Novel insights on the treatment of hypercholesterolemia

Abstract

The diagnosis of dyslipidemia is increasing both in adulthood and in childhood because of not only the steadily increasing prevalence of obesity but also a rise of medical attention in detecting unfavorable genetic conditions in patients of all ages. Attempts in lifestyle changes are frequently failing and thus the pharmacological treatment of dyslipidemia is spreading in medical practice to reduce cardiovascular risk. In childhood, statins are authorized by 8 years of age. Nevertheless, data on their long-term safety and efficacy are still lacking, especially in ones with high cardiovascular risk and/or primary dyslipidemia such as homozygous familial hypercholesterolemia, considerable as a mainly exclusively pediatric disease. Thus, new pharmacological approaches are needed and have to be evaluated in all categories of patients. In this context, the update and the critical revision of new medications have become a new duty for scientists and clinicians.

Keywords:

• alirocumab
• cardiovascular risk
• children
• cholesterol ester transfer protein inhibitors
• ezetimibe
• hypercholesterolemia
• lomitapide
• mipomersen
• proprotein convertase subtilisin/kexin-9
• statins

Novel insights on the treatment of hypercholesterolemia

Hypercholesterolemia is a well-known risk factor to develop cardiovascular disease both in childhood and in adulthood. The cornerstone of lipid-lowering treatment is a healthy lifestyle, but diet alone fails to lower cholesterol levels to acceptable values namely in patients with genetic hypercholesterolemia needing pharmacological treatment [1].

Despite results already obtained in lowering cholesterol, over recent years, many attempts of new drugs to limit the progression of atherosclerosis are bloomed.

The urgent necessity to find new drugs arises by common dilemmas that lipidologists may face in clinical practice: specifically, patients on traditional lipid-lowering medications may manifest intolerance and/or do not reach therapeutic goals despite maximum doses of conventional drugs, mainly those with severe forms of hypercholesterolemia.

What is new about statins?

Statins efficacy is already well established both in adult and in children, and they are currently the mainstay in the treatment of hypercholesterolemia.

A recent study confirms the hypothesis that statins not only decrease LDL-cholesterol (LDL-C) levels but also may have lipid-independent pleiotropic effects altering inflammatory responses and local atherosclerotic plaque morphology mediated through the inhibition of mevalonate pathway and the direct effects on atherosclerotic plaque macrophages [2].

Considering the safety concerns posed for long-term treatment with statins, especially for those beginning in children and adolescents, many efforts have been made to overcome these problems.

New pharmacological formulations are exploring statin-containing nanoparticles with a higher bioavailability and a reduction of their potential toxicity and adverse effects [3]. In this technology (involving liposomes, polymeric particles, hydrogels, micelles, inorganic/solid particles, dendrimers, nanotubes and quantum dots), therapeutic agents are typically encapsulated, entrapped, adsorbed or chemically attached to the nanoparticle surface to prolong their presence into circulation and microcirculation, to specifically accumulate them in target tissues, to select cellular uptake by target endothelial cells and to control their release [4]. Recently, in an apolipoprotein E-knockout mouse model of atherosclerosis, the in vivo use of intravenously prolonged low-dose and short-term high-dose statin-reconstituted high-density lipoproteins (rHDL) nanoparticles shows that they accumulate in atherosclerotic lesions in which seem to directly suppress plaque macrophages without exhibiting myo- or hepatotoxic effects [2].

Another way to improve the statin therapy could derive from data evaluating genetic aspects. Recent studies have been performed on the polymorphism of P450 oxidoreductase (POR) enzyme involved in transferring electrons from NADPH to CYP enzymes including CYP3A, which metabolize atorvastatin and simvastatin. Children with familial hypercholesterolemia (FH) carriers of POR*28 allele seem to be associated with reduced effect of atorvastatin on total cholesterol and LDL-C, so this allele identifies subjects that may require higher atorvastatin doses to achieve full therapeutic benefits [5]. Nevertheless, published data are discordant and considering the current state-of-the-art further studies involving wider and different populations are required [6].

Combined therapy

A way to improve the safety of lipid-lowering treatment is to associate different new agents at lower doses.

Ezetimibe decreases cholesterol absorption through inhibition of Niemann-Pick C1-like 1 protein leading to a clinical reduction of LDL-C by 23%. It seems to be well tolerated and is nowadays commonly used in association with statins. Available data suggest that this combination may not restore endothelial dysfunction [7] and that ezetimibe does not influence high-density-lipoprotein cholesterol (HDL-C), a well-known independent risk factor for cardiovascular diseases.

However, very recent data from the IMPROVE-IT study, enlisting about 18,000 adults affected by acute coronary syndrome, have been disclosed: relative to simvastatin alone, the association of simvastatin and ezetimibe reduced ischemic stroke by 21% and myocardial infarction by 13% and led to a significantly lower incidence of the primary combined endpoint (cardiovascular death, myocardial infarction, re-hospitalization for unstable angina, coronary revascularization or stroke; 34.7 vs 32.7%; p = 0.016) [8].

