MASH / NAFLD
Hepatic fat with inflammatory progression; reduce liver/visceral fat.
Decision support, not prescription. You decide.
Candidate agents
8 agents · tap to expand▶SemaglutideLeadStrongA GLP-1 receptor agonist that is now the most robustly evidenced pharmacotherapy for MASH, backed by a positive phase 3 histology trial. Take this seriously as a leading disease-modifying option for biopsy-confirmed steatohepatitis with fibrosis.expand
A GLP-1 receptor agonist that is now the most robustly evidenced pharmacotherapy for MASH, backed by a positive phase 3 histology trial. Take this seriously as a leading disease-modifying option for biopsy-confirmed steatohepatitis with fibrosis.
▸Full clinical story
In MASH the driver is caloric excess, insulin resistance and lipotoxic hepatic fat that fuels inflammation and fibrogenesis. Semaglutide acts largely upstream and indirectly: substantial weight loss, improved insulin sensitivity and reduced substrate delivery lower hepatic fat and inflammatory activity, rather than any confirmed direct hepatocyte GLP-1 effect.
Strong for steatohepatitis resolution. The phase 3 ESSENCE trial (part 1, 72-week interim analysis of an ongoing 240-week trial) showed resolution of steatohepatitis without worsening fibrosis in 62.9% vs 34.3% placebo, and fibrosis improvement in 36.8% vs 22.4%; an earlier phase 2 NASH RCT established dose-dependent resolution (59% at 0.4 mg vs 17% placebo) but, notably, did not show a significant fibrosis-stage benefit (P=0.48). The fibrosis-improvement signal, now significant in phase 3, is more modest than the resolution signal.
Anecdotal community signal only: patients with fatty liver widely use semaglutide off-label (often compounded or via telehealth for weight loss) and report symptom and enzyme improvement, and clinicians increasingly prescribe it for metabolic MASH even before biopsy. These are unverified reports reflecting real-world practice and marketing pressure, not proof of hepatic benefit in any given patient.
Trial dosing was once-weekly subcutaneous 2.4 mg titrated over ~16 weeks; the 1.0-2.4 mg weight-management range is what is seen clinically. Context only, not a protocol.
Condition-specific concerns: many MASH patients have advanced fibrosis/cirrhosis where GI intolerance and weight loss must be monitored against sarcopenia risk. Watch for volume/renal effects with diuretics, hypoglycemia when stacked with insulin/sulfonylureas, and gallbladder events with rapid weight loss; effect on hard fibrosis/cirrhosis outcomes is still being established in the ongoing trial.
The current front-runner for pharmacologic MASH management, with the strongest human evidence for steatohepatitis resolution and a real but smaller fibrosis benefit. Reasonable to prioritize in metabolically driven MASH, while acknowledging long-term hepatic outcome data are still maturing.
▶SurvodutideStrongA glucagon/GLP-1 dual receptor agonist with a positive biopsy-controlled phase 2 MASH trial. A promising investigational candidate, graded emerging because it is not yet approved and phase 3 data are pending.expand
A glucagon/GLP-1 dual receptor agonist with a positive biopsy-controlled phase 2 MASH trial. A promising investigational candidate, graded emerging because it is not yet approved and phase 3 data are pending.
▸Full clinical story
Combines GLP-1's metabolic and weight effects with glucagon-receptor agonism, which directly increases hepatic energy expenditure and lipid oxidation. This dual action is mechanistically well suited to MASH because glucagon agonism can lower hepatic fat through liver-intrinsic pathways beyond weight loss alone.
Promising human RCT evidence at phase 2. The 48-week biopsy-based trial reported MASH improvement without worsening fibrosis in up to 62% (4.8 mg) vs 14% placebo, with liver-fat reduction of at least 30% in up to 67% vs 14%; fibrosis improvement by at least one stage was more modest (34-36% vs 22%). Emerging is the appropriate grade: a controlled histology endpoint from a single phase 2 program, still awaiting phase 3 confirmation.
