Albiglutide

Two DPP-4-resistant GLP-1(7-36) sequences carrying an Ala8Gly substitution are expressed in tandem and genetically fused to recombinant human albumin. Albumin's natural FcRn recycling gives a half-life of about five days. Like dulaglutide, the large protein penetrates the CNS poorly, so appetite suppression and weight loss were minimal - typically under 1 kg - while HbA1c reduction was decent. HARMONY OUTCOMES nonetheless showed a clear reduction in major cardiovascular events, which makes the commercial withdrawal an unusual footnote in the field.

Targets: GLP-1 receptor

• · 30 mg weekly, increased to 50 mg if glycaemic response was inadequate. Note the very large milligram doses - a consequence of the albumin fusion, where most of the molecular mass is carrier, not active peptide.

Work out your exact syringe units →

• commonInjection-site reaction— Notably more frequent than with other GLP-1 agonists.
• commonNausea— Markedly milder than small-molecule GLP-1 analogues.
• commonDiarrhoea
• rarePancreatitis

• Personal or family history of medullary thyroid carcinoma or MEN2 - carried the class boxed warning.
• History of pancreatitis.
• Pregnancy.

• cautioninsulin-analogues — Hypoglycaemia risk in combination.
• redundantdulaglutide — Both are large fusion-protein GLP-1 agonists with the same profile.

• · HbA1c.
• · Injection-site tolerance.

Formerly FDA- and EMA-approved; withdrawn worldwide in 2018 and no longer manufactured.

• Hernandez et al. 2018, HARMONY OUTCOMES, The Lancet (trial)
• HARMONY phase 3 programme in type 2 diabetes (trial)

Albiglutide is the second and larger demonstration of the same principle dulaglutide illustrates: a GLP-1 receptor agonist that cannot get into the brain is a good glucose drug and a useless weight drug. At roughly 73 kDa it is even larger than dulaglutide, and the weight effect was correspondingly smaller - typically under a kilogram, which is close to noise. The protraction mechanism is albumin's own FcRn-mediated recycling pathway rather than reversible non-covalent albumin binding, which is a genuinely different piece of engineering to the fatty-acid approach: instead of borrowing albumin from the circulation, the drug is albumin. The tandem GLP-1 arrangement gives two receptor-binding domains per molecule. What makes albiglutide worth remembering is HARMONY OUTCOMES, which showed a 22% reduction in major adverse cardiovascular events - one of the largest relative risk reductions in the entire GLP-1 cardiovascular literature - in a drug that produced almost no weight loss. That is a useful piece of evidence for anyone claiming the cardiovascular benefit of this class is simply downstream of weight: it is not, at least not entirely. GSK withdrew the product in July 2018 for commercial reasons, with the cardiovascular data published later that year, which is one of the odder sequences of events in modern diabetes drug development.

Historically: the reconstitution pen. Albiglutide was supplied as a lyophilised powder requiring in-device reconstitution and a fifteen-minute wait, in a market where competitors offered ready-to-use autoinjectors, and it had to be used within eight hours of reconstitution. Combined with a near-zero weight effect and frequent injection-site reactions, that was enough to kill the product commercially despite excellent outcome data. The current failure mode is different: anyone offered albiglutide today is being sold something that is not albiglutide.

1. 30 mgWeek 1 onward — Standard starting and usually maintenance dose. Note that the milligram numbers are large because most of the molecular mass is albumin carrier, not active peptide.
2. 50 mgAfter at least 4 weeks if HbA1c response was inadequate — The only escalation step.

• GLP-1 receptor (GLP1R) — Reported as substantially lower affinity than native GLP-1, compensated by very high and sustained plasma concentrations; not re-verified in this session

  Pancreatic glucose-dependent insulin secretion and glucagon suppression with minimal central satiety signalling, because a 73 kDa protein does not reach the relevant brain regions.

• HARMONY OUTCOMES Phase 3 cardiovascular outcomes · n=9463 · 82 weeks · 2018

  22% relative reduction in major adverse cardiovascular events in type 2 diabetes with cardiovascular disease - one of the largest effect sizes in the class, in a drug with almost no weight effect.

Glycaemic effect over 2-4 weeks, steady state at 3-5 weeks. Historical only.

Not applicable. The drug was withdrawn worldwide in 2018 and is not manufactured. It is included here so that the cardiovascular literature makes sense and so nobody is misled by grey-market listings claiming to sell it - there is no legitimate source of albiglutide anywhere.

Against dulaglutide: the same architectural idea executed with albumin instead of Fc, with a worse delivery device and a better cardiovascular outcome. Against semaglutide: no contest on weight, and semaglutide's SELECT result in non-diabetics is a broader claim than HARMONY's. The reason albiglutide still matters is as the counterexample to weight-mediated cardioprotection.

Withdrawn worldwide in 2018 and no longer manufactured. There is no price because there is no product.

• ?Pharmacokinetic parameters were taken from the historical literature and product information and could not be re-verified against a current label in this session, since none exists - treat the volume of distribution and clearance figures as approximate.
• ?Receptor affinity relative to native GLP-1 was not verified.
• ?Whether HARMONY's effect size reflects the molecule, the population or chance has never been tested, because no confirmatory trial was run.

• Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial Hernandez AF et al., Lancet, 2018 · PMID 30291013

  The strongest argument that GLP-1 cardiovascular benefit is not simply a weight-loss effect - a drug that lost under a kilogram cut events by 22%.