October 2017
3031     44
Lipid Club Newsletter

September 2013


The new EAS Consensus position on Familial Hypercholesterolemia is just published!


Reports from the 81st EAS Congress, Lyon ,June 2-5, 2013
With the help of the Highlights from the EAS and of the site: theheart.org.


Download PDF


Cholesterol: Myths or facts ?

  • Cholesterol: Myths or facts ?

Download PDF


Reports from the 81st EAS Congress, Lyon ,June 2-5, 2013

Arterial pathophysiology

Professor Peter Libby, Chief of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA, was awarded the 2013 Anitschkow Prize.

Over the past three decades, Professor Libby has had a major impact on understanding of the aetiology and management of atherosclerotic cardiovascular disease. He has been instrumental in translating concepts of inflammation in arterial pathophysiology to the clinical setting, ensuring inflammation is at the forefront of thinking about the diagnosis, risk stratification, and therapeutic approaches to atherosclerotic cardiovascular disease.

In his Anitschkow Lecture, Professor Libby presented a unified view of the pathogenesis of atherosclerosis. Inflammation not only drives the initiation, progression and complications of atherosclerosis, but there is also evidence that the systemic inflammatory reaction to acute myocardial infarction can accelerate atherosclerosis.This is the subject of a recent review, which may help to explain why recurrent thrombotic events are common in the early period following the acute event.

Plaque rupture is the cause of the majority of fatal coronary events. This raises a key question: What then are the underlying mechanisms?

The vulnerable atheromatous plaque is characterised by a lipid- and macrophage rich core, which is separated from the blood compartment by a thin fibrous cap. The paucity of smooth muscle cells prompted the hypothesis: Do inflammatory mediators inhibit smooth muscle cell collagen synthesis and augment collagen degradation, thereby playing a role in plaque rupture? Evidence implicates molecular mediators of collagen metabolism in atherogenesis. Indeed, because inflammatory cells accumulate at the site of ruptured plaques, and since biomarkers of inflammation predict ACS, macrophages and their associated mediators might play a role in disrupting collagen in the plaque, leading in turn to the ACS. There is evidence that exposure to interferon-γ, a product of activated T cells, strongly inhibits the ability of smooth-muscle cells to make new collagen that is necessary to maintain the integrity of the fibrous cap.


Enzymes from the matrix-metalloproteinase (MMP) family, specifically MMP-1, MMP-8, and MMP-13, have been shown to play a role in the breakdown of collagen in the plaque. Professor Libby indicated evidence that MMP-13 predominates over MMP-8 as the functional interstitial collagenase in mouse atheromata. The T-cell–derived cytokine CD40 ligand has been shown to increase MMP production by human macrophages. There appears to be cross-talk between adaptive immune cells (T cells) and innate immune effector cells (macrophages) in this process. These data, provide a mechanism linking inflammation to the thinning and weakening of the fibrous cap, and precipitation of the ACS event. When a plaque is disrupted, tissue factor triggers thrombin generation and platelet activation and aggregation. The proinflammatory signal that augments collagenase production — CD154 — also induces the expression of tissue factor in macrophages, thereby helping to explain the association between inflammation and the thrombotic complications of atherosclerosis.

Inflammation may also provide a mechanism linking traditional risk factors, including dyslipidaemia, to altered arterial wall function. Given evidence that inflammatory pathways are important drivers of plaque disruption and thrombosis, would targeted anti-inflammatory therapy reduce cardiovascular event rates?

Two ongoing trials are currently testing this hypothesis in the secondary prevention setting. The first of these, Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS), is evaluating canakinumab, a monoclonal antibody that inhibits the endogenous pro-inflammatory protein interleukin-1-beta (IL-1β) in patients with stable coronary artery disease. IL-1β promotes atherothrombosis and also plays a role in the autoimmune process that causes insulin resistance. Currently, 6,000 patients in over 40 countries have been randomised.The second trial is evaluating the use of low-dose methotrexate on top of the current standard of care (including high-dose statin therapy) in stable post-MI patients.

‘CANTOS provides the opportunity to test the inflammatory hypothesis of atherosclerosis, and if positive, may provide a novel therapy to address the residual risk in secondary prevention.’

Ref :
Libby P. Mechanisms of acute coronary syndromes and their implications for therapy. N Engl J Med 2013; 368:2004-2013


↑  Top



The promise of the microRNAs?

In the last decade, there has been an explosion of interest in the microRNAs (miRNAs). These are small RNA molecules, typically 20 to 25 nucleotides in length, which regulate gene expression by repressing or destabilising messenger RNAs by binding to target sites in their untranslated regions.

Targeting specific miRNAs with ‘antisense’ oligonucleotide inhibitors may have potential as a novel class of therapeutics, as overviewed by Professor Kathryn Moore (New York University School of Medicine, USA).


Attention has focused on two related miRNAs, miR-33a and miR-33b. These are located in the sterol-regulatory element-binding factor-2 (Srebf-2) and Srebf-1 genes, respectively. These genes encode for sterol-regulatory element-binding protein-2 (SREBP-2) and SREBP-1, which play key roles in transcriptional regulation of cholesterol uptake and synthesis, and fatty acid oxidation.


