Metabolic dysfunction-associated steatotic liver disease (MASLD) is a condition where excessive fat accumulates in liver cells, driven by metabolic factors like obesity and insulin resistance. Type 2 diabetes (T2D) and MASLD frequently coexist, largely due to the shared mechanism of insulin resistance, where cells fail to respond effectively to insulin. Each condition exacerbates the other, accelerating liver damage toward inflammation and scarring, known as Metabolic Dysfunction-Associated Steatohepatitis (MASH). Up to 70% of people with T2D also have MASLD, and the presence of both dramatically increases the risk of severe complications, including advanced liver fibrosis, cirrhosis, and cardiovascular disease.
Foundational Therapy: Weight Loss and Lifestyle Modifications
Lifestyle changes are the most effective and fundamental treatment for improving both liver health and insulin sensitivity. The degree of weight loss directly correlates with the reversal of liver disease severity. A modest body weight reduction of 5% is often sufficient to improve hepatic steatosis. However, a greater weight loss of 7% to 10% is generally required to achieve resolution of the more severe MASH, which involves inflammation and cellular injury. Sustained weight loss exceeding 10% is associated with the highest rates of fibrosis regression and is the primary goal before considering pharmacological or surgical interventions.
Dietary composition plays a crucial role beyond simple calorie restriction, focusing particularly on reducing refined sugars and carbohydrates. Fructose, found in many processed foods and sugary drinks, is a potent stimulator of de novo lipogenesis (the liver’s production of fat). Limiting the intake of these items directly reduces the fat load on the liver. Adopting a Mediterranean-style eating pattern is often recommended, as it emphasizes whole grains, legumes, nuts, olive oil, and fish while limiting red meat and processed foods. This approach reduces liver fat and improves insulin sensitivity, even independent of significant weight loss.
Physical activity, combining both aerobic exercise and resistance training, offers further independent metabolic benefits. Aerobic exercise, such as brisk walking or jogging, helps reduce overall fat mass, including visceral fat surrounding the internal organs. Resistance training, like weightlifting, improves the ability of skeletal muscle to take up and store glucose, thereby directly improving systemic insulin resistance.
Medications Targeting Dual Disease
Certain drug classes originally developed for T2D management have demonstrated measurable benefits for both glucose control and liver disease progression. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), such as semaglutide and liraglutide, are effective due to their dual action of promoting weight loss and improving insulin sensitivity. These medications can resolve MASH and reduce liver fibrosis. For instance, once-weekly semaglutide has been shown to achieve MASH resolution in over 60% of patients with moderate-to-advanced fibrosis in clinical trials.
Sodium-glucose cotransporter-2 (SGLT2) inhibitors, including empagliflozin and dapagliflozin, work by causing the kidneys to excrete excess glucose in the urine. This mechanism leads to improved glycemic control, modest weight loss, and a reduction in liver fat content. While SGLT2 inhibitors are valued for their protective effects against cardiovascular and renal complications, they also improve liver steatosis and liver enzyme levels.
Pioglitazone, an older oral agent from the thiazolidinedione class, is a recognized option for improving liver health. It functions by directly targeting insulin resistance, which reduces hepatic fat and can lead to MASH resolution. However, its use is often limited by potential side effects, such as fluid retention and weight gain, especially in patients with heart failure. These pharmacological options are typically utilized when lifestyle modifications alone are insufficient to achieve metabolic and hepatic goals.
The Role of Metabolic Surgery
For individuals with severe obesity and high disease burden, metabolic or bariatric surgery represents an effective intervention for achieving sustained weight loss and disease remission. Procedures like Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG) lead to rapid and substantial weight loss, triggering profound metabolic changes. These changes often result in the resolution or significant improvement of T2D and MASLD.
T2D remission, defined as achieving non-diabetic glucose levels without medication, occurs in over 90% of patients following gastric bypass surgery, often within days or weeks. The surgery’s effect on MASLD is equally dramatic, with RYGB demonstrating the highest rates of steatosis resolution, sometimes exceeding 95%. Bariatric surgery is also associated with fibrosis regression in approximately 70% of patients, improving long-term survival by reducing liver-related complications.
Metabolic surgery is typically recommended for patients with a Body Mass Index (BMI) of 35 kg/m² or higher, regardless of comorbidities, or for those with a BMI of 30 kg/m² or higher who also have difficult-to-manage T2D. For certain populations, such as those of Asian descent, lower BMI thresholds starting at 27.5 kg/m² are often applied due to a higher prevalence of metabolic disease at lower body weights.
Long-Term Monitoring and Management Goals
Managing the intertwined conditions of T2D and MASLD requires continuous monitoring focused on preventing disease progression and reducing overall cardiovascular risk. Non-invasive tests are preferred for assessing liver health over the invasive liver biopsy. The Fibrosis-4 (FIB-4) index is the preferred initial screening tool, using age and routine blood values (ALT, AST, and platelet count) to calculate the likelihood of advanced liver fibrosis.
A low FIB-4 score, typically below 1.3, reliably suggests a low risk of advanced fibrosis, allowing for management in the primary care setting. Patients with an indeterminate or high FIB-4 result, particularly above 2.67, require further assessment using advanced non-invasive methods. These secondary tests include Vibration-Controlled Transient Elastography (VCTE), also known as FibroScan, which measures liver stiffness and fat content.
The primary long-term goal of therapy is the prevention of progression to cirrhosis and a reduction in cardiovascular events, which is the leading cause of death in this population. While A1C targets for T2D are individualized, maintaining a goal between 7% and 8% is recommended for most non-pregnant adults to minimize microvascular complications. Effective management necessitates an interdisciplinary approach, involving collaboration among primary care physicians, endocrinologists, and hepatologists to ensure metabolic and hepatic health goals are simultaneously addressed.