Lomitapide: Navigating Cardiovascular Challenges

# Lomitapide: navigating cardiovascular challenges with innovative therapies ## Abstract Dyslipidemia is the most significant risk factor for cardiovascular diseases (CVDs). Secondary dyslipidemia, its treatments, and association with atherosclerosis. Glob Health Med; Efficacy and safety of sarogl...

# Lomitapide: navigating cardiovascular challenges with innovative therapies ## Abstract Dyslipidemia is the most significant risk factor for cardiovascular diseases (CVDs). Secondary dyslipidemia, its treatments, and association with atherosclerosis. Glob Health Med; Efficacy and safety of saroglitazar for the management of dyslipidemia: A systematic review and meta-analysis of interventional studies. The current treatment strategies for managing dyslipidemia focus on reducing low-density lipoprotein cholesterol (LDL-C) to minimize the risks of atherosclerosis and myocardial infarction (MI). Homozygous Familial Hypercholesterolemia (HoFH) is an inherited autosomal dominant disease caused by a mutation in the LDL receptor (LDLr), which can lead to extremely high levels of LDL-C. The Beneficial Effect of Lomitapide on the Cardiovascular System in LDLr(-/-) Mice with Obesity; The microsomal triglyceride transfer protein inhibitor lomitapide improves vascular function in mice with obesity. Although statin therapy has been the primary treatment for dyslipidemia, HoFH patients do not respond well to statins, requiring alternative therapies. Microsomal triglyceride transfer protein (MTP) inhibition has emerged as a potential therapeutic target for treating HoFH. MTP is primarily responsible for transferring triglyceride and other lipids into apolipoprotein B (ApoB) during the assembly of very low-density lipoprotein (VLDL) particles in the liver. Lomitapide, an inhibitor of MTP, has been approved for treating of HoFH adults. Unlike statins, lomitapide does not act on the LDLr to reduce cholesterol. Instead, lomitapide lowers the levels of ApoB-containing proteins, primarily VLDL, eventually decreasing LDL-C levels. Studies have shown that lomitapide can reduce LDL-C levels by more than 50% in patients with HoFH who have failed to respond adequately to other treatments. Lowering LDL-C levels is important for preventing atherosclerosis, reducing cardiovascular risk, improving endothelial function, and promoting overall cardiovascular health, especially for patients with HoFH. Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study. This review paper focuses on research findings regarding the therapeutic benefits of lomitapide, highlighting its effectiveness in lowering cholesterol levels and reducing the risk of CVDs. The microsomal triglyceride transfer protein inhibitor lomitapide improves vascular function in mice with obesity. ## Keywords Lomitapide, Cardiovascular diseases (CVDs), Low-density lipoprotein cholesterol (LDL-C), Homozygous familial hypercholesterolemia (HoFH) ## Introduction Dyslipidemia is a metabolic disorder that affects the lipid profile in the body [1]. One of the critical components of dyslipidemia is an increased level of low-density lipoprotein cholesterol (LDL-C) [1, 6]. LDL-C plays an important role in the development of atherosclerosis, a condition characterized by arterial wall damage, inflammation, plaque formation, wall rupture, thrombosis, and vascular injury [1]. When LDL-C oxidizes, it becomes a reactive agent within the arterial walls, leading to platelet aggregation and a risk for thrombus growth. If not managed, the clot disrupts the blood supply to the heart or brain, leading to ischemia that may develop into a myocardial infarction or stroke, respectively [7]. Thus, managing dyslipidemia, particularly elevated LDL-C, is critical for preventing or slowing the progression of atherosclerosis [8]. Indeed, reducing cholesterol levels in the bloodstream by 10% can significantly decrease the risk of cardiovascular disease (CVD) mortality by 13% [7]. Statin therapy has been the primary treatment for lowering LDL-C in dyslipidemia [1]. Unfortunately, statins are inefficient in reducing LDL-C in patients with homozygous familial hypercholesterolemia (HoFH) [9]. LDL receptor (LDLr) is a transmembrane protein that plays a vital role in metabolic homeostasis. HoFH is an inherited, autosomal dominant disorder mainly