PMC9883702_01
The effect of long-term microsomal triglyceride transfer protein inhibitor and angiopoietin-like protein 3 inhibitor combination therapy on xanthelasma. Shown are the patient's xanthelasma at baseline (statins + ezetimibe), 6 years post-lomitapide treatment (2015) and 5 years post evinacumab (2020).
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She was diagnosed with HoFH during childhood, presenting severe phenotype features (e.g. angina, coronary heart disease, stenosis of the carotid arteries) (see Timeline) associated with extremely elevated plasmatic levels of LDL-C, such as apparent arcus senilis, obvious xanthelasma in both eyes, and significant tuberous/tendinous xanthomas (no concurrent medical conditions are reported; Figure 1). ANGPTL3 inhibitors also showed a clear regression of tendinous xanthomas and xanthelasma in both eyes, as a consequence of diminished levels of cholesterol (Figure 1). Another important finding showing evidence of lipid mobilization is the evaluation of plaque deposition in carotid arteries.
Long-term lipid-lowering efficacy of the combination therapy (microsomal triglyceride transfer protein and angiopoietin-like protein 3 inhibitors) as an add-on treatment in homozygous familial hypercholesterolaemia. (A) Shown are the mean low-density lipoprotein cholesterol levels since the patient's first visit at the clinic (treatment naive; 1982) until 2020 (on quadruple therapy: statin + ezetimibe + microsomal triglyceride transfer protein inhibitor + angiopoietin-like protein 3 inhibitor). An illustration of the low-density lipoprotein-receptor expression and binding percentage of the patient's familial hypercholesterolaemia-causing mutation (Trp87Gly) using wild-type low-density lipoprotein receptor as a positive control and comparing % before and after the evinacumab treatment is also presented (top inset). The green zone shows the initiation of lipid-lowering therapies based on low-density lipoprotein-receptor-independent pathways. (B-D) According to each selected year, the mean levels of low-density lipoprotein cholesterol (B), non-high-density lipoprotein cholesterol (C), and high-density lipoprotein cholesterol (D) are shown across lomitapide and evinacumab treatments. A lifespan presentation of non-high-density lipoprotein cholesterol and high-density lipoprotein cholesterol is also shown across different lipid-lowering agents, including resins, statins, and ezetimibe (top insets). *When compared with wild-type low-density lipoprotein receptor with statin + ezetemibe + microsomal triglyceride transfer protein inhibitor treatments. #When compared with wild-type low-density lipoprotein receptor with statin + ezetimibe + microsomal triglyceride transfer protein inhibitor + angiopoietin-like protein 3 inhibitor treatments. Statistical significance is defined with a P-value <0.05. **Statin and ezetimibe were temporarily stopped during pregnancy.  Low-density lipoprotein cholesterol level from 2009 as a pre-treatment baseline.
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The patient underwent conventional LLTs (i.e. statins and ezetimibe) for many years [statins (atorvastatin up to 80 mg daily/rosuvastatin up to 40 mg daily) for 13 years; ezetimibe (up to 10 mg daily) for 9 years)]; however, LDL-C concentrations never reached the recommended target levels with a mean of LDL-C at 755 mg/dL (19.53 mmol/L; during pregnancy at age 32; Figure 2). Lomitapide reduced LDL-C levels by 68.3% [from 658 to 205 mg/dL; i.e. 16.76-5.31 mmol/L; Figure 2AandB] and non-high-density lipoprotein cholesterol (non-HDL-C) levels by 67.4% [from 670 to 218 mg/dL; i.e. 17.33-5.65 mmol/L; Figure 2C] but did not show significant changes in HDL-C levels (Figure 2D) when compared with baseline.
The effect of long-term treatment of microsomal triglyceride transfer protein inhibitor and angiopoietin-like protein 3 inhibitor combination therapy on atheromatous plaque regression. (A) Table presenting plaque areas at the right and left carotid segments. Four segments (Right carotid: CCA1 near, bulb near, bulb far; Left carotid: bulb far) were selected for quantifying plaque regression across time. Missing measurements were shown as empty cases, due to low quality of selected images. (B) Illustration of four selected carotid regions from which serially imaged plaques were measured across time. (C) Shown are total plaque areas (mm2) of four selected segments (left y-axis, top insets) as well as per carotid segment (right y-axes, bottom insets), showing frank regression (35.6%) of plaque when comparing 2020 to 2011. (D) Representative images showing the regression of the atheromatous plaque at the left bulb segment from the far wall of the carotid. These carotid ultrasound images were captured at the age of 43 [in 2011 (2 years post-lomitapide)], 45 [in 2013 (4 years post-lomitapide)], and 52 [(in 2020 (5 years post-evinacumab)].
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The comparison of carotid plaques between 2-year (2011), 4-year (2013) post-lomitapide and combination therapy (lomitapide + evinacumab) (2020) showed a net regression of 35.6% on the basis of 4 serially images segments, and cessation of progression in other lesions, as presented in Figure 3.
Long-term safety evaluation of the combination therapy (microsomal triglyceride transfer protein and angiopoietin-like protein 3 inhibitors) as an add-on treatment in homozygous familial hypercholesterolaemia. According to each selected year, the mean levels of aspartate transaminase (A) and alanine transaminase (B) are shown across different treatment regimen, including statins, ezetimibe, microsomal triglyceride transfer protein inhibitor and angiopoietin-like protein 3 inhibitor. (C) Shown are results of liver steatosis and fibrosis obtained by a specialized ultrasound-based machine (fibroscan). A lifespan presentation of both aspartate transaminase and alanine transaminase levels is also shown across different lipid-lowering agents, including resins, statins, and ezetimibe (top insets).
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Whenever transaminase levels reached >1.5x ULN, dose adjustment led to a prompt decrease of the hepatic enzymes levels (Figure 4). The evaluation demonstrated moderate grade of steatosis (Figure 4C) without presence of fibrosis, therefore, supporting the evidence that this quadruple therapy would probably not induce serious liver side effects over long-term treatment for this patient.