Conventional and Emerging Therapies for Non-Alcoholic Fatty Liver Disease

What is Non-Alcoholic Fatty Liver Disease?

Excess fat accumulation in the liver results in a condition known as fatty liver that may lead to inflammation, scarring, and liver damage. There are mainly two types of fatty liver diseases: alcoholic fatty liver disease (AFLD) and non-alcoholic fatty liver disease (NAFLD).

As the name indicates, alcoholic fatty liver disease is caused as a result of excessive alcohol consumption. The excess alcohol is metabolized to form fat accumulated in the liver. If left untreated, AFLD leads to inflammation, scarring, and liver cirrhosis.

On the other hand, non-alcoholic fatty liver disease may not result from alcohol consumption but rather due to metabolic factors such as obesity, type 2 diabetes, insulin resistance, and high cholesterol, as well as genetic predisposition, poor diet, and a sedentary lifestyle. Several lipid metabolism dysfunctions, as well as insulin resistance, can contribute to NAFLD. Some of these are:

1. Increased fatty acid uptake
2. Impaired fatty acid oxidation
3. Increased de novo lipogenesis
4. Decreased VLDL secretion

NAFLD starts with asymptomatic simple fatty liver (steatosis) without causing inflammation or damage. If left untreated at this stage, NAFLD can lead to a severe condition of inflammation and liver cell damage, known as non-alcoholic steatohepatitis (NASH). It subsequently leads to the next stage of life-threatening conditions: fibrosis, cirrhosis, and liver cancer.

Both types of fatty liver diseases require early detection, intervention, management, and lifestyle modifications to minimize liver damage and return to a healthy life.

Why is Early Detection Challenging for NAFLD?

Early stages of NAFLD are often asymptomatic, meaning there might not be noticeable symptoms until the condition progresses to the following severe stages, such as NASH, fibrosis, or cirrhosis.  Some individuals may experience mild symptoms such as fatigue or abdominal discomfort, which may be overlooked or attributed to other non-specific health issues.

Undetected NAFLD can progress silently until liver damage becomes significant with severe symptoms such as:

• Fatigue
• Abdominal pain
• Loss of appetite
• Unexpected weight loss
• Jaundice
• Swelling on the legs
• Itchy skin

How to Detect NAFLD Early?

A proactive healthcare approach is needed to conduct routine screenings for NAFLD, especially in individuals with known risk factors like hypertension, obesity, high cholesterol, and type 2 diabetes.

Routine liver function tests (LFTs) offer important clues for detecting NAFLD.

1. Elevated levels of liver enzymes such as Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) can indicate liver inflammation, a distinctive feature of NAFLD.
2. Elevated Alkaline Phosphatase (ALP) levels can be a direct clue for bile duct obstruction or liver damage.
3. Increased bilirubin levels point to impaired liver function.

LFT results can be an initial screening tool for detecting NAFLD and other liver conditions. Further diagnostic tests, such as a liver ultrasound or biopsy, may be necessary to confirm the diagnosis.

Advanced Diagnostic Tools for Fatty Liver

Advanced diagnostic tools, such as FibroScan (Transient Elastography), CT Scan (computed tomography), and MRI (magnetic resonance imaging), give more detailed and measurable information about fat deposition and fibrosis than standard ultrasound scanning. These advancements enable early detection, intervention, and tracking of NAFLD progression.

Conventional Therapies and Treatments for NAFLD

These therapies and treatments focus on reducing the accumulated liver fat, addressing the underlying metabolic causes, preventing the progression to NASH, cirrhosis, or liver cancer, and finally managing the symptoms.