caused by a mutation in the LDLr, which is necessary to remove LDL-C from the bloodstream by facilitating its uptake by cells, leading to extremely high LDL-C levels in plasma [9-11]. Reducing this extremely high LDL-C is complex, often requiring LDL apheresis, a procedure that filters the blood to remove the LDL-C, or liver transplantation [10, 12]. If left untreated, HoFH can lead to the rapid formation of atherosclerotic plaque, which increases the risk of cardiovascular complications [13-16]. Patients with HoFH do not survive beyond the age of 30 [16, 17]. Recently, a new drug, lomitapide, a microsomal triglyceride transfer protein (MTP) inhibitor, has been identified as a potential treatment for HoFH [17, 18]. MTP is primarily responsible for transferring triglyceride (TG) and other lipids onto apolipoprotein B (ApoB) during the assembly of very low-density lipoprotein (VLDL) particles in the liver [18]. Unlike other treatments, lomitapide directly binds to MTP and prevents the assembly of ApoB-containing lipoproteins, thus reducing the release of VLDL into the systemic circulation and eventually decreasing LDL-C levels in the plasma [5, 19]. Therefore, lomitapide has an important role in preventing atherosclerosis, reducing cardiovascular risk, enhancing endothelial function, and improving the overall quality of life in patients with HoFH [5]. Moreover, several research studies have indicated that lomitapide exhibits anti-inflammation effect, further contributing to its potential therapeutic benefits. This innovative approach potentially provides a more effective treatment for HoFH, which could benefit patients struggling with this condition [20]. However, the exact nature of its benefits and impacts on the cardiovascular system is not well established. In this review, we will discuss the potential effects of lomitapide on cardiovascular diseases. ## Low-density lipoprotein cholesterol and atherosclerosis Microsomal triglyceride transfer protein (MTP) regulates the assembly of chylomicrons in the intestine and very low-density lipoprotein (VLDL) in the liver [21]. VLDL carries triglycerides, cholesterol, apolipoprotein B100 (apoB100), and other lipids through the bloodstream. When VLDL circulates, lipoprotein lipase (LPL) breaks down TGs into free fatty acids and glycerol [22]. This partial removal of TGs converts VLDL into intermediate-density lipoprotein (IDL). IDL can then either be taken up by the liver or further metabolized into low-density lipoprotein cholesterol (LDL-C) particles [23]. LDL-C contains predominantly free triacylglycerols, cholesterol, phospholipids, cholesteryl esters, and apoB100. LDL-C plays a crucial role in delivering cholesterol that serves vital functions in maintaining cell structure and function to various tissues throughout the body. Under normal metabolic conditions, LDL-C is typically eliminated from circulation through LDL receptors (LDLr) found on hepatocytes' surfaces [24]. Nevertheless, excessive liver secretion of lipoproteins and ineffective plasma LDL-C clearance due to lack or mutation of the LDLr can lead to elevated LDL-C levels in circulation [25]. Multiple studies have revealed that elevated plasma LDL-C concentrations are linked to the onset and progression of atherosclerosis [24, 25]. This elevates the risk of atherosclerosis-related diseases such as cardiovascular disease. Multiple lines of evidence showed that when LDL-C is deposited in the walls of blood vessels, it can trigger a progressive proliferation of endothelial cells and macrophages, causing inflammation and damage to the vessels, ultimately compromising their functional lumen [26]. Over time, lipoprotein accumulations develop foam cells that can obstruct the arteries with plaques, restricting blood flow through the vessels and leading to atherosclerotic cardiovascular diseases (CVDs). The atherosclerotic process is complex, involving the accumulation of lipids and activating inflammatory responses [26]. For example, oxidized LDL-C (ox-LDL-C) is a significant trigger of the atherosclerotic process, leading to endothelial dysfunction, activation of macrophage, and formation of foam cells. This cascade of events promotes further inflammation, plaque formation, plaque rupture, thrombosis, and vascular injury [27]. Additionally, reactive oxygen species (ROS) produced