Anecdotal community signal only: survodutide is not commercially available, so genuine off-label use is minimal; interest is largely limited to trial participants and forum discussion of glucagon-containing multi-agonists. Any secondhand reports should be treated as speculative.
Trial dosing escalated once-weekly subcutaneous survodutide to target maintenance doses (2.4, 4.8 or 6.0 mg studied); there is no established clinical dose. Context only, not a protocol.
Condition-specific: glucagon agonism can raise glucose and blood pressure and increase heart rate, which matters in the cardiometabolic MASH population; nausea, diarrhea and vomiting were common in the trial, and hepatic-enzyme and glycemic monitoring are relevant. As an unapproved agent, quality and identity of any non-trial product cannot be assured.
A mechanistically attractive dual agonist with solid phase 2 histology data, an emerging MASH candidate that remains investigational and unavailable outside trials pending phase 3 results.
▶TirzepatideStrongA dual GIP/GLP-1 receptor agonist with a positive biopsy-controlled phase 2 MASH trial. A promising emerging option, graded emerging rather than established because phase 3 histology confirmation is still pending.expand
A dual GIP/GLP-1 receptor agonist with a positive biopsy-controlled phase 2 MASH trial. A promising emerging option, graded emerging rather than established because phase 3 histology confirmation is still pending.
▸Full clinical story
Adds GIP agonism to GLP-1 activity, producing greater weight loss and insulin sensitization than GLP-1 alone. In MASH this translates to larger reductions in hepatic and visceral fat and in the metabolic drivers of steatohepatitis, again predominantly an indirect, weight- and metabolism-mediated effect.
Promising human RCT evidence, but only at phase 2. In SYNERGY-NASH (52 weeks, biopsy-confirmed MASH with F2-F3 fibrosis), MASH resolution without worsening fibrosis occurred in 44%, 56% and 62% across the 5, 10 and 15 mg arms vs 10% placebo, with supportive fibrosis-improvement signals (51-55% vs 30%). Emerging is the honest grade: a single controlled phase 2 histology trial, with no completed phase 3 MASH outcomes trial yet.
Anecdotal community signal only: given its weight-loss dominance, tirzepatide is heavily used off-label (branded and compounded) by people with fatty liver, who report enzyme and imaging improvement. These are unverified accounts of real-world enthusiasm, not evidence for a specific patient's liver histology.
Trial arms used once-weekly subcutaneous 5, 10 and 15 mg after gradual titration; the same range is what appears clinically. Context only, not a protocol.
Condition-specific: pronounced weight loss warrants attention to sarcopenia and nutritional status in cirrhotic MASH patients, and to hypoglycemia when combined with insulin or sulfonylureas. GI intolerance can limit titration; gallbladder disease and pancreatitis history deserve scrutiny in this comorbid population.
Among the most promising MASH agents, with convincing phase 2 histology data and best-in-class weight effects, but graded emerging — one tier behind semaglutide — because its confirmatory phase 3 histology trial has not yet read out.
▶RetatrutideEmergingA triple GIP/GLP-1/glucagon receptor agonist with dramatic liver-fat reduction on imaging but no MASH histology outcome data yet. Emerging and promising, but do not overstate: the evidence is imaging-based, not biopsy-proven disease modification.expand
A triple GIP/GLP-1/glucagon receptor agonist with dramatic liver-fat reduction on imaging but no MASH histology outcome data yet. Emerging and promising, but do not overstate: the evidence is imaging-based, not biopsy-proven disease modification.
▸Full clinical story
Triple agonism stacks GLP-1 and GIP metabolic effects with glucagon-driven hepatic lipid oxidation and energy expenditure, plus very large weight loss. For MASH this combination targets both the systemic metabolic drivers and hepatic fat handling directly, plausibly explaining the outsized steatosis reductions.
