What are effective treatment approaches for Metabolic Associated Steatohepatitis Liver Disease (MASLD) in pediatric patients with Diabetes Mellitus (DM)?

Effective Treatment Approaches for MASLD in Pediatric Patients with Diabetes Mellitus

The most effective treatment approach for Metabolic Associated Steatohepatitis Liver Disease (MASLD) in pediatric patients with diabetes mellitus is a combination of personalized lifestyle interventions for weight reduction with potential adjunctive pharmacotherapy targeting both liver disease and glycemic control. 1

Current Understanding of Pediatric MASLD with Diabetes

• MASLD is now the most prevalent chronic liver disease in children in industrialized countries, primarily due to increasing rates of obesity and overweight 2
• Pediatric patients with both MASLD and diabetes mellitus face increased risk of progressive liver damage and extra-hepatic morbidity, particularly cardiovascular disease 2, 3
• The pathophysiology involves shared mechanisms between MASLD and cardiometabolic diseases: unhealthy dietary habits, dysfunctional adipose tissue, insulin resistance, and subclinical inflammation 3

First-Line Treatment: Lifestyle Interventions

• Personalized lifestyle and dietary approaches for weight reduction remain the cornerstone of treatment for pediatric MASLD with diabetes 1
• Research is needed to identify individuals most likely to benefit from non-pharmacological interventions alone and to maintain healthy behaviors long-term 1
• Weight loss has been shown to be the most effective non-pharmacological approach for improving liver health in MASLD 3

Pharmacological Management Options

Diabetes Medications with Potential MASLD Benefits

• Metformin has been studied in pediatric patients with type 2 diabetes (mean FPG 182.2 mg/dL) and showed significant improvement in glycemic control compared to placebo 4
• However, metformin has failed to demonstrate beneficial effects specifically on MASLD progression despite its glucose-lowering properties 5
• Research is needed to determine weight loss-independent mechanisms of MASLD improvement for incretin-based, weight loss-based or glucose-lowering treatments 1
• Newer glucose-lowering agents such as GLP-1 receptor agonists and SGLT-2 inhibitors are currently being investigated for efficacy across the spectrum of MASLD 5

MASLD-Specific Treatments

• Topiramate has shown promise as an adjunct to lifestyle intervention in pediatric MASLD, with one study showing ALT improvement (76 vs 50 U/L, p = 0.001) and 43% of patients achieving either ALT normalization or reduction by >50% from baseline 6
• Resmetirom, a thyroid hormone receptor-beta agonist recently approved for adults with MASH, has shown positive effects on cardiovascular risk factors, but pediatric data is lacking 5
• Research is needed to identify early predictors of non-response to pharmacological intervention and to define clear stopping rules for MASH-targeted pharmacotherapy in non-responders 1

Monitoring and Assessment

• Non-invasive tests (NITs) should be optimized for pediatric patients with MASLD and diabetes mellitus 1
• Research is needed to determine if changes in NITs mirror histological changes and if NITs can be used as surrogates of treatment response 1
• Regular monitoring of liver function, glycemic control, and cardiovascular risk factors is essential 2, 5

Research Priorities for Pediatric MASLD with Diabetes

• Developing effective pharmacological treatments for pediatric MASLD, particularly in the context of diabetes mellitus 1
• Evaluating the impact of controlling diabetes on the hepatic disease course in MASLD 1
• Determining whether improvement in steatotic liver injury will have a beneficial effect on metabolic dysfunction and control of diabetes 1
• Prospectively assessing potential additive or synergistic effects of combining drugs intended to treat both MASLD and diabetes 1

Clinical Approach Algorithm

1. Diagnosis and Risk Assessment:

   • Confirm MASLD diagnosis using new diagnostic criteria that allow for positive diagnosis rather than diagnosis of exclusion 2
   • Assess severity of both MASLD and diabetes 2, 3

2. Initial Management:

   • Implement personalized lifestyle modifications focused on weight reduction 1
   • Optimize diabetes management with appropriate glucose-lowering medications 4, 5

3. For Patients with Inadequate Response to Initial Management:

   • Consider adjunctive therapy with topiramate if lifestyle modification fails and patient cannot tolerate or qualify for other obesity pharmacotherapy 6
   • Evaluate for potential combination therapy targeting both MASLD and diabetes 1, 5

4. Monitoring and Follow-up:

   • Regular assessment of liver function tests, glycemic control, and anthropometrics 6, 2
   • Adjust treatment based on response and emerging evidence 1

Important Caveats

• Substantial heterogeneity exists in the contributors to MASLD pathophysiology, which may influence disease progression and treatment response 3
• Some effective pharmacological approaches to improve liver health in MASLD may be associated with no change in body weight or even weight gain 3
• Long-duration, large, high-quality randomized controlled trials are needed to assess the efficacy of cardiometabolic drugs in reversing MASLD progression in pediatric patients with diabetes 5