Efinopegdutide

Efinopegdutide is an oxyntomodulin-derived peptide linked via Hanmi's LAPSCOVERY platform to a human IgG4 Fc fragment for weekly dosing. Relative potency is around 2:1 GLP-1R to GCGR. In a head-to-head phase 2a against semaglutide 1 mg in MASLD, efinopegdutide 10 mg weekly reduced liver fat content by roughly 72.7% versus about 42.3% for semaglutide over 24 weeks - a striking demonstration that the glucagon arm does something to the liver that GLP-1 alone does not. Development has been steered toward metabolic liver disease including compensated cirrhosis rather than obesity.

Targets: GLP-1 receptor, Glucagon receptor

• · The phase 2a liver-fat trial used 10 mg weekly reached via stepped escalation over several weeks.

Work out your exact syringe units →

• very commonNausea
• commonVomiting
• commonDiarrhoea
• commonIncreased heart rate— Glucagon-receptor effect.

• Pregnancy.
• History of pancreatitis - class caution.
• Safety in advanced liver disease is still being characterised.

• redundantsemaglutide — Direct comparator; overlapping GLP-1 agonism.
• redundantsurvodutide — Same dual-receptor approach to liver disease.

• · Liver fat by MRI-PDFF where available.
• · Liver enzymes.
• · Heart rate.
• · Glucose.

Investigational; not approved in any jurisdiction.

• Romero-Gomez et al. 2023, efinopegdutide vs semaglutide in MASLD, Journal of Hepatology (trial)
• MK-6024-017 phase 2 study in compensated cirrhosis due to steatohepatitis (trial)

Efinopegdutide is the clearest demonstration in this class that liver fat and body weight are separable endpoints. In the phase 2a study against semaglutide, efinopegdutide produced a roughly 73% relative reduction in liver fat over 24 weeks versus about 41% for semaglutide, while the weight difference between the two arms was far smaller. That gap is the glucagon arm doing hepatic work directly - increasing fatty-acid oxidation and reducing de novo lipogenesis in hepatocytes - rather than liver fat falling as a passive consequence of losing weight. It is a useful result for anyone trying to think clearly about MASLD: if the goal is hepatic steatosis specifically, a glucagon-containing agent does something a pure GLP-1 agonist does not, and the effect size difference is large. Merck has developed it as a liver drug rather than an obesity drug, including a study in compensated cirrhosis, and there is no phase 3 obesity programme. Because the protraction mechanism is Fc conjugation rather than a fatty acid, the molecule is large and central nervous system penetration is correspondingly poor, which fits with weight loss being modest relative to the hepatic effect.

Nothing, because nobody can get it. The relevant caution for a reader is not to over-generalise the 73% figure: it is a 24-week imaging endpoint in a phase 2a study of 145 people, not a fibrosis outcome, and liver fat reduction has repeatedly failed to predict histological benefit in other drug classes.

• Glucagon receptor (GCGR) — Not verified

  Direct hepatic fatty-acid oxidation and suppression of de novo lipogenesis - the mechanism behind the 73% liver-fat reduction, which is disproportionate to the weight change.

• GLP-1 receptor (GLP1R) — Not verified

  Glucose-dependent insulin secretion, glucagon suppression, and modest appetite suppression limited by the molecule's size.

• Efinopegdutide phase 2a in NAFLD Phase 2a · n=145 · 24 weeks · 2023

  Relative reduction in liver fat content of approximately 73% versus about 41% for semaglutide 1.0 mg, in an active-comparator design.

Liver fat reductions were substantial by 24 weeks and the trajectory suggests most of the effect arrives in the first 12. Weight effects are modest and slow.

Contains a full GLP-1 arm and is therefore redundant with every incretin. Not obtainable outside a trial. If liver fat is the goal and efinopegdutide is not available, the practical alternatives with real data are tirzepatide (SYNERGY-NASH), survodutide (biopsy fibrosis improvement) and semaglutide, in roughly that order of hepatic evidence strength.

Against semaglutide: beat it directly on liver fat in a head-to-head, 73% versus 41%, which is the cleanest demonstration available that glucagon agonism adds hepatic benefit. Against survodutide: survodutide has biopsy-confirmed fibrosis improvement, which is the harder and more meaningful endpoint. Against pemvidutide: similar concept, similar hepatic effect size, pemvidutide has the breakthrough designation and the obesity positioning. As an obesity drug efinopegdutide is uncompetitive and was never developed as one.

Investigational; no legitimate supply and no price.

• ?No verifiable pharmacokinetic parameters.
• ?No published titration ladder could be verified.
• ?Receptor affinities and the GLP1R-to-GCGR ratio are not published in verifiable form.
• ?The 73% liver-fat figure is an imaging endpoint at 24 weeks and has not been shown to translate into histological fibrosis benefit.
• ?The 145-participant figure was not individually re-verified against the paper.

• A phase IIa active-comparator-controlled study to evaluate the efficacy and safety of efinopegdutide in patients with non-alcoholic fatty liver disease Romero-Gomez M et al., J Hepatol, 2023 · PMID 37355043

  The head-to-head against semaglutide on liver fat, and the single most informative study on why a glucagon arm matters for the liver.