Featured Commentary

Issue No. 5; 2011

First joint ESC/EAS guidelines for dyslipidemia published

A key highlight of this year’s meeting was presentation of the First Joint ESC/EAS Guidelines for the Management of Dyslipidemia. The guidelines were presented at the Wednesday Plenary session and discussed at a Post-Congress Satellite, and were simultaneously published in Atherosclerosis¹ and the European Heart Journal.² The guidelines have been reported by nearly 30 news agencies including theheart.org. The key points of the guidelines are summarized:

• Categorisation of cardiovascular risk into four levels: - very high, high, moderate or low risk, as defined by SCORE.
• Reaffirmation of low-density lipoprotein (LDL) cholesterol as the primary lipid target; with specific goals defined according to risk category:

- Very high risk: <1.8 mmol/L (≈70 mg/dL) and/or at least 50% reduction if this target cannot be reached
- High risk: <2.5 mmol/L (≈100 mg/dL)
- Moderate risk <3.0 mmol/L (≈115 mg/dL).
Non-HDL cholesterol and apolipoprotein B were recommended as alternative targets to LDL cholesterol, especially in patients with type 2 diabetes, metabolic syndrome or combined dyslipidemia. The targets for non-HDL cholesterol are 0.8 mmol/L (≈30 mg/dL) higher than the corresponding LDL cholesterol target. For apoB, the targets are <80 mg/dL and <100 mg/dL in patients at very high or high total cardiovascular risk.

• Recognition of the importance of managing low plasma levels of high-density lipoprotein (HDL) cholesterol and elevated triglycerides, atherogenic dyslipidemia. Indeed, in the Post-Congress Satellite, Professor Marja-Riitta Taskinen, Biomedicum, Helsinki, Finland, a member of the Guidelines Writing Group highlighted atherogenic dyslipidemia as the major cardiovascular risk factor in individuals with type 2 diabetes and metabolic syndrome. This emphasis is consistent with the recent European Consensus Panel paper which recognised the high cardiovascular risk associated with elevated triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in high-risk individuals despite levels of low-density lipoprotein (LDL) cholesterol at target.³

• Renewed importance of lifestyle as the first key step for prevention of cardiovascular disease. For the first time, guidelines have included specific recommendations for the inclusion of functional foods - phytosterol-enriched foods (1-2 g/day) - in individuals with elevated total and LDL cholesterol levels which may not justify the use of cholesterol-lowering pharmacotherapy. More recently, a study in Circulation⁴ has highlighted the potential importance of dietary phytosterols as adjunctive therapy for hypercholesterolemia. In this study, phytosterol supplementation significantly enhanced the effects of ezetimibe on lowering plasma levels of LDL cholesterol in individuals with mild hypercholesterolemia.

Phytosterol-supplementation might have other benefits beyond lipid-lowering, as suggested by findings from the RECIPE (Reduce Cholesterol Involving Patient Endorsement) study, a prospective observational study.⁵ In the first report from this study based on data from 1,048 patients (median age 56 years, 57% female), regular intake of phytosterol-supplemented yoghurt as part of a comprehensive lifestyle modification programme not only improved the lipid profile, but also acted as a tool to help hypercholesterolemic patients sustain improvements in lifestyle likely to positively impact on their cardiovascular risk (Fig 1).

Fig 1. RECIPE study: Phytosterol supplementation as part of intensive risk factor modification programme helped to sustain improvements in body mass index (BMI) and waist circumference

• Diagnosis and treatment of genetic dyslipidemias. This is the first time that guidelines have included guidance relating to the diagnosis and management of a range of genetic dyslipidemias. In particular, the guidelines draw attention to familial combined hyperlipidemia, characterised by high LDL cholesterol, high triglycerides or both, which affects about one in 100 people. In many cases, this is only diagnosed after the individual has been admitted to the coronary care unit with an acute myocardial infarction.

A clinician’s pocket guide is being prepared as a practical reference to the guidelines and should be available shortly.

