An update on lipidology and cardiovascular risk management. Lipids, Metabolism & Vascular Risk Section - Royal Society of Medicine

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1 An update on lipidology and cardiovascular risk management Lipids, Metabolism & Vascular Risk Section - Royal Society of Medicine National and international lipid modification guidelines: A critical appraisal Claudia STEFANUTTI (Rome, Italy, EU) London, UK, September 9, 6

2 Guidelines: why? The guidelines nowadays represent an evidence-based consensus The guidelines have been developed to support healthcare professionals communicating with individuals about their cardiovascular (CV) risk and the benefits of a healthy lifestyle and early modification of their CV risk In addition, the guidelines provide tools for healthcare professionals to promote population-based strategies and integrate these into international, national or regional prevention frameworks and to translate these in locally delivered healthcare services This is in line with the recommendations of the World Health Organization (WHO) global status report on non-communicable diseases.

3 Health impact pyramid. Alberico L. Catapano et al. Eur Heart J 6;eurheartj.ehw7 6 European Society of Cardiology and European Atherosclerosis Association. All rights reserved. For permissions please journals.permissions@oup.com.

4 Problems with Guidelines Institutional conflicts Inter-relationship between related diseases Commercial funding Personal conflicts Personal stakes Academic stakes Government conflicts Cost containment Priorities in healthcare Courtesy of Dr. Handrean Soran

5 The US guidelines for the treatment of dyslipidemia

6 Backframe

7 Similarities between the ACC/AHA Guidelines and the NLA Recommendations Lipid screening for primary prevention is recommended at -year intervals Lifestyle therapy is supported as first step in all treatment algorithms ASCVD (*) risk reduction is the goal of therapy Moderate- or high-intensity statin therapy is the central focus of pharmacotherapy Patient- MD (provider) discussion of risk/benefit ratio precedes all decisions on drug treatment Regular lipid and lipoprotein FU is necessary to assess adherence to therapy (*): Atherosclerotic Cardio- Vascular Disease

8 Evidence base ACC/AHA RCT(s) with ASCVD outcomes Meta-analyses of RCT NLA RCT(s) with ASCVD outcomes Meta-analyses of RCT Selected post-hoc analyses of RCT Observational epidemiologic studies Genetic studies Metabolic studies Mechanistic studies

9 Genetic Studies Genetic epidemiology reduces the likelihood of confounding by focusing on single variables: genetic mutations Identification of specific mutations may serve to generate hypotheses for other types of trials Often limited in patient selection and costly

10 Data Demonstrating Genetic Variants affecting ASCVD Risk Loss of function mutations in the gene encoding for PCSK9 are associated in Black subjects with 8% LDL-C reduction and 88% CHD relative risk reduction Loss of function mutations in the gene encoding for NPCL are associated with mg/dl reduction in LDL-C and a % CHD relative risk reduction Cohen JC, et al: Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 6 Mar ;():6-7. Myocardial Infarction Genetics Consortium Investigators: Inactivating mutations in NPCL and protection from coronary heart disease. N Engl J Med. Nov 7;7():7-8.

11 Risk Calculator ACC/AHA supports use of pooled Cohort risk calculator as initial step in non-hispanic white and African-American non-diabetics, age - 79, with no ASCVD and with LDL-C 7-89 mg/dl to assess statin benefit; consider using long-term risk assessment in -9 year-old individuals not in high-risk groups NLA recommends risk factors counting and assessment of other ASCVD risk indicators first, with optional use of any of risk calculators in patients with major risk factors to aid in clinical decision-making

12 ACC/AHA Guideline Additional Markers of Increased ASCVD Risk Consider for additional measurement of ASCVD risk in patients who do not fall into one of the statin benefit groups (-7.% year risk) LDL-C 6mg/dL Family history of premature ASCVD CAC score Agatston units or 7%th-ile Hs-CRP mg/l Ankle-brachial index <.9 High lifetime -9

13 European Heart Journal (), SCORE chart: year risk of fatal cardiovascular disease (CVD) in populations at low CVD risk % and over %-% %-9% %-% % % < % SCORE -year risk of fatal CVD in populations at Low CVD risk Non-smoker Smoker Women Systolic blood pressure (mmhg) Cholesterol (mmol/l) Age 6 6 Non-smoker Smoker Men mg/dl Note: the SCORE chart is for use in people without overt CVD, diabetes, chronic kidney disease, or very high levels of individual risk factors because such people are ALREADY at HIGH RISK and need INTENSIVE RISK FACTOR ADVICE

14 ACC/AHA Statin Benefit Groups H: High intensity statin M: Moderate intensity statin Clinically ASCVD (H preferred; M if age > 7 or if not candidate for H Primary elevations of LDL-C 9 mg/dl (H preferred; M if not candidate for H) Age -7 years with diabetes, and LDL-C 7-89 mg/dl, no clinical ASCVD (M if -year risk < 7.%; H if 7.%) Age -7 years, no clinical ASCVD or diabetes, LDL-C 7-89 mg/dl, and estimated -year ASCVD risk 7.% using Pooled Cohort Equations (M or H)