by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase contribute to ox-LDL-C, leading to chronic inflammation, adipocyte proliferation, and other metabolic abnormalities, resulting in CVDs [28-30]. Moreover, plaques, the lipid-rich buildups on arterial walls, may lose stability and rupture due to persistent inflammation and enzymatic processes occurring within them. When an unstable plaque ruptures, it exposes the underlying materials to circulation, triggering thrombus formation and an acute inflammatory response. This can obstruct the arterial lumen, leading to severe health conditions such as heart attack or stroke [31]. Taken together, while LDL-C plays essential roles in lipid transport and cellular health, elevated levels of LDL-C, specifically when oxidized, create a pro-atherogenic environment conducive to CVD development (Fig. 1). ## Familial hypercholesterolemia Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder of lipid metabolism mainly caused by a mutation in the LDLr protein [3, 32]. This transmembrane protein regulates circulating cholesterol levels in the body [33]. Deficiencies in LDLr, particularly in the liver and peripheral tissues, will result in extremely high LDL-C levels in plasma, leading to hyperlipidemia. FH manifests in two forms: Heterozygous FH (HeFH) and homozygous FH (HoFH). Both forms significantly increase the risk of developing atherosclerosis and CVD. HeFH is the most prevalent form that affects approximately 1:250, predominantly among Caucasians. The 2019 European Atherosclerosis Society guideline recommended a target LDL-C<55 mg/dl for adult patients with a high risk of atherosclerotic CVD and to consider an even lower goal of <40 mg/dl [34]. Patients with HeFH typically exhibit LDL-C levels of 200 to 400 mg/dl and require treatment with a combination of lipid-lowering agents [35, 36]. HoFH is less common, with a prevalence of 1:300,000, yet it is more aggressive [36, 37]. Patients with HoFH have extremely high total cholesterol and LDL-C levels from birth, often exceeding 400-1000 mg/dl, surpassing four times the normal levels [38]. Individuals with an LDLr mutation face a compromised ability for hepatocytes to clear LDL-C effectively from the circulation system, resulting in a prolonged LDL-C half-life. Under normal circumstances, the half-life of LDL-C is usually 1.5 days. However, in cases of HeFH, the half-life of LDL-C increases to 3-4 days, while in cases of HoFH, it can exceed 6 days [38]. Lifelong exposure to LDL-C in FH patients puts them at high risk of premature CVD developing at a younger age, even during their teenage years, leading to damage of the endothelium [38]. This excessive accumulation of LDL-C in the blood can lead to various cardiovascular complications and can significantly reduce life expectancy if not managed effectively. Without medical intervention, most patients with HoFH do not survive beyond the age of 30 [16, 17]. The primary goal of FH therapy involves reducing LDL-C and preventing the development of coronary artery disease. Early identification and immediate follow-up by effective treatment are essential in managing FH, typically requiring lifestyle changes such as diet, exercise, and conventional lipid-lowering therapy [39]. Three major classes of LDL-lowering drugs include statins, bile acid sequestrants, and cholesterol absorption inhibitors. FH patients who have a lack of functional LDLr exhibit minimal to no response to this standard drug therapy. In a clinical study, high doses of statins only reduced LDL-C by 0-25%, bile acid sequestrants by 0-10%, and cholesterol absorption inhibitors (ezetimibe) by 0-10% in HoFH patients [37]. Treating patients with HoFH shows significant challenges and often requires advanced interventions such as LDL apheresis and liver transplantation [3]. LDL apheresis is a procedure designed to remove cholesterol from the blood that can transiently reduce LDL-C levels by more than 50% [40, 41]. Unfortunately, the effect is temporary, usually lasting a few weeks, and LDL-C can quickly build up again in the blood. It also necessitates frequent repetition and may induce some side effects, including hypotension, nausea, hypocalcemia, anemia, and allergic reactions. Although some individuals have reported that this LDL apheresis can reduce the risk of atherosclerotic CVD, it