Experimental studies have shown that miR-33 post transcriptionally represses key genes involved in cellular cholesterol export and HDL metabolism, fatty acid oxidation and glucose metabolism.1 In mouse peritoneal macrophages, miR-33 and Srebf-2 expression was down-regulated by cholesterol loading, and up-regulated when the macrophages were depleted of cholesterol by treatment with simvastatin. In vivo, in a mouse model, miR-33 levels were inversely correlated with cholesterol levels and positively correlated with Srebf-2 expression. In vitro binding studies to investigate the function of miR-33 showed that it specifically repressed the expression of ABCA1 (ATP-binding cassette A1). Thus, by increasing miR-33 levels in mice, there was a corresponding decrease in hepatic ABCA1 expression and plasma levels of HDL. Alternatively, inhibition of miR-33 expression increased both hepatic ABCA1 expression and plasma levels of HDL and apolipoprotein A-I. These findings have generated much interest in the therapeutic potential of antagonists of miR-33 to raise plasma levels of HDL cholesterol and reduce or slow atherosclerosis. In LDL receptor deficient mice fed a Western diet, treatment with an oligonucleotide inhibitor of miR-33 for 4 weeks increased plasma levels of HDL cholesterol by 35%, and reduced both plaque size and lipid content. Additionally, the lesions in these treated mice showed increased markers of plaque stability, including reduction in pro-inflammmatory M1 macrophages and inflammatory gene expression, and an increase in M2 reparative macrophage markers.
MiR-33b has been shown to inhibit expression of 5′ adenosine monophosphate-activated protein kinase (AMPK), which promotes hepatic fatty acid β-oxidation and inhibits cholesterol and triglyceride synthesis. However, because mice lack miRNA-33b, but it is present in humans, there is a need to investigate this in a more appropriate model, such as the non-human primate. In this model, treatment with anti-miR-33 increased plasma levels of HDL cholesterol by 50% after 8 weeks, with levels sustained for the remainder of the study. Triglyceride-rich lipoprotein levels were also reduced by 50%.

For the future, the focus will undoubtedly be on whether agents targeting miR-33 are translatable to man and are able to impact atherosclerosis clinically.

Effects of microRNAs( and anti miR-33 therapy) on metabolism of liver and on arterial wall

Ref :

  • Rayner KJ, Suarez Y, Davalos A et al. miR-33 contributes to the regulation of cholesterol homeostasis. Science 2010;328:1570-3.
  • Rayner KJ, Sheedy FJ, Esau CC et al. Antagonism of miR-33 in mice promotes reverse cholesterol transport and regression of atherosclerosis. J Clin Invest 2011;121:2921–31.
  • Rayner KJ, Esau CC, Hussain FN et al. Inhibition of miR-33a/b in non-human primates raises plasma HDL and lowers VLDL triglycerides. Nature 2011;478:404-7. doi: 10.1038/nature10486.


↑  Top



Predicting or preventing plaque rupture

Rupture of the vulnerable (unstable) atherosclerotic plaque leading to subsequent thrombotic occlusion of the coronary artery accounts for the majority of acute events. While it is now well recognised that the risk of thrombosis depends more on plaque composition, understanding of the pathophysiology of human atherothrombosis remains incomplete. Improving our ability to prospectively predict plaques at risk of rupture is a key priority, with important implications for prevention and treatment of the ensuing atherothombotic complications.

What causes the unstable plaque to rupture – can we predict this?

Intraplaque haemorrhage, a consequence of neovascularization, is an important determinant of plaque progression and risk for the development of future events. However the key question is: How does intraplaque haemorrhage provoke fibrous plaque rupture?

Intraplaque haemorrhage is the main source of blood-borne mediators of proteolytic and oxidative activity, some of which have been investigated as possible biomarkers of plaque vulnerability. These include matrix metalloproteinases, myeloperoxidase, neutrophil elastase and markers of activated platelets and vascular calcification. However, it should be borne in mind that these are only markers of the specific biology associated with the vulnerable plaque, and are not predictive of plaque vulnerability.

Endothelial shear stress (ESS) is also implicated in the underlying pathophysiology of the vulnerable plaque, as overviewed by Professor Yiannis Chatzizisis, AHEPA University General Hospital, Aristotle University, Thessaloniki, Greece.

Despite the fact that the coronary tree is uniformly exposed to systemic risk factors, atherosclerotic lesions exhibit a focal distribution, predominantly located within the lateral walls of bifurcations, ostia of branches and inner aspect of curvatures of the vascular bed. This suggests the possibility of a dynamic interplay between local haemodynamic factors, and vascular biology. Indeed, there is experimental evidence that low ESS promotes excessive expansive remodelling; thinning of the fibrous cap, and adventitial inflammation, suggesting that it may have a role as a potential predictor of the formation of the vulnerable plaque. Indeed, in the PREDICTION trial, low ESS and increased plaque burden were independent predictors of plaque progression and lumen narrowing; longer-term follow-up is evaluating whether this translates to reduced clinical events. These findings provide a rationale for the development of diagnostic and therapeutic approaches for identifying the vulnerable plaque. The combination of ESS with inflammation may provide a strategy for risk stratification of coronary lesions, as being evaluated in the SMILE project (Combination of Shear Stress and Molecular Imaging of InfLammation to PrEdict High-Risk Atherosclerotic Plaque). Additionally, 3-dimensional optical coherence tomography (OCT) imaging has shown that inflamed plaques develop in regions of low ESS. Taken together, these recent findings hint at the prospect of using ESS, vascular remodelling and inflammation for risk stratification of early fibroatheroma.

Low ESS is a major determinant of high risk plaque formation, by promoting plaque inflammation, increasing collagenolytic activity and leading to fibrous cap thinning and expansive remodeling.
Consequences of low Shear Stress on Endothelium(ESS)

The vulnerable plaque is characterised by the presence of a lipid-rich necrotic core covered by a thin fibrous cap. Both the size of the necrotic core and the thickness of the fibrous cap are important determinants of vulnerability, and therefore key targets for visualisation. However, current non-invasive imaging approaches do not have sufficient resolution. Professor Filippo Crea (Institute of Cardiology, Catholic University of the Sacred Heart, Rome, Italy) overviewed developments aimed at achieving the Holy Grail of prospective identification of plaques at risk of thrombosis. Optical Coherent Tomography (OCT), which offers improved resolution over non-invasive imaging modalities, has advantages.

Coronary Images from OCT ( Left: pathological , Right: Normal)

Further advances in this technology (such as polarisation-sensitive OCT and microOCT, a hybrid imaging) may offer the possibility of evaluating both collagen content and smooth muscle density in the fibrous cap of the plaque. Metabolic-based methodologies, for example those based on assessment of glucose uptake, or more recently, rho kinase activity, may have value in assessment of the biological characteristics of plaques that contribute to plaque evolution.