Even if these recent findings may help in answering some questions about ezetimibe studies in children and adolescent are still needed.

In terms of combined therapies, old lipid-lowering agents like resins deserve to be mentioned because of their recent discovered positive impact on glucose homeostasis [9].

Inhibition of PCSK9 pathway

Subjects with loss-of-function mutations in the pro-protein convertase subtilisin/kexin-9 (PCSK9) gene have less lysosomal degradation of the LDL-C receptor (LDLR), greater surface expression of the LDLR, reduced plasma LDL-C and reduced vascular risk during their lifetimes [10]. The inhibition of PCSK9 pathway immediately appears one of the most promising novel targets for additional LDL-C reduction [11]. Alirocumab (REGN-727), evolocumab (AMG-145) and bococizumab (RN-316) are human monoclonal antibodies that bind circulating PCSK9 and block its interactions with surface LDLR. They have recently demonstrated a great potentiality in reducing LDL-C in adulthood and alirocumab is now tested in Phase I–III clinical trials [12]. Data from the ODYSSEY ALTERNATIVE study, reported at the last American Heart Association meeting, demonstrate that alirocumab provides significantly higher lipid reduction in statin-intolerant patients with high LDL-C levels relative to ezetimibe. Specifically, 314 patients enrolled in the study were randomized to receive alirocumab as a 75 mg self-administered injection fortnightly (n = 126), 10 mg ezetimibe daily (n = 125) or 20 mg atorvastatin daily (n = 63) for 24 weeks. At the end of the study, subjects receiving alirocumab had a reduction in LDL-C concentrations of 45% from baseline, despite the 14.6% reduction obtained in patients receiving ezetimibe [8]. Nevertheless, all these agents need to be given as subcutaneous injections every 2 weeks or monthly because of their relatively short in vivo half-lives: this aspect could increase the cost/benefit ratio limiting their use exclusively in high-risk patients and making their diffusion in childhood problematic. Moreover, evidences on their efficacy to improve cardiovascular outcome should be obtained only in 2016–2018. Recently, PCSK9-specific active vaccines approaches have being developed and their long-term efficacy and safety have being assessed in different preclinical models to circumvent the drawbacks of alirocumab [13].

Therapies targeting LDL & HDL

To improve cardiovascular health, other suitable drugs targets have been identified. Clinical trials on therapies targeting HDL-C particle metabolism as cholesterol ester transfer protein (CETP) inhibitors or apoA1 mimetics are in progress. Recalling physiology, CETP shuttles cholesterol esters from HDL-C to the atherogenic LDL-C and very low-density lipoprotein (VLDL) in exchange for triglycerides, resulting in a decrease in HDL-C, with a concomitant increase in LDL-C. To date, four small molecules inhibitors of CETP reach the clinical stage of development. Torcetrapib hopes use felt down in December 2006 when it was demonstrated to be associated with increased cardiovascular mortality in the large Phase III endpoint trial Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE). This adverse effect was correlated to its off-target actions in increasing aldosterone, corticosterone, endothelin-1 levels and, thus, blood pressure [14]. Despite an increase in HDL-C levels, an analog unhappy end marked the second irreversible CETP inhibitor, dalcetrapib [15]. Very recently, other two drugs, anacetrapib and evacetrapib, have been developing. Both raise HDL-C by 80–120% and reduce LDL-C by 30–40%. Outcome studies are underway, and results are expected in 2016–2017 [16].

Therapy for HoFH

The dramatic cardiovascular outcomes of homozygous FH (HoFH) [17] has allowed the development and the use of some orphan drugs. Being rare diseases, examples and resources are scarce. Mipomersen, an antisense oligonucleotide, targets the apolipoprotein B (an essential component of all atherogenic lipoproteins and Lp(a)) mRNA mainly in the liver causing its cleavage and reduces LDL-C by 25% in HoFH patients [18,19]. Lomitapide, a microsomal transfer protein (MTP) inhibitor, targets the lipidation of apolipoprotein B and can reduce LDL-C by 50% in HoFH patients [20]. The conceptual basis for inhibition of MTP with lomitapide partly derives from the observation in human beings of a rare recessive genetic disorder known as abetalipoproteinemia, in which functional MTP is absent, VLDL cannot be secreted from hepatocytes, and there are no apolipoprotein B-containing lipoproteins in the systemic circulation [20]. Some severe side effects are described for both drugs and comprise injection site reactions, transient influenza-like symptoms, diarrhea, nausea, abdominal pain, hepatic fat accumulation leading to steatosis and transaminase elevations for the latter. Data from other patients’ populations (heterozygous FH subjects on high-dose conventional therapies or primary hypercholesterolemia ones intolerant to conventional drugs) are going to develop, and first data appear variable [21]. Nowadays, mipomersen has only an orphan drug license in US, and lomitapide is licensed for HoFH both in Europe and in US.

In conclusion, although we are still far from the complete comprehension of the lipid metabolism, the better understanding of its physiology and pathophysiology has already permitted the introduction of new therapeutic opportunities, namely for patients with severe genetic forms of hypercholesterolemia.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.