This year’s annual European Society of Cardiology (ESC) Congress hit a new record, with over 33,000 delegates from across all continents attending this key event in the cardiologist’s calendar. The start of the Congress was also when the eagerly awaited update to the 2011 Joint ESC/European Atherosclerosis Society (EAS) Guidelines for Dyslipidaemia Management was published (1). The guidelines are very much aligned with the Joint Task Force Guidelines for Cardiovascular Disease Prevention launched earlier this year (2), but add important information in a number of areas. Both guidelines highlight the importance of population approaches for lowering lipids, with lifestyle intervention as the fundamental first step in cardiovascular disease prevention.
Key message 1: Lifestyle intervention: Adherence is key
The effect of dietary components on plasma lipids has been expanded from the previous version of the guidelines. Of dietary approaches, the Mediterranean diet and Dietary Approaches to Stop Hypertension (DASH) diet are regarded as the gold standards in preventive medicine, the latter diet especially in relation to blood pressure control. Both feature a high intake of fruit, vegetables and wholegrain cereal products and moderate intake of legumes, nuts, ﬁsh, poultry and low fat dairy products, with limited sweets, sugar-sweetened drinks and red meat.
Previous findings from the PREDIMED study clearly showed the benefits of such an approach in primary prevention patients at high cardiovascular risk, with a 30% reduction in the risk of major cardiovascular events (notably stroke) with the addition of extra virgin olive oil or nuts to a control diet versus control diet alone (3). Added to this, new results from the observational Moli-Sani study show that these benefits also extend to the secondary prevention setting (4). In 1,197 individuals with a history of cardiovascular disease followed for a median of 7.3 years, there was a 21% reduction in mortality among those with increased adherence to a Mediterranean style diet (defined as a 2-point increase in the 9-point Mediterranean diet score), even after controlling for a number of confounders including age, energy intake, leisure time physical activity, waist-to-hip ratio, and conventional cardiovascular risk factors at baseline. Importantly, individuals with the highest adherence to this diet (i.e. with a score of 6–9) had a 37% reduction in mortality compared with those in the bottom category (0–3). Despite the inherent limitations associated with observational study design, it is clear that the benefits gained by adherence to a Mediterranean style diet may outweigh the effects of treatment with a statin, of particular relevance for patients at low risk with only moderately elevated cholesterol levels (5). Further support comes from 10-year follow-up data from the ATTICA study, in which strong adherence to the Mediterranean diet was shown to moderate the impact of increasing age on cardiovascular risk (6).
Physical activity is also a key component of lifestyle intervention. A report earlier this year showed that among younger women (aged <45 years at baseline in 1991) moderate physical activity (brisk walking for at least 2.5 hours per week) led to 35% reduction in the risk of coronary heart disease over 20 years compared with women who did not exercise. Importantly, this association was independent of body weight, reinforcing the value of regular physical activity, irrespective of whether individuals are normal weight, overweight or obese (7). Results from the FINRISK Study in 2,409 older men and women (aged 65-74 years), which were presented at the ESC Congress 2016, add to this (8). Over an 11.8 year follow up, individuals who sustained moderate physical activity had a 31% reduction in the risk of a cardiovascular event, as well as 54% reduction in the risk of cardiovascular death compared with those with low activity. The current 2016 ESC/EAS guidelines recommend at least 30 minutes of physical activity every day; however, even less than this may benefit individuals who are typically sedentary every day (probably most office workers) (9).
For all lifestyle intervention the challenge is how to improve and sustain adherence. The 2016 ESC/EAS Guidelines for Management of Dyslipidaemia place a premium on the role of the clinician in education, support and monitoring to ensure adherence, and offer hints to aid adherence with lifestyle changes (see Table 1) (1). Clinicians should also be aware of socio-economic, cultural and environmental factors that may affect the patient’s ability to change their lifestyle, and be prepared to spend dedicated time to support and follow-up patients. Finally, policy changes may be relevant, as in the case of food labelling, to encourage healthier dietary behaviour (10).
Table 1. Hints to improve adherence to lifestyle change
|• Explore motivation and identify ambivalence to change: weigh up the pros and cons, and build up the patient’s self-efficacy and confidence.|
• Offer support and establish an alliance with the patient and his/her family.
• Involve the partner, other household members or caregiver who may be influential in the lifestyle of the patient.
• Use the OARS method (Open-ended questions, Affirmation, Reflective listening, Summarising; http://www.smartrecovery.org/resources/UsingMIinSR.pdf) when discussing behaviour changes.