Hot topic: HDL particle functionality

HDL functionality was a ‘hot topic’ at EAS2011. Indeed, some experts suggested that HDL functionality was at least as relevant to cardiovascular risk as plasma levels of HDL cholesterol. This thinking is supported by experimental evidence showing that HDL have a spectrum of potentially atheroprotective, vasculoprotective and antithrombogenic activities. Indeed, a recent study, reviewed in the January EAS newsletter, showed that the capacity of HDL to promote cellular cholesterol efflux was independently predictive of a decrease in carotid intima media thickness and risk of coronary artery disease. This association remained robust even when HDL cholesterol levels were included as a covariate in the model.⁶

In the Monday plenary session, Professor M. John Chapman, EAS President, reviewed evidence that the functional significance of HDL subpopulations reflects the integrated biological activity of both lipid (lipidome) and protein (proteome) components. This may be especially relevant in the context of cardiometabolic disease associated with atherogenic dyslipidemia. Emerging evidence suggests that in individuals with atherogenic dyslipidemia, HDL - especially small, dense protein-rich HDL3 particles - are less capable of protecting LDL against oxidative modification.⁷ However, Professor Chapman stressed that these particles although functionally defective, do not exhibit a complete lack of function and are not pro-inflammatory. Cholesteryl ester transfer protein (CETP) plays a key role in driving the production of small, triglyceride-rich HDL on a background of elevated CETP activity.

CETP is at the heart of the lipid modulating action of niacin and statins. Statins mainly shift the spectrum of HDL particles towards HDL2 with reduction in smaller particles, enhanced lipidation and prolonged residence time of apolipoprotein A-I. This is due to both reduction in the numbers and concentration of acceptor particles such as VLDL and LDL for CETP-mediated transfer of cholesteryl ester from HDL, as well as reduction in the mass of CETP. Niacin increases larger HDL particles to a greater extent than either statins or fibrates, decreases small pre beta HDL particles, and is also a strong driver of apo-AI production; the corresponding increase in HDL cholesterol levels are mediated via CETP, via reduction in mass and activity by up to 30%.

Professor Chapman identified a number of key challenges for future research in this area. These include investigating key abnormalities in the HDL particle profile in patients with cardiometabolic disease throughout the atherosclerotic process, as well as defining the optimal profile of HDL particles in healthy subjects at low cardiometabolic risk. The latter will be of benefit in the development of personalised therapies, targeted to optimise HDL protection across a wide range of patient phenotypes at high cardiometabolic risk.

Gut microbioata: future therapeutic target?

Emerging evidence suggests that the human gut microbiota may be an environmental factor influencing obesity. For example, studies showed that germ-free mice had 40% less total body fat than normal mice, even if their calorie intake was almost one-third higher. Additionally, when germ-free mice were fed a high-fat, high-carbohydrate Western diet, they were protected against diet-induced obesity, glucose intolerance and insulin resistance. These data were reviewed during the Monday plenary session by Professor Fredrik Bäckhed, Sahlgrenska Center for Cardiovascular and Metabolic Research/Wallenberg Laboratory, University of Gothenburg, Sweden.

Although the mechanism(s) of these effects is not yet fully understood, data implicate an inhibitor of adipose tissue lipoprotein lipase, fasting-induced adipose factor (FIAF, also known as angiopoietin-like protein 4). This is supported by evidence that the expression of FIAF was increased in germ-free mice and there was also activation of hepatic and muscle fatty acid oxidative pathways. These effects may be mediated via an effect on host lipid metabolism, in turn modulating the expression of genes involved in bile acid secretion, as well as effects due to low-grade endotoxins from the bacteria which counteract inflammation. These emerging data on suggest the possibility of new therapeutic approaches mediated via the gut microbiota for preventing atherosclerotic heart disease.

New directions in treating vulnerable plaque

This was the focus of the Tuesday plenary session. Professor Ira Tabas, the Richard J. Stock Professorship, Department of Medicine of Columbia University, New York, USA has been investigating how vulnerable plaque could be identified earlier in an attempt to avert plaque rupture and the associated clinical sequaleae. In particular, his interest relates to the cellular mechanisms underlying the necrotic core formation, most notably, the defective phagocytosis response, “efferocytosis”.Work from his group suggests that several mechanisms may be relevant, including oxidative stress, lipoprotein-associated hydrolysis of oxidized phosphatidylserine on the surface of apoptotic cells by phospholipase A2, as well as protease-mediated cleavage of efferocytosis receptors.

However, macrophages are not the only cells that undergo phagocytosis. Immature dendritic cells have also been shown to be very good efferocytes. Studies showed that about one-third of the cells in atherosclerotic lesions have markers of dendritic cells. These lesional dendritic cells activate T cells in the lesion, and are also capable of proliferation and foam cell formation. Using an experimental model, Professor Tabas and his group were able to show that blocking the maturation of dendritic cells resulted in defective phagocytosis. Ultimately, understanding this process may help in delineation of possible therapeutic targets that impact efferocytosis and atherosclerosis progression.

