New ES Guidelines on ardiovascular Disease Prevention in linical Practice Lipids Professor Željko Reiner, MD, PhD, FRP(Lond), FES, FA University Hospital enter Zagreb School of Medicine, University of Zagreb, roatia My Declaration of Interest: I have the following interests to declare - speaker for Abbott, AstraZeneca, Bayer
MOST IMPORTANT: New Joint Guidelines on ardiovascular Disease Prevention in linical Practice and ES/EAS Guidelines for the Management of Dyslipidaemias published in 0 are fully accordant
Guideline recommendations versus achievements in patients with established HD ( EUROASPIRE III) Guideline Recommendations Proportions at goal (%) ------------------------------------------------------------------------------------ Smoking cessation among smokers 48 Regular physical activity 4 BMI < 5 kg/m² 8 Waist circumference < 94 cm ( men) 5 < 80 cm ( women) Blood pressure < 40/90 mmhg 50 Total cholesterol < 4.5 mmol/l ( 75 mg/dl) 49 LDL cholesterol <.5 mmol/l ( 00 mg/dl) 55 Among patients with diabetes type : fasting glycaemia < 7.0 mmol/l (5 mg/dl) 7 HbAc < 6.5% 5
Estimated risk as a function of HDL-cholesterol for men in populations at high VD risk Non-smoker Smoker Without HDL HDL 0.8 HDL.0 HDL.4 HDL.8 5. 6.6 5.9 4.9 4. 80 60 40 0 9 6 4 4 0 7 5 6 8 6 7 9 4 0 6 8 Age 65 6 8 9 4 8 8 0 5 7 6 7 0 5 Without HDL HDL 0.8 HDL.0 HDL.4 HDL.8 9..6 0.4 8.5 7. Without HDL HDL 0.8 HDL.0 HDL.4 HDL.8 4.4 5.6 5.0 4..5 80 60 40 0 9 6 4 0 4 7 8 0 5 6 7 4 4 5 6 8 6 60 5 8 6 8 9 6 8 0 5 4 7 9 8 0 5 Without HDL HDL 0.8 HDL.0 HDL.4 HDL.8 5.5 7.0 6. 5. 4. Without HDL HDL 0.8 HDL.0 HDL.4 HDL.8 4.6 6. 5.4 4..5 80 60 40 0 6 4 6 5 8 5 4 9 7 5 8 6 4 55 0 7 5 4 8 6 4 4 0 7 5 6 9 6 9 4 0 7 Without HDL HDL 0.8 HDL.0 HDL.4 HDL.8 5. 6.8 6.0 4.6.6 Without HDL HDL 0.8 HDL.0 HDL.4 HDL.8.6 4.6 4..4.8 80 60 40 0 4 4 5 6 4 7 5 4 50 6 5 7 5 4 9 6 5 8 9 5 7 4 5 Without HDL HDL 0.8 HDL.0 HDL.4 HDL.8 4.7 6.6 5.9 4.6.6 Systolic blood pressure (mmhg) 80 60 40 0 0 0 0 40 4 5 6 7 8 4 5 6 7 8 4 Without HDL HDL 0.8 HDL.0 HDL.4 HDL.8.7 4.9 4...6 Total holesterol (mmol/l) Reiner Ž et al. European Heart Journal 0; (4):769 88
Recommendations for lipid analyses for screening for VD risk Recommendations lass Level Total cholesterol is recommended to be used for the estimation of total V risk by means of the SORE system. LDL-cholesterol is recommended to be used as the primary lipid analysis for screening and risk estimation. I I TG adds information on risk and is indicated for risk estimation. I HDL- is a strong risk factor and is recommended to be used for risk estimation. I Non-HDL- should be considered as an alternative risk marker, especially in combined hyperlipidaemias, diabetes, the MetS or KD. Lp(a) should be recommended in selected cases at high risk and in subjects with a family history of premature VD. Apo B should be considered as an alternative risk marker, especially in combined hyperlipidaemias, diabetes, the MetS or KD. The ratio apo B/apo A combines the risk information of apo B and apo A and may be recommended as an alternative analysis for risk screening. The ratio non-hdl-/hdl- may be recommended as an alternative analysis for risk screening. Reiner Ž et al. European Heart Journal 0; (4):769 88 IIb IIb
Recommendations for lipid analyses for characterization of dyslipidaemias before treatment Recommendations lass Level LDL- is recommended to be used as the primary lipid analysis. I TG adds information to risk and is indicated for diagnosis and choise of treatment. I HDL- is recommended to be analysed before initiation of treatment. I Non-HDL- should be recommended for further characterization of combined hyperlipidaemias and dyslipidaemia in diabetes, the MetS or KD. Apo B should be recommended for further characterization of combined hyperlipidaemias and dyslipidaemia in diabetes, the MetS or KD. Lp(a) should be recommended in selected cases at high risk and in subjects with a family history of premature VD. Total cholesterol may be considered but is usually not enough for the characterization of dyslipidaemia before initiation of treatment. IIb Reiner Ž et al. European Heart Journal 0; (4):769 88