Ref :

  • Michel JB, Delbosc S, Ho-Tin-Noé B et al. From intraplaque haemorrhages to plaque vulnerability: biological consequences of intraplaque haemorrhages. J Cardiovasc Med 2012;13:628-34
  • Wentzel JJ, Chatzizisis YS, Gijsen FJ, Giannoglou GD, Feldman CL, Stone PH. Endothelial shear stress in the evolution of coronary atherosclerotic plaque and vascular remodelling: current understanding and remaining questions. Cardiovasc Res 2012;96:234-43.
  • Crea F, Liuzzo G. Pathogenesis of acute coronary syndromes. J Am Coll Cardiol 2013;61:1-11.


↑  Top




Diet is the cornerstone of lifestyle approaches.

PREDIMED is a large primary-prevention trial that randomized 7447 patients at high CV risk (but no CVD) to a control diet (including advice to reduce dietary fat) or Mediterranean diet (MedDiet) supplemented with extra virgin olive oil or mixed nuts (walnuts, almonds, and hazelnuts). After 4.8 years, the risk of major CV events (MI, stroke, death from CV causes) was reduced by 30% in the Mediterranean groups combined, compared with the control diet.(see previous reports in our website) Although there has been debate about the study findings, the data reinforce previous studies showing the benefits of a Mediterranean-type diet in preventing cardiovascular disease and type 2 diabetes. Professor Angela A. Rivellese (Federico II University, Naples, Italy) presented new data showing that a diet rich in polyphenols (such as in fruit, vegetables including onions, and tea and coffee) can lower postprandial lipaemia and reduce urinary isoprostanes, a measure of oxidative stress; these findings clearly warrant further study. High adherence to a Mediterranean diet appears to slow the progression of carotid plaque, (as a PREDIMED substudy suggests).

In their latest analysis, Sala-Vila and colleagues looked at plaque volume and mean and maximum internal carotid-artery intima-media thickness (ICA-IMT). ICA-IMT may be a better indication of subclinical atherosclerosis and more predictive of CVD than measurements of common carotid-artery IMT.

A total of 61 patients in the control group, 57 in the MedDiet plus supplementary olive-oil group, and 46 in the MedDiet plus nuts group underwent carotid ultrasound imaging at baseline and after a minimum of two years on their assigned diet.

After controlling for duration of time on the diet and changes in use or dose of statins, investigators saw a significant reduction in carotid plaque in the combined MedDiet group and MedDiet-plus-nuts group, but not in the MedDiet-plus-olive-oil group. A similar pattern was seen in both mean and maximum ICA-IMT

Measurement Control (low-fat diet) MedDiet plus olive oil MedDiet plus nuts Combined MedDiet
Plaque volume (maximum, mm3) +0.137 +0.044 -0.086* -0.013*
ICA-IMT (mean, mm) +0.049 -0.006 -0.076* -0.037*
ICA-IMT (maximum, mm) +0.177 +0.032 -0.023* +0.008*

ICA-IMT=internal carotid artery intima-medial thickness*p<0.05 vs control

Atherosclerosis always progresses in the control group.On IMT, this progression is typically in the range of 0.02 mm per year.So, there is progression in the control group, there is delayed progression in the olive-oil group, and there is a slight regression in the nuts group.


↑  Top



What is the role of functional foods?

As diet is a cornerstone of cardiovascular disease prevention, there have been questions about the potential value of functional foods, specifically foods with added plant sterols/plant stanols (‘phytosterols’). The Joint ESC/EAS guidelines previously indicated that these functional foods (2 g/day) lower low-density lipoprotein (LDL) cholesterol by about 10%.2 Studies have shown consistent LDL cholesterol lowering in statin-treated patients, which is more than the effect of doubling the statin dose (6%). There is also some evidence to suggest a possible benefit on triglycerides.

Recent data from a meta-analysis of Mendelian randomisation studies showed that prolonged exposure to lower LDL cholesterol levels from early life is associated with a substantially greater reduction in the burden of coronary disease than the conventional approach of targeting intervention later in life. Therefore, it could be hypothesised that incorporating foods with added plant sterols/stanols in the diet may offer potential opportunities for reducing the burden of elevated LDL cholesterol and hence lifetime cardiovascular risk.

However, the key issue is whether benefit/risk considerations justify this strategy; also product cost needs to be taken into account. There is an ongoing EAS Phytosterols Consensus Panel initiative which is appraising evidence for the role of these functional foods in dyslipidaemia management.

Undoubtedly the gold standard to show whether lipid changes associated with consumption of phytosterol-added foods translate to reduction in cardiovascular risk is an outcomes trial. However, practically such trials are extremely difficult in a lower risk population, based on power calculations of the number of patients required to show a benefit. Consequently, studies investigating the effects of phytosterol supplementation on surrogate cardiovascular endpoints, such as flow mediated dilatation (FMD), or on measures of arterial structure or function using carotid intima mediate thickness (CIMT), brachial artery size, and arterial stiffness may offer insights. Individually, these studies have generally failed to show benefit, although it should be noted that they were small, mostly of short duration and in several studies, the subjects had normal vascular function at baseline. However, there is some evidence suggestive of benefit when data from six studies that measured FMD were combined.

Given benefit/risk considerations, the key question is whether there are any safety issues associated with the phytosterols. The ATP-binding cassette co-transporters G5 and G8 (ABCG5/ABCG8), play a crucial role in controlling the absorption of plant sterols/stanols. In a long-term (1-year) study in subjects with mild to moderate hypercholesterolaemia, intima media thickness progressed more in those with a specific variation (400K allele) of ABCG8, than in those without it, suggesting a gene-regulated interaction between cholesterol metabolism and vascular function/structure. In addition, evidence from cohort and case-control studies has been conflicting, with suggestion of a pro-atherogenic, neutral or atheroprotective effect. Mechanistically, other studies with endpoints including coagulation, platelet aggregation measures, oxidant stress, inflammation or other biomarkers have failed to show convincing benefit. The EAS Phytosterols Consensus Panel initiative is therefore highly relevant to resolve these ongoing controversies, and their recommendations have the potential to impact public health policy.