15 High- and Moderate-Intensity Daily Statin Therapy High intensity (Lowers Moderate Intensity (Lowers LDL-C %) LDL-C -%) Atorvastatin -8 mg Rosuvastatin - mg Bold= Tested in RCT and reviewed by Expert Panel Yellow= Not tested in RCT s reviewed by Expert Panel Atorvastatin () mg Fluvastatin XL 8 mg Fluvastatin mg x/day Lovastatin mg Pitavastatin - mg Pravastatin (8) mg Rosuvastatin () mg Simvastatin - mg Simvastatin 8 mg* *Although simvastatin 8 mg was evaluated in RCTs, initiation of simvastatin 8 mg or titration to 8 mg is not recommended by the FDA due to the increased risk of myopathy, including rhabdomyolysis

16 ACC/AHA Perspective on Statin Therapy Statin intensity trial showed clear benefit of high-intensity vs moderate intensity statins Because fixed doses, no dosage titrations, were employed, one should not assume that a dosage titration strategy is correct or that addition of non-statins to achieve low LDL-C is indicated ACC/AHA Perspective on Non-statin Lipid Drug Therapy Non-statin therapies, as compared to statin therapy, do not provide acceptable ASCVD risk reduction benefits relative to their potential for adverse effects in the routine prevention of ASCVD Niacin in AIM-HIGH and HPS- THRIVE Fibrates in ACCORD-Lipids and FIELD

17 Overview of the NLA Recommendations. All preventive therapy begins with risk assessment and a provider (Specialist MD is supposed!)-patient discussion of the pros and cons of therapy. Life-style therapy is the first step in all ASCVD preventive recommendations, regardless of baseline risk. Judicious use of evidence-based drug therapy, particularly M- and H-dose statins, is associated with optimal ASCVD risk reduction. When excessive circulating atherogenic cholesterol (non-hdl-c [primary target] and LDL-C) persists after appropriate lifestyle and statin therapy, the use of non-statin therapy should be considered. Long-term follow-up fostered by provider -patient communication is essential for optimal ASCVD prevention

18 What is the advantage of Non-HDL-C over LDL-C in Assessing ASCVD RISK? Non-HDL-C is more predictive of ASCVD risk than LDL-C in observational studies. The same is true for on-treatment levels in clinical trials of statin therapy When Non-HDL-C and LDL-C are discordant, risk follows Non-HDL-C Non-HDL-C testing is universally available, requires no additional cost, and accurate values may be obtained in the non-fasting state Boekholdt SM, et al: Lipid-related markers and cardiovascular disease prediction. JAMA. Jun ;7():99-6. Jacobson TA, et al: National Lipid Association recommendations for patient-centered management of dyslipidemia: part - executive summary. J Clin Lipidol. Sep-Oct;8():7-88. Robinson JG, Wang S, Smith BJ, Jacobson TA. Meta-analysis of the relationship between non-high-density lipoprotein cholesterol reduction and coronary heart disease risk. J Am Coll Cardiol. 9 Jan 7;():6-.

19 NLA Recommendations: Stepwise Approach to Risk Assessment. Identify the highest ASCVD risk category that applies to the patient. If very high risk, begin with moderate- or high-intensity statin with non- HDL-C and LDL-C goals < and < 7 mg/dl, respectively. In remaining patients count number of major risk factors and treat to goals for non-hdl-c < and LDL-C < mg/dl, respectively Further Risk Assessment in Patients with Two Major Risk Factors Key Clinical Criteria: multipack/day cigarette smoking; strong family history of premature CHD; non-hdl-c > 9 mg/dl or LDL-C > 6 mg/dl High Risk Quantitative Scoring: -year FRS %; ACC/AHA -year risk %; lifetime risk % High Risk Biomarkers: CAC score Agatston units or 7th%-ile; hscrp. mg/l; Lp(a) mg/dl (protein; isoform insensitive assay); or urine albumine/creatinine ratio mg/g

20 Joint British Societies- non-hdl-c (TC minus HDL-c=non-HDL-c) to replace LDL-C professional lifestyle support to improve lipid profiles. Cholesterol lowering drug therapy is recommended in: Patients with established CVD Individuals at high risk of CVD: diabetes age > years, patients with CKD stages, or FH Individuals with high -year CVD risk (defined by NICE guidance) Individuals with high lifetime CVD risk estimated from heart age and other JBS calculator metrics, in whom lifestyle changes alone are considered insufficient JBS- board; Heart ; ii : -67 Courtesy of Dr. Handrean Soran