is also important to note that the procedure has certain downsides. First, the treatment can be expensive, with calculated annual costs in the US of $66,374 to $228,956 in 2015 per patient for weekly treatment [10], making it difficult for some individuals to access. Second, applying for this treatment can be challenging and require specialized personnel and equipment, which may not be readily available in certain countries or can lead to failure in reaching lipid targets [42] (Fig. 2). Liver transplantation can also be used for patients with high LDL-C levels [43]. However, the shortage of donors and the complexity of the procedure underscores the urgent need for novel medical interventions [12]. Recent studies have shown that using lomitapide to inhibit VLDL production in the liver could be a promising approach to lowering LDL-C levels in HoFH patients. The section below will discuss the medication lomitapide and its effect on the cardiovascular system in HoFH patients. ## Lomitapide Conventional therapies to lower plasmatic LDL-C concentration by increasing LDL-C clearance are insufficient for patients with HoFH. A new drug, lomitapide, has been approved for the treatment of hyperlipidemia in adults with HoFH [44]. Lomitapide is an oral inhibitor of MTP, mainly expressed in the lumen of the endoplasmic reticulum (ER) of hepatocytes and enterocytes [19]. Lomitapide has a unique mechanism of action that can effectively lower LDL-C levels by bypassing the conventional LDLr clearance pathway seen with statin and other traditional therapies. Lomitapide works by directly binding to MTP in the ER, blocking the transfer of lipids and inhibiting the assembly of VLDL and chylomicrons [10]. This process prevents the formation of ApoB-containing lipoproteins in both the intestine and the liver. As a result, the release of VLDL and chylomicrons into the system circulation is reduced, eventually leading to decreased LDL-C levels in the bloodstream. Many studies have demonstrated that lomitapide effectively reduces LDL-C and other lipid parameters, including total cholesterol, VLDL, TG, and ApoB [5]. A prospective clinical study involving 9 patients with HoFH showed that lomitapide reduced total cholesterol by 55.3%, LDL-C by 65.5%, and TG by 41.3%. There were no significant changes in high-density lipoprotein (HDL) [20]. Furthermore, a reduction in inflammatory markers (TNFα, IL-13, IL-7) was observed in those patients' plasma, suggesting lomitapide may have an anti-inflammatory effect [20]. In a retrospective study conducted in Italy, 15 adults with HoFH were enrolled [45]. These patients were treated with lomitapide for 8 to 86 months with a combination low-fat diet plan and LDL apheresis. LDL-C levels were reduced by 68.2% compared to baseline. At the last visit, 60% of patients reached LDL-C below 100 mg/dl, and 46.6% reached LDL-C below 70 mg/dl. During the study, none of the patients had to stop lomitapide due to side effects. A few patients experienced minor side effects, mainly gastrointestinal (GI) symptoms like diarrhea and nausea. After three years of follow-up, eight patients no longer required LDL apheresis after taking lomitapide [45]. Other studies discussed that lomitapide lowers plasma LDL-C levels, improves endothelial function. Microsomal triglyceride transfer protein (MTP); very-low-density lipoprotein (VLDL); triglycerides (TG); Fatty acids (FA); oxidized LDL-C (ox-LDL-C); Endoplasmic reticulum (ER); Reactive oxygen species (ROS); NFkB: Nuclear factor kappa B acts independently on the LDLr pathway, significantly reducing LDL-C levels in patients with different mutation types [46]. These studies have reported common minor side effects of lomitapide, including the risk of liver toxicity and GI adverse reactions. However, there have been no signs of increased risk of liver fibrosis or significant damage [36, 46]. The Lomitapide Observational Worldwide Evaluation Registry (LOWER) was established to evaluate lomitapide's long-term safety, tolerability, and effectiveness in adult patients with HoFH. It is a multicenter global exposure program and the largest dataset of patients with HoFH-treated lomitapide [47]. In a summary report from 2014 to 2019, 189 patients were enrolled in the study. The drug dose ranged from 5 mg to 40 mg per day. The study reported that a lower lomitapide