Recommendations for lipid analyses as treatment target in the prevention of VD Recommendations lass Level LDL-cholesterol is recommended as target for treatment. I A Total cholesterol should be considered as treatment target if other analyses are not available. A TG should be analysed during the treatment of dyslipidaemias with high TG levels. Non-HDL- should be considered as a secondary target in combined hyperlipidaemias, diabetes, the MetS or KD. B B Apo B should be considered as a secondary treatment target. B HDL-cholesterol is not recommended as a target for treatment. III The ratios apo B/apo A and non-hld-/hdl- are not recommended as targets for treatment. III Reiner Ž et al. European Heart Journal 0; (4):769 88
Recommendations for treatment targets for LDL-cholesterol Recommendations lass Level In patients at VERY HIGH V risk (established VD, type diabetes *, type diabetes with target organ damage, moderate to severe KD or a SORE level 0%) the LDL- goal is <.8 mmol/l (less than ~ 70 mg/dl) and/or 50% LDL- reduction when target level cannot be reached. I A In patients at HIGH V risk (type diabetes **, markedly elevated single risk factors, a SORE level 5 to < 0%) an LDL- goal <.5 mmol/l (less than ~ 00 mg/dl) should be considered. A In subjects at MODERATE risk (SORE level > to 5%) an LDL- goal <.0 mmol/l (less than ~ 5 mg/dl) should be considered. * (over the age of 40) with one or more other VD risk factor(s) or target organ damage ** no other V risk factor nor target organ damage Reiner Ž et al. European Heart Journal 0; (4):769 88
Intervention strategies as a function of total V risk and LDL-cholesterol level Total V risk (SORE) % < 70 mg/dl <.8 mmol/l 70 to < 00 mg/dl.8 to <.5 mmol/l LDL- levels 00 to < 55 mg/dl.5 to < 4.0 mmol/l 55 to < 90 mg/dl 4.0 to < 4.9 mmol/l < No lipid intervention No lipid intervention Lifestyle intervention Lifestyle intervention > 90 mg/dl > 4.9 mmol/l Lifestyle intervention, consider drug if uncontrolled lass/level I/ I/ I/ I/ /A to < 5 Lifestyle intervention Lifestyle intervention Lifestyle intervention, consider drug if uncontrolled Lifestyle intervention, consider drug if uncontrolled Lifestyle intervention, consider drug if uncontrolled lass/level I/ I/ /A /A I/A > 5 to < 0, or high risk Lifestyle intervention consider drug* Lifestyle intervention consider drug* Lifestyle intervention and immediate drug intervention Lifestyle intervention and immediate drug intervention Lifestyle intervention and immediate drug intervention lass/level /A /A /A I/A I/A 0 or very high risk Lifestyle intervention consider drug* Lifestyle intervention and immediate drug intervention Lifestyle intervention and immediate drug intervention Lifestyle intervention and immediate drug intervention Lifestyle intervention and immediate drug intervention lass/level /A /A I/A I/A I/A Reiner et al. European Heart Journal (0), 769 88
Nutrition and dyslipidaemia Saturated fatty acids to account for <0% of total energy intake, through replacement by polyunsaturated fatty acids. Trans unsaturated fatty acids: as little as possible, preferably no intake from processed food, and <% of total energy intake from natural origin <5 g of salt per day. 0 45 g of fibre per day, from wholegrain products, fruits and vegetables. 00 g of fruit per day (- servings). 00 g of vegetables per day (- servings). Fish at least twice a week, one of which to be oily fish. onsumption of alcoholic beverages should be limited to glasses per day (0 g/d of alcohol) for men and glass per day (0 g/d of alcohol) for women.