Ref :

  • Catapano AL, Reiner Z, De Backer G, et al. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Atherosclerosis 2011;217 Suppl -1:S1-44.
  • Musa-Veloso K, Poon T H, Elliot JA, Chung C. A comparison of the LDL-cholesterol efficacy of plant stanols and plant sterols over a continuous range: Results of a meta-analysis of randomized, placebo-controlled trials. Prostaglandins Leukot Essent Fatty Acids 2011;85:9-28.
  • Scholle JM, Baker WL, Talati R, Coleman CI. The effect of adding plant sterols or stanols to statin therapy in hypercholesterolemic patients: systematic review and meta-analysis. J Am Coll Nutr 2009;28:517-24.
  • Demonty I, Ras RT, van der Knaap HC, Meijer L, Zock PL, Geleijnse JM, Trautwein EA. The effect of plant sterols on serum triglyceride concentrations is dependent on baseline concentrations: a pooled analysis of 12 randomised controlled trials. Eur J Nutr 2013;52:153-160
  • Raitakari OT, Salo P, Gylling H, Miettinen TA. Plant stanol ester consumption and arterial elasticity and endothelial function. Br J Nutr 2008;100:603-8.


↑  Top



Statins in metabolic syndrome: does CAPITAIN offer new insights?

Statins represent the cornerstone of therapy for lowering low-density lipoprotein (LDL) cholesterol, the primary priority for reducing cardiovascular risk. However, in individuals with metabolic syndrome, there are two issues with statin therapy: efficacy against other non-LDL lipids, and the risk of new-onset diabetes.

The relative importance of lipid parameters to attenuation of atheroma was discussed by Professor MJ Chapman (EAS Past-President, INSERM U939, Pitié-Salpetriere University Hospital, Paris, France) at the Special Lecture: Normalising dyslipidemia and reversing atherosclerosis in cardiometabolic disease: Insights from statin pharmacotherapy.

There is clear evidence that the beneficial effects of statins in attenuating atherosclerosis are driven not only by lowering LDL cholesterol, but also by effects on HDL cholesterol and triglyceride-rich lipoproteins, including remnants. Indeed, a recent EAS Consensus Panel paper has highlighted atherogenic dyslipidaemia, the combination of elevated triglyceride-rich lipoproteins and low HDL cholesterol, as a key driver of atherogenic risk in individuals with cardiometabolic disease, such as metabolic syndrome. Thus, to attenuate or reverse atherosclerosis, a multi-targeted approach including LDL, HDL and remnant cholesterol, as well as inflammatory mediators, may be the ideal. Recent controversy has also added another dimension regarding HDL, the quantity versus quality debate.

Thus, it might be argued that the impact of the statin on HDL quantity/quality might be a key determinant of its effects in attenuating atherosclerosis. The VOYAGER analysis indicated that statins that raise HDL to a greater extent may offer improved benefit, against a background of similar dose-related LDL lowering efficacy. In this context, long-term data from phase III studies showing that pitavastatin increases HDL to a greater extent that atorvastatin, provide a rationale to investigate the impact of treatment on the plaque. Supportive evidence from the OPTIMAL and KISHIMEN studies showed that pitavastatin induced favourable changes in the plaque, with greater plaque volume reduction per unit increase in HDL cholesterol, compared with other statins.

Emerging evidence suggests that improving HDL quality might be at least as important as raising HDL cholesterol levels in influencing the attenuation of atherosclerosis in individuals with cardiometabolic disease. Smaller, triglyceride-enriched and cholesteryl-ester depleted HDL associated with the metabolic syndrome have altered apoA-I conformation, increased serum amyloid A, and modified protein components due to oxidation and glycation. Studies have shown that these particles have impaired functionality, i.e. they have less capacity for macrophage cholesterol efflux, as well as impaired anti-oxidative and anti-inflammatory function. This combination of defective HDL function and low HDL cholesterol levels may act synergistically to accelerate atherosclerosis in diabetes. Given this evidence, Professor Chapman challenged whether pitavastatin impacts HDL functionality.

In this context, new data from the CAPITAIN study (Chronic effects of pitavastatin on plasma lipid transport and atheroma biomarkers in patients at elevated risk for the premature development of atherosclerosis) are highly pertinent. CAPITAIN was a hypothesis-generating study in patients at high cardiovascular risk with metabolic syndrome, defined in accordance with the International Diabetes Federation criteria, who were treated with pitavastatin 4mg daily for 6 months. The study had several aims, including investigation of the effects of pitavastatin on plasma biomarkers of inflammation and atherosclerosis, including monocytes, lymphocytes, endothelial adhesion proteins, atherogenic lipoproteins and cardioprotective HDL, as well as effects on glycaemic control. Glycaemic control was assessed by fasting plasma glucose, the Homeostasis Model Assessment (HOMA) index, insulin levels, insulin/glucose ratios, and haemoglobin A1c levels.

Investigation of the HDL lipidome of the CAPITAIN subjects, using a metabolomics approach, was reported by Dr Peter Meikle (Baker IDI Heart and Diabetes Research Institute, Melbourne, Australia) at the Latebreaker session. Pitavastatin improved the plasmalogen content of HDL, which may be associated with improved anti-oxidative capacity of HDL.

In addition, normalisation of the sphingomyelin lipids in HDL may have a favourable impact on surface fluidity of the HDL particle. In concluding the presentation, Dr Meikle suggested these lipodomic changes may translate to improvement in HDL functionality in metabolic syndrome patients.

Two forms of HDL : Anti-inflammatory versus pro-inflammatory

A key concern also relates to the diabetogenic potential of statins. This is especially important in the context of patients with metabolic syndrome, given emerging evidence that low HDL is a key driver of the underlying pathogenesis of diabetes. Findings from the CAPITAIN study that pitavastatin had a neutral effect on glycaemic control in individuals with metabolic syndrome is clearly relevant. Could acting earlier to raise HDL cholesterol levels in the pre-diabetic patient delay progression to diabetes? For a definitive answer, we await the results from the J-PREDICT (Japan Prevention Trial of Diabetes by Pitavastatin in Patients with Impaired Glucose Tolerance) study, which is expected in 2015.

