Fixed-ratio combinations of basal insulin and glucagon-like peptide-1 receptor agonists as a promising strategy for treating diabetes

Table 1 Details of the fixed-ratio combinations of basal insulin and glucagon-like peptide-1 receptor agonists

	IDegLira	IGlarLixi
Combination	Insulin degludec + liraglutide	Insulin glargine + lixisenatide
Proportion (/dose)	Insulin degludec 1 unit + liraglutide 0.036 mg	(1) Glargine 1 unit + lixisenatide 0.33–0.50 μg; and (2) Glargine 1 unit + lixisenatide 1.0 μg1
Frequency	Once daily	Once daily
Indication	Adults with type 2 diabetes	Adults with type 2 diabetes
Dosage	Up to 50 doses/day	(1) Up to 20–60 doses/day; and (2) up to 20 doses/day
CVOT for GLP-1RA component	Liraglutide: LEADER[21]	Lixisenatide: ELIXA[62]
CVOT for insulin component	DEVOTE[63]	ORIGEN[64], DEVOTE[63]

¹The combination of insulin glargine 1 unit + lixisenatide 1.0 μg/unit is only approved in Japan.

GLP-1RA: Glucagon-like peptide-1 receptor agonist; IDegLira: Insulin glargine/liraglutide; IGlarLixi: Insulin glargine/lixisenatide: CVOT: Cardiovascular outcome trial.

Table 2 Major phase III trials of fixed-ratio combinations of basal insulin and a glucagon-like peptide-1 receptor agonist

FRC	Name	Baseline treatment	Comparator	Duration	Relative reduction in HbA1c vs comparator
IDegLira	Dual I[31]	OADs	IDeg or Lira	26 wk	−0.47% vs IDeg (P < 0.0001); −0.64% vs Lira (P < 0.0001)
	Dual II[35]	Basal insulin + Met	IDeg	26 wk	−1.1% (P < 0.0001)
	Dual III[36]	GLP-1RA	GLP-1RA	26 wk.	−0.94% (P < 0.001)
	Dual IV[37]	SU or SU + Met	Placebo	26 wk	−1.02% (P < 0.001)
	Dual V[33]	Basal insulin	IGlar U100	26 wk	−0.59% (P < 0.001)
	Dual VII[38]	Basal insulin + Met	Basal-bolus therapy	26 wk	−0.02% (P < 0.0001)
	Dual IX[39]	SGLT2i	IGlar U100	26 wk	−0.36% (P < 0.0001)
IGlarLixi	LixiLan-O[32]	Met ± other OADs	IGlar or Lixi	30 wk	−0.3% vs IGlar (P < 0.0001); −0.8% vs Lira (P < 0.0001)
	LixiLan-L[34]	Basal insulin ± OADs	IGlar U100	30 wk	−0.5% (P < 0.001)
	LixiLan JP-O1[40]	OADs	Lixisenatide	26 wk	-1.07% (P < 0.0001)
	LixiLan JP-O2[41]	OADs	IGlar U100	26 wk	-0.63% (P < 0.0001)
	LixiLan JP-L[42]	Met + basal insulin	IGlar U100	26 wk	-0.74% (P < 0.0001)
	LixiLan-L-CN[43]	Basal insulin ± OADs	IGlar U100	30 wk	-0.7% (P < 0.0001)

FCR: Fixed-ratio combination; GLP-1RA: Glucagon-like peptide-1 receptor agonist; IDegLira: Insulin glargine/liraglutide; IGlarLixi: Insulin glargine/lixisenatide; OADs: Oral anti-diabetic agents; Met: Metformin; SU: Sulfonylurea; SGLT2i: Sodium/glucose cotransporter 2 inhibitor; IDeg: Insulin degludec; Lira: Liraglutide; IGlar: Insulin glargine.