Doctors may prescribe lifestyle modifications for early and mild symptoms associated with NAFLD. These may include:

• Achieving a weight loss of 5-10% by reducing liver fat and inflammation
• Consuming a healthy diet rich in fruits, vegetables, whole grains, healthy fats, and lean proteins
• Reducing sugar, refined carbs, saturated fats, and processed foods
• Engaging in regular physical activity to improve liver health and reduce fat accumulation

For the management of underlying metabolic conditions associated with NAFLD, the following therapies may be prescribed by your healthcare team:

• Lifestyle modifications to manage obesity
• A combination of diet control and medications like metformin for managing diabetes
• Statins to reduce high cholesterol and omega-3 fatty acids to lower triglycerides in managing dyslipidemia
• Medications and diet control to manage high blood pressure (hypertension)

NAFLD and NASH are associated with specific symptoms or secondary effects that require proactive management:

• Antioxidant therapy with vitamin E for reducing liver inflammation
• Pioglitazone for improving insulin sensitivity and reducing liver fat and inflammation
• Anti-inflammatory agents for controlling inflammation
• Anti-fibrotic agents for more advanced liver fibrosis and cirrhosis
• Omega-3 fatty acids for reducing triglycerides

When lifestyle changes and medications become insufficient for treating obesity and liver fat accumulation, doctors may prescribe bariatric surgery, an effective weight-loss surgery.

Regular liver health monitoring and preventive care are also crucial in NAFLD management. This includes:

• Regular liver function tests and imaging to track disease progression
• Vaccinations for hepatitis A and B to prevent further liver damage
• Complete abstinence from alcohol and unnecessary medications that may worsen liver damage

A more personalized treatment plan that combines lifestyle modifications and targeted therapies for underlying metabolic conditions and specific symptoms is essential for effective NAFLD management.

Emerging Therapies for NAFLD

The Gap in Conventional Therapies for NAFLD

So far, conventional therapies for NAFLD have been effective in managing associated conditions, controlling diabetes, reducing cardiovascular risks, and slowing disease progression. The affordability, accessibility, and safety of conventional therapies make them essential for initial management. On the other hand, these therapies have not been fully effective in addressing the root causes of the disease.

To reach the overall therapeutic aim of any NAFLD treatment, it was necessary to innovate therapies that can directly target the cellular and molecular-level processes such as lipid metabolism dysregulation (leading to liver fat accumulation), oxidative stress, mitochondrial dysfunction, and cytokine signaling driving NAFLD. Furthermore, additional innovations were needed to target the inflammatory pathways (driving persistent liver damage) and fibrosis pathways (promoting scarring and long-term complications).

Here is a list of gaps in NAFLD treatment that emerging therapies have addressed:

1. Though conventional therapies were effective in managing the secondary effects or comorbidities such as obesity, diabetes, hypertension, and high cholesterol, the need for specific targeted pharmacological interventions directly or comprehensively targeting the root mechanisms that cause NAFLD or NASH has been unmet. These interconnected mechanisms include insulin resistance, chronic inflammation, oxidative stress, lipid metabolism dysregulation, and overactivation of fibrosis pathways.
2. Conventional therapies like lifestyle changes may slow disease progression but cannot actively reverse fibrosis or repair liver damage.
3. Weight loss therapies and dietary changes are the first-line treatments, but adherence can be difficult for many individuals, and their effectiveness may vary.
4. Conventional therapies like vitamin E or pioglitazone provide modest anti-inflammatory effects but are not suitable for individuals with diabetes or other comorbidities. As a result, chronic liver inflammation leads to fibrosis and liver failure.
5. Treatments like statins and omega-3 fatty acids aim to reduce cardiovascular risks and triglycerides but do not address liver inflammation or fibrosis.
6. Existing treatments primarily address the symptoms or associated conditions (e.g., diabetes, hypertension) without directly targeting the liver-specific mechanisms driving fat accumulation, inflammation, and fibrosis.
7. Conventional treatments provide only limited options, such as supportive care or liver transplantation for advanced NAFLD stages when fibrosis or cirrhosis develops.

How Emerging Therapies Fill These Gaps

Most of the emerging therapies for NAFLD and NASH are under clinical studies and focus on targeting the diseases’ underlying mechanisms, including liver fat accumulation, inflammation, and fibrosis. These therapies aim to achieve the following outcomes:

1. Molecular-level intervention to target pathways like lipid metabolism, insulin resistance, fat accumulation, inflammation, and fibrotic signaling.
2. Reversal or reduction of fibrosis to prevent cirrhosis.
3. Broader applicability to work across various stages of NAFLD and NASH, from early fatty liver to advanced fibrosis.
4. A holistic approach by providing additional tools alongside lifestyle interventions to improve liver health and reduce disease progression.