Ref :

  • Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet 2010; 375:735–42.
  • Nicholls SJ, Tuzcu EM, Sipahi I et al. Statins, high-density lipoprotein cholesterol, and regression of coronary atherosclerosis. JAMA 2007;297:499-508.
  • Varbo A, Benn M, Tybjærg-Hansen A, Jørgensen AB, Frikke-Schmidt R, Nordestgaard BG. Remnant cholesterol as a causal risk factor for ischemic heart disease. J Am Coll Cardiol 2013;61:427-36.
  • Kishida K, Funahashi T, Shimomura I. Importance of assessing the effect of statins on the function of high- density lipoproteins on coronary plaque. Cardiovascular & Hematological Disorders Drug Targets 2012;12:28-34.
  • Chapman MJ, Ginsberg HN, Amarenco P et al. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. Eur Heart J 2011;32:1345-61.
  • Barter PJ, Brandrup-Wognsen G, Palmer MK, Nicholls SJ. Effect of statins on HDL-C: a complex process unrelated to changes in LDL-C: analysis of the VOYAGER Database. J Lipid Res 2010;51:1546-53.
  • Teramoto T, Shimano H, Yokote K, Urashima M: New evidence on pitavastatin: efficacy and safety in clinical studies. Expert Opin Pharmacother 2010; 11:817-28.
  • Hattori K, Ozaki Y, Ismail TF et al. Impact of statin therapy on plaque characteristics as assessed by serial OCT, grayscale and integrated backscatter-IVUS. JACC Cardiovasc Imaging 2012;5:169-77.
  • Kishida K, Funahashi T, Shimomura I: Importance of assessing the effect of statins on the function of high-density lipoproteins on coronary plaque. Cardiovasc Hematol Disord Drug Targets 2012, 12:28-34.
  • Meikle PJ, Wong G, Tan AR et al. New insights into statin action on the dyslipidemia of the metabolic syndrome: normalisation of bioactive plasmalogens and sphingolipids in HDL. Abstract 1643, EAS Lyon 2013.


↑  Top



New Drugs to improve management of the high-risk patient

A major focus of EAS Lyon 2013 was how to improve the management of high-risk patients. Although there has been increased uptake of statins, attainment of LDL cholesterol goals in high-risk patients is still far from optimal. In addition, recent studies indicate that statin intolerance is more common than previously thought, highlighting the need for new therapeutic approaches. These data indicate an urgent unmet clinical need, especially relevant in the context of a changing paradigm of cardiovascular risk including patients with genetic dyslipidaemias (such as familial hypercholesterolaemia and familial combined hyperlipidaemia).

Combination lipid-lowering treatment offers benefits over statin monotherapy, especially given the likelihood of polypharmacy in high-risk patients. For example, the EZ-Switch study, showed that switching to the combination of ezetimibe with a statin (atorvastatin 20 mg) resulted in almost 2-fold increase in the proportion of high-risk patients with primary hypercholesterolaemia achieving an LDL cholesterol level <100 mg/dL or 2.6 mmol/L) compared with doubling the dose of atorvastatin (20 mg to 40 mg). The combination of ezetimibe and statin was also well tolerated.

Emerging novel treatments also focus on LDL, the primary lipid priority. These either target LDL production or clearance. The former include lomitapide, a microsomal transfer protein inhibitor and mipomersen, the first systemic antisense therapy to be licensed, which inhibits hepatic synthesis of apolipoprotein B-100, an essential component of the LDL particle. Professor Marina Cuchel (Perelman University of Pennsylvania School of Medicine, USA) overviewed evidence for lomitapide,which is a microsomal triglycerides transport protein (MTP) inhibitor, a protein responsible for transferring triglycerides and phospholipids onto the assembling chylomicron and very low-density lipoproteins in the intestine and the liver, respectively. In the recently reported Phase III study, 23/29 patients completed both efficacy assessment at 26 weeks and long-term safety follow-up after another year.

Treatment with lomitapide at maximum tolerated doses was associated with reduction in LDL cholesterol levels of ~50%, on top of the standard of care including LDL apheresis. Overall, 55% of patients achieved LDL cholesterol levels <2.6 mmol/L (100 mg/dL) and 31% achieved LDL cholesterol levels <1.8 mmol/L (70 mg/dL). LDL reductions were sustained in the long-term even with changes in concomitant treatment allowed after 26 weeks.

The main tolerability issues with lomitapide are gastrointestinal symptoms (the main reason for failure to achieve maximal lomitapide doses), and liver fat accumulation; both are expected given the mode of action of the lomitapide. Liver fat increased from 1% at baseline to 8.6% after 26 weeks, but stabilized at this level for the rest of the study (8.3% at week 78). Elevated transaminases (> 3 x ULN) were reported for 10 patients (34%); four patients had liver transaminases > 5 x ULN, one of whom had elevation >10 x ULN. Most were transient and manageable with temporary dose reduction.


↑  Top



PCSK9 attracted much attention at EAS Lyon

PCSK9 inhibition has emerged as one of the most active lines of investigation in cholesterol research, with promising results in a number of phase 2 trials in heterozygous FH and in patients intolerant to statins. Homzygous FH—a rare heritable disorder that leads to severely elevated LDL-cholesterol and CVD that typically manifests in childhood—is the latest testing ground for this new class of agent.

PCSK9 antibodies work by inhibiting the PCSK9 protein, which binds to LDL receptors, resulting in their degradation so that fewer are available on liver cells to remove excess LDL-C from the blood. Statins, by contrast, actually stimulate the production of PCSK9, which limits their own ability to lower LDL-C. By blocking the PCSK9 pathway, the new monoclonal antibodies upregulate the recycling of LDL receptors, thereby lowering LDL.

As reviewed by Dr Evan Stein (University of Cincinnati, USA), evidence from a series of clinical trials indicates that fully humanised monoclonal antibody therapy to circulating PCSK9, given as a subcutaneous injection every 2 or 4 weeks, results in sustained reduction in plasma LDL cholesterol levels (in excess of 50%) in statin-treated patients with primary or familial hypercholesterolaemia, as well as those with statin intolerance.15-17 To date, there are no significant adverse signals based on safety data from about 1,200 patients treated, although it is acknowledged that longer-term safety data are still needed. To address the issue of long-term efficacy and safety, two large prospective studies have been initiated with the two agents most advanced in development, alirocumab (previously known as REGN727/ SAR236553) in the ODYSSEY Outcomes trial, and AMG 145 in the FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk .

HoFH (Homozygous Familial hypercholesterolemia) is a rare life-threatening condition which is defined clinically by plasma cholesterol levels exceeding 13 mmol/L (500 mg/dL), with extensive cutaneous or tendon xanthomas and markedly premature and progressive cardiovascular disease. HoFH is due to defective or absent LDLR function, most commonly due to mutations in both LDLR alleles, although less frequently, mutations in three other associated genes (APOB and PCSK9) and, more rarely, the autosomal recessive hypercholesterolemia adaptor protein (LDLRAP1), may lead to a similar phenotype. Elevated lipoprotein(a), a cardiovascular risk factor,2 is also closely associated with HoFH.

Even at maximal statin doses, LDL cholesterol levels are usually only lowered modestly, by 10-25% in most patients. Although the addition of ezetimibe can provide an additional 10-15% LDL lowering, additional therapy (bile acid sequestrants and niacin) are usually added in an attempt to provide further LDL cholesterol reduction. However, at best, these have limited efficacy, and there are also issues with adherence and tolerability. Lipid apheresis is undoubtedly the cornerstone of management, but is costly, time-consuming and there are practical limitations, especially in the setting of young patients where it may be impossible to achieve access. Therefore, HoFH confers a substantial burden for the patient.

Speaking at the Educational Symposium: New Strategies for the management of patients with HoFH, Professor Eric Bruckert (Pitié-Salpetriere University Hospital, Paris, France) said:”Despite current management strategies, the prognosis of patients with HoFH remains poor. There is clearly an unmet clinical need for new therapeutic options in these patients.

HoFH affects approximately one in a million people, but some population-screening studies suggest the number is higher, perhaps as high as one in 40 000. The homozygosity is an unbelievably serious disease; it's like cystic fibrosis, with these patients dying at the same age. It's truly the worst disease related to cholesterol.But maybe in five years, or more, it won't be a problem to be a homozygous FH patient anymore.”

The problem, as Prof. E.Stein explained here, is that up to 70% of HoFH patients have defective LDL receptors and 10% are LDL-receptor negative (less than 2% function), so "it is unknown and uncertain whether PCSK9 inhibition will be effective in patients who have minimal or no LDL-receptor function," . In the Late-breaker session, Dr Stein reported data from a proof of concept study in eight HoFH patients treated with the PCSK9 monoclonal antibody AMG 145 (420 mg every 4 weeks for ≥12 weeks, followed by every 2 weeks for an additional 12 weeks).19 Six patients had defective LDL function and two were LDL receptor negative. All were on stable multidrug therapy (high-dose statin plus ezetimibe, in addition to a bile acid sequestrant and/or niacin) for at least 4 weeks before study entry. Among patients with defective LDL receptor function, the average LDL cholesterol reduction was 19.3% after 12 weeks with the 4-weekly dosing regimen, and 26.3% after 12 weeks with the 2-weekly dosing regimen, which compares with the effect of statins in this patient group. No serious side effects or increases in liver and muscle enzymes were reported, despite the doubling of the dose. Given proof of concept, the larger TESLA (Trial to Evaluate PCSK9 Inhibition on LDL-C Achievement in Homozygous Familial Hypercholesterolaemia) study in about 50 patients is now underway.

The EAS Consensus Panel, led by Co-Chairs Professor M. John Chapman, EAS Past-President (INSERM U939, Pitié-Salpetriere University Hospital, Paris, France) and Professor Henry N. Ginsberg (Columbia University, New York, USA), is currently reviewing evidence for HoFH in an ongoing Consensus Panel Initiative.

Ref :

  • European Medicines Agency. Summary of opinion. Lojuxta lomitapide. 30th May 2013.www.ema.europa.eu/docs/en_GB/document_library/Summary of_opinion
  • Nordestgaard BG, Chapman MJ, Ray K, et al; European Atherosclerosis Society Consensus Panel. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J 2010;31:2844-53.
  • Raal FJ, Pilcher GJ, Panz VR et al. Reduction in mortality in subjects with homozygous familial hypercholesterolemia associated with advances in lipid-lowering therapy. Circulation 2011;124:2202-7.
  • Gagne C, Gaudet D, Bruckert E. Efficacy and safety of ezetimibe coadministered with atorvastatin or simvastatin in patients with homozygous familial hypercholesterolemia. Circulation 2002;105:2469-75.
  • Cuchel M, Meagher EA, du Toit Theron H, et al. Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study. Lancet 2013;381:40-6.


↑  Top



Familial LCAT deficiency

The first report of enzyme replacement therapy with ACP-501, a recombinant human lecithin:cholesterol acyltransferase (LCAT) in a patient with familial LCAT deficiency and severe renal dysfunction was reported in the Lyon EAS Congress by Dr Robert Shamburek (Cardiovascular and Pulmonary Branch, National Heart, Lung and Blood Institute, Bethesda, MD, USA). LCAT converts free cholesterol into cholesteryl ester (a more hydrophobic form of cholesterol), which then forms the core of the lipoprotein particle.

Individuals with the rare genetic condition, familial LCAT deficiency, have very low plasma levels of HDL cholesterol, corneal opacities, anaemia, splenomegaly and severe renal disease, the major cause of morbidity and mortality in these individuals.

In this 53-year-old male patient (baseline HDL cholesterol < 5 mg/dL or 0.13 mmol/L, stage 4/5 renal disease and anaemia) ACP-501 (0.9, 3.0, and 9.0 mg/kg as single 1-hour infusions) over 2 weeks, followed by 9 mg/kg every 1-2 weeks, increased plasma HDL cholesterol levels 4-fold (to 24 mg/dL or 0.62 mmol/L), and was associated with improvement in markers of renal function and anaemia. There were no infusion-related reactions. These are promising data in a rare condition for which there are no therapeutic options, other than symptomatic treatment. The company developing the product is also testing the agent in patients with very low HDL and coronary artery disease, demonstrating some early success


↑  Top



HDL: what is the message from trials?

At EAS Milan 2012, HDL cholesterol was very much in the limelight.

This year, the focus was on placing recent trial results in context, as discussed by Professor Chris Packard (University of Glasgow, UK) in the final Plenary session.