dose can significantly reduce LDL-C while providing fewer adverse effects [47]. An interesting finding from a female patient with severe hypertriglyceridemia (> 2000 mg/dl) due to familial chylomicronemia was treated with lomitapide for 13 years [48]. Lomitapide reduced the average TG to 1000 mg/dl during the first six years of treatment, and her transaminase levels were normal. However, a liver biopsy conducted five years later revealed fatty liver and progressive fibrosis. Since there was no liver biopsy performed at the initiation of lomitapide treatment, it is unclear whether it directly contributed to liver fibrosis. Currently, lomitapide is being considered as a treatment for pancreatitis caused by severe hypertriglyceridemia [49]. A recent study suggests using lomitapide therapy for autosomal recessive hypercholesteremia [50]. Numerous studies have shown that lomitapide is a powerful LDL-C lowering agent. However, lomitapide is currently approved only for use in adults with HoFH and has not been authorized for other hyperlipoproteinemia disorders [3]. This requires further studies, as its safety and efficacy have also not been established in the pediatric population. Surprisingly, no direct studies assess the effect of lomitapide on cardiovascular disease in HoFH patients [3]. In our previous studies [3, 4], we investigated the impact of lomitapide on the cardiovascular system using a mouse model of HoFH (LDL receptor knock-out) and wild type (C57B6). Obesity in both models was induced by a high-fat diet (HFD). Our studies have shown that obesity triggers chronic elevation of LDL-C, which significantly contributes to endothelial dysfunction by increasing the level of oxidative stress (ROS) [51], inflammation [52, 53], endoplasmic reticulum (ER) stress [54], and inhibition of the endothelial nitric oxide (NO) signaling pathway [55, 56]. Endothelial cell dysfunction is a significant factor that contributes to plaque formation [27]. In our obese LDL receptor knock-out mice, endothelial dysfunction was associated with plaque buildup in the arteries [3]. Hence, lowering LDL-C levels is fundamental in both treating and preventing diseases. Our studies showed that treatment with lomitapide by oral gavage for 12 weeks decreased body weight and glucose levels and improved lipid profiles by reducing LDL-C and vascular endothelial function compared to the untreated HFD group [3]. Furthermore, the treatment reduced oxidative and ER stress and inflammation (Fig. 3.). Our reported results suggest that lomitapide is crucial in preventing complications associated with HoFH in obese individuals [3]. Additionally, our findings indicated that lomitapide may slow the progression of atherosclerosis, highlighting its potential as a treatment for atherosclerotic cardiovascular disease [4]. ## HoFH Conclusion HoFH represents one of the most severe types of dyslipidemia primarily triggered by a mutation in the LDL receptor which alters clearing LDL-C from the bloodstream. As a result, an individual with HoFH is at markedly elevated levels of LDL-C from birth. This elevated LDL-C level contributes to the development of aggressive cardiovascular diseases, such as heart attacks and strokes. Lomitapide is an FDA-approved medication for adults with HoFH, which functions by inhibiting MTP, thereby reducing the assembly and secretion of lipoproteins in the liver. By reducing lipoprotein production, lomitapide significantly decreases circulating ox-LDL-C levels. This reduction can enhance cardiovascular health by reducing ROS and inflammation, thus improving endothelial function and reducing arterial stiffness. Many studies showed that lomitapide effectively lowered LDL-C and other lipid profiles. This innovative drug shows promising potential in managing LDL-C-related conditions and averting the onset of cardiovascular disorders (Fig. 4). ## Author contributions UM, MK and AK wrote the main manuscript text. KA prepared the figures. AS, EA, AA, KA edited the paper. All authors reviewed the manuscript. ## Funding None. ## Data availability No datasets were generated or analysed during the current study. ## Declarations ## Ethics approval and consent to participate None. ## Competing interests The authors declare no competing interests. ## References 1. Yanai H, Yoshida H (2021) Secondary dyslipidemia: