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The Evolution of GLP-1 Receptor Agonists

By February 21, 2017 No Comments

Glucagon-like peptide 1 (GLP-1) receptor agonists (RAs) are an evolving treatment option for patients with Type 2 Diabetes Mellitus, and are an attractive one, as they carry a low risk of causing hypoglycaemia. GLP-1 RAs mimic the action of GLP-1, one of two natural hormones (the other being GIP) responsible for the incretin effect.

GLP-1 is normally released from the gut in response to glucose ingestion. It stimulates insulin secretion and reduces glucagon secretion in the pancreas, and in addition it delays gastric emptying. In people with T2DM, the pancreas can become unresponsive to GIP, and so GLP-1 RAs are seen as a way to bolster the effect of GLP-1 signalling in order to compensate for this deficit (Nauck 2016). Since the approval of the first GLP-1 RA in 2005, the development of short-acting and long-acting GLP-1 RAs has continued.

GLP-1 Receptor Agonists: Daily Dosing

Exenatide (Bydetta®, Astra Zeneca) was the first approved GLP-1 RA, and is a synthetic version of a peptide found in the saliva of the lizard Heloderma suspectum. At the molecular level, it is ~50 per cent identical to native GLP-1, and a single structural change renders it resistant to enzymatic inactivation by dipeptidyl peptidase-4 (DPP-4). This means that the half-life of exenatide is extended to over 2 hrs, compared to ~2 mins for native GLP-1. This property made it suitable for twice daily dosing.

Liraglutide (Victoza®, Novo Nordisk) is almost identical to native GLP-1, sporting one amino acid change from the original, and has a fatty acid chain tacked on to it. This fatty acid chain allows albumin to bind to it, which stabilises the drug and shields it from inactivation by DPP-4. In addition, the fatty acid chain helps the drug molecules to self-assemble into heptamers. Heptamer formation is thought to slow absorption from the subcutis, which enables to once-daily dosing.

Sanofi-Aventis has recently been granted approval for lixisenatide (Lyxumia® (EU)). Lixisenatide is almost identical to exenatide, but has a tail of lysines attached to one end of the molecule, which helps to prevent enzymatic inactivation. Its half-life of 2.8 hrs allows once daily dosing.

GLP-1 Receptor Agonists: Weekly Dosing

Bydureon® (Astra Zeneca) is the extended release (ER) version of exenatide which uses a formulation change (microspheres that slowly degrade and release the drug) to prolong its effect, making it suitable for once weekly dosing. Steady state concentrations are achieved in about 6-7 weeks.

Eli Lilly (stalwarts of insulin production and one of the early developers of exenatide) have engineered dulaglutide (Trulicity®), a fusion protein consisting of two copies of a GLP-1 analogue linked to an antibody fragment. Amino acid substitutions makes dulaglutide resistant to DPP-4 inactivation and due to its larger size, absorption and renal clearance are reduced. These features prolong its half-life to 4.7 days, which allows for once-weekly administration, and steady state concentrations are achieved in about 2-4 weeks.

Albiglutide (Eperzan® (EU), GSK) is a fusion protein comprising two copies of a GLP-1 analogue joined in series to human albumin. Again, the substitution of one amino acid protects albiglutide from DPP-4 degradation, and albumin extends the half-life to five days, allowing once weekly dosing. Steady state concentrations are achieved in about 3-5 weeks

In December 2016, Novo-Nordisk filed Semaglutide, a once-weekly GLP-1 RA, with the FDA and EMA, so it is likely that there will be another competitor in the market soon.

A note on novel combination therapies

Combination therapies which couple a GLP-1 RA with insulin in a once-daily formulation have received regulatory approval in 2016, opening a new chapter in the development of this drug class. Insulin degludec and liraglutide (IDegLira) have been paired to produce Xultophy® (Novo-Nordisk), whilst insulin glargine and lixisenatide are combined to make Soliqua™ (Sanofi-Aventis).

The short and long of it

The development of short-acting and long-acting GLP-1RAs has improved dosing options open to clinicians, and may serve to increase a patient’s acceptance of and compliance with injectable therapy (all GLP-1 RAs are delivered via a pen-type injection). When choosing the most appropriate option for patients with T2DM, a couple of reviews suggest that short-acting GLP-1 RAs may be more suitable for patients with predominantly postprandial hyperglycaemia, whereas long-acting GLP-1 RAs would be more suitable for those with predominantly fasting hyperglycaemia (Uccellatore et al 2015, Guo 2016). As we learn more about the use of GLP-1 RAs, we can expect them to become an even more familiar part of care options for people with T2DM.

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