a case study on lipid metabolism

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Case Study: Pharmacotherapy for Dyslipidemia and Metabolic Dysfunction-Associated Steatotic Fatty Liver Disease

Clinical Case

The patient is a 67-year-old white gentleman with type 2 diabetes mellitus (T2DM), hypertension (HTN), 20-pack-year smoking history, and dyslipidemia. He presented to the Lipidology Clinic for a follow-up of his diabetes and atherogenic dyslipidemia. He has never experienced any atherosclerotic cardiovascular disease (ASCVD) events. Due to his moderate risk profile, the decision was made to perform an advanced “carotid-femoral plaque scan” 1-6 , which showed significant bilateral femoral plaques to be present.

His current medications include:

dapagliflozin 10 mg daily,
rosuvastatin 20 mg daily,
metformin 750 mg ER twice daily,
ezetimibe 10 mg daily,
ASA 81 mg daily,
losartan 100 mg daily, and
icosapent ethyl 2 g twice daily.

His vital signs include a blood pressure of 120/78 mmHg and a heart rate of 76 beats per minute. His weight is 175 pounds, height is 70 inches, and body mass index (BMI) is 26.5 kg/m 2 .

Lipid profile findings show:

A total cholesterol level of 99 mg/dL,
Low-density lipoprotein cholesterol LDL-C level of 35 mg/dL,
Triglyceride level of 110 mg/dL,
High-density lipoprotein cholesterol (HDL-C) level of 44 mg/dL,
ApoB level of 51 mg/dL.

The patient's glycated hemoglobin (HbA1c) was 5.8%. A Fibroscan revealed stage F1 (no scarring) and stage S3 (severe steatosis, with more than 67% of the liver being fatty).

Liver enzyme tests demonstrated aspartate aminotransferase (AST) and alanine aminotransferase (ALT) within the normal range.

Further laboratory testing revealed a FIB4 score of 1.67, indicating indeterminate risk for serious liver disease (the fibrosis 4 (FIB4) index is a liver fibrosis biomarker that is a potential alternative to liver biopsy for diagnosing and managing liver disease).

Diagnostic Assessment

The decision to perform an advanced carotid-femoral plaque scan was made due to his moderate to high risk of an ASCVD event. Most moderate to high-risk primary prevention patients seen in the Lipid Clinic are assessed for subclinical atherosclerotic disease using advanced carotid ultrasound testing. This test is consistent with coronary artery calcium (CAC) scoring but offers patients the option of simple and cost-effective testing that identifies plaque at an earlier “pre-calcified” plaque stage.

It has been established that there is a gradient of ASCVD risk in T2DM patients. The presence and amount of non-hemodynamically significant plaque in the cervical carotid arteries and the femoral arteries has been shown in multiple studies 7-10 to significantly improve the accuracy of ASCVD risk prediction compared to traditional risk factor assessment. These various studies have used different parameters to quantify plaque, so there is yet no consensus on the best method for measuring plaque quantity. Therefore, several metrics are included in this report, from which an overall relative risk assessment is provided. The revised definition of “significant plaque” is >1.2 mm AND >50% increase in intimal media thickness (IMT) compared to surrounding IMT. Increased risk derived from increased presence and amount of significant plaque increases the pre-test probability for developing cardiovascular disease beyond the risk identified by traditional risk factors and usually warrants risk factor modification intensification, for example, treatment of low-density-lipoprotein cholesterol (LDL-C) and apolipoprotein B (apoB) to lower targets, such as recognized secondary prevention targets.

Diagnosis, Treatment, and Follow-up

Although liver biopsy remains the “gold standard” for diagnosing and staging metabolic dysfunction-associated steatotic fatty liver disease (MASLD), non-invasive testing, such as the FIB4 score, has a very high negative predictive value and can serve as a screening tool in patterns at high risk for MASLD including insulin-resistant patients, T2DM patients, obese patients, patients with more than two cardiometabolic risk factors, patients with steatosis on imaging studies, and those with persistently elevated ALT or AST.11 See figuresbelow for information on FIB4 test and screening with FIB4 and Fibroscan testing. The American Diabetes Association (ADA) now advises universal screening of people with T2DM and prediabetes for fatty liver disease. It provides new recommendations for management in those with the condition or who are at risk. 12

Many patients with non-elevated AST and ALT, in fact, do have MASLD identified by the FIB4 test. Abnormal FIB4 scores should be further evaluated by elastography (Fibroscan). 3 The ultimate goals for these patients are to reduce their ASCVD risk and prevent further progression of MASLD. Therefore, treatment options include achieving at least a 5% weight loss, ethanol abstinence, implementing an exercise regimen (at least 150 minutes of moderate-intensity cardio and two sessions of resistance training lasting over 30 minutes) every week, considering a switch to a GLP-1 receptor agonist due to extensive evidence supporting its efficacy in reversing steatosis, addressing the need to quit smoking, and continuing statin therapy as it has shown benefits in reversing steatosis. Additionally, a follow-up Fibroscan should be obtained in two years to assess liver disease progression.

