Treatment of Severe Genetic Dyslipidemia: Where Are We Going?

Homozygous Familial Hypercholesterolemia (HoFH), refractory/intolerant Heterozygous Familial Hypercholesterolemia (HeFH), and HyperLp(a)lipoproteinemia (HyperLpa) are pernicious diseases with high rate of precocious insurgence of cardiovascular ischemic complications. Early detection and treatment is crucial. All these forms deserve dramatic treatment that must be intensive and at the same time effective and continuous. Furthermore, the possible precocious onset of a coronary event in a patient affected by a severe form of genetically determined dyslipidemia such as HoFH, double heterozygous (compound) familial hypercholesterolemia (DHeFH), HeFH, or HyperLp(a) requires a personalized therapeutic approach. The relative risk of death of HeFH patients not treated with HMGCOA-reductase inhibitors is between three- and fourfold. Aggressive cholesterol lowering has been adopted by clinicians as standard treatment regimen for FH patients with coronary artery disease (CAD), including those who have had recent revascularization (bypass surgery, percutaneous transluminal coronary angioplasty) 1, 2. According to the National Cholesterol Education Program Adult Treatment Panel III (NCEP III) guidelines, those patients who have documented CAD (high risk individuals) should have their low-density lipoprotein-cholesterol LDL-C) lowered to less than 70 mg/dL (1.8 mmol/L) 3. On the other hand, the threshold of risk in subjects with HyperLp(a) is reported to be below 30 mg/dL (300 mg/L) 4. Aggressive LDLC lowering therapy is known to be more effective in the regression of the carotid intima media thickness than conventional LDL therapy in FH patients. However, pharmacologic therapy alone (statins, ezetimibe, statins plus ezetimibe) does not obtain adequate results in the HoFH form, and in only about 20% of cases of the He form of FH. After more than 30 years, the use of extracorporeal cholesterol removal techniques (lipid-apheresis, low density lipoprotein-apheresis, lipoprotein apheresis) (La; LDLa; LA) has increased the chance of regression of atherosclerosis in HeFH compared with controls by 15% to 40% and has decreased the chance of progression by 25% to 35% 1, 2. It is universally known that the main indication of LA is FH, in the form homozygous, "compound," and heterozygous, not responding or intolerant to maximum pharmacologic therapy with or without associated CAD. Extracorporeal cholesterol elimination is effective also in the treatment of autosomal recessive hypercholesterolemia (ARH) and other severe lipid metabolism disorders associated with elevated cardiovascular risk such as HyperLp(a) 2, 4. Studies using angiography to determine changes in coronary obstruction have indicated progression, stabilization, or regression of coronary lesions associated with changes in plasma lipids and lipoproteins in patients undergoing LA 1, 2, 5. Outstanding experimental data have also shown that LA exhibits pleiotropic or pleiotropic-equivalent effects that can beneficially impact progressively occlusive atherosclerotic disease, including inhibition of smooth muscle proliferation and platelet aggregation, enhancement of endothelial function, and anti-inflammatory actions such as reduction of proinflammatory cytokines, and adhesion molecules in plasma 6. Despite, the aforementioned recognized favorable clinical performances of LA, a considerable number of subjects with a severe form of hyperlipidemia are not treated by LA. The cost of disposables, the need of highly qualified centers and of very experienced staff are still the most serious limiting factor for LA, even in the so called "rich" countries. Another formidable challenge to the last 30 years of proven superiority of LA in the treatment of genetically determined pro-atherogenic hyperlipidemias is coming from the advent of a novel class of mighty lipid and lipoprotein altering drugs. MTP, PCSK9, CETP inhibitors, antisense apoB synthesis inhibitor (mipomersen), and high-density lipoprotein-enhancers are currently in an advanced phase of investigation undermining the consolidated certainties of all those who have so far played a role in the world of therapeutic apheresis 2, 7, 8. Will this mean that LA will soon be relegated to the history of medicine hounded by new advances? As scientists we must accept that the process of scientific discovery is, in effect, a continual conflict of wonders as Albert Einstein taught us 9. However, as clinicians we are firmly convinced that LA still has a long way to go. Moreover, we guess that LA and the upcoming lipid altering drugs trajectories will not steadily diverge. On the contrary, we are convinced that in most cases the aforementioned drugs will be combined with LA opening new treatment schemes and not entirely predictable new therapeutic protocols. This will give shape to new forms of treatment. Just imagine the combination of a powerful LDL-C lowering drug with an HDL-enhancer and LA. Never seen before. Are we ready to change the way we administer apheresis (changing intervals of treatment, reducing plasma and blood volumes to be processed, etc.)? Are we ready to deal with dose titration, drugs association, interaction, contraindication and side-effects? And in addition apheresis? If the answer is yes, we are probably ready for the future and for a new frontier of medical science, where existing and upcoming therapeutic tools will all be aimed at better fighting the scourge of the most severe ischemic complications induced by genetically determined atherogenic dyslipidemias.