Practical Pearls: Dyslipidemia Management in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)

Key points

• MASLD is a risk factor for atherosclerotic cardiovascular disease and is associated with cardiometabolic risk factors, such as obesity (adiposopathy), hypertension, insulin resistance, diabetes and dyslipidemia.
• The cornerstone of MASLD management is aggressive treatment of risk factors, lifestyle interventions, and reducing excess adiposity.
• Dyslipidemia occurs in approximately 60-70% of individuals with MASLD.
• Comprehensive lipid management in this population includes identification of the type of dyslipidemia, risk stratification, initiation of lipid-lowering therapy, lifestyle interventions, and serial monitoring for response.
• Statins are first-line therapy for dyslipidemia management (for elevated LDL-C) in MASLD. Mild to moderately elevated transaminases should not preclude statin initiation.
• Ezetimibe, PCSK9 targeted therapy, icosapent ethyl, fibrates, and omega-3 fatty acids are common second-line agents that can be co-administered to achieve therapeutic objectives.
• Side effects of lipid-lowering medications in this population are similar to the general population. Except for decompensated cirrhosis, patients with all other stages of MASLD, including transplant, should be optimally treated.
• There are no approved therapeutic agents for MASLD (Phase II and III clinical trials are in process).

Nonalcoholic fatty liver disease (NAFLD) is the accumulation of hepatic fat in ≥ 5% of hepatocytes in the absence of other etiologies of liver disease. NAFLD can be reversed with lifestyle interventions and risk factor modifications; however, if left unaddressed, it may progress into steatohepatitis, cirrhosis, and resultant liver failure.¹ NAFLD is a risk factor for atherosclerotic cardiovascular disease (ASCVD) and is strongly associated with obesity, diabetes, hyperlipidemia, and hypertension. The multifactorial etiology and impact of fatty liver deposition has prompted a change in nomenclature from NAFLD to metabolic dysfunction-associated steatotic liver disease (MASLD) to better portray the overwhelming influences of metabolic dysfunction in this disorder.² MASLD is the leading cause of chronic liver disease and the most common indication for liver transplants among women in the United States.³ Individuals with MASLD are known to have higher levels of inflammation, higher risk of cardiovascular disease, worse clinical outcomes, and reduced life expectancy by 2.6 years on average. Currently, there are no approved therapeutic agents for MASLD specifically. The cornerstone of management is treatment of all associated metabolic risk factors.¹ 

Dyslipidemia in MASLD is characterized by elevated low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG) concentrations, as well as decreased high-density lipoprotein cholesterol (HDL-C) concentrations. This lipid profile is prevalent in nearly 60-70% of individuals with MASLD.¹ The results of studies have demonstrated a high concentration of small, dense LDL particles, associated with the atherogenic dyslipidemia manifested in the dysfunctional metabolic states of insulin resistance and diabetes.⁶ This profile precipitates a vicious cycle whereby dyslipidemia becomes a risk factor for the development of MASLD. When MASLD manifests clinically, the pathophysiological changes in the hepatocytes further worsen serum concentrations of atherogenic lipoproteins.

Insulin resistance, inflammation, and excess adiposity are the hallmarks of MASLD. Accumulation of lipid remnants within hepatic tissue leads to the inhibition of insulin signaling pathways and subsequent insulin resistance. This key step results in a cascade of inflammatory processes mediated by the release of cytokines (either locally or systemically). These cytokines (tumor necrosis factor-alpha, interleukin-6, interleukin-10, adiponectin) then aggravate a chronic inflammatory state in adipose tissue, liver, and multiple organ systems. There is a direct association between atherogenic lipoprotein lipid levels in the serum and the severity of MASLD. The overarching goal of therapy beyond reducing hepatic fat is to reverse inflammation and increase insulin sensitivity in patients with MASLD.^7,8

