Familial Hypercholesterolemia & Evkeeza
Familial hypercholesterolemia is a disease that is commonly inherited and characterized by a dysfunction in cholesterol metabolism. The disease results in higher-than-normal levels of low-density lipoprotein (LDL), which many people may know as the “bad cholesterol”. This happens due to an impaired function of LDL receptors due to a genetic defect. There are typically five ways in which the LDL receptor is dysfunctional: the LDL receptor is not synthesized, the LDL receptor is not expressed on the cell surface because of improper transport, the LDL receptor does not bind to LDL, the LDL receptor does not properly cluster in clathrin-coated pits for endocytosis, or the LDL receptor is not recycled back to the cell surface. All of these lead the way to higher-than-normal levels of LDL. With familial hypercholesterolemia, there is a lifetime exposure to LDL that can cause complications from an early age. This disease state is not rare, but it is oftentimes missed, and an early diagnosis and treatment can prevent the complications such as the development of premature atherosclerotic cardiovascular disease.
Manifestations of familial hypercholesterolemia usually begin in adulthood, but the clinical effects can be seen earlier in life which is why diagnosis early on is very important. Being able to identify and treat the disease early is key to preventing complications and death. Many barriers exist in the diagnosis of familial hypercholesterolemia including mistaking other coronary artery disease risk factors for familial hypercholesterolemia factors, which can leave the disease undiagnosed for several generations. Cascade screening is a method in which providers screen for familial hypercholesterolemia in first- and second-degree relatives of patients that are diagnosed, but this method can still miss some individuals. The diagnosis of familial hypercholesterolemia is based on lipid levels, family history, physical findings, and genetic analysis. The physical findings can include tendon xanthomas, tuberous xanthomas, arcus corneae, or xanthelasma. It is important to note that these physical findings may not be present in those who have familial hypercholesterolemia and that they help aid in the differential diagnosis. There are three well-defined tools that are currently used to diagnose familial hypercholesterolemia: The US Make Early Diagnoses Prevent Early Deaths Program Diagnostic Criteria (MEDPED), The Dutch Lipid Clinic Network Diagnostic Criteria, and The Simon Broome Register Diagnostic Criteria.
The treatment of familial hypercholesterolemia should optimally start early, but as it is underdiagnosed it is often treated later in life. Long-term drug treatment can reduce or even eliminate the lifetime risk of coronary heart disease. In addition to lifestyle modifications, statins are the initial drug choice for all adults with familial hypercholesterolemia and children eight years or older with heterozygous familial hypercholesterolemia. Statins increase the expression of LDL receptors by reducing HMG-CoA reductase. It is important to note that the low potency statins are usually not enough to treat this disease and moderate to high potency statins should be used. Combination therapy will most likely need to be employed in many patients. There are now novel drugs on the market to treat familial hypercholesterolemia including a recently approved monoclonal antibody, evinacumab-dgnb, under the brand name Evkeeza. The indication is for an injectable add-on therapy for patients 12 years of age and older with homozygous familial hypercholesterolemia. The FDA designated Evkeeza as an orphan drug meaning that it is considered a breakthrough therapy design for rare diseases.
References:
1. Bouhairie VE, Goldberg AC. Familial hypercholesterolemia. Cardiol Clin. 2015;33(2):169-179. doi:10.1016/j.ccl.2015.01.001
2. Center for Drug Evaluation and Research. FDA approves add-on therapy for patients with genetic form of severely. U.S. Food and Drug Administration. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-add-therapy-patients-genetic-form-severely-high-cholesterol-0. Accessed January 18, 2022.