Managing Dyslipidemia: Role in MASLD

HMG-CoA reductase inhibitors, otherwise known as statins, primarily used for LDL-C lowering therapy, have shown potential benefits in managing MASLD, which encompasses a spectrum of liver conditions ranging from simple steatosis (accumulation of fat in the liver) to non-alcoholic steatohepatitis (NASH), which includes liver inflammation and fibrosis. 4

Ezetimibe can also play a potential role in MASLD patients by reducing intestinal cholesterol absorption (reducing hepatic steatosis) and conferring anti-inflammatory effects in hepatocytes. 5 A recent meta-analysis of 5 lipid-lowering studies that included 199 patients with MASLD showed a decrease in FIB4 scores and improvement in transaminase levels but not hepatic steatosis. 6

Icosapent ethyl (IPE) has been shown in the REDUCE-IT trial to dramatically reduce ASCVD events in diabetic patients with triglycerides >150 mg/dL on maximum tolerated statin therapy, as this patient originally had. 13 The effect of IPE on MASLD progression is unknown, but because CVD event reduction is one of our top priorities in MASLD patients, IPE is often an important part of a risk reduction strategy in patients like this.

The most common liver disease in the United States to date is MASLD affecting up to 70% of patients with diabetes .7 Metabolic syndrome and MASLD share hallmark characteristics of dyslipidemia, arterial hypertension, T2DM, and visceral obesity. The pathogenesis of these processes is closely linked to insulin resistance. Insulin resistance in MASLD and T2DM determines a decrease in muscle glucose uptake, an increase in hepatic gluconeogenesis and hepatic lipogenesis, and a decrease in adipose tissue lipolysis, which increases both circulating free fatty acid (FFA) and glucose levels. High levels of FFAs lead to worsening insulin resistance by inhibiting post-receptor insulin signaling. 1

Glucagon-like peptide-1 (GLP-1) receptor agonists delay gastric emptying, reduce appetite, decrease glucagon secretion, and increase hyperglycemia-induced insulin secretion. 8 In addition to glycemic control, GLP-1 receptor agonists have been shown to reduce the rates of myocardial infarction, ischemic stroke, and related mortality. 9 Furthermore, GLP-1 receptor agonists significantly impact body weight, hepatic biomarkers, and hepatic fibrosis. 7 Although the only proven treatment effective in MASLD is a 7-10% weight loss, liraglutide and semaglutide both (GLP-1 receptor agonists) have been approved for the treatment of obesity in both diabetic and non-diabetic patients.

Currently, two available human monoclonal antibodies (mAbs) inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9). While efficacious in reducing LDL-C levels 10 , PCSK9 inhibitors may also play a role in preventing the progression of MASLD. In a retrospective chart review-based study, NAFLD patients on PCSK9 inhibitors had a complete resolution of NAFLD radiologic features in 8 of 11 patients with hepatic steatosis. 14

Improvement in Liver Enzymes and Steatosis

Several studies have demonstrated that statin therapy can improve liver enzyme levels, particularly ALT and AST, markers of liver damage. A randomized controlled trial (RCT) meta-analysis by Ciardullo et al. demonstrated that statins significantly reduced ALT and AST levels in MASLD patients. 15 Moreover, statins have decreased hepatic steatosis, as assessed by imaging techniques such as ultrasound or magnetic resonance imaging (MRI). 16

Anti-inflammatory and Antifibrotic Effects

MASLD is associated with chronic low-grade inflammation and liver fibrosis. Statins possess anti-inflammatory properties and can inhibit the activation of pro-inflammatory pathways. Statins also have antifibrotic effects by interfering with the production of fibrogenic mediators. Animal studies and in vitro experiments have demonstrated the potential of statins in reducing liver inflammation and fibrosis. 17,18

Reduction of Cardiovascular Risk

MASLD is frequently linked to an increased cardiovascular disease (CVD) risk, given its association with metabolic syndrome and atherosclerosis. The role of statins is well-established in reducing cardiovascular risk by lowering LDL-C levels. As MASLD patients frequently have dyslipidemia, statin therapy can provide dual benefits by addressing the disease's hepatic and cardiovascular aspects. 16

Prevention of MASLD Progression

Although the available evidence is limited, some studies suggest that statin use may slow the progression of MASLD. A retrospective study showed that MASLD patients on statin therapy had a lower risk of developing advanced liver fibrosis than those not receiving statins. 19 However, further research is needed to establish the long-term effects of statins on MASLD progression.

It is important to note that the use of statins in MASLD patients should be individualized, considering factors such as liver function, medication interactions, and potential side effects. The decision to initiate statin therapy should consider the patient's overall cardiovascular risk profile and liver health.

