(Part 2) The Fat You Can't Always See: The Path to Metabolic Recovery

Co-authored by: Dr Tim Trodd (Specialist in Family Medicine)

No Single Fix: Why Treatment Needs a Whole-Person Approach

No single drug reverses Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). European liver guidelines make this clear: addressing lifestyle is essential for all patients.^[1] But lifestyle change alone is often not enough, and medication support is increasingly recognised as an important part of a comprehensive approach. Below, we explore three of the most promising options in depth.

1. The Ketogenic Diet: Cutting Carbohydrates as Metabolic Medicine for the Liver

The ketogenic diet (KD), which involves very low carbohydrate intake (typically under 20 to 50 g per day), higher fat, and moderate protein, has emerged as one of the most compelling dietary options for MASLD.

Why does it work? 

When we eat carbohydrates, particularly sugary and starchy foods, the body releases insulin to manage rising blood sugar. Insulin also signals the liver to convert those carbohydrates directly into fat. The more carbohydrates we eat, the more fat the liver produces and stores.

By dramatically cutting carbohydrates, the KD lowers insulin levels, switches off the liver's fat-making process, and encourages the liver to burn its stored fat as fuel instead.^[2,3] It also directly reduces visceral fat around the organs.^[4]

What medical teams have found

The results across multiple comparisons point in the same direction:

Just six days on a KD reduced liver fat by 31% and liver insulin resistance by 58%, with barely any change in body weight, showing the liver was responding to carbohydrate restriction itself, not simply to weight loss.^[2]

When compared head-to-head with a Mediterranean diet and with standard low-calorie diets, the KD consistently produced greater reductions in liver fat as measured by Magnetic Resonance Imaging (MRI).^[5,6,7]

People with MASLD who cut carbohydrates below 30 g per day, without any calorie counting, still achieved a 43.8% reduction in liver fat despite losing less than 2% of their body weight.^[3]

The consistent message: cutting carbohydrates does something specific and beneficial for the liver, over and above any weight loss it produces.

2. GLP-1 Receptor Agonists: A New-Generation Medication for Liver Fibrosis

Glucagon-Like Peptide-1 (GLP-1) receptor agonists, including liraglutide and semaglutide, were first developed to treat type 2 diabetes and obesity. Their benefits for the liver have since emerged as one of the most exciting developments in liver medicine over the last decade.

How do they work?

GLP-1 receptor agonists act through several complementary pathways:^[8]

• They stimulate insulin release and reduce glucose production by the liver

• They slow digestion and increase the feeling of fullness, promoting weight loss

• They directly reduce fat production in the liver and dampen inflammation, through receptors found on liver cells^[9]

• They improve insulin sensitivity, addressing a core driver of MASLD^[10]

Semaglutide: the current frontrunner 

Semaglutide has built the strongest track record of any medication for MASLD/Metabolic Dysfunction-Associated Steatohepatitis (MASH). In a large trial, 59% of patients taking semaglutide daily saw their MASH resolve, compared to 17% on placebo.^[11] A more recent large-scale Phase 3 trial in patients with confirmed MASH and significant liver scarring found that over 60% of those on semaglutide achieved resolution of liver inflammation without any worsening of scarring, compared to around a third on placebo. Meaningful improvement in scarring itself was also seen.^[12]

Across multiple trials, these results hold up consistently, and semaglutide ranked among the most effective options for bringing down liver enzyme levels (alanine aminotransferase or ALT, and aspartate aminotransferase or AST), which are markers of liver stress.^[11,13]

In August 2025, semaglutide at the 2.4 mg weekly dose received formal approval from the United States Food and Drug Administration (FDA) specifically for the treatment of MASH with moderate-to-advanced liver scarring (F2-F3 fibrosis) in adults.^[12]

3. Pioglitazone (Actos): A Well-Established Medication Worth Knowing About 

Pioglitazone is an older diabetes medication that has also shown meaningful benefits for the liver in certain patients, and it remains one of the most studied off-label options for MASH.

How does it work?

Pioglitazone works by encouraging fat cells throughout the body to store fat more efficiently, redirecting it away from the liver and toward safer storage under the skin. It also boosts a helpful hormone called adiponectin, which improves the body's sensitivity to insulin. On top of that, it has a direct calming effect on liver inflammation and helps slow the build-up of scar tissue in the liver.^[14,15,16]

What has been found

A landmark trial showed that pioglitazone significantly improved liver fat and inflammation in patients with MASH who did not have diabetes.^[17]

When results from multiple trials were combined, it showed meaningful improvements in liver cell damage, inflammation, and fat content in both diabetic and non-diabetic MASH patients.^[14] Most data also show a positive trend toward reduced liver scarring, though this has not been consistent across all trials, which is why pioglitazone has not been formally endorsed as a targeted treatment for MASH by major international liver guidelines.^[18]

Current American liver guidelines consider pioglitazone a reasonable option primarily for patients with biopsy-proven MASH who also have type 2 diabetes, after an open discussion of its risks and benefits.^[19] It continues to be used off-label in selected patients where other options are limited or unavailable.

Considerations and side effects 

Pioglitazone works best as a long-term commitment; stopping it is associated with the liver worsening again.^[14] Side effects include:^[20]

• Weight gain of 3 to 5 kg in the majority of patients

• Caution in heart failure, though pioglitazone has not been shown to increase the risk of dying from heart failure, and may reduce deaths from ischaemic heart disease

• Increased fracture risk, particularly in post-menopausal women

• A small, not clearly established, potential link with bladder cancer

For the right patient, particularly those with confirmed MASH and type 2 diabetes, the benefits can outweigh the risks. However, because the treatment landscape is rapidly evolving, having regular reviews and open discussions with your doctor is essential to determine if newer options are better suited for your specific diagnosis.

Putting It All Together: The Integrated View 

MASLD and excess visceral fat are deeply connected. Visceral fat drives insulin resistance, fuels chronic low-grade inflammation, and sends a constant stream of harmful signals to the liver, all of which push fat accumulation forward and accelerate the journey toward MASH and its whole-body consequences.

Effective treatment must therefore address the whole person, not just one organ.

A healthy lifestyle, built on a good diet and regular physical activity, remains the essential foundation for preventing MASLD and preserving long-term health. It must be part of every treatment plan.

No single approach is right for every patient. In practice, combining dietary change (such as a low-carbohydrate or ketogenic approach) and exercise with medication (GLP-1 agonists or pioglitazone, depending on the individual) offers the best prospect of meaningful and sustained improvement. The science increasingly supports a holistic approach: treating the underlying metabolic terrain, not just managing a single blood test result.

So here is yet another reason to make regular check-ups a habit and catch early MASLD before its long-term consequences take hold.

Dr Shiba Poon

General Practice, Family Medicine

• LMCHK
• MBBS (Lond)
• DRCOG
• DCH (RCPCH)
• PGDipClinDerm (Lond)
• MRCGP
• Honorary Clinical Assistant Professor In Family Medicine (HKU)

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References

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