New insights into the management of homozygous familial hypercholesterolemia patients treated with lomitapide: a single-center experience

Abstract

Familial hypercholesterolemia (FH) is a genetic disease, usually with onset during childhood, characterized by elevated blood LDL cholesterol levels and potentially associated with severe cardiovascular complications. Concerning mutated genes in FH, such as LDLR, a small subset of FH patients presents a homozygous genotype, resulting in homozygous FH (HoFH) disease with a generally aggressive phenotype. Besides statins, ezetimibe and PCSK9 inhibitors, lomitapide (an anti-ApoB therapy) was also approved in 2012-2013 as an adjunctive treatment for HoFH. Despite its clinical efficacy, lomitapide administration should be done with caution because of the possible occurrence of side effects, such as hepatosteatosis, increased blood transaminase levels and gastrointestinal symptoms, as well as the possible deleterious interactions with other drugs. In this context, we decided to report the main available evidence on the management and monitoring of HoFH patients treated with lomitapide and to accompany this literature review with a description of our clinical experience with a subset of six HoFH patients. In conclusion, this paper aims to address an important topic for HoFH-related clinical practice that, to our knowledge, is not yet formally regulated by proper national and/or international guidelines.

Keywords: HoFH; hypercholesterolemia; lomitapide; management; monitoring.

Figure 1

Trend of serious adverse events in HoFH patients treated with lomitapide. The follow-up period is 5 years, n=185. This graph was generated with GraphPadPrism software using from the data of the LOWER study (9).

Figure 2

Temporal trends of cholesterol, hepatic enzymes and triglycerides in patient 1. The follow-up period was 6 years. Total and LDL cholesterol decreased overall during the period, but both increased when evinacumab was discontinued. The y-axis represents the blood levels of the various biochemical parameters examined. TC, LDL cholesterol, TGs and HDL cholesterol are measured in mg/dL, whereas ALT, AST and CPK are measured in U/L. TC, total cholesterol; LDL, low-density lipoprotein; HDL, high-density lipoprotein; TG, triglycerides; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CPK, creatinine phosphokinase.

Figure 3

Temporal trends of cholesterol, hepatic enzymes and triglycerides in patient 2. The follow-up period was 5 years. Lomitapide was not as effective when considering that total cholesterol increased after starting the therapy; this could be due to an increase in HDL cholesterol, but the trend of the latter during the same period of increase in total cholesterol (2017–2018) is missing. The y-axis represents the blood levels of the various biochemical parameters examined. TC, LDL cholesterol, TGs and HDL cholesterol are measured in mg/dL, whereas ALT, AST and CPK are measured in U/L. TC, total cholesterol; LDL, low-density lipoprotein; HDL, high-density lipoprotein; TG, triglycerides; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CPK, creatinine phosphokinase.

Figure 4

Temporal trends of cholesterol, hepatic enzymes and triglycerides in patient 3. The follow-up period was 5 years. Total and LDL cholesterol decreased with therapy relative to baseline values but fluctuated importantly over time, suggesting either incomplete therapy efficacy in this patient or an external contribution due to an inadequately balanced dietary regimen. In addition, a peak in CPK value was recorded at the end of the follow-up period. The y-axis represents the blood levels of the various biochemical parameters examined. TC, LDL cholesterol, TGs and HDL cholesterol are measured in mg/dL, whereas ALT, AST and CPK are measured in U/L. TC, total cholesterol; LDL, low-density lipoprotein; HDL, high-density lipoprotein; TG, triglycerides; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CPK, creatinine phosphokinase.

Figure 5

Temporal trends of cholesterol, hepatic enzyme, and triglycerides in patient 4. The follow-up period was 6 years. Compared with the other patients, the time point measurements of the various biochemical parameters were few for patient 4 despite the long follow-up period. A significant reduction in both total and LDL cholesterol occurred during therapy; only a slight increase in both parameters occurred by changing the PCSK9i used (alirocumab → evinacumab). The y-axis represents the blood levels of the various biochemical parameters examined. TC, LDL cholesterol, TGs and HDL cholesterol are measured in mg/dL, whereas ALT and AST are measured in U/L. TC, total cholesterol; LDL, low-density lipoprotein; HDL, high-density lipoprotein; TG, triglycerides; ALT, alanine aminotransferase; AST, aspartate aminotransferase.

Figure 6

Temporal trends of cholesterol, hepatic enzymes and triglycerides in patient 5. The follow-up period was 6 years. Overall, the combined therapies induced a reduction in total and LDL cholesterol, with levels of both parameters increasing only after stopping evinacumab. The y-axis represents the blood levels of the various biochemical parameters examined. TC, LDL cholesterol, TGs and HDL cholesterol are measured in mg/dL, whereas ALT, AST and CPK are measured in U/L. TC, total cholesterol; LDL, low-density lipoprotein; HDL, high-density lipoprotein; TG, triglycerides; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CPK, creatinine phosphokinase.

Figure 7

Temporal trends of cholesterol, hepatic enzymes and triglycerides in patient 6. The follow-up period was 12 years. In this patient, the standard LLT + novel pharmacological agents proved effective in reducing both total and LDL cholesterol levels. The y-axis represents the blood levels of the various biochemical parameters examined. TC, LDL cholesterol, TGs and HDL cholesterol are measured in mg/dL, whereas ALT, AST and CPK are measured in U/L. TC, total cholesterol; LDL, low-density lipoprotein; HDL, high-density lipoprotein; TG, triglycerides; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CPK, creatinine phosphokinase.