The lack of benefit in dal-OUTCOMES21 with the cholesteryl ester transfer protein (CETP) inhibitor dalcetrapib might have related to the nature of the patient population studied, i.e. high-risk patients with acute coronary syndrome (ACS). It is notable that there was a lack of association between baseline HDL cholesterol and cardiovascular events in the placebo group in dal-OUTCOMES, a finding also observed in another trial in ACS patients (IMPROVE-IT). In vitro studies indicate that HDL particles from patients with recent ACS appear to have functionally defective anti-oxidative and anti-inflammatory activities, which may result from the inflammatory milieu associated with ACS. Thus, although dalcetrapib raised HDL cholesterol (by 11 mg/dL versus placebo), the HDL may have been functionally defective in terms of atheroprotective capacity. Ongoing studies are continuing with other CETP inhibitors (anacetrapib and evacetrapib), although both of these also lower LDL cholesterol and Lp(a).

Most recently, HPS2-THRIVE (Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events)22 which investigated niacin/laropiprant in more than 25,000 patients with or at risk of cardiovascular disease, was also negative. There were also significant safety issues (notably, increases in diabetes complications, new-onset diabetes, infections, and gastrointestinal, musculoskeletal, bleeding and skin adverse events) which led to the withdrawal of this treatment in Europe. However, it should be borne in mind that the HPS2-THRIVE patient population was not representative of patients who would have been prescribed niacin in routine practice; the study population was characterised by well-controlled LDL cholesterol (mean 63 mg/dL or 1.6 mmol/L) and did not have low HDL cholesterol (mean 44 mg/dL or 1.15 mmol/L) at baseline.

HPS2-THRIVE design

Ongoing intravascular imaging studies are continuing with other novel therapy targeting HDL, including RVX-208, a first in class small molecule which promotes apolipoprotein A-I synthesis via an epigenetic mechanism involving inhibition of the Bromodomain and Extraterminal Domain (BET) proteins. The ASSURE (ApoA-I Synthesis Stimulation and Intravascular Ultrasound for Coronary Atheroma Regression Evaluation) study is evaluating the ability of RVX-208 to regress atherosclerotic disease versus placebo in high risk patients with cardiovascular disease; data are expected later this year. In addition, CSL-112, an HDL mimetic, has now entered phase II trials.

According to Professor Philip Barter, President of the International Atherosclerosis Society: ‘Despite robust evidence from population studies that HDL cholesterol is a cardiovascular risk factor, the studies to date have been disappointing. Whether these findings may be explained by the nature of the patient population as in dal-OUTCOMES, or the fact that patients were very well-treated in HPS2-THRIVE, is open to debate.’ The studies also underline our so far limited understanding of HDL biology, in contrast to that of LDL. Given promising experimental evidence, perhaps antisense oligonucleotide inhibitors targeting miR-33, which post transcriptionally represses key genes involved in cellular cholesterol export and HDL metabolism, fatty acid oxidation and glucose metabolism, might offer potential, suggested Dr Steve Nissen (Cleveland Clinic, USA), although such studies are very much for the future.

HDL raising as therapeutic target?

• Consistent strong but in part confounded with CHD risk in general populations.
• Variable inverse associations in statin trials when on treatment LDL is very low.
• Insufficient impact : fibrates : 6 % ;niacin :15 % but CETP inhibitors: 30 to 100 %
• HDL is very complex, are we influencing the good subcomponent ?
• Off-target effects?

Ref :

  • The Emerging Risk Factors Collaboration. Major lipids, apolipoproteins, and risk of vascular disease. JAMA 2009;302:1993–2000.
  • Barter P, Gotto AM, LaRosa JC et al, Treating to New Targets Investigators. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med 2007; 357:1301–10.
  • Catapano AL, Reiner Z, De Backer G, et al. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Atherosclerosis 2011;217 Suppl 1:S1-44.
  • Schwartz GG, Olsson AG, Abt M et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med 2012;367:2089-99.
  • Cannon CP, Braunwald E, McCabe CH et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004; 350:1495-504.
  • The AIM-HIGH Investigators. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. New Engl J Med 2011; 365:2255-67.
  • HPS2-THRIVE results, Presented as a late-breaker at the American College of Cardiology Scientific Sessions, March 10, 2013. Results available at www.thrivestudy.org.


↑  Top



Therapies under investigation( with results soon)

A renin inhibitor (aliskerin)
An ApoA1 inducer (RVX-208)
A wild type ApoA1 mimetic (CER -201)
An HDL mimetic derived from plasma (CSL-112)


↑  Top



Lp(a) and diabetes

In a previous position statement, the EAS Consensus Panel concluded that Lp(a) was a cardiovascular risk factor. However, a paradoxical inverse association of Lp(a) levels with risk of type 2 diabetes, was reported from combined analysis of the Women’s Health Study and the Copenhagen City Heart Study.

A study reported by Dr Pia Kamstrup (Herlev Hospital, Copenhagen University Hospital, University of Copenhagen, Herlev, Denmark) aimed to investigate whether it was plasma Lp(a) levels per se or the genetics of kringle IV type 2 (KIV-2) responsible for this finding. Investigators used a Mendelian randomisation approach, with Lp(a) data from 77,901 individuals (including 4,078 with type 2 diabetes) from two large general population studies, the Copenhagen City Heart Study and the Copenhagen General Population Study. Two genetic instruments that directly relate to KIV-2 (Lp(a) isoform size and levels), as well the single nucleotide polymorphism rs10455872 genotype (mainly Lp(a) levels) were also included in the analysis.

Structure of isoforms of Lp(a)

KIV-2 genetic variance was shown to be causally related to type 2 diabetes risk, whereas low Lp(a) levels per se were not. These findings imply that it is the genetic structure of Lp(a), i.e. the LPA KIV-2 genotype, that is the cause of the association of Lp(a) with increased risk of diabetes. Based on these data, it could be concluded that lowering Lp(a) levels to prevent cardiovascular disease is unlikely to increase the risk of type 2 diabetes.