• Tailor advice to an individual patient’s culture, habits and situation.
• Use SMART goal setting–negotiate goals for change that are Specific, Measurable, Achievable, Realistic and Timely. Follow up on goals and record progress on a shared record.
|Source: Catapano AL et al (1).|
Key message 2: LDL and atherosclerotic cardiovascular disease
The 2016 ESC/EAS Guidelines for Management of Dyslipidaemia clearly state that low-density lipoprotein (LDL) is causal to atherosclerotic cardiovascular disease (ASCVD), and thus remains the primary target for intervention. Individual LDL cholesterol targets, based on global risk (as defined by co-morbidities and 10-year risk of fatal cardiovascular disease), remain the same as per the previous guidelines, i.e. <2.6 mmol/L (100 mg/dL) in high risk and <1.8 mmol/L (70 mg/dL) in very high risk patients (for definition of these groups, see Table 2). Furthermore, for both high risk and very high risk patients, at least 50% reduction from baseline in LDL cholesterol should also be achieved (1).
Table 2. Global risk and LDL-C targets
|Risk category||Definition||LDL-C targets|
|Very high risk||• Documented CVD*|
• Diabetes mellitus with target organ damage (e.g. proteinuria) or with a major risk factor (i.e. smoking, hypertension or dyslipidaemia).
• Severe chronic kidney disease (CKD, i.e. glomerular filtration rate (GFR) <30 mL/min/1.73 m2).
• Calculated SCORE ≥10% for 10-year risk of fatal CVD.
|<1.8 mmol/L (70 mg/dL) or a reduction of ≥50% if the baseline is between 1.8 and 3.5 mmol/L (70 and 135 mg/dL|
|High risk||• Markedly elevated single risk factors, in particular cholesterol >8 mmol/L (>310 mg/dL) (e.g. in familial hypercholesterolaemia) or blood pressure ≥180/110 mmHg|
• Most other people with diabetes mellitus (some young people with type 1 diabetes may be at low or moderate risk).
• Moderate CKD (GFR 30–59 mL/min/1.73 m2).
• A calculated SCORE ≥5% and <10% for 10-year risk of fatal CVD.
|<2.6 mmol/L (100 mg/dL) or a reduction of ≥50% if the baseline is between 2.6 and 5.2 mmol/L (100 and 200 mg/dL)|
|Moderate risk||• SCORE ≥1% and <5% for 10-year risk of fatal CVD||<3.0 mmol/L (115 mg/dL)|
|Low risk||• SCORE <1% for 10-year risk of fatal CVD||<3.0 mmol/L (115 mg/dL)|
|*Documented cardiovascular disease (CVD) is defined as clinical or unequivocal on imaging. This includes previous myocardial infarction, acute coronary syndrome, coronary revascularisation, coronary artery bypass graft surgery and other arterial revascularization procedures, stroke and transient ischaemic attack (TIA), and peripheral arterial disease (PAD).|
Statins are the mainstay of pharmacotherapy to lower LDL cholesterol levels to prevent cardiovascular disease. Adding ezetimibe is the recommended second-line therapy, supported by evidence from IMPROVE-IT, which showed incremental benefit in the secondary prevention setting, especially among those at highest risk such as the elderly and those with diabetes (11,12). Moreover, subgroup analyses from the HIJ-PROPER (Heart Institute of Japan-PRoper level of lipid lOwering with Pitavastatin and Ezetimibe in acute coRonary syndrome) trial suggested that measurement of the cholesterol absorption marker sitosterol may help to identify those high risk individuals likely to derive most benefit (13). While the combination of pitavastatin and ezetimibe did not influence cardiovascular outcomes for the total study population (hazard ratio 0.89, 95% confidence interval 0.76-1.04, p=0.152), the subgroup of patients with higher baseline levels of sitosterol (median >2.2 μg/mL) did derive significant benefit (hazard ratio 0.71, 95% 95% confidence interval, 0.56-0.91. p for interaction=0.010). Further investigation is merited.
What role for PCSK9 inhibitors? In the absence of outcomes data and taking account of financial restraints in healthcare budgets, the 2016 ESC/EAS Guidelines for Management of Dyslipidaemia recommend that these treatments should be reserved for use in the third line setting in high and very high risk patients with persistently elevated high LDL cholesterol levels despite statin and ezetimibe therapy. The first of the outcomes studies with these agents, FOURIER with evolocumab, is eagerly anticipated early in 2017.