Recommendations for the pharmacological treatment of hypercholesterolaemia Recommendations lass Level Prescribe statin up to the highest recommended dose, or highest tolerable dose to reach the target level. I A In the case of statin intolerance, bile acid sequestrants or nicotinic acid should be considered. A cholesterol absorption inhibitor, alone or in combination with bile acid sequestrants or nicotinic acid, may also be considered in the case of statin intolerance. If target level is not reached, statin combination with a cholesterol absorption inhibitor or bile acid sequestrant or nicotinic acid may be considered. IIb IIb B Reiner Ž et al. European Heart Journal 0; (4):769 88
Recommendations for the pharmacological treatment of hypertriglyceriaemia Recommendations lass Level In particular high risk patients, lowering of HTG by using the following drugs: is recommended: fibrates should be considered: nicotinic acid nicotinic acid + laropiprant n- fatty acids B statin + nicotinic acid A statin + fibrate may be considered: combinations with n- fatty acids I IIb B B B Reiner Ž et al. European Heart Journal 0; (4):769 88
Recommendations if drug treatment of low HDL-cholesterol is considered Recommendations lass Level Nicotinic acid is currently the most efficient drug to raise HDL- and should be considered. A Statins and fibrates raise HDL- with similar magnitude and these drugs may be considered. The efficacy of fibrates to increase HDL- may be attenuated in people with type diabetes. IIb IIb B B Reiner Ž et al. European Heart Journal 0; (4):769 88
Dyslipidaemia in diabetes Recommendations lass Level GRADE The target HbA c for the prevention of VD in diabetes of < 7.0% (<5 mmol/mol) is recommended. I A Strong Statins are recommended to reduce cardiovascular risk in diabetes I A Strong Hypoglycaemia and excessive weight gain must be avoided and individual approaches (both targets and drug choices) may be necessary in patients with complex disease. I B Strong Metformin should be used as first-line therapy if tolerated and not contraindicated. B Strong Further reductions in HbA c to a target of < 6.5% (<48 mmol/mol) (the lowest possible safely reached HbA c ) may be useful at diagnosis. For patients with a long duration of diabetes this target may reduce risk of microvascular but not macrovascular outcomes. IIb B Weak BP targets in diabetes may be <40/80 mmhg. IIb B Weak Target LDL cholesterol is <.5 mmol/l, for patients without atherosclerotic disease total cholesterol may be < 4.5 mmol/l, with a lower LDL-cholesterol target of <.8 mmol/l (using higher doses of statins) for diabetic patients with angiographically proven VD or following an AS or coronary revascularization, or for patients with KD or very high risk. Antiplatelet therapy with aspirin is not recommended for people with diabetes who do not have clinical evidence of atherosclerotic disease. IIb B Weak III A Strong
Dyslipidaemia in metabolic sy. and type diabetes Dyslipidaemia in MetS represents a cluster of lipid and lipoprotein abnormalities including elevation of both fasting and postprandial TGs, apo B, and small dense LDL and low HDL- and apo AI. Non-HDL- or apo B are good surrogate markers of TRLs and remnants and are a secondary objective of therapy. Non-HDL- <. mmol/l (less than ~0 mg/dl) or apo B < 00 mg/dl is desirable. Increased waist circumference and elevation of TGs seems to be a simple tool to capture the high risk subjects with MetS Atherogenic dyslipidaemia characterized by high TG and low HDL-cholesterol is one of the major risk factors for VD in people with type diabetes Reiner Ž et al. European Heart Journal 0; (4):769 88.
Potential adverse effects of increasing body weight A. Increases in insulin resistance (glucose intolerance, type diabetes mellitus, metabolic syndrome) B. Increased blood pressure. Increased systemic inflammation and prothrombotic state D. Albuminuria E. Dyslipidaemia (elevated total cholesterol, LDL cholesterol, non-hdl cholesterol, triglycerides, apolipoprotein B, small dense LDL particles, decreased HDL cholesterol, apolipoprotein A) F. ardiovascular and cerebrovascular abnormalities (endothelial dysfunction, heart failure, coronary heart disease, atrial fibrillation, stroke, abnormal left ventricular geometry, systolic and diastolic dysfunction, increased sympathetic activity)
Efficacy of drug combinations for the management of mixed dyslipidaemias In combined dyslipidaemia an increase of HDL-cholesterol and a decrease of TG, on top of the LDL-cholesterol reduction that can be achieved with a statin, may be considered. Therefore a combination of statin with nicotinic acid can be considered (AIM-HIGH!!), but the adverse effect of flushing may affect compliance. A combination of statins with fibrates can also be considered while monitoring for myopathy, but the combination with gemfibrozil should be avoided. If TG are not controlled by statins or fibrates, prescription of n- fatty acids may be considered to decrease TG further, and these combinations are safe and well tolerated. Reiner Ž et al. European Heart Journal 0; (4):769 88
