BI 456906
Evidence Grade C — Moderate human evidence. 60 published studies, 38 human. 0 registered clinical trials.
Survodutide is a once-weekly injection in Phase III development by Boehringer Ingelheim that activates both GLP-1 and glucagon receptors. The glucagon component adds a mechanism that burns liver fat and increases energy expenditure — effects that pure GLP-1 drugs do not provide. It is being developed for both obesity and fatty liver disease (MASH).
60 published studies: 38 human, 0 animal, 1 in-vitro, 31 reviews
Survodutide is in Phase III development (not yet approved). In a Phase II obesity trial (387 patients, 46 weeks), the highest planned dose achieved approximately 15% weight loss. A separate Phase II MASH trial (293 patients) showed MASH improvement without worsening fibrosis in up to 62% of patients, compared to 14% with placebo.
Phase III trials are ongoing for both obesity and MASH indications. Survodutide's dual development strategy — targeting both weight loss and liver disease — reflects the growing recognition that these conditions are closely interconnected.
Survodutide activates both the GLP-1 receptor (appetite suppression, insulin enhancement) and the glucagon receptor (energy expenditure, liver fat oxidation). The glucagon component directly stimulates the liver to burn stored fat, which is particularly relevant for MASH — a condition characterised by liver fat accumulation and inflammation. The drug is designed with a deliberate bias toward GLP-1 receptor activity.
In a Phase II obesity trial (387 patients), the highest planned dose achieved approximately 15% weight loss at 46 weeks, with head-to-head Phase II data showing superiority over semaglutide. A separate Phase II MASH trial showed improvement in liver disease without worsening scarring in up to 62% of patients (versus 14% on placebo) — among the strongest liver results for any drug in this class. Phase III trials are ongoing for both indications but no Phase III results are yet available. Key concerns include a 24.6% treatment discontinuation rate in the Phase II obesity trial and a puzzling finding where the highest MASH dose was less effective than the second-highest, requiring careful dose optimisation in Phase III. If the liver disease programme succeeds, regulatory filing could occur around 2027.
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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.