Pharmacologic Agents

Statins are the first-line pharmacotherapy for elevated non-HDL-C, apolipoprotein B, or LDL particle concentration, because LDL-C is not elevated in pure MASLD. In addition to exerting lipid-lowering effects through inhibition of hydroxymethylglutaryl-CoA (HMG-CoA) reductase, statins exhibit additional benefits in the setting of MASLD through reduction of free fatty acid delivery to the liver⁹, increasing levels of plasma adiponectin, and demonstrating antiproliferative effects.¹⁰ In a study evaluating the effect of 10 mg atorvastatin over 6 months in 27 patients with hyperlipidemia, total serum cholesterol, alanine transaminase (ALT) and gamma-glutamyl transpeptidase (GGT) levels significantly reduced, while liver density assessed by CT imaging increased, suggesting less fat burden.¹¹ Several other studies have also shown a favorable safety profile for the use of statins in MASLD.^12-14 Moderately elevated transaminases should not preclude initiation of statins in MASLD. On the contrary, it appears statins exhibit an even greater cardiovascular disease risk reduction in individuals with mild to moderately elevated transaminases in MASLD compared to those with normal levels. However, it is advised to obtain a baseline liver function assessment prior to initiation of therapy. As in other populations, statins reduce incidence of cardiovascular disease in patients with MASLD.¹⁵
 
Other pharmacologic options for dyslipidemia management in patients with MASLD include ezetimibe, proprotein convertase subtilisin/kexin type 9 (PCSK9) targeted therapy, icosapent ethyl, and fibrates. There is a large but nevertheless inconsistent body of evidence supporting the use of omega-3 fatty acids in MASLD.¹⁶ Fenofibrates are indicated in cases of severe hypertriglyceridemia (fasting TG level ≥ 500 mg/dL). It is important to note that the non-statin medications are to be used as adjuncts when treatment goals are not achieved with statins, or in cases of statin intolerance.⁶ Newer lipid-lowering therapeutic agents, such as bempedoic acid, are used in the ASCVD at-risk population as secondary lipid-lowering therapies.⁶ There is a lack of evidence regarding the impact of bempedoic acid on disease progression in MASLD; however, for the purposes of treating dyslipidemia in this clinical setting, its use serves as a cardiovascular disease risk modifier.¹⁷ 

The glucagon‐like peptide‐1 receptor agonists (GLP-1 RAs) and gastric inhibitory polypeptides (GIPs) are game changers in the field of cardiometabolic health. Initially indicated for treatment of type 2 diabetes, more recent evidence suggests that, among people with and without diabetes, GLP-1 RAs and GIPs induce significant weight loss, as well as improve cardiovascular outcomes.¹⁸ In people with diabetes, they improve blood glucose control and promote weight loss, which plays an important role in suppression of chronic inflammation and decreasing adipose content of hepatic parenchyma.¹⁹

Nutrition and Lifestyle Interventions

The role of nutrition interventions for dyslipidemia management among patients with MASLD cannot be overemphasized. The Dietary Approaches to Stop Hypertension (DASH) and Mediterranean dietary patterns are widely known and constitute guideline-supported nutritional recommendations for individuals with MASLD.²⁰ Reducing excess adiposity is known to regress MASLD even in advanced stages, or at least slow disease progression. Although there are significant individual variations, weight loss ranging from 5-10% has been correlated with histopathological improvement in early disease and reverse scarring in later stages of disease.²¹ Guidelines also propose moderate- to high-intensity exercise of 150-300 min/week. Other interventions, such as smoking cessation, adequate quantity and quality of sleep, and alcohol abstinence, are encouraged.²² 

Dyslipidemia management in the setting of other hepatic diseases, such as alcoholic liver disease, cirrhosis, end stage liver disease, and liver transplant recipients, are equally important. Chronic inflammation is also present in these other hepatic disease states, conferring an elevated risk of ASCVD, and thus reinforcing the importance of optimization of lipoprotein lipid levels to mitigate this concern.

Summary

MASLD is a disease state related to metabolic dysfunction. Thus, a holistic, multidisciplinary approach focused on prevention and management is essential. MASLD should be recognized as a masked state of chronic inflammation and thus be treated aggressively.

In conclusion, available evidence encourages management of concomitant cardiovascular risk factors, such as dyslipidemia, among patients with MASLD. Considerations in dyslipidemia management for patients with MASLD include identification of the type of dyslipidemia, institution of lifestyle interventions and pharmacotherapy, monitoring of response to therapy, and intensification of treatment as needed. 

Dr. Alebna has no financial relationships to disclose. Dr. Khokhlov has no financial relationships to disclose. Dr. Mehta has received research support from Novartis.
 

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