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Evidence-based GLP-1 & peptide discussion since 2023
ForumsMASH / Liver DiseaseDe novo lipogenesis reduction on GLP-1 — looking for input

De novo lipogenesis reduction on GLP-1 — looking for input

kate.chem Sat, Mar 28, 2026 at 11:30 AM 30 replies 896 viewsPage 1 of 6
kate.chem
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Mar 28, 2026 at 11:30 AM#1

Putting this up for argument rather than for agreement. I have read it twice and I am still not certain what it supports.

The liver data is among the strongest non-weight findings in the class. The semaglutide MASH programme reported a large advantage over placebo on MASH resolution, with a substantial minority also achieving fibrosis improvement — and fibrosis is the endpoint that predicts outcomes. Mechanistically it is reduced hepatic lipogenesis, increased fatty-acid oxidation, less hepatic inflammation, and possibly a direct effect on stellate-cell activation.

Where I think it is weakest: the subgroup findings are the part I trust least — with enough subgroups something is always significant, and these were not all pre-registered.

The question I want answered is whether normalised enzymes tell you anything about fibrosis, and what the right follow-up measurement is. Tell me what I have not thought of.

Note on sourcing:
Figures above are from the primary publication rather than the press summary. If a number here disagrees with one you have, post yours and we will work out which of us is reading a secondary source.
40 10steve_okc, dave_SLC, FDA_TrackerJim and 37 others
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JennaRN
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Mar 28, 2026 at 11:39 AM#2
kate.chem said:
The liver data is among the strongest non-weight findings in the class.

Liver imaging follow-up for liver and MASH: FibroScan at baseline showed CAP score 334 dB/m (moderate steatosis) and stiffness 9.8 kPa (possible fibrosis). Diagnosed with NAFLD.

After 14 months: CAP dropped to 227 dB/m (minimal steatosis) and stiffness normalized to 5.5 kPa. Hepatologist says the liver is essentially healing itself as the metabolic stress resolves.

GLP-1 agonists may become first-line NASH therapy. The Phase 3 data on semaglutide for NASH is very promising.

39 9PeptideSynthNJ, Dr.KarenChen, Dr.NateNeph and 36 others
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CarlaRPh_TPA
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Mar 28, 2026 at 11:48 AM#3
kate.chem said:
The liver data is among the strongest non-weight findings in the class.

NASH/MAFLD therapeutic landscape and liver and MASH: GLP-1 agonists are emerging as potential first-line NASH therapy. The Phase 2b data for semaglutide showed 59% NASH resolution (vs 17% placebo) with 43% achieving fibrosis improvement[1].

Mechanism: GLP-1R activation reduces hepatic lipogenesis, increases fatty acid oxidation, reduces hepatic inflammation, and may directly reduce hepatic stellate cell activation (fibrosis pathway).

With resmetirom (thyroid hormone receptor agonist) recently approved for NASH, the field is evolving rapidly. Combination approaches (GLP-1 + resmetirom) are being explored.

References:
[1] Newsome PN, et al. N Engl J Med. 2021;384(12):1113-1124.
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DeniseRN_TPA
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Mar 28, 2026 at 11:57 AM#4
CarlaRPh_TPA said:
NASH/MAFLD therapeutic landscape and liver and MASH: GLP-1 agonists are emerging as potential first-line NASH therapy.

ATTAIN trial (survodutide) context for liver and MASH: survodutide, a GLP-1/glucagon dual agonist, showed -18.7% body weight at 46 weeks in the Phase 3 ATTAIN trial. NASH resolution was achieved in ~60% of patients[1].

This is relevant to liver and MASH because survodutide's glucagon agonism specifically targets hepatic lipid metabolism — making it potentially the best-in-class agent for NASH/MAFLD comorbid with obesity.

References:
[1] Sanyal AJ, et al. N Engl J Med. 2024.
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VanRx_Mike
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Mar 28, 2026 at 12:42 PM#5
JennaRN said:
Liver imaging follow-up for liver and MASH: FibroScan at baseline showed CAP score 334 dB/m (moderate steatosis) and stiffness 9.8 kPa (possible…

Second this.

36 6mike_mod, SarahChen_PharmD, sarah.morrison and 33 others
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