Emerging. In a phase 2a MASLD substudy (n=98, 24-week endpoint), retatrutide reduced MRI-PDFF liver fat by roughly 81-82% at 8-12 mg vs +0.3% placebo, with normal liver fat (<5%) achieved in up to ~86%. This is a strong imaging signal but a surrogate endpoint over short duration, without histologic MASH resolution or fibrosis data, so emerging is the honest grade.
Anecdotal community signal only: retatrutide is unapproved, yet it has an unusually active gray-market and research-chem following, and some users self-report large weight and 'fatty liver' improvements. These accounts are unverified, involve unregulated product, and are not evidence of liver benefit.
Phase 2 used once-weekly subcutaneous doses of 1, 4, 8 or 12 mg after titration; the higher doses drove the largest fat reductions. No established or approved dose exists. Context only, not a protocol.
Condition-specific: as with survodutide, the glucagon component can raise heart rate and affect glucose in cardiometabolic MASH patients. Gray-market sourcing carries dosing and purity risks; the lack of histology and longer-term hepatic outcome data means benefit on fibrosis is unproven.
The most potent liver-fat reducer seen so far on imaging, but still early: no biopsy-based MASH or fibrosis outcomes and no approval. Genuinely emerging and worth watching, not yet a substantiated disease-modifying therapy.
▶TesamorelinEmergingA GHRH analog that modestly reduces hepatic fat, with the best evidence confined to people with HIV-associated NAFLD and visceral adiposity. Emerging and niche; do not generalize its liver benefit to the broad MASH population.expand
A GHRH analog that modestly reduces hepatic fat, with the best evidence confined to people with HIV-associated NAFLD and visceral adiposity. Emerging and niche; do not generalize its liver benefit to the broad MASH population.
▸Full clinical story
Tesamorelin restores pulsatile GH/IGF-1 signaling, preferentially reducing visceral adipose tissue. Because visceral fat and low GH tone contribute to ectopic hepatic fat, raising GH activity can lower liver fat and may blunt fibrosis progression, a rationale most relevant to the lipodystrophic, visceral-fat phenotype.
Emerging, in a specific population. A randomized double-blind trial in people with HIV and NAFLD showed tesamorelin 2 mg daily reduced hepatic fat fraction by a relative ~37% vs placebo over 12 months, with a secondary signal toward less fibrosis progression. Evidence outside HIV-associated NAFLD is limited, so emerging (population-restricted) is accurate.
Anecdotal community signal only: tesamorelin is used off-label in bodybuilding and anti-aging/peptide circles for visceral fat loss, where users occasionally cite liver-fat benefit. This is unmonitored, unverified use extrapolated from a narrow indication and should not be presented as MASH evidence.
The studied and approved dose is 2 mg subcutaneously once daily; peptide-community regimens vary and are not validated. Context only, not a protocol.
Condition-specific: GH stimulation can worsen glucose tolerance and insulin resistance, directly relevant to the diabetic/prediabetic MASH population, and IGF-1 elevation raises theoretical malignancy concerns. It is contraindicated with active malignancy and requires glucose monitoring; injection-site reactions are common.
A legitimate but narrow option: real randomized evidence for reducing hepatic fat exists chiefly in HIV-associated NAFLD. In general MASH it is at best emerging and unproven, and its metabolic downsides temper enthusiasm.
▶MazdutidePreclinicalA glucagon/GLP-1 dual agonist whose MASH-specific evidence is currently preclinical. Interesting mechanistically, but treat direct hepatic claims as unproven in humans for this condition.expand
A glucagon/GLP-1 dual agonist whose MASH-specific evidence is currently preclinical. Interesting mechanistically, but treat direct hepatic claims as unproven in humans for this condition.
▸Full clinical story
Like other GCG/GLP-1 dual agonists, mazdutide pairs GLP-1 metabolic effects with glucagon-driven hepatic lipid oxidation and energy expenditure. Preclinical work additionally implicates modulation of PERK/ER-stress and NF-kB inflammatory signaling, and downregulation of lipogenic regulators (SREBP-1, C/EBPbeta, PPARgamma), as a proposed liver-intrinsic route to reduced steatosis and injury.