its treatments and association with atherosclerosis. Glob Health Med 3(1):15-23 2. Chhabra M et al (2022) Efficacy and safety of saroglitazar for the management of dyslipidemia: a systematic review and meta-analysis of interventional studies. PLoS ONE 17(7):e0269531 3. Munkhsaikhan U et al (2023) The Beneficial Effect of Lomitapide on the Cardiovascular System in LDLr(-/-) mice with obesity. Antioxid (Basel), 12(6) 4. Munkhsaikhan U et al (2022) The microsomal triglyceride transfer protein inhibitor lomitapide improves vascular function in mice with obesity. Obes (Silver Spring) 30(4):893-901 5. Cuchel M et al (2013) Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study. Lancet 381(9860):40-46 6. Gholamzad A et al (2023) Association between serum vitamin D levels and lipid profiles: a cross-sectional analysis. Sci Rep 13(1):21058 7. de Faire U et al (1997) Retardation of coronary atherosclero-sis: the Bezafibrate Coronary atherosclerosis intervention trial (BECAIT) and other angiographic trials. Cardiovasc Drugs Ther 11(Suppl 1):257-263 8. Li Z, Cheng J, Wang L (2015) Edaravone attenuates monocyte adhesion to endothelial cells induced by oxidized low-density lipoprotein. Biochem Biophys Res Commun 466(4):723-727 9. Morofuji Y et al (2022) Beyond Lipid-Lowering: effects of statins on Cardiovascular and Cerebrovascular diseases and Cancer. Pharmaceuticals (Basel), 15(2) 10. Wang A et al (2016) Systematic review of low-density lipoprotein cholesterol apheresis for the treatment of familial hypercholesterolemia. J Am Heart Assoc, 5(7) 11. Yang CH et al (2021) Regulation of pancreatic ẞ-Cell function by the NPY System. Endocrinology, 162(8) ## Figure Captions **Figure 1:** Low-density lipoprotein cholesterol and atherosclerosis. In the liver, MTP facilitates the production of VLDL by assembling TG, cholesterol, and apoB100. A partial removal of triglycerides transforms VLDL into LDL-C. An excess of LDL-C, along with its oxidation, contributes to the accumulation of foam cells, leading to the formation of plaque. Microsomal triglyceride transfer protein (MTP); very-low-density lipoprotein (VLDL); triglycerides (TG); apolipoprotein B100 (apoB100); oxidized LDL-C (ox-LDL-C); low-density lipoproteins cholesterol (LDL-C) **Figure 2:** LDL-C Apheresis. A schematic figure showing the LDL apheresis procedure using plasma separation and dialysis, a therapeutic technique to selectively remove LDL cholesterol from the blood **Figure 3:** LDL-C contributes to endothelial dysfunction. Ox-LDL-C contributes to endothelial dysfunction by increasing the level of ROS, inflammation, ER stress, and inhibition of the endothelial nitric oxide (NO) signaling pathway. oxidized LDL-C (ox-LDL-C); Endoplasmic reticulum (ER); Reactive oxygen species (ROS) **Figure 4:** Schematic figure summarizing lomitapide effect. Increased plasma oxLDL-C levels activate ER stress, induce inflammation (NFkB), and increase oxidative stress, leading to endothelial dysfunction and reduction in smooth muscle cell relaxation. This ultimately will lead to cardiovascular disease. Lomitapide treatment, which works by directly binding to MTP in the ER, blocking the transfer of lipids and inhibiting the assembly of VLDL and chylomicrons [10]. This process prevents the formation of ApoB-containing lipoproteins in both the intestine and the liver. As a result, the release of VLDL and chylomicrons into the system circulation is reduced, eventually leading to decreased LDL-C levels in the bloodstream. Many studies have demonstrated that lomitapide effectively reduces LDL-C and other lipid parameters, including total cholesterol, VLDL, TG, and ApoB [5]. A prospective clinical study involving 9 patients with HoFH showed that lomitapide reduced total cholesterol by 55.3%, LDL-C by 65.5%, and TG by 41.3%. There were no significant changes in high-density lipoprotein (HDL) [20]. Furthermore, a reduction in inflammatory markers (TNFα, IL-13, IL-7) was observed in those patients' plasma, suggesting lomitapide may have an anti-inflammatory effect [20]. In a retrospective study conducted in Italy, 15 adults with HoFH were enrolled [45]. These patients were treated with lomitapide for 8 to 86 months with a combination low-fat diet plan and LDL apheresis. LDL-C levels were reduced by 68.2% compared to baseline. At the last visit, 60% of patients reached