Genetic and Pharmacologic Inactivation of ANGPTL3 and Cardiovascular Disease

Abstract

BACKGROUND Loss-of-function variants in the angiopoietin-like 3 gene (ANGPTL3) have been associated with decreased plasma levels of triglycerides, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. It is not known whether such variants or therapeutic antagonism of ANGPTL3 are associated with a reduced risk of atherosclerotic cardiovascular disease. METHODS We sequenced the exons of ANGPTL3 in 58,335 participants in the DiscovEHR human genetics study. We performed tests of association for loss-of-function variants in ANGPTL3 with lipid levels and with coronary artery disease in 13,102 case patients and 40,430 controls from the DiscovEHR study, with follow-up studies involving 23,317 case patients and 107,166 controls from four population studies. We also tested the effects of a human monoclonal antibody, evinacumab, against Angptl3 in dyslipidemic mice and against ANGPTL3 in healthy human volunteers with elevated levels of triglycerides or LDL cholesterol. RESULTS In the DiscovEHR study, participants with heterozygous loss-of-function variants in ANGPTL3 had significantly lower serum levels of triglycerides, HDL cholesterol, and LDL cholesterol than participants without these variants. Loss-of-function variants were found in 0.33% of case patients with coronary artery disease and in 0.45% of controls (adjusted odds ratio, 0.59; 95% confidence interval, 0.41 to 0.85; P = 0.004). These results were confirmed in the follow-up studies. In dyslipidemic mice, inhibition of Angptl3 with evinacumab resulted in a greater decrease in atherosclerotic lesion area and necrotic content than a control antibody. In humans, evinacumab caused a dose-dependent placebo-adjusted reduction in fasting triglyceride levels of up to 76% and LDL cholesterol levels of up to 23%. CONCLUSIONS Genetic and therapeutic antagonism of ANGPTL3 in humans and of Angptl3 in mice was associated with decreased levels of all three major lipid fractions and decreased odds of atherosclerotic cardiovascular disease. (Funded by Regeneron Pharmaceuticals and others; ClinicalTrials.gov number, NCT01749878.)

Antisense Oligonucleotides and Therapeutical Monoclonal Antibodies as a Basement for Novel Biological Lipidlowering Drugs

“…Влияние препарата на активность липопротеинлипазы увеличивало гидролиз ТГ-обогащенных частиц липопротеидов, тогда как снижение ХС-ЛВП было опосредовано вли-янием на активность эндотелиальной липазы. По мнению исследователей препарат МкАт может быть эффективен для коррекции ХС-ЛНП у пациен-тов с гомозиготной формой СГХС с отсутствием ЛНП рецептора, поскольку может действовать на клиренс ЛНП по механизму, не зависящему от рецептора ЛНП, а также других известных механизмов [55]. Согласно базе данных КИ, проводимых по всему миру в 2018 году, запланировано несколько исследо-ваний для оценки эффективности и безопасности применения эвинакумаба у пациентов с гомозигот-ной формой СГХС и гиперлипопротеидемий IIa в рамках III фазы КИ в Канаде, США, Греции и Австрии (ClinicalTrials.gov).…”

“…Никто из участников исследования не прекратил прием препарата из-за серьезных неблагоприятных событий [55].…”

Antibody Based Therapy in Coronary Artery Disease and Heart Failure

“…Increasing LPL activity in this manner increases breakdown of triglycerides in addition to LDL cholesterol. 11 Like PCSK9, genetic investigations indicate LPL to be another promising target. In this case, loss of function variants increases risk of coronary artery disease and gain of function variants lower it.…”

“…In this case, loss of function variants increases risk of coronary artery disease and gain of function variants lower it. 11 Further, loss of function variants of ANGPTL3 are associated with decreased triglyceride, LDL and HDL cholesterol and lower incidence of cardiovascular events. At present, Evinacumab has been tested in Phase I with promising results; it was well tolerated and lipid levels were reduced in participants with mild to moderate (otherwise healthy) circulating triglyceride or LDL levels.…”

“…At present, Evinacumab has been tested in Phase I with promising results; it was well tolerated and lipid levels were reduced in participants with mild to moderate (otherwise healthy) circulating triglyceride or LDL levels. 11 A phase II trial is planned to assess the benefits in disease cohorts.…”