Preclinical only for MASH. The cited evidence is a high-fat-diet mouse model plus a free-fatty-acid hepatocyte model showing reduced steatosis, lower liver-injury markers and dampened inflammation via ER-stress (PERK) and NF-kB pathways. There is no dedicated human MASH histology trial for mazdutide, so preclinical is the correct grade despite the drug's broader clinical development in obesity.
Anecdotal community signal only: mazdutide is largely a China-market/investigational agent, so off-label MASH use is minimal and confined to weight-loss-focused discussion. No credible patient-reported liver outcomes exist to cite.
No MASH dosing is established; clinical obesity programs use once-weekly subcutaneous dosing, but this cannot be translated to a liver protocol. Context only, not a protocol.
Condition-specific: the glucagon component can raise glucose, heart rate and blood pressure in cardiometabolic patients, and hepatic/glycemic effects in MASH are uncharacterized in humans. Any use for liver disease would be entirely investigational.
Mechanistically plausible and worth tracking as its clinical program matures, but for MASH the evidence is animal/in-vitro only. It does not yet belong in clinical decision-making for this condition.
▶Empagliflozin (Jardiance)EmergingAn SGLT2 inhibitor that produces a modest reduction in liver fat on imaging, useful mainly as an adjunct in cardiometabolic MASH. Emerging with a small effect size; not a primary MASH therapy.expand
An SGLT2 inhibitor that produces a modest reduction in liver fat on imaging, useful mainly as an adjunct in cardiometabolic MASH. Emerging with a small effect size; not a primary MASH therapy.
▸Full clinical story
SGLT2 inhibition induces glucosuria and a mild caloric/glucose deficit, promoting weight and visceral-fat loss and a shift toward lipid oxidation and ketogenesis. In MASH this lowers hepatic fat and improves the metabolic milieu, but the magnitude is inherently limited compared with incretin agents.
Emerging. A 52-week RCT in non-diabetic MASLD (n=98) showed empagliflozin 10 mg reduced MRI-PDFF more than placebo (-2.49% vs -1.43%, P=0.025), with greater weight and waist reduction; steatosis resolution and ALT/PDFF-response secondary endpoints were not significant. The effect is statistically real but small and imaging-based, without robust histologic MASH-resolution data, supporting an emerging grade with a modest ceiling.
Anecdotal community signal only: clinicians commonly continue or add empagliflozin in MASH patients who also have type 2 diabetes, heart failure or CKD, citing incidental liver and weight benefit. This reflects sensible comorbidity-driven prescribing, not evidence that it meaningfully modifies MASH histology.
Studied at 10 mg orally once daily; 10-25 mg daily is the standard cardiometabolic range. Context only, not a protocol.
Condition-specific: euglycemic DKA risk rises with the low-carbohydrate/weight-loss states common in motivated MASH patients, and volume depletion can matter in cirrhosis with ascites or diuretic use. Genital mycotic infections are frequent; benefit on fibrosis is unproven.
A reasonable adjunct that modestly lowers liver fat and adds cardiorenal protection, best reserved for MASH patients with a co-indication. On its own it is an emerging, low-magnitude option rather than a core MASH treatment.
▶SLU-PP-332PreclinicalA mechanistic maybe for fatty-liver disease — no dedicated SLU-PP-332 liver study yet.expand
A mechanistic maybe for fatty-liver disease — no dedicated SLU-PP-332 liver study yet.
▸Full clinical story
Increased hepatic and systemic fatty-acid oxidation plus reduced adiposity and insulin resistance could, in theory, reduce hepatic steatosis.
Only indirect: metabolic-syndrome mice showed improved lipid handling; no MASH/NAFLD histology study of SLU-PP-332 published.
No verifiable community reports.
No human dose established.
Extrapolated from metabolic data; direct hepatic evidence absent.
Plausible but unproven for MASH — mechanistic rationale only.
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