Notable emerging therapies for NAFLD and NASH

FXR Agonists

The Farnesoid X Receptor (FXR) is a regulatory nuclear receptor that regulates bile acid metabolism, lipid homeostasis, and inflammatory pathways. FXR acts as a sensor for bile acids, regulating their synthesis, transport, and excretion. Furthermore, they involve various metabolic processes, including glucose regulation and lipid metabolism.

Medical researchers believe they can develop new therapies to improve liver function and overall metabolic health by modulating FXR activity. Scientists have identified FXR as a potential therapeutic target for developing new drugs to treat metabolic disorders, including NAFLD and other related conditions.

FXR agonists are drugs that activate the FXR receptor, thereby modulating bile acid metabolism and reducing liver fat, inflammation, and fibrosis. This mechanism of action makes FXR agonists a promising therapeutic approach for various liver disorders like NAFLD. Prominent FXR agonist drugs include:

1. Approved drugs like Obeticholic Acid (OCA) help reduce liver inflammation, bile buildup, and fibrosis in primary biliary cholangitis (PBC) patients.
2. Experimental FXR agonists like Tropifexor aim to reverse liver fibrosis and inflammation in NASH patients.
3. Drugs like Cilofexor are under clinical trials for treating liver diseases.

PPAR Agonists

They activate the Peroxisome Proliferator-Activated Receptors (PPAR), a group of nuclear receptors that regulate the genes involved in metabolism, inflammation, and energy homeostasis. PPAR agonists are drugs that bind to and activate these PPAR receptors, triggering the expression of specific genes involved in metabolic regulation, including lipid and glucose metabolism. These actions help treat liver disorders, including NAFLD and NASH, by:

1. Reducing liver fat
2. Improving insulin sensitivity
3. Lowering inflammation
4. Correcting dyslipidemia

Prominent PPAR agonist drugs include:

1. PPAR-α agonist drugs, such as Fenofibrate and Gemfibrozil, help break down fats, raise fatty acid oxidation in the liver, lower triglyceride levels, and stop fat from building up. They are approved for hypertriglyceridemia and dyslipidemia and are under clinical trials for NAFLD and NASH treatments.
2. PPAR-γ agonist drugs like Pioglitazone and Rosiglitazone improve insulin sensitivity and reduce liver inflammation and fibrosis. They are under clinical trials for NAFLD and NASH treatment and are approved for treating type-2 diabetes.
3. PPAR-δ agonist drugs such as Elafibranor and Lanifibranor are under clinical trials for treating NAFLD and NASH. Their potential benefits include increasing fatty acid oxidation, improving liver insulin sensitivity, reducing inflammation, and preventing liver fibrosis by modulating pro-inflammatory pathways.
4. Dual and Pan-PPAR Agonists are newer drugs that target more than one PPAR subtype for broader therapeutic effects. Elafibranor (PPAR-α/δ agonist), under clinical trials for treating NASH and fibrosis, improves lipid and glucose metabolism and reduces liver inflammation. Lanifibranor is a pan-PPAR agonist that has shown promise in treating advanced NASH.

GLP-1 Receptor Agonists

Glucagon-like peptide-1 Receptor Antagonists are a group of drugs that work by activating the GLP-1 receptors. These special proteins are very important for controlling metabolic processes like glucose metabolism. This activation helps regulate blood sugar, insulin secretion, appetite, and weight. Initially developed for treating type 2 diabetes and obesity, the GLP-1 Receptor agonists are now being explored for treating NAFLD and NASH due to their capabilities in:

• Reducing liver fat
• Improving insulin sensitivity
• Lowering inflammation
• Preventing fibrosis
• Cardiometabolic protection

Common GLP-1 Receptor Agonists include:

1. Liraglutide, approved for type 2 diabetes and obesity, has been shown to reduce liver fat in NAFLD patients.
2. Semaglutide, approved for type 2 diabetes and obesity, has demonstrated significant liver fat reduction in clinical trials.
3. Dulaglutide, approved for type 2 diabetes and obesity, has been explored for liver disease management.