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24 Recommendations for treatment targets for LDL-C Recommendations Class Level In patients at VERY HIGH CV risk (established CVD, type diabetes, type diabetes with target organ damage, moderate to severe CKD or a SCORE level %) the LDL-C goal is <.8 mmol/l (less than ~ 7 mg/dl) and/or % LDL-C reduction when target level cannot be reached. I A In patients at HIGH CV risk (markedly elevated single risk factors, a SCORE level to < %) an LDL-C goal <. mmol/l (less than ~ mg/dl) should be considered. IIa A In subjects at MODERATE risk (SCORE level > to %) an LDL-C goal <. mmol/l (less than ~ mg/dl) should be considered. IIa C European Heart Journal (),

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26 Intervention strategies as a function of total CV risk and LDL-C level Total CV risk (SCORE) % < 7 mg/dl <.8 mmol/l 7 to < mg/dl.8 to <. mmol/l LDL-C levels to < mg/dl. to <. mmol/l to < 9 mg/dl. to <.9 mmol/l < No lipid intervention No lipid intervention Lifestyle intervention Lifestyle intervention > 9 mg/dl >.9 mmol/l Lifestyle intervention, consider drug if uncontrolled Class/Level I/C I/C I/C I/C IIa/A to < Lifestyle intervention Lifestyle intervention Lifestyle intervention, consider drug if uncontrolled Lifestyle intervention, consider drug if uncontrolled Lifestyle intervention, consider drug if uncontrolled Class/Level I/C I/C IIa/A IIa/A I/A > to <, 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 Class/Level IIa/A IIa/A IIa/A I/A I/A 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 Class/Level IIa/A IIa/A I/A I/A I/A European Heart Journal (),

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29 NLA Perspective on Statin Therapy Statin therapy is the most potent and evidence-based approach to lowering non-hdl-c and LDL-C and reduces ASCVD events Statin intensity trial showed clear benefit for high-intensity vs moderate-intensity statins Broad-based evidence supports «lower is better» concept. Clinicians should address residual risk by appropriately-dosed statin therapy

30 Efficacy of Intensive Lowering LDL-C in Subjects with Low Baseline LDL-C Meta-analysis of RCT of > participants and years treatment duration or more vs less intense statin trials involving 69,8 subjects The major vascular event (MVE) reduction, among in those with baseline LDL-C < 77 mg/dl per further 9 mg/dl reduction was 9%; in those with baseline LDL-C < 7 mg/dl, similar reduction in LDL-C continued to demonstrate MVE reduction Cholesterol Treatment Trialists (CTT) Collaboration: Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 7, participants in 6 randomised trials. Lancet. Nov ;76(97):67-8.

31 Joint British Societies- Statins are recommended They are highly effective at reducing CVD events Benefit to LDL-c levels < mmol/l so intensive non-hdl- C lowering required. Statins are safe There is a small increase in risk of developing diabetes The benefits of cholesterol lowering greatly exceed any risk associated with diabetes. If statin intolerance develops use a stepwise strategy switch agents and re-challenge dosing. Low HDL-C values contributes to CVD risk, Drug therapy to raise HDL-c no effect on CVD risk Drug therapy for HDL-C is not currently indicated. JBS- board; Heart ; ii : -67 Courtesy of Dr. Handrean Soran

32 NLA Perspective on Non-Statin Lipid Drug Therapy If non-hdl-c and LDL-C goals are not achieved with statin therapy, the addition of evidence-based non-statin therapy should be considered to lower atherogenic cholesterol level and to achieve goals Ezetimibe is a safe, evidence-based non-statin therapy that may be considered in post MI patients and selected other patients with elevated non-hdl-c and/or LDL-C Resins or Niacin can be considered in selected patients Meta-analyses of Fibrate therapy in subgroups with atherogenic dyslipidemia suggest ASCVD risk reduction

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36 Central Focus of Guidelines: Summary ACC/AHA define statin benefit groups; risk-benefit discussion; use moderate- or high-intensity statin therapy with life-style change as background therapy; generally avoid non-statin drug therapy; no lipid goals NLA identify ASCVD risk level; risk-benefit discussion; emphasize healthy life-style; use moderate- or high-intensity statin therapy, and under appropriate circumstances, adjunctive non-statin therapy, to lower atherogenic cholesterol; maintain lipid goals (non-hdl-c is favored lipoprotein lipid target)

37 The differences Evidence base Central focus Lipid and lipoprotein goals Non-statin therapies Risk estimation (calculator) ACC/AHA NLA

38 TAKE HOME MESSAGE Major advances have been made in the clinical management of LDL-C. Many RCTs in the past decades have shown that LDL-C lowering therapy reduces the risk for ASCVD Despite advances made on different international guidelines and clinical recommendations, the real world management remains far from what is recommended in these guidelines, in terms of best practice for both lifestyle and drug intervention In addition, significant ASCVD risk persists despite the use of current lipid lowering standard of care, like the available therapies and treatment targets for patients at high ASCVD risk, HeFH, HoFH, statin intolerant patients, as well as HyperLp(a)lipoproteinaemic subjects (Isolated and Combined forms) Use careful clinical judgement when treat dyslipidaemia and/or any metabolic disorder predictive of ASCVD risk