Key message 3: Fasting is no longer required
Finally, in line with a recent joint consensus statement from the EAS and the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) (14), the 2016 ESC/EAS Guidelines for Management of Dyslipidaemia recommend that fasting is no longer required before routine screening for lipid levels. However, fasting lipid measurement may be indicated to help in refining diagnosis and assessment on an individual basis.
Finally, while these updated guidelines focus on lipids, it should be borne in mind that the development of cardiovascular disease is a multifactorial process, and intervention should be targeted across all of the key risk factors. To emphasise this point, a study highlights the benefit of long-term exposure to both low LDL cholesterol and systolic blood pressure, each shown to have independent and cumulative effects on cardiovascular risk (15). In a Mendelian randomization study (a type of ‘natural’ randomized trial) using data from 102,773 individuals in 14 prospective cohort or case-control studies, the combination of modest reduction in LDL cholesterol by 1 mmol/L (18 mg/dL) and systolic blood pressure by 10 mmHg was associated with 86% lower risk of major vascular events, as well as 84% reduction in coronary heart disease mortality. Moreover, given that these benefits extend to individuals both above and below ‘normal’ levels for LDL cholesterol and blood pressure, this reaffirms the importance of lifestyle intervention as the critical first step in cardiovascular disease prevention at the population level.
1. Catapano AL, Graham I, De Backer G et al. 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias: The Task Force for the Management of Dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS). Eur Heart J 2016 Aug 27. pii: ehw272. [Epub ahead of print].
2. Piepoli MF, Hoes AW, Agewall S et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice. Eur Heart J 2016;37:2315-81.
3. Estruch R, Ros E, Salas-Salvadó J et al; PREDIMED Study Investigators. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med 2013;368:1279-90.
4. Bonaccio M, Di Castelnuovo A, Costanzo S et al. Higher adherence to Mediterranean diet is associated with lower risk of overall mortality in subjects with cardiovascular disease: prospective results from the MOLI-SANI study [Abstract P2749]. Eur Heart J 2016;37(Abstract Supplement): 555-6.
5. Cholesterol Treatment Trialists’ (CTT) Collaborators, Mihaylova B, Emberson J, Blackwell L et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 2012;380:581-90.
6. Georgousopoulou EN, Pitsavos C, Panagiotakos DB et al. Adherence to Mediterranean diet moderates the aggravating effect of increasing heart age: 10 year follow up (2002-12) of the attica study. [Abstract P2738]. Eur Heart J 2016;37(Abstract Supplement): 553.
7. Chomistek AK, Henschel B, Eliassen AH et al. Frequency, type, and volume of leisure-time physical activity and risk of coronary heart disease in young women. Circulation 2016;134:290-9.
8. Barengo NC, Antikainen RL, Borodulin K, et al. Leisure time physical activity reduces the risk of cardiovascular death and an acute CVD event also among older adults [Abstract 390]. Eur Heart J 2016;37(Abstract Supplement):37.
9. de Souto Barreto P. Global health agenda on non-communicable diseases: has WHO set a smart goal for physical activity? BMJ 2015;350:h23.
10. Bonanni AE, Bonaccio M, di Castelnuovo A et al. Food labels use is associated with higher adherence to Mediterranean diet: results from the Moli-sani study. Nutrients 2013;5:4364-79.
11. Cannon CP, Blazing MA, Giugliano RP et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015;372:2387-97.
12. Banach M, Nikolic D, Rizzo M, Toth PP. IMPROVE-IT: what have we learned? Curr Opin Cardiol 2016;31:426-33.
13. Hagiwara N et al. HIJ-PROPER – LDL cholesterol targeting with pitavastatin + ezetimibe for patients with acute coronary syndrome and dyslipidemia. Abstract FP 3157. European Society of Cardiology 2016 Congress. August 27, 2016; Rome, Italy.
14. Nordestgaard BG, Langsted A, Mora S et al. Fasting is not routinely required for determination of a lipid profile: clinical and laboratory implications including flagging at desirable concentration cut-points-a joint consensus statement from the European Atherosclerosis Society and European Federation of Clinical Chemistry and Laboratory Medicine. Eur Heart J 2016; 62:930-46.
15. Ference B et al. A naturally randomized trial comparing the effect of long-term exposure to lower LDL-C, lower SBP, or both on the risk of cardiovascular disease. Abstract 3163. European Society of Cardiology 2016 Congress. August 27-31, 2016; Rome, Italy.