Table 1.
Pharmacological properties of currently marketed glucagon-like peptide-1 receptor agonists (GLP-1RAs)
| Parameter | Twice daily | Once daily | Once weekly | |||
|---|---|---|---|---|---|---|
| Exenatide IR [4, 5] | Liraglutide [6, 7] | Lixisenatide [8, 9] | Dulaglutide [10, 11] | Exenatide ER [12–14] | Semaglutide [15, 16] | |
| Structural properties | ||||||
| Type of derivative or modification | Exendin-4 derivative | Human GLP-1 modification | Exendin-4 derivative | Human GLP-1 modification | Exendin-4 derivative | Human GLP-1 modification |
| Molecular weight | ≈ 3300 Da | ≈ 3700 Da | 4858 g/mol | ≈ 63,000 Da | ≈ 3300 Da | 4114 g/mol |
| % homology of AA sequence to human GLP-1 | 53 | 97 | 50 | 90 | 53 | 94 |
| Modification of the N terminal sequence to ↑ resistance to DDP-4 | Substitution of AA at position 2 | None | Substitution of AA at position 2 | Substitution of AA at position 8a | Substitution of AA at position 2 | Substitution of AA at position 8a |
| Modification to ↓ renal clearance and ↑ duration of effect | None | C16 fatty acid + glutamic acid spacer added to AA at position 26 | None | Linked to a modified human IgG4-Fc heavy chainb | None | C18 fatty di-acid + hydrophilic spacer added to AA at position 26 (↑ albumin binding) |
| Duration of activityc | Short | Long | Short | Long | Long | Long |
| Pharmacokinetic properties following subcutaneous injection | ||||||
| Time to Cmax | 2.1 h | 8–12 h | 1–3.5 h | 2 days | Wk 2 + wk 6–7d | 1–3 days |
| Apparent Vd (L) | 28.3 | ≈ 13 | ≈ 100 | 17–19 | 28.3 | ≈ 12.5 |
| Plasma protein binding (%) | < 98 | 55 | > 99 (albumin) | |||
| Apparent clearance (L/h) | 9.1 | 1.2 | 35 | 0.01 | 9.1 | 0.05 |
| Terminal half-life | 2.4 h | 13 h | 3 h | ≈ 5 days | ≈ 1 wk | |
AA amino acid, Cmax maximum plasma concentration, DPP-4 dipeptidyl peptidase-4, ER extended-release, GLP-1 glucagon-like peptide-1, IR immediate release, Vd volume of distribution, wk week(s), ↑ increase/s, ↓ decrease/s
aEquivalent to position 2 in exendin-4 derivatives
bAlso ↓ immunogenicity
cBased on the duration of activation of the GLP-1 receptor
dLong-acting as microsphere formulation initially releases surface-bound exenatide (Cmax at wk 2), followed by a gradual release of exenatide from the microspheres (Cmax at wk 6–7) over a total period of ≈10 wk