MK-6024, HM12525A
Evidence Grade E — Very limited evidence. 6 published studies. 5 registered clinical trials.
Efinopegdutide is a dual GLP-1/glucagon agonist in Phase II development, jointly developed by Hanmi Pharmaceutical and MSD (Merck). Its standout result is a head-to-head trial against semaglutide showing dramatically greater liver fat reduction — making it a candidate for fatty liver disease (MASH) treatment.
6 published studies: 5 human, 0 animal, 0 in-vitro, 4 reviews
Efinopegdutide is in Phase II development (not yet approved). A Phase IIa head-to-head trial against semaglutide (145 patients) showed significantly greater liver fat reduction (72.7% versus 42.3%, P<0.001) despite similar overall weight loss. A Phase IIb MASH trial is ongoing.
The head-to-head superiority over semaglutide on liver fat — the key pathological feature of MASH — positions efinopegdutide for the liver disease indication. Whether the liver fat advantage translates to superior histological outcomes will be determined by the Phase IIb trial.
Efinopegdutide combines GLP-1 receptor activation (appetite suppression, glucose control) with glucagon receptor activation (hepatic fat oxidation, energy expenditure). The PEGylated Fc-fusion design extends the half-life for less frequent dosing. The glucagon component's direct liver fat-burning effect may explain the superior liver fat reduction compared to GLP-1-only approaches.
A Phase IIa head-to-head trial (145 patients) showed significantly greater liver fat reduction with efinopegdutide compared to semaglutide (72.7% versus 42.3%) despite similar overall weight loss. This suggests the glucagon component provides liver-specific fat burning above and beyond what weight loss alone achieves. The development focus has pivoted away from obesity (likely due to the increasingly competitive landscape) toward MASH, where the liver-specific advantage positions it more distinctly. A Phase IIb MASH trial with liver biopsy endpoints is ongoing. Key limitations include the small Phase IIa sample size and the absence of biopsy-confirmed MASH outcomes in completed trials.
Alternate Dosing Study of MK-6024 in Adults With Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) (MK-6024-016)
A Clinical Study of Efinopegdutide in People With Compensated Cirrhosis Due to Steatohepatitis (MK-6024-017)
A Study of Efinopegdutide in Healthy Obese Participants (MK-6024-015)
A Study of Efinopegdutide in Participants With Hepatic Impairment (MK-6024-014)
A Clinical Study of Efinopegdutide (MK-6024) in Healthy Chinese Volunteers (MK-6024-011)
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Liraglutide is marketed as Victoza for type 2 diabetes (approved 2010) and Saxenda for weight management (approved 2014). The LEADER trial, involving over 9,300 patients followed for nearly four years, established that liraglutide reduced the risk of major cardiovascular events by 13% — a landmark finding that helped establish GLP-1 treatments as a class with heart benefits. Saxenda is also approved for adolescents aged 12 and older. While historically significant, liraglutide has been substantially surpassed by newer agents. In a direct comparison, semaglutide achieved 15.8% weight loss compared to liraglutide's 6.4%. Liraglutide remains relevant as a lower-intensity option and as a benchmark against which newer treatments are measured. It has over a decade of real-world safety data, making it one of the best-understood medications in this class.
Setmelanotide is marketed as Imcivree (Rhythm Pharmaceuticals; approved November 2020 for POMC, PCSK1, or LEPR deficiency; June 2022 for Bardet-Biedl syndrome; December 2024 expanded to patients aged 2 years and older). Genetic testing confirming an eligible mutation is required before treatment. In patients with POMC or PCSK1 deficiency, approximately 80% achieved at least 10% weight loss in clinical trials. In Bardet-Biedl syndrome, 32.3% achieved the same threshold. The most common side effects are injection-site reactions and skin darkening (due to the melanocortin pathway's connection to pigmentation). Setmelanotide exemplifies precision medicine — it is highly effective in the specific genetic populations it targets but is not indicated for common obesity.
HGH Fragment 176-191 has no marketing authorisation. A Phase IIa trial in obesity (approximately 300 patients) failed to demonstrate statistically significant weight loss at any dose tested. The clinical development programme was discontinued. The disconnect between animal data (which showed significant fat reduction in obese mice) and the failed human trial is the defining feature of this compound's development history. Products available through unregulated channels lack pharmaceutical quality assurance. The failed Phase II trial represents the highest level of clinical evidence available.