Dr James Rudd, Senior Lecturer and Consultant in Cardiology at Addenbrooke's Hospital and the University of Cambridge, UK overviewed new approaches to imaging early vulnerable plaque. These include the use of positron emission tomography (PET) using 2-[18]-fluoro-2-deoxy- D-glucose PET (PET/FDG), an analogue of glucose which accumulates in cells that actively metabolise glucose. Recent studies show that FDG uptake can be used as a surrogate marker of carotid plaque inflammation and for vascular risk in patients with acute coronary syndrome. FDG PET may also have application in evaluation of the early efficacy of anti-atheroma drugs. In a recent study, 18-F FDG PET-CT was a surrogate marker in the assessment of changes in vascular inflammation associated with treatment with losmapimod.⁸

Finally, Professor Peter Libby, Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, USA discussed the potential of new anti-inflammatory therapies for treating atherosclerosis and reducing residual cardiovascular risk.

Two randomized, placebo-controlled trials are testing whether anti-inflammatory agents normally used in other indications may have potential. The Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) is evaluating canakinumab, an 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. The primary endpoint is major cardiovascular events, defined as recurrent MI, stroke and cardiovascular-associated death. A second trial, the Cardiovascular Inflammation Reduction Trial (CIRT) 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. Professor Libby concluded that despite considerable advances in the diagnosis and treatment of vulnerable plaque, much remains to be done to translate these experimental findings to clinical practice.

BMI as a biomarker for heart disease risk

In the Wednesday plenary session, Professor Borge Nordestgaard, Copenhagen City Hospital, University of Copenhagen, provided interesting data showing that BMI is preferable to C-reactive protein (CRP) in evaluating cardiovascular disease risk.

In an analysis based on data from over 71,000 Danish subjects in three large observational studies, the Copenhagen General Population study, the Copenhagen City Heart study and the Copenhagen Ischaemic Heart Disease study, he demonstrated a simple cause and effect relationship between BMI and ischaemic heart disease (IHD) risk.

Using an observational analysis approach, for every 4 kg/m² increase in BMI there was a 26% increase in risk of IHD. The investigators then evaluated the effect of specific genes known to be associated with obesity (FT0, MC4R, TMEM18), on IHD risk. The greater the frequency of these alleles, the greater the risk of IHD; individuals with 3 or 4 alleles (of 6 in total) had 20-22% increase in IHD risk. When the data were analysed using an instrumental variable approach, taking into account the effect of these genes, each 4 kg/m² increase in BMI was associated with a 52% increase in IHD risk. These data have practical relevance, as BMI is a simple marker that can be easily measured in routine practice, with potential impact on public health policy.

New light on ILLUMINATE: CETP inhibition improves glycaemic control

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A post hoc analysis of the ILLUMINATE (Investigation of Lipid Level Management to Understand Its Impact in Atherosclerotic Events) trial showed that the CETP inhibitor, torcetrapib, improves glycaemic control in statin-treated diabetic patients.⁹ These data were previously presented EAS2011 at the Anitschkow Lecture given by Professor Philip Barter, this year’s recipient of the award.

A key question remains: is this effect is due to an increase in HDL cholesterol levels resulting from CETP inhibition or to an off-target effect of torcetrapib unrelated to CETP inhibition?

Previous experimental studies have suggested that HDL may contribute to pancreatic beta-cell function, raising the possibility that HDL might have antidiabetic properties.^10-12 Additionally, observational studies showed that in individuals with genetic CETP deficiency, markedly elevated HDL cholesterol levels were also associated with decreased plasma glucose levels.¹³ These findings provided the rationale for a post hoc analysis of the ILLUMINATE database to investigate the effects of torcetrapib on glycaemic control in 6661 diabetic statin-treated patients.

In the atorvastatin monotherapy group, there was a progressive increase in plasma glucose and HbA_1c, as well as deterioration in insulin levels and insulin resistance. These findings were consistent with a recent meta-analysis showing that statins have a detrimental effect on glycaemic control (although it should be borne in mind that the clinical benefits of statin therapy outweigh these effects).¹⁴ However, in the atorvastatin-torcetrapib group there was improvement in glycaemic control, as indicated by significant decreases in glucose and HbA_1c, and decreases in serum insulin levels (mean decrease vs. atorvastatin 11.7 µU/mL, p=0.0007) and insulin resistance (mean decrease vs. atorvastatin 4.46, p<0.0001). These effects were evident after only one month and sustained for 12 months (p<0.0001) (Figs. 2 and 3).

Adjustment for HDL cholesterol attenuated the effects of torcetrapib on glucose, HbA_1c and serum insulin, suggesting that there might be a threshold for HDL cholesterol above which there is no further benefit.

