Unpacking and understanding the impact of proprotein convertase subtilisin/kexin type 9 inhibitors on apolipoprotein B metabolism

No abstract available

LDL cholesterol: how low to go?

Epidemiology and the results of large-scale outcome trials indicate that the association of LDL with atherosclerotic cardiovascular disease is causal, and continuous not only across levels seen in the general population but also down to sub-physiological values. There is no scientific basis, therefore, to set a target or 'floor' for LDL cholesterol lowering, and this presents a clinical and conceptual dilemma for prescribers, patients, and payers. With the advent of powerful agents such as proprotein convertase/subtilisin kexin type 9 (PCSK9) inhibitors, LDL cholesterol can be lowered profoundly but health economic constraints mandate that this therapeutic approach needs to be selective. Based on the need to maximize the absolute risk reduction when prescribing combination lipid-lowering therapy, it is appropriate to prioritize patients with the highest risk (aggressive and established CVD) who will obtain the highest benefit, that is, those with elevated LDL cholesterol on optimized statin therapy

Determinants of achieved LDL cholesterol and "Non-HDL" cholesterol in the management of dyslipidemias

Purpose of Review: The advent of combination therapy to provide LDL lowering beyond that achieved with statins necessitates the development of greater understanding of how drugs work together, what changes occur in key lipoprotein fractions, and what residual risk remains. Recent Findings: Clinical trials of agents that, when added to statins, generate profound LDL lowering have been successful in reducing further the risk of cardiovascular disease. LDL cholesterol can be now decreased to unprecedented levels, so the focus of attention then shifts to other apolipoprotein B-containing, atherogenic lipoprotein classes such as lipoprotein(a) and remnants of the metabolism of triglyceride-rich particles. “Non-HDL cholesterol” is used increasingly (especially if measured in the non-fasting state) as a more comprehensive index of risk. Summary: Metabolic studies reveal how current drugs act in combination to achieve profound lipid lowering. However, care is needed in interpreting achieved LDLc and non-HDLc levels in the emerging treatment paradigm

Strategies to alter the trajectory of atherosclerotic cardiovascular disease

Purpose of review: Cardiovascular disease prevention trials of lipid lowering with statins have shown unexpected long-term benefits after the formal randomized treatment stopped. This finding needs further exploration because it raises the possibility that the trajectory of the disease can be modified. Recent findings: Extended follow up data are now available from further major primary prevention studies and from meta-analyses of the legacy effect of statin trials. New outcome studies have been proposed and launched to test the ability of early intervention to slow or regress atherosclerosis. Summary: Legacy effects are apparent in trials of LDL lowering in hypercholesterolemic and hypertensive patient cohorts. Over follow up periods of decades, both cardiovascular mortality and all-cause mortality are reduced in individuals who received 3 to 5 years of statin therapy. The phenomenon is observed also in studies of intensive glycemic control suggesting that it is possible to impact plaque development with long-term beneficial consequences. Novel strategies for primary prevention are being devised that include the early use of both prolonged-moderate and short-term aggressive LDL lowering

Triglyceride lowering 2.0: back to the future?

No abstract available

Emerging Evidence that ApoC-III Inhibitors Provide Novel Options to Reduce the Residual CVD

Purpose of ReviewApolipoprotein C-III (apoC-III) is known to inhibit lipoprotein lipase (LPL) and function as an important regulator of triglyceride metabolism. In addition, apoC-III has also more recently been identified as an important risk factor for cardiovascular disease. This review summarizes the mechanisms by which apoC-III induces hypertriglyceridemia and promotes atherogenesis, as well as the findings from recent clinical trials using novel strategies for lowering apoC-III.Recent FindingsGenetic studies have identified subjects with heterozygote loss-of-function (LOF) mutations in APOC3, the gene coding for apoC-III. Clinical characterization of these individuals shows that the LOF variants associate with a low-risk lipoprotein profile, in particular reduced plasma triglycerides. Recent results also show that complete deficiency of apoC-III is not a lethal mutation and is associated with very rapid lipolysis of plasma triglyceride-rich lipoproteins (TRL). Ongoing trials based on emerging gene-silencing technologies show that intervention markedly lowers apoC-III levels and, consequently, plasma triglyceride. Unexpectedly, the evidence points to apoC-III not only inhibiting LPL activity but also suppressing removal of TRLs by LPL-independent pathways.SummaryAvailable data clearly show that apoC-III is an important cardiovascular risk factor and that lifelong deficiency of apoC-III is cardioprotective. Novel therapies have been developed, and results from recent clinical trials indicate that effective reduction of plasma triglycerides by inhibition of apoC-III might be a promising strategy in management of severe hypertriglyceridemia and, more generally, a novel approach to CHD prevention in those with elevated plasma triglyceride.Peer reviewe

