👤 Anne Langsted

For decades, studies have tried to identify the cholesterol marker that best reflects risk of atherosclerotic cardiovascular disease(ASCVD). Comparing low-density-lipoprotein(LDL) cholesterol, non-high-density-lipoprotein(non-HDL) cholesterol, and apolipoprotein B(apoB) as ASCVD risk markers has been challenged by high correlation between them. Thus, discordance analyses, directly addressing disagreements between the cholesterol markers, have emerged. Approaches adopted to define discordance originate in one of three methods: discordance by cut-points, discordance by percentiles, or discordance by residuals. Commonly, concordant lipid levels serve as reference examining the association between discordant lipid levels with risk of ASCVD. Importantly, concordant reference groups present heterogeneity of clinical relevance across different discordance methods as concordant low lipid levels associate with lowest ASCVD risk while concordant high lipid levels associate with highest risk. Thus, results from different discordance approaches cannot be directly compared. Moreover, discordance between cholesterol markers is more frequently seen in individuals treated with lipid-lowering medication than in individuals not treated with lipid-lowering medication. Accordingly, studies performing discordance analyses have reported inconsistent and even conflicting results. Discordance by cut-points appears the most intuitive and clinically applicable method; results from these analyses suggest that elevated LDL cholesterol, non-HDL cholesterol, or apoB levels in individuals not treated with lipid-lowering medication confer increased ASCVD risk while in individuals treated with lipid-lowering medication, elevated non-HDL cholesterol and apoB levels best indicate residual risk. Results from discordance analyses comparing LDL cholesterol, non-HDL cholesterol, and apoB in risk of ASCVD as well as complexities of discordance analyses and considerations regarding interpretations are discussed in this review. Show less

Randomized clinical trials of remnant cholesterol lowering drugs show 50 % and 80 % reduction in remnant cholesterol with apolipoprotein C3 (APOC3) and angiopoietin-like 3 (ANGPTL3) inhibitors. However, how many of atherosclerotic cardiovascular disease(ASCVD) cases that could be prevented lowering remnant cholesterol by these therapies is unknown. The aim of the study was to estimate the potential of APOC3 and ANGPTL3 inhibitors to reduce the ASCVD burden through lowering of remnant cholesterol. Of 98,311 individuals from the Copenhagen General Population Study without ASCVD at study entry 8,506 were statin users and 89,805 were statin non-users. Cause-specific Cox regression was used to model rates of ASCVD and non-cardiovascular death conditional on remnant cholesterol and risk factors. Based on these models the potential 10-year absolute risk reduction of ASCVD in individuals with remnant cholesterol >1 mmol/L (>39 mg/dL) for 15 %, 30 %, 50 %, and 80 % lower remnant cholesterol was predicted. The predicted average 10-year absolute risk of ASCVD was 20 % for statin users and 11 % for statin non-users with remnant cholesterol >1 mmol/L (>39 mg/dL). The predicted 10-year absolute risk reduction of ASCVD in individuals with remnant cholesterol >1 mmol/L (>39 mg/dL) for 50 % and 80 % lower remnant cholesterol were 2.7 % (95 % confidence interval: 2.2-3.2 %), and 4.1 % (3.4-4.8 %) for statin users and 1.4 % (1.3-1.5 %), and 2.1 % (2.0-2.3 %) for statin non-users. We have shown that significant ASCVD risk reductions are expected for remnant cholesterol lowering drugs in at-risk populations, if intervention trials with novel remnant cholesterol lowering drugs show expected reductions in remnants in large cardiovascular outcomes trials. Show less

High lipoprotein(a) levels are observationally and causally, from human genetics, associated with increased risk of cardiovascular disease including myocardial infarction and aortic valve stenosis. The European Atherosclerosis Society recommends screening for elevated lipoprotein(a) levels in high-risk patients. Different therapies have been suggested and some are used to treat elevated lipoprotein(a) levels such as niacin, PCSK9 inhibitors, and CETP inhibitors; however, to date, no randomized controlled trial has demonstrated that lowering of lipoprotein(a) leads to lower risk of cardiovascular disease. Synthetic oligonucleotides can be used to inactivate genes involved in disease processes. To lower lipoprotein(a), two antisense oligonucleotides have been developed, one targeting apolipoprotein B and one targeting apolipoprotein(a). Mipomersen is an antisense oligonucleotide targeting apolipoprotein B and thereby reducing levels of all apolipoprotein B containing lipoproteins in the circulation. Mipomersen has been shown to lower lipoprotein(a) by 20-50% in phase 3 studies. AKCEA-APO(a)-L Show less

New treatment opportunities are emerging in the field of lipid-lowering therapy through gene-silencing approaches. Both antisense oligonucleotide inhibition and small interfering RNA technology aim to degrade gene mRNA transcripts to reduce protein production and plasma lipoprotein levels. Elevated levels of LDL, remnant lipoproteins, and lipoprotein(a) all cause cardiovascular disease, whereas elevated levels of triglyceride-rich lipoproteins in some patients can cause acute pancreatitis. The levels of each of these lipoproteins can be reduced using gene-silencing therapies by targeting proteins that have an important role in lipoprotein production or removal (for example, the protein products of ANGPTL3, APOB, APOC3, LPA, and PCSK9). Using this technology, plasma levels of these lipoproteins can be reduced by 50-90% with 2-12 injections per year; such dramatic reductions are likely to reduce the incidence of cardiovascular disease or acute pancreatitis in at-risk patients. The reported adverse effects of these new therapies include injection-site reactions, flu-like symptoms, and low blood platelet counts. However, newer-generation drugs are more efficiently delivered to liver cells, requiring lower drug doses, which leads to fewer adverse effects. Although these findings are promising, robust evidence of cardiovascular disease reduction and long-term safety is needed before these gene-silencing technologies can have widespread implementation. Before the availability of such evidence, these drugs might have roles in patients with unmet medical needs through orphan indications. Show less

We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD. Show less