↑  Top



Suggested articles from the 81st EAS Congress

  1. Ahmed HM, Blaha MJ, Nasir K et al. Low-risk lifestyle, coronary calcium, cardiovascular events, and mortality: results from MESA. Am J Epidemiol. 2013; June 10 (Epub ahead of print] doi:10.1093/aje/kws453.
  2. Catapano AL, Reiner Z, De Backer G et al. ESC/EAS Guidelines for the management of dyslipidaemias. The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Atherosclerosis 2011;217:3-46.
  3. Brady AJ, Perry C, Murdoch DL, McKay G. Sustained benefits of a health project for middle-aged football supporters, at Glasgow Celtic and Glasgow Rangers Football Clubs. Eur Heart J 2010;31:2696-8.
  4. Estruch R, Ros E, Salas-Salvado J; PREDIMED Investigators. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med 2013;Epub ahead of print 25 February, 2013.
  5. Trichopoulou A, Bamia C, Trichopoulous D. Mediterranean diet and survival among patients with coronary heart disease in Greece. Arch Intern Med 2005; 165: 929-35
  6. Giugliano D, Esposito K. Mediterranean diet and metabolic diseases. Curr Opin Lipidol 2008; 19: 63-8.
  7. Musa-Veloso K, Poon T H, Elliot JA, Chung C. A comparison of the LDL-cholesterol efficacy of plant stanols and plant sterols over a continuous range: Results of a meta-analysis of randomized, placebo-controlled trials. Prostaglandins Leukot Essent Fatty Acids 2011;85:9-28.
  8. Scholle JM, Baker WL, Talati R, Coleman CI. The effect of adding plant sterols or stanols to statin therapy in hypercholesterolemic patients: systematic review and meta-analysis. J Am Coll Nutr 2009;28:517-24.
  9. Demonty I, Ras RT, van der Knaap HC, Meijer L, Zock PL, Geleijnse JM, Trautwein EA. The effect of plant sterols on serum triglyceride concentrations is dependent on baseline concentrations: a pooled analysis of 12 randomised controlled trials. Eur J Nutr 2013;52:153-160.
  10. Ference BA, Yoo W, Alesh I et al. Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease: a Mendelian randomization analysis. J Am Coll Cardiol 2012;60:2631-9.
  11. Kotseva K, Wood D, De Backer G, De Bacquer D, Pyorala K, Keil U, on behalf of EUROASPIRE Study Group. Cardiovascular prevention guidelines-the clinical reality: a comparison of EUROASPIRE I, II and III surveys in 8 European countries. Lancet 2009;372:929–40.
  12. Zhang H, Plutzky J, Skentzos S et al. Discontinuation of statins in routine care settings: a cohort study. Ann Intern Med 2013;158:526-34.
  13. Mansi IA, Mortensen EM, Pugh MJ, Wegner M, Frei CR. Incidence of musculoskeletal and neoplastic diseases in patients on statin therapy: results of a retrospective cohort analysis. Am J Med Sci 2013;345:343-8.
  14. Farnier M, Averna M, Majul C et al. Efficacy and safety of ezetimibe added to atorvastatin versus atorvastatin up-titration or switching to rosuvastatin in patients with primary hypercholesterolemia at high cardiovascular risk (the EZ-Switch Study). Poster presented at EAS Lyon 2013.
  • McKenney JM, Koren MJ, Kereiakes DJ et al. Safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy. JACC 2012;59:2344–53.
  • Roth EM, McKenney JM, Hanotin C, Asset G, Stein EA. Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia.N Engl J Med 2012;367:1891-¬‐1900.
  • Raal F, Scott R, Somaratne R, Bridges I, Li G, Wasserman SM, Stein EA. Low-density lipoprotein cholesterol-lowering effects of AMG 145, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease in patients with heterozygous familial hypercholesterolemia: the Reduction of LDL-C with PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder (RUTHERFORD) randomized trial. Circulation 2012;126:2408–17.
  • Raal FJ, Pilcher GJ, Panz VR et al. Reduction in mortality in subjects with homozygous familial hypercholesterolemia associated with advances in lipid-lowering therapy. Circulation 2011;124:2202-7.
  • Stein EA, Honarpour N, Wasserman SM, Xu F, Scott R, Raal F. Trial evaluating AMG 145, a PCSK9 antibody, in patients with homozygous FH: results of an initial dose-scheduling study. EAS Lyon 2013, 2-5 June, Abstract 1625.
  • Shamburek R, Bakker-Arkema R, Krause B, Auerbach B, Freeman L, Homan R, Asztalos B, Schaefer E, Schwartz C, Amar M, A. Remaley A. First report of enzyme replacement therapy in a patient with familial LCAT deficiency. Rapid improvement of lipid and clinical manifestations. EAS Lyon 2-5 June, Abstract 1635.
  • Schwartz GG, Olsson AG, Abt M et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med 2012;367:2089-99.
  • HPS2-THRIVE Collaborative Group. HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of ER niacin/laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment. Eur Heart J 2013;341279-91.
  • Elkind MS. Infectious burden: a new risk factor and treatment target for atherosclerosis. Infect Disord Drug Targets 2010;10:84-90.
  • Kozarov E. Bacterial invasion of vascular cell types: vascular infectology and atherogenesis. Future Cardiol 2012;8:123-38.
  • Kozarov E, Kalachikov S, Morozov A, Chalmers N, Chien M. Metagenomics reveals gut signatures in atherosclerosis microbiome. EAS LYON 2013, Abstract 758.
  • Greiner T, Backhed F. Effects of the gut microbiota on obesity and glucose homeostasis. Trends in Endocrinology and Metabolism 2011;22:117-23.
  • Kallus SJ, Brandt LJ. The intestinal microbiota and obesity. J Clin Gastroenterol 2012;46:16-24.
  • Nordestgaard BG, Chapman MJ, Ray K et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J 2010;31:2844-53.
  • Mora S, Kamstrup PR, Rifai N, et al. Lipoprotein(a) and risk of type 2 diabetes. Clin Chem2010;56:1252-60.
  • Kamstrup PR, Nordestgaard BG. Lipoprotein(a) is causally associated with type 2 diabetes. EAS LYON 2013. Abstract 1177.

    ↑  Top