Table 3 Real-world evidence regarding the efficacy of fixed-ratio combinations of basal insulin and a glucagon-like peptide-1 receptor agonist for glycemic control

Ref.	Target patients	Design	Duration	Representative outcomes
Morieri et al[44], 2019	Treated w/o GLP-1RA	Retrospective, observational	5.7 mo	FRCs were associated with a larger reduction in HbA1c, whereas GLP-1RA reduced body mass
Egede et al[45], 2020	(1) OADs ± basal insulin or GLP-1RA alone; and (2) MDIs or GLP-1RA with insulin	Retrospective, observational	6 mo	(1) IDegLira use was associated with a reduction in HbA1c; and (2) Switching to IDegLira did not reduce HbA1c
Persano et al[50], 2021	MDIs	Prospective, observational	6 mo	Switching from MDIs to IDegLira improved HbA1c, body mass, and the QOL score
Kawaguchi et al[51], 2022	OADs ± basal insulin	RCT	2 wk	IDegLira resulted in a significantly longer time in the target glucose range than IDegAsp
Oe et al[52], 2022	IDeg + DPP-4i	Prospective, observational	2 wk	Switching from IDeg + DPP-4i to IDegLira significantly improved glucose fluctuations and the QOL score
Guja et al[46], 2022	GLP-1RA + OADs	RCT/prospective, observational	6 mo/26 wk	IGlarLixi significantly improved HbA1c, regardless of the use of an SGLT2i
Bala et al[47], 2022	OADs ± basal insulin	Prospective, observational	24 wk	Introduction of IGlarLixi significantly reduced HbA1c
Ramírez-Rincón et al[48], 2022	OADs and/or insulin	Retrospective, observational	3–7 mo	Introduction of IDegLira significantly reduced HbA1c and insulin requirements
Bilic-Curcic et al[49], 2022	Insulin therapy	Retrospective, observational	> 6 mo	Switching to FRCs (IDegLira and IGlarLixi) significantly reduced HbA1c and body mass

GLP-1RA: Glucagon-like peptide-1 receptor agonist; OADs: Oral anti-diabetic agents; MDIs: Multiple daily insulin injections; IDeg: Insulin degludec; DPP-4i: Dipeptidyl peptidase-4 inhibitor; RCT: Randomized, controlled trial; FRC: Fixed-ratio combination; IDegLira: Insulin glargine/liraglutide; IGlarLixi: Insulin glargine/lixisenatide; QOL: Quality of life; IDegAsp: Insulin degludec/aspart; SGLT2i: Sodium/glucose cotransporter 2 inhibitor; Lira: Liraglutide; IGlar: Insulin glargine.

Table 4 Real-world evidence regarding patients’ satisfaction with fixed-ratio combinations of basal insulin and a glucagon-like peptide-1 receptor agonist

Ref.	Target patients	Design	Duration	Representative outcomes
Persano et al[50], 2021	MDIs	Prospective, observational	6 mo	Switching from MDIs to IDegLira improved HbA1c, body mass, and the QOL score
Rizza et al[55], 2021	MDIs, basal insulin + OADs, and OADs alone	Prospective, interventional	6 mo	The DTSQ score improved, but CASP-19 did not, after switching to IDegLira
Polonsky et al[56], 2022	Basal insulin + OADs	RCT	26 wk	Switching from basal insulin to IGlarLixi improved patient-reported outcomes vs twice daily BIAsp 30
Oe et al[57], 2023	IDeg + DPP-4i	Prospective, observational	2 wk	Switching from IDeg + DPP-4i to IDegLira improved QOL, as assessed using DTR-QOL

GLP-1: Glucagon-like peptide-1; MDIs: Multiple daily insulin injections; OADs: Oral anti-diabetic agents; IDeg: Insulin degludec; DPP-4i: Dipeptidyl peptidase-4 inhibitor; RCT: Randomized, controlled trial; IDegLira: Insulin glargine/liraglutide; QOL: Quality of life; DTSQ: Diabetes Treatment Satisfaction Questionnaire; CASP-19: 19-item Control, Autonomy, Self-realization, Pleasure scale; IGlarLixi: Insulin glargine/lixisenatide; BIAsp 30: Biphasic insulin aspart 30/70; DTR-QOL: Diabetes therapy-related QOL.