3. Surma S, Romańczyk M, Filipiak KJ. Evinacumab - The new kid on the block. Is it important for cardiovascular prevention?. Int J Cardiol Cardiovasc Risk Prev. 2021;11:200107. Published 2021 Sep 22. doi:10.1016/j.ijcrp.2021.200107
FAMILIAL HYPERCHOLESTEROLEMIA AND EVINACUMAB
Familial Hypercholesterolemia (FH) is a genetic disorder that is characterized by high cholesterol levels (Low-density liproprotein, also known as LDL-C) from birth. There are four main mutations in patients diagnosed with FH. These are mutations of the LDL receptor, apolipoprotein B (Apo B), proprotein convertase subtilin/kexin 9 (PCSK9), and low-density lipoprotein receptor adaptor protein (LDLRAP). Heterozygous FH is more common, however the homozygous FH is the more dangerous version of the disease. Heterozygous FH is found in 1 in 250 people and is recessive without symptoms. However people with heterozygous FH has 50% chance of having a child with homozygous familial hypercholesterolemia. Homozygous familial hypercholesterolemia can lead to Cardiovascular disease if left untreated. There is a risk of early onset of CHD, especially since diagnosing for FH usually in adulthood. Diagnosing occurs in children with consistent levels of LDL >160 mg/dl and adults with LDL >190 mg/dl. Patients with parents who have heterozygous FH should be tested regularly in order to avoid CHD. Other symptoms that can occur is atherosclerosis, which are arteries covered in plaque, CAD, cerebrovascular disease, and aortic aneurysm. Lifestyle modifications include stop smoking, exercise, and lose weight if obese. If a patient was diagnosed with hypertension and diabetes mellitus, they should treat those diseases as well to decrease ASCVD risk.
Commonly used lipid lowering therapies include statins, ezetimibe, bile acid sequestrates, niacin, and PCSK9 inhibitors. First- line treatment includes high intensity statin such as atorvastatin 40-80 mg/day and rosuvastatin 20-40 mg/day. A new drug emerged to treat Homozygous familial hypercholesterolemia. Evinacumab (Evkeeza) is a humanized monoclonal antibody and angiopoietin-like 3 (ANGPTL3) inhibitor approved for adjuvant treatment in patients 12 years old and older. By inhibiting angiopoietin, Evinacumab results in an increase of lipid metabolism, a decrease in LDL-C, HDL-C, and triglycerides (TG). This is the first ANGPTL3 inhibitor approved in the United States. It is given 15 mg/kg every 4 weeks in an iv infusion over 60 minutes. It should be used in combination with other LDL-C lowering medications. Side effects includes nasopharyngitis, abdominal pain, flu-like symptoms, infusion related reaction, and dizziness. Watch out for hypersensitivity reaction, which includes rash, hives, itching, and burning. If patient has a hypersensitivity reaction, discontinue medication and monitor. In studies done on animals, evinacumab caused fetal malformations, therefore pregnant woman should avoid taking this medication. WOmen should take a pregnancy test before beginning the treatment and avoid pregnancy for at least 5 months after alst dose. In addition, humanized monoclonal antibodies are expensive, therefore patients should be warned about payments before beginning treatment.
Bouhairie VE, Goldberg AC. Familial hypercholesterolemia. Cardiol Clin. 2015 May;33(2):169-79. doi: 10.1016/j.ccl.2015.01.001. PMID: 25939291; PMCID: PMC4472364.
Raal FJ, Rosenson RS, Reeskamp LF, Hovingh GK, Kastelein JJP, Rubba P, Ali S, Banerjee P, Chan KC, Gipe DA, Khilla N, Pordy R, Weinreich DM, Yancopoulos GD, Zhang Y, Gaudet D; ELIPSE HoFH Investigators. Evinacumab for Homozygous Familial Hypercholesterolemia. N Engl J Med. 2020 Aug 20;383(8):711-720. doi: 10.1056/NEJMoa2004215. PMID: 32813947.
Singh S, Bittner V. Familial hypercholesterolemia--epidemiology, diagnosis, and screening. Curr Atheroscler Rep. 2015;17(2):482. doi: 10.1007/s11883-014-0482-5. PMID: 25612857.