.02 (−0.27–0.24)	Not reported	IDegAsp vs BIAsp 30: −17.8 (−30.2 to −5.2)¥ AF vs BIAsp 30: −15.8 (−28.4 to −3.2)¥
Birkeland et al†,^Citation19 Phase III O, R, treat-to-target	457	26	Age: 56; BMI 29; HbA1c: 8.4; FPG: not reported	IDegFlex vs IDegOD	<90	IDegFlex: −1.3 IDegOD: −1.1	IDegFlex vs IDegOD: −0.13 (−0.29–0.03)	IDegFlex: −57.6 IDegOD: −54	IDegFlex vs IDegOD: −0.9 (−8.1–6.3)
Meneghini et al, Atkin et al, Bain et al†,^Citation18,Citation20,Citation50 Phase III O, R	459	26	Age: 56; BMI: 30; HbA1c: 8.4; FPG: 161	IDegFlex vs IGlar	<90	IDegFlex: −1.28 IGlar: −1.26	IDegFlex vs IGlar: −0.04 (−0.12–0.20)	IDegFlex: −57 IGlar: −49	IDegFlex vs IGlar: −7.6 (−14.8– to −0.4)¥
Garber et al, Hollander et al†,^Citation32,Citation33 Phase III O, R, treat-to-target	992	52	Age: 58.9; HbA1c: 8.3; FPG: 166	IDeg vs IGlar	<90	IDeg: −1.2 IGlar: −1.3	IDeg vs IGlar: −0.08 (−0.05–0.21)	IDeg: −43 IGlar: −38	IDeg vs IGlar: −5.2 (−11.7–1.1)

Notes:

§ Trials using two formulations of insulin degludec (IDeg (A) = 600 μmol/L, 1 unit/6 nmol; IDeg (B), 900 μmol/L, 1 unit/9 nmol);

† Abstract.

* Full publication;

¥ Statistically significant, P < 0.05.

‡ Vaag – baseline for each unknown; subtracted end of study values (IDegAsp = 6.7, IDegAspAF = 6.6, BIAsp 30 = 6.7) from mean HbA_1c of 8.5.

Abbreviations: M, multicenter; R, randomized; C, controlled; P, parallel-group; O, open-label; ETD, estimated mean treatment difference; BMI, body-mass index; HbA_1c, glycosylated hemoglobin; FPG, fasting plasma glucose; IDeg, insulin degludec; IGlar, insulin glargine; IDeg 3TW, insulin degludec three times a week; IDegAsp is a soluble co-formulation of IDeg (70%) and insulin aspart (IAsp; 30%); AF, alternative formulation (55% IDeg and 45% IAsp); BIAsp 30, biphasic insulin aspart 30; IDegOD, administered same time daily with evening meal, IDegFlex, administered on flexible schedule (alternating between morning and evening creating an 8–40 hour interval between basal insulin doses).

Table 3 Incidence of hypoglycemia in type 1 diabetes

Study	Weeks	Confirmed hypoglycemia < 56 mg/dL (3.0 mmol/L)		Nocturnal hypoglycemiaII
		Events/patient-year	vs IGlar (ERR (95% CI))	Events/patient-year	vs IGlar (ERR (95% CI))
Birkeland et al§,^Citation29	16	47.9, 59.5, 66.2 IDeg (A), IDeg (B), IGlar	IDeg (A): −28% (0.72 (0.52–1.00))‡ IDeg (B): −10% (0.90 (0.65–1.24))	5.1, 8.8, 12.3 IDeg (A), IDeg (B), IGlar	−58% (0.42 (0.25–0.69))‡ −29% (0.71 (0.44–1.16))
Russell-Jones et al, Heller et al^Citation26,Citation28	52	42.5 vs 40.2 IDeg vs IGlar	No Change (1.07 (0.89–1.28))	4.4 vs 5.9	−25% (0.75 (0.59–0.96))‡
			vs insulin detemir
Hirsch et al±,^Citation36,Citation37	26	39 vs 44 IDegAsp vs detemir	0.9 (0.76–1.09)	3.7 vs 5.7	−37% (0.63 (0.49–0.81))‡

Notes:

‡ Statistically significant (P < 0.05);

§ Trials using two formulations of insulin degludec (IDeg (A), 600 μmol/L, 1 unit/6 nmol; IDeg (B), 900 μmol/L, 1 unit/9 nmol);

± IDegAsp (IDeg 70%; IAsp 30%); ERR, estimated rate ratio; IGlar, insulin glargine;

II Nocturnal hypoglycemic episodes was defined as confirmed hypoglycemia < 56 mg/dL occurring between 2300 and 0559 hours (inclusive)^29,36,37 and not defined in the following studies.^26,28

Table 4 Incidence of hypoglycemia in type 2 diabetes

Study	Weeks	Confirmed hypoglycemia < 56 mg/dL (3.0 mmol/L)		Nocturnal hypoglycemiaII
		Events/patient-year	vs IGlar (ERR (95% CI))	Events/patient-year	vs IGlar (ERR (95% CI))
Zinman et al^Citation34	16	41, 10, 15, 20¶	IDeg 3TW: 1.17 (0.46–2.96) IDegOD (A): 0.44 (0.15–1.28) IDegOD (B): 0.54 (0.19–1.51)	4, 2, 1, 0	Not reported
Heise et al^Citation38	16	1.2, 2.4, 0.7± IDegAsp vs AF vs IGar	Not reported	Not reported	Not reported
Garber et al, Hollander et al^Citation32,Citation33	52	11.1 vs 13.6 IDeg vs IGlar	−18% (0.82 (0.69–0.99))‡	1.4 vs 1.8 IDeg vs IGlar	−25% (0.75(0.58–0.99))‡
Meneghini et al, Atkin et al, Bain et al^Citation18,Citation20,Citation50	26	3.6 vs 3.5 IDegFlex* vs IGlar	1.03 (0.75–1.40)	0.6 vs 0.8 (IDegFlex vs IGlar)	0.77 (0.44–1.35)
Birkeland et al^Citation19	26	3.6 (both groups) IDegFlex* vs IDegOD	1.10 (0.79–1.52)	0.6 (both groups) IDegFlex vs IDeg QD	1.18 (0.66–2.12)
			vs BIAsp 30 (biphasic insulin aspart 30) (ERR (95% CI))
Vaag et al^Citation41,Citation49,Citation51	16	2.9 vs 7.3 IDegAsp vs BIAsp 30¥	−58% (0.42 (0.23–0.75))‡	Not reported	Not reported

Notes:

¶ IDeg three times a week (3TW) vs IDeg (A) (600 nmol/mL formulation) once daily vs IDeg (B) (900 nmol/mL formulation) once daily vs IGlar (insulin glargine) once daily;

± IDegAsp is a soluble co-formulation of IDeg (70%) and insulin aspart (IAsp, 30%); AF = alternative formulation 55% IDeg and 45% IAsp;

* IDeg Flex = administered on flexible schedule (alternating between morning and evening creating an 8–40 hour interval between basal insulin doses);

¥ IDeg Asp = IDeg (70%) and insulin aspart (IAsp 30%) versus BIAsp 30 = Biphasic insulin aspart 30;

‡ Statistically significant;

II nocturnal hypoglycemic episodes was defined as confirmed hypoglycemia < 56 mg/dl occurring between 2300 and 0559 hours (inclusive)^32–34,38 and not defined in the following studies.^{18–20,41,48–50}

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