Causes and Consequences of Hypertriglyceridemia

Elevations in plasma triglyceride are the result of overproduction and impaired clearance of triglyceride-rich lipoproteins-very low-density lipoproteins (VLDL) and chylomicrons. Hypertriglyceridemia is characterized by an accumulation in the circulation of large VLDL-VLDL1-and its lipolytic products, and throughout the VLDL-LDL delipidation cascade perturbations occur that give rise to increased concentrations of remnant lipoproteins and small, dense low-density lipoprotein (LDL). The elevated risk of atherosclerotic cardiovascular disease in hypertriglyceridemia is believed to result from the exposure of the artery wall to these aberrant lipoprotein species. Key regulators of the metabolism of triglyceride-rich lipoproteins have been identified and a number of these are targets for pharmacological intervention. However, a clear picture is yet to emerge as to how to relate triglyceride lowering to reduced risk of atherosclerosis.Peer reviewe

Interleukin-6 blockade raises LDL via reduced catabolism rather than via increased synthesis: a cytokine-specific mechanism for cholesterol changes in rheumatoid arthritis

Objectives Patients with rheumatoid arthritis (RA) have reduced serum low-density lipoprotein cholesterol (LDL-c), which increases following therapeutic IL-6 blockade. We aimed to define the metabolic pathways underlying these lipid changes. Methods In the KALIBRA study, lipoprotein kinetic studies were performed on 11 patients with severe active RA at baseline and following three intravenous infusions of the IL-6R blocker tocilizumab. The primary outcome measure was the fractional catabolic rate (FCR) of LDL. Results Serum total cholesterol (4.8 vs 5.7 mmol/L, p=0.003), LDL-c (2.9 vs 3.4 mmol/L, p=0.014) and high-density lipoprotein cholesterol (1.23 vs 1.52 mmol/L, p=0.006) increased following tocilizumab therapy. The LDL FCR fell from a state of hypercatabolism to a value approximating that of the normal population (0.53 vs 0.27 pools/day, p=0.006). Changes in FCR correlated tightly with changes in serum LDL-c and C-reactive protein but not Clinical Disease Activity Index. Conclusions Patients with RA have low serum LDL-c due to hypercatabolism of LDL particles. IL-6 blockade normalises this catabolism in a manner associating with the acute phase response (and thus hepatic IL-6 signalling) but not with RA disease activity as measured clinically. We demonstrate that IL-6 is one of the key drivers of inflammation-driven dyslipidaemia

The Roles of ApoC-III on the Metabolism of Triglyceride-Rich Lipoproteins in Humans

Cardiovascular disease (CVD) is the leading cause of death globally. It is well-established based on evidence accrued during the last three decades that high plasma concentrations of cholesterol-rich atherogenic lipoproteins are causatively linked to CVD, and that lowering these reduces atherosclerotic cardiovascular events in humans (1-9). Historically, most attention has been on low-density lipoproteins (LDL) since these are the most abundant atherogenic lipoproteins in the circulation, and thus the main carrier of cholesterol into the artery wall. However, with the rise of obesity and insulin resistance in many populations, there is increasing interest in the role of triglyceride-rich lipoproteins (TRLs) and their metabolic remnants, with accumulating evidence showing they too are causatively linked to CVD. Plasma triglyceride, measured either in the fasting or non-fasting state, is a useful index of the abundance of TRLs and recent research into the biology and genetics of triglyceride heritability has provided new insight into the causal relationship of TRLs with CVD. Of the genetic factors known to influence plasma triglyceride levels variation inAPOC3- the gene for apolipoprotein (apo) C-III - has emerged as being particularly important as a regulator of triglyceride transport and a novel therapeutic target to reduce dyslipidaemia and CVD risk (10).Peer reviewe

Long-term safety and efficacy of lowering low-density lipoprotein cholesterol with statin therapy : 20-year follow-up of West of Scotland Coronary Prevention Study

The study was supported by a grant from Merck, Sharp & Dohme, Kenilworth, NJ, as part of an Investigator Initiated Program.BACKGROUND Extended follow-up of statin-based low-density lipoprotein cholesterol lowering trials improves the understanding of statin safety and efficacy. Examining cumulative cardiovascular events (total burden of disease) gives a better appreciation of the clinical value of statins. This article evaluates the long-term impact of therapy on mortality and cumulative morbidity in a high-risk cohort of men. METHODS AND RESULTS The West of Scotland Coronary Prevention Study was a primary prevention trial in 45- to 64-year-old men with high low-density lipoprotein cholesterol. A total of 6595 men were randomized to receive pravastatin 40 mg once daily or placebo for an average of 4.9 years. Subsequent linkage to electronic health records permitted analysis of major incident events over 20 years. Post trial statin use was recorded for 5 years after the trial but not for the last 10 years. Men allocated to pravastatin had reduced all-cause mortality (hazard ratio, 0.87; 95% confidence interval, 0.80-0.94; P=0.0007), attributable mainly to a 21% decrease in cardiovascular death (hazard ratio, 0.79; 95% confidence interval, 0.69-0.90; P=0.0004). There was no difference in noncardiovascular or cancer death rates between groups. Cumulative hospitalization event rates were lower in the statin-treated arm: by 18% for any coronary event (P=0.002), by 24% for myocardial infarction (P=0.01), and by 35% for heart failure (P=0.002). There were no significant differences between groups in hospitalization for noncardiovascular causes. CONCLUSION Statin treatment for 5 years was associated with a legacy benefit, with improved survival and a substantial reduction in cardiovascular disease outcomes over a 20-year period, supporting the wider adoption of primary prevention strategies.Publisher PDFPeer reviewe