Atherogenic dyslipidemia, highly prevalent in MASLD, is characterized by a combination of high triglyceride-rich lipoproteins and low HDL concentrations. Dyslipidemia and insulin resistance play important pathogenic roles in MASLD development and progression. Insulin resistance and the associated dyslipidemia play critical roles in MASLD pathogenesis through multiple mechanisms. These mechanisms include impaired triglyceride storage in adipose tissue with subsequent hepatic fat accumulation, de novo lipogenesis, and activating pro-fibrotic and pro-inflammatory pathways. 3

This case report highlights the complex management of a 67-year-old gentleman with multiple cardiovascular risk factors, evidence of subclinical disease, and lifestyle challenges. The report underscores the importance of addressing weight loss, implementing an exercise regimen, insulin-sensitizing, reducing ASCVD risk, considering medication adjustments, smoking cessation, and regular follow-up to manage the patient's condition effectively.

Dr. Baecher has no financial relationships to disclose. Dr. Block has no financial relationships to disclose. Dr. Pokrywka has no financial relationships to disclose.

References

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Lonardo A, Arab JP, Arrese M. Perspectives on Precision Medicine Approaches to NAFLD Diagnosis and Management. Adv Ther. 2021;38(5):2130-2158. doi:10.1007/s12325-021-01690-1
Gheorghe G, Bungău S, Ceobanu G, et al. The non-invasive assessment of hepatic fibrosis. J Formos Med Assoc. 2021;120(2):794-803. doi:10.1016/j.jfma.2020.08.019
Tsai SF, Yang CT, Liu WJ, Lee CL. Development and validation of an insulin resistance model for a population without diabetes mellitus and its clinical implication: a prospective cohort study. eClinicalMedicine. 2023;58. doi:10.1016/j.eclinm.2023.101934
Sfikas G, Psallas M, Koumaras C, et al. Prevalence, Diagnosis, and Treatment with 3 Different Statins of Non-alcoholic Fatty Liver Disease/Non-alcoholic Steatohepatitis in Military Personnel. Do Genetics Play a Role? Curr Vasc Pharmacol. 2021;19(5):572-581. doi:10.2174/1570161118666201015152921
Tzanaki I, Agouridis AP, Kostapanos MS. Is there a role of lipid-lowering therapies in the management of fatty liver disease? World J Hepatol. 2022;14(1):119-139. doi:10.4254/wjh.v14.i1.119
Sillesen H, Sartori S, Sandholt B, Baber U, Mehran R, Fuster V. Carotid plaque thickness and carotid plaque burden predict future cardiovascular events in asymptomatic adult Americans. Eur Heart J Cardiovasc Imaging. 2018;19(9):1042-1050. doi:10.1093/ehjci/jex239
Gepner AD, Young R, Delaney JA, et al. Comparison of Carotid Plaque Score and Coronary Artery Calcium Score for Predicting Cardiovascular Disease Events: The Multi-Ethnic Study of Atherosclerosis. J Am Heart Assoc. 6(2):e005179. doi:10.1161/JAHA.116.005179
Nicolaides AN, Panayiotou AG, Griffin M, et al. Arterial Ultrasound Testing to Predict Atherosclerotic Cardiovascular Events. J Am Coll Cardiol. 2022;79(20):1969-1982. doi:10.1016/j.jacc.2022.03.352
Ibanez B, García-Lunar I, Fuster V. The Intima-Media Thickness Age Is Over: The Time of Multiterritorial Subclinical Plaque Quantification Has Come. J Am Coll Cardiol. 2022;79(20):1983-1985. doi:10.1016/j.jacc.2022.03.361
American Association of Clinical Endocrinology Clinical Practice Guideline for the Diagnosis and Management of Nonalcoholic Fatty Liver Disease in Primary Care and Endocrinology Clinical Settings: Co-Sponsored by the American Association for the Study of Liver Diseases (AASLD) - ScienceDirect. Accessed September 28, 2023. https://www.sciencedirect.com/science/article/pii/S1530891X22000908
Improving Care and Promoting Health in Populations: Standards of Care in Diabetes—2023 | Diabetes Care | American Diabetes Association. Accessed September 28, 2023. https://diabetesjournals.org/care/article/46/Supplement_1/S10/148045/1-Improving-Care-and-Promoting-Health-in
Bhatt DL, Steg PG, Miller M, et al. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. N Engl J Med. 2019;380(1):11-22. doi:10.1056/NEJMoa1812792
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Article By:

University of Rochester Department of Public Health Sciences Rochester, NY

University of Rochester Department of Public Health Sciences, Cardiology Division Department of Medicine Center for Community Health and Prevention Rochester, NY

Director Baltimore Lipid Center Assistant Professor of Medicine Johns Hopkins University School of Medicine Baltimore, MD