Therapeutic approaches which incorporate the use of multiple lipid-lowering drugs combinations should be more widely adopted since combination therapy increases the likelihood of therapeutic success in patients with dyslipidemia and might offer a means to increase the number of patients able to meet their lipoprotein goals according to the guidelines. Reiner Ž. Fundament lin Pharmacol 009; 4:9-8
Although today most of the patients with dyslipidemia are treated with statins as monotherapy, this will change in the near future The pattern might follow what happened with antihypertensive treatment, which was also several decades ago, based upon monotherapy. However, at present, combinations of two, three or even four drugs lowering the blood pressure by influencing different blood pressure-lowering mechanisms are widely used to achieve the treatment goals as defined by the guidelines Reiner Ž. lin Lipidol 00; 5:5-8
Management of dyslipidaemia in women Statin treatment is recommended for primary prevention of AD in high risk women. Statins are recommended for secondary prevention in women with the same indications and targets as in men. Lipid-lowering drugs should not be given when pregnancy is planned, during pregnancy or during the breast feeding period. Reiner Ž et al. European Heart Journal 0; (4):769 88
Recommendations for treatment of dyslipidaemia in the elderly Recommendations lass Level Treatment with statins is recommended for elderly patients with established VD in the same way as for younger patients. I B Since elderly people often have comorbidities and have altered pharmacokinetics, it is recommended to start lipid-lowering medication at a low dose and then titrate with caution to achieve target lipid levels which are the same as in the younger subjects. I Statin therapy may be considered in elderly subjects free of VD, particularly in the presence of at least one other V risk factor besides age. IIb B Reiner Ž et al. European Heart Journal 0; (4):769 88
A systematic review and meta-analysis on the therapeutic equivalence of statins
Selected drugs that may increase risk of myopathy and rhabdomyolysis when used concomitantly with statin YPA4 inhibitors/substrates yclosporin, tacrolimus Macrolides (azithromycin, clarithromycin, erythromycin) Azole antifungals (itraconazole, ketoconazole, fluconazole) alcium antagonists (mibefradil, diltiazem, verapamil) Nefazodone HIV protease inhibitors (amprenavir, indinavir, nelfinavir, ritonavir, saquinavir) Sildenafil Others Digoxin, niacin, fibrates (particularly gemfibrozil)
Recommendations lass Level GRADE The recommended target levels are <5 mmol/l (<~90 mg/dl) for total plasma cholesterol and < mmol/l (<~5 mg/dl) for LDL cholesterol for subjects at low or moderate risk. In patients at very high VD risk, the recommended LDL cholesterol target is <.8 mmol/l (<~70 mg/dl) or a 50% LDL-cholesterol reduction when the target level cannot be reached. In patients at high VD risk, a LDL-cholesterol goal <.5 mmol/l (<~00 mg/dl) is recommended. I A Strong I A Strong I A Strong All patients with familial hypercholesterolaemia must be recognized as high-risk patients and be treated with lipid-lowering therapy. I A Strong In patients with an AS, statin treatment in high doses has to be initiated while the patients are in the hospital. I A Strong Prevention of non-haemorrhagic stroke: Treatment with statins must be started in all patients with established atherosclerotic disease and in patients at high risk for developing VD. Treatment with statins must be started in patients with a history of non-cardioembolic ischaemic stroke. Occlusive arterial disease of the lower limbs and carotid artery disease are HD riskequivalent conditions and lipid-lowering therapy is recommended. Statins should be considered as the first-line drugs in transplant patients with dyslipidaemia. hronic kidney disease (stages 5 i.e. GFR < 90 ml/min/.7m) is acknowledged as a HD risk-equivalent and the LDL-cholesterol target in these patients should be <.8 mmol/l (~ 70 mg/dl). I A Strong I A Strong B Strong Strong
Adherence Recommendations lass Level GRADE Physicians must assess adherence to medication, and identify reasons for non-adherence in order to tailor further interventions to the individual needs of the patient or person at risk. In clinical practice, reducing dosage demands to the lowest acceptable level is recommended. In addition, repetitive monitoring and feedback should be implemented. If feasible, multisession or combined behavioural interventions should be offered in case of persistent non-adherence. I A Strong A Strong
How to promote medication adherence Provide clear advice regarding the benefits and possible adverse effects of the medication, and the duration and timing of dosing. onsider patients habits and preferences. Reduce dosage demands to the lowest feasible level. Ask patients in a non-judgemental way how the medication works for them, and discuss possible reasons for non-adherence (e.g. side effects, worries). Implement repetitive monitoring and feedback. In case of lack of time, introduce physicians assistants and/or trained nurses whenever its necessary and feasible.
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