Hormonal
The optimal ratio of GLP-1 to glucagon/GIP agonism in combination therapies is unknown, and the balance between efficacy (liver fat reduction) and safety (hyperglycemia, side effects) remains a key challenge.
There is no single 'best' combination therapy yet. The field is still debating whether to maximize GLP-1, add glucagon, or add GIP. Current trials are testing different ratios (e.g., 1:1 vs 5:1 GLP-1:glucagon). Patients should expect that these therapies are evolving and that side effects (nausea, hyperglycemia) may limit the dose that can be tolerated.
There is also uncertainty regarding the optimal ratio of glucagon and GIP agonism to GLP-1 agonism in combination agents, and as to whether GIP agonism or antagonism is the optimal approach.
Why this rating
The paper states that long-term outcome data is needed to determine the optimal approach; current data is mixed or from early phases.
Source
Incretins (GLP-1 receptor agonists and dual/triple agonists) and the liver
Philip N. Newsome et al. · Journal of Hepatology · 2023
DOI 10.1016/j.jhep.2023.07.033
More from this paper
- GLP-1 receptor agonists (e.g., liraglutide, semaglutide) resolve MASH histology primarily through substantial weight loss and improved insulin resistance, rather than direct hepatocyte effects.Good
- Dual GLP-1/glucagon agonists (e.g., cotadutide, pemvidutide) provide greater reductions in liver fat and fibrosis markers than GLP-1 mono-agonists, likely due to glucagon-mediated mitochondrial turnover and glycogenolysis.Moderate
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