Fig.2 Impact of torcetrapib on plasma glucose in ILLUMINATE post hoc analysis


Fig.3 Impact of torcetrapib on HbA_1c in ILLUMINATE post hoc analysis

It needs to be borne in mind that this is a post hoc analysis, and therefore interpretation of the findings should be made with caution due to the usual limitations associated with this type of analysis. However, given that the direction of these effects of CETP inhibition with torcetrapib on diabetic control were consistent and sustained across 12 months implies that this is a real finding. However, the analysis does not answer the question whether this antidiabetic effect is attributable to HDL functionality, or an off-target effect of torcetrapib.

The analysis also poses another leading question. Do these findings seen with torcetrapib also apply to other CETP inhibitors? These is especially relevant in the light of ongoing trials with dalcetrapib (dal-OUTCOMES) and anacetrapib (HPS 3-REVEAL-TIMI 55), neither of which appear to share the safety concerns of torcetrapib.^15,16 Professor Barter stressed the importance of future analyses of these trials to address this question.

Dalcetrapib in high-risk patients with type 2 diabetes mellitus and/or metabolic syndrome

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Dalcetrapib raised HDL cholesterol levels to similar extents in patients with and without type 2 diabetes or metabolic syndrome, according to a post hoc pooled analysis of Phase II trials, published ahead of print in Diabetes, Obesity and Metabolism.¹⁷

Data from 5 previous trials of dalcetrapib (600 mg/day or 900 mg/day) in combination with statin therapy. The duration of treatment was 4 weeks (3 trials), or 12 or 48 weeks (one trial each). The patients were dyslipidemic according to the individual study definitions or were considered at high cardiovascular risk (coronary heart disease [CHD] or CHD risk equivalents or Framingham 10-year CHD risk >20%). In total, 651 were included in a pooled 4-week analysis, of whom 63% (409) had type 2 diabetes and/or metabolic syndrome at baseline. 79% of 135 patients included in a 24-week analysis had type 2 diabetes/metabolic syndrome. At baseline, HDL cholesterol levels were similar irrespective of the presence of type 2 diabetes/metabolic syndrome, although triglycerides were higher in those with these conditions.
Dalcetrapib increased HDL cholesterol by 23-34% depending of the dose and duration of treatment. Increases in HDL cholesterol were similar regardless of type 2 diabetes/metabolic syndrome status (Fig 4).

Fig 4. Percent change in HDL cholesterol levels in patients with and without type 2 diabetes/metabolic syndrome: results from a post-hoc analysis of 5 trials

In the 48-week study, treatment with dalcetrapib 900 mg/day was associated with ≈26% reduction in triglyceride level relative to placebo (statin alone) in patients with type 2 diabetes/metabolic syndrome versus ≈19% reduction in those without. There was no significant effect on LDL cholesterol or apolipoprotein B levels across the cohorts. Dalcetrapib reduced CETP activity by 26–58%, depending on dose, and to a similar extent in patients with and without type 2 diabetes and/or metabolic syndrome.

Dalcetrapib was generally well tolerated, with an adverse event profile that was similar regardless of type 2 diabetes/metabolic syndrome status. There were no significant treatment-related increases in blood pressure or aldosterone levels, consistent with previous reports.^15,18

The findings from this post hoc analysis indicate that dalcetrapib is effective and well tolerated in high-risk individuals with type 2 diabetes and/or metabolic syndrome. Definitive data are awaited from pre-planned analysis of patients with type 2 diabetes/metabolic syndrome in the dal-OUTCOMES trial.

ESC 2011

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Two key trials with dalcetrapib – dal-VESSEL and dal-PLAQUE - are reported at ESC 2011.

• Dal-VESSEL investigated the effects of treatment with dalcetrapib on vascular function in statin-treated patients with low HDL cholesterol and appropriately treated LDL cholesterol. The primary efficacy variable was brachial flow-mediated dilatation, a validated marker of endothelial function. The primary safety objective was to evaluate the effect of dalcetrapib on blood pressure as measured by 24-hour ambulatory blood pressure monitoring at week 4. Patients were treated for a total period of 36 weeks.
• Dal-PLAQUE investigated the effect of dalcetrapib on atherosclerotic plaque inflammation at 6 months using PET/CT and on plaque burden/progression after 12 months using MRI. Patients received treatment for 24 months. investigated the effect of dalcetrapib on atherosclerotic plaque inflammation at 6 months using PET/CT and on plaque burden/progression after 12 months using MRI. Patients received treatment for 24 months.

EAS will be reporting on these and other trials at ESC in the next newsletter.