Anti-Fibrotic Therapies

These are medical treatments designed to reduce or reverse fibrosis that can affect many organs, including the liver. In NAFLD and NASH, fibrosis results from persistent liver inflammation, fat buildup, and immune response dysregulation and can lead to cirrhosis, liver failure, and liver cancer. Anti-fibrotic therapies target various fibrotic pathways to prevent or reverse liver scarring by:

• Reducing inflammation
• Blocking fibrogenesis by inhibiting hepatic stellate cells, which are key drivers of liver fibrosis
• Reversing fibrosis by promoting the breakdown of existing scar tissue
• Improving liver regeneration

Different types of anti-fibrotic therapies for NAFLD and NASH include:

1. FXR agonists
2. PPAR agonists
3. GLP-1 receptor agonists
4. Anti-inflammatory agents like Cenicriviroc and Emricasan reduce inflammation by blocking key inflammatory pathways. These are currently in clinical trials.
5. Anti-fibrotic small molecules such as Simtuzumab and Selonsertib, which are in clinical trials, can inhibit enzymes involved in collagen production and slow down tissue scarring.
6. Biomolecules that fight fibrosis are still being studied. These include monoclonal antibodies that target pro-fibrotic factors like TGF-β, which is a major fibrotic mediator.
7. Other emerging anti-fibrotic approaches include gene and cell therapies and antioxidant and combination therapies.

Thyroid Hormone Receptor Beta Agonists

THR-β agonists are a class of drugs designed to selectively activate THR-β receptors, which are primarily found in the liver. These receptors control lipid metabolism, cholesterol regulation, and fat breakdown. On the other hand, the THR-α receptors are found in the heart, bones, and muscles and influence heart rate and bone health. By activating the THR-β receptors, the THR-β agonists help to improve lipid metabolism and reduce liver fat without causing adverse effects related to the THR-α activation, such as heart palpitations or osteoporosis. Consequently, the THR-β agonists have gained attention for treating NAFLD and NASH due to their ability to:

• Reduce liver fat
• Improve insulin sensitivity
• Improve liver function
• Decrease inflammation and fibrosis
• Cardiometabolic benefits, including reduced triglycerides and LDL cholesterol

Key THR-β agonists in development are:

1. Resmetirom, currently in phase 3 clinical trials, has significantly reduced hepatic fat, improved insulin sensitivity, and lowered cholesterol levels.
2. In phase 2 clinical trials, VK2809 has shown that it selectively targets THR-β more than Resmetirom. It also has strong effects on lowering lipids and liver fat.

Sodium-Glucose Co-Transporter 2 Inhibitors

SGLT2 inhibitors, a class of medications originally developed to treat type 2 diabetes, have demonstrated additional benefits such as weight loss, reduced inflammation and oxidative stress, reduced cardiovascular risk, and kidney protection. Due to their multi-faceted metabolic effects, SGLT2 inhibitors have emerged as potential treatments for NAFLD and NASH through the following potentials:

• Reduction in liver fat (hepatic steatosis)
• Improved insulin sensitivity, reducing the risk of liver inflammation and fibrosis
• Weight loss and caloric deficit, indirectly lowering liver fat and reducing the overall metabolic workload
• Anti-inflammatory effects
• Fibrosis reduction

Several SGLT2 inhibitors, already approved for diabetes and cardiovascular conditions, are now being investigated for their potential efficacy in treating NAFLD and NASH.

1. Empagliflozin reduces cardiovascular risk and shows promising liver-protective effects.
2. Dapagliflozin, approved for diabetes, heart failure, and kidney disease, has been studied for NAFLD and NASH.
3. Canagliflozin reduces cardiovascular risks and may lower liver fat.
4. Ertugliflozin is used in diabetes treatment and is under investigation for metabolic conditions.

