Liraglutide

Overview

Liraglutide is a synthetic analogue of glucagon-like peptide-1 (GLP-1), and historically one of the first GLP-1 agonists to enable once-daily rather than multiple-daily administration.

The key is a single fatty-acid modification: a palmitoyl chain (C16) via a glutamate spacer on Lys26, binding serum albumin and extending the half-life to about 13 hours. This is where liraglutide differs from the later, weekly semaglutide.

Liraglutide is the compound behind approved medicines (Victoza, Saxenda). That regulatory status is a fact about the respective authorities. At Peptalis, strictly research use only: in-vitro, not for human or animal use.

Mechanism of action

Liraglutide activates the GLP-1 receptor on pancreatic beta cells and in satiety regions of the brain; the response is glucose-dependent.

GLP-1 receptor activation

• In the pancreas liraglutide enhances insulin release, but only when blood glucose is elevated (glucose-dependent).
• It suppresses glucagon, slows gastric emptying and reduces appetite.

Pharmacokinetics: the first generation

• The C16 palmitoyl–albumin binding gives a half-life of ~13 hours: once-daily dosing.
• Liraglutide thus shows, within the domain, how pharmacokinetics, not the receptor, distinguish the successive generations (Knudsen 2000; Knudsen & Lau 2019).

Research findings

• Preclinical: NN2211 identified as a GLP-1 derivative suited to once-daily dosing (Knudsen 2000)
• LEADER (n=9,340, T2D): primary cardiovascular endpoint 13.0% vs 14.9% placebo, hazard ratio 0.87 (Marso 2016)
• SCALE (n=3,731, obesity without diabetes): mean weight change −8.0% vs −2.6% over 56 weeks (Pi-Sunyer 2015)

Preclinical evidence

• In development a series of acylated GLP-1 derivatives were tested; the palmitoyl-γ-glutamate variant (NN2211) combined retained receptor potency with extended duration via albumin binding (Knudsen 2000).
• In animal models of glucose regulation the compound lowered blood glucose in line with the GLP-1 mechanism.

Human studies

• LEADER (Marso 2016): 9,340 people with type 2 diabetes at high cardiovascular risk received up to 1.8 mg per day; primary cardiovascular endpoint 13.0% vs 14.9% (hazard ratio 0.87).
• SCALE (Pi-Sunyer 2015): 3,731 adults without diabetes received 3.0 mg per day; mean weight change −8.0% (−8.4 kg) vs −2.6% (−2.8 kg) over 56 weeks.

Research context

This profile describes what has been done and found in research. Regulatory and clinical facts are facts about the respective trials and authorities, not claims about a Peptalis product; the compound is for in-vitro laboratory research only (RUO).

Open questions

• Liraglutide is dosed daily and, in weight studies, produces a smaller mean reduction than the later weekly and dual-acting agents.
• Direct head-to-head comparisons exist (including vs semaglutide), but not for every combination of dose and outcome.

Research outlook

Liraglutide is a well-characterized first-generation reference molecule for GLP-1 receptor signalling and acylation-based half-life extension.

It sharply shows the role of the fatty-acid modification in duration of action.

Scientific interest

First-generation GLP-1 agonist (daily), the reference point of the class.

Shows how pharmacokinetics distinguish the generations (daily vs weekly).

Broad human dossier including a cardiovascular outcome trial.

Specifications

References

1. Potent derivatives of glucagon-like peptide-1 with pharmacokinetic properties suitable for once daily administration · Knudsen LB, et al. · J Med Chem · 2000
2. GLP-1 receptor agonists and the thyroid: C-cell effects in mice are mediated via the GLP-1 receptor and not associated with RET activation. · Madsen LW, et al · Endocrinology · 2012
3. The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss. · Secher A, et al · J Clin Invest · 2014
4. A Randomized, Controlled Trial of 3.0 mg of Liraglutide in Weight Management · Pi-Sunyer X, et al. · N Engl J Med · 2015
5. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes · Marso SP, et al. · N Engl J Med · 2016
6. The Discovery and Development of Liraglutide and Semaglutide · Knudsen LB, Lau J · Front Endocrinol (Lausanne) · 2019

Availability

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