LDL-C below 100 mg/dl, and 46.6% reached LDL-C below 70 mg/dl. During the study, none of the patients had to stop lomitapide due to side effects. A few patients experienced minor side effects, mainly gastrointestinal (GI) symptoms like diarrhea and nausea. After three years of follow-up, eight patients no longer required LDL apheresis after taking lomitapide [45]. Other studies discussed that lomitapide lowers plasma LDL-C levels, improves endothelial function. Microsomal triglyceride transfer protein (MTP); very-low-density lipoprotein (VLDL); triglycerides (TG); Fatty acids (FA); oxidized LDL-C (ox-LDL-C); Endoplasmic reticulum (ER); Reactive oxygen species (ROS); NFkB: Nuclear factor kappa B acts independently on the LDLr pathway, significantly reducing LDL-C levels in patients with different mutation types [46]. These studies have reported common minor side effects of lomitapide, including the risk of liver toxicity and GI adverse reactions. However, there have been no signs of increased risk of liver fibrosis or significant damage [36, 46]. The Lomitapide Observational Worldwide Evaluation Registry (LOWER) was established to evaluate lomitapide's long-term safety, tolerability, and effectiveness in adult patients with HoFH. It is a multicenter global exposure program and the largest dataset of patients with HoFH-treated lomitapide [47]. In a summary report from 2014 to 2019, 189 patients were enrolled in the study. The drug dose ranged from 5 mg to 40 mg per day. The study reported that a lower lomitapide dose can significantly reduce LDL-C while providing fewer adverse effects [47]. An interesting finding from a female patient with severe hypertriglyceridemia (> 2000 mg/dl) due to familial chylomicronemia was treated with lomitapide for 13 years [48]. Lomitapide reduced the average TG to 1000 mg/dl during the first six years of treatment, and her transaminase levels were normal. However, a liver biopsy conducted five years later revealed fatty liver and progressive fibrosis. Since there was no liver biopsy performed at the initiation of lomitapide treatment, it is unclear whether it directly contributed to liver fibrosis. Currently, lomitapide is being considered as a treatment for pancreatitis caused by severe hypertriglyceridemia [49]. A recent study suggests using lomitapide therapy for autosomal recessive hypercholesteremia [50]. Numerous studies have shown that lomitapide is a powerful LDL-C lowering agent. However, lomitapide is currently approved only for use in adults with HoFH and has not been authorized for other hyperlipoproteinemia disorders [3]. This requires further studies, as its safety and efficacy have also not been established in the pediatric population. Surprisingly, no direct studies assess the effect of lomitapide on cardiovascular disease in HoFH patients [3]. In our previous studies [3, 4], we investigated the impact of lomitapide on the cardiovascular system using a mouse model of HoFH (LDL receptor knock-out) and wild type (C57B6). Obesity in both models was induced by a high-fat diet (HFD). Our studies have shown that obesity triggers chronic elevation of LDL-C, which significantly contributes to endothelial dysfunction by increasing the level of oxidative stress (ROS) [51], inflammation [52, 53], endoplasmic reticulum (ER) stress [54], and inhibition of the endothelial nitric oxide (NO) signaling pathway [55, 56]. Endothelial cell dysfunction is a significant factor that contributes to plaque formation [27]. In our obese LDL receptor knock-out mice, endothelial dysfunction was associated with plaque buildup in the arteries [3]. Hence, lowering LDL-C levels is fundamental in both treating and preventing diseases. Our studies showed that treatment with lomitapide by oral gavage for 12 weeks decreased body weight and glucose levels and improved lipid profiles by reducing LDL-C and vascular endothelial function compared to the untreated HFD group [3]. Furthermore, the treatment reduced oxidative and ER stress and inflammation (Fig. 3.). Our reported results suggest that lomitapide is crucial in preventing complications associated with HoFH in obese individuals [3]. Additionally, our findings indicated that lomitapide may slow the progression of atherosclerosis, highlighting its potential as a treatment for atherosclerotic cardiovascular disease [4]