Apolipoprotein C-III Inhibitors

Apolipoprotein C-III (ApoC-III) is a key regulator of triglyceride metabolism. Elevated ApoC-III levels are associated with hypertriglyceridemia, NAFLD, and NASH. ApoC-III inhibitors are a new class of drugs designed to reduce triglyceride levels in the blood and liver by blocking ApoC-III activity, which can help manage and treat NAFLD and NASH. ApoC-III inhibitors play a multi-target role in managing NAFLD and NASH, conditions driven by triglyceride accumulation, insulin resistance, and chronic liver inflammation. Below is a list of their actions:

• Reduction in liver fat (hepatic steatosis)
• Lowering of liver inflammation by lowering triglycerides
• Improved insulin sensitivity
• Reduced fibrosis progression
• Cardiovascular protection by reducing cardiovascular risks associated with NAFLD/NASH

The following ApoC-III inhibitors are under clinical trials or development:

1. Volanesorsen has been explored for hypertriglyceridemia in NAFLD/NASH, and research is ongoing to prove its efficacy further.
2. ARO-APOC3 is in clinical trials for severe hypertriglyceridemia and NASH.
3. Olezarsen is under investigation for lowering triglycerides and reducing liver fat in NAFLD/NASH.

Combined Therapies

While most conventional therapies for NAFLD and NASH rely on the one-drug-for-one-condition approach, the emerging combined therapy strategies target different disease mechanisms simultaneously. These treatments are based on the idea that NAFLD and NASH are complicated conditions with many factors that affect different metabolic, inflammatory, and fibrotic pathways. Because of this, they need a targeted approach.

The following primary considerations necessitated the evolution of combination therapies:

1. The multifactorial nature of NAFLD/NASH, since they are driven by insulin resistance, lipid metabolism dysregulation, chronic inflammation, oxidative stress, and fibrosis. So far, no single drug could address these factors simultaneously.
2. Enhanced treatment efficacy due to the synergistic combination of therapies targeting various disease drivers.
3. Reduced drug resistance, compared to the high risks of drug resistance or treatment failure that are common when relying on monotherapy.
4. Minimized side effects by combining low doses of different drugs, thus reducing the risks of adverse impacts common with high-dose monotherapies.

Several combined drug classes are currently undergoing active clinical investigation for NAFLD/NASH:

1. FXR Agonists and PPAR Agonists: The efficacy and safety of this synergistic combination to address metabolic dysfunction, inflammation, and fibrosis are under evaluation.
2. GLP-1 Receptor Agonists and SGLT2 Inhibitors: More research is being done to see how the combination’s effects on lowering glucose and weight affect the metabolic pathways for NAFLD/NASH.
3. ApoC-III Inhibitors and PPAR Agonists: Studies are currently underway to evaluate this combination’s potential to concurrently lower triglyceride levels, enhance fat metabolism, and slow the progression of fibrosis.
4. Anti-Fibrotic Agents with Metabolic Modulators: Their potency to concurrently reduce liver fibrosis and address underlying metabolic disturbances is under investigation.

Potential Side Effects of Emerging Therapies

Even though emerging therapies offer promising capabilities to address the underlying mechanisms leading to effective management of NAFLD and are well-tolerated, they also come with potential side effects, especially with long-term use, like conventional therapies. These concerns are to be addressed to make the therapies viable and safe for individuals suffering from liver diseases. Some of these side effects are:

• FXR agonists may produce itching and elevated LDL cholesterol in some individuals, as well as fatigue and gastrointestinal issues with long-term use.
• PPAR agonists are reported to cause weight gain, fluid retention, elevated LDL cholesterol, and bone loss.
• GLP-1 receptor agonists may result in gastrointestinal issues, appetite loss, and gallbladder problems.
• THR-β agonists may cause gastrointestinal issues and metabolic changes.
• SGLT2 inhibitors may result in urinary tract infections and dehydration.
• ApoC-III inhibitors have potential side effects, including injection site reactions, liver enzyme elevation, platelet count reduction, and gastrointestinal issues.

Final Thoughts

In conclusion, NAFLD is a complex disease with a growing global health impact. While conventional therapies have proven effective in managing associated conditions, there remains a significant need for innovative approaches targeting the underlying mechanisms of the disease. Emerging therapies, such as those targeting metabolic pathways and inflammation, hold promise and hope in addressing the unmet needs of NAFLD patients. As research continues to advance through clinical investigations and trials, we can anticipate the development and approval of more effective treatments for this challenging condition.