Gonna, H

Ray, KK

Webb, J

Clinical Medicine

English

Spiral - Imperial College Digital Repository

618 © Royal College of Physicians, 2013. All rights reserved.CME Cardiology Clinical Medicine 2013, Vol 13, No 6: 618–20stable CAD to acute coronary syndromes (ACS) and stroke demonstrate that statins prevent fatal and non-fatal CVD events and reduce all-cause mortality.5,6 Meta-analyses of individual trials demonstrate an approx-imate 23% reduction in CVD events per 1 mmol/l reduction in LDL-C, with a log linear relationship with no threshold below which benefit ceases. The benefit is observed equally across a range of baseline lipids and demographic groups.7Recent trials have focused on more (vs less) intensive statin therapy; for example, the median on-treatment LDL-C in the intensive arm (atorvastatin 80 mg) of the PROVE- IT trial was 1.6 mmol/l vs a LDL-C of about 2.4 mmol/l (pravastatin 40 mg) resulting in 16% CVD risk reduction.8 Similarly, in stable CAD (TNT and IDEAL trials) a 0.6 mmol/l greater reduction in LDL-C (the average on-treatment LDL-C was approximately 2 mmol/l) resulted in significant reductions in CVD events with intensive therapy (atorvastatin 80 mg). In contrast, the AZ (ACS patients) and the SEARCH (stable CAD patients) trials failed to demonstrate a benefit of simvastatin 80 mg vs 20 mg, largely because of the very small incremental reduction in LDL-C.7,9 Importantly, the risk of myopathy with sim-vastatin 80 mg was 2,000-fold higher than with atorvastatin 80 mg, resulting in the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) warning against the use of simvastatin 80 mg. The Medicines and Healthcare Products Regulatory Agency (MHRA) guidance warns against co-prescription of a number of car-diovascular drugs, including calcium antag-onists and amiodarone, with simvastatin at doses above 20 mg. To date, trials have not been designed to assess the benefit of any specific LDL-C target, hence guidance on specific targets is based on extrapolations from trial data and the absolute risk of the patient, with lower LDL-C goals advised for those at highest risk – for example, estab-lished CVD. NICE recommends an LDL-C goal of 2 mmol/l for such high-risk patients, whereas the ESC/EAS recommend a lower target of 1.8 mmol/l (and 2.5 mmol/l for high-risk primary prevention patients).There is no evidence for excess risk of liver or muscle side effects or for excess risk of cancers with low achieved LDL-C; side effects fasting non-HDL-C (TC-HDL-C) is the preferred measure of atherogenic risk.3 Both non-HDL-C and apo B can be obtained from non-fasting samples, but the latter is more expensive, less available and not stand-ardised. The European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guidelines recommend non-HDL-C as a secondary target when HDL-C is low or TG is high, or both. Several statin trials now suggest that non-HDL-C is a better marker of on-treatment risk than LDL-C.4 Finally, among subjects with a family history of pre-mature CVD or elevation in lipoprotein a (Lp(a)), the ESC/EAS recommend meas-uring Lp(a) levels, with levels of >50 mg/dl identifying high-risk groups. Lifestyle adjustmentCardiovascular disease prevention begins with lifestyle change: smoking cessation, alcohol consumption, blood pressure, diet and exercise (which affect body mass index and blood glucose), should be addressed. The National Institute for Health and Care Excellence (NICE) guidelines recommend a diet with total fat intake of <30% and saturated fats <10% of total energy intake, dietary cholesterol of <300 mg/day and replacement of saturated fat with mono- and poly-unsaturated fats. Such measures reduce cholesterol modestly, but response varies considerably between individuals.Risk assessmentLipid modification therapy is indicated as part of primary prevention for adults with a predicted 20% or greater 10-year risk of developing CVD. Several risk equations exist: Framingham, QRISK (UK specific) and SCORE (European). LMT must be initiated simultaneously with lifestyle advice for those with established CVD. Chronic kidney disease (CKD) and Lp(a) levels do not contribute to many risk engines, but can potentially reclassify an intermediate- into a high-risk individual.Statin therapyStatins are the cornerstone of LMT and more than 20 trials conducted in settings ranging from primary prevention and Lipid management: maximising reduction of cardiac riskJ Webb,1,2 cardiology registrar; H Gonna,1,2 cardiology registrar; KK Ray,1,2 professor of cardiovascular disease prevention1Cardiac and Vascular Sciences Research Centre, St George’s, University of London; 2St Georges Hospital NHS Trust, London, UKIntroductionCardiovascular disease (CVD), particularly coronary artery disease (CAD), is the leading cause of death and disability in the western world and contributes substan-tially to healthcare budgets.1 Lipid modifi-cation therapies (LMTs) have revolution-ised contemporary approaches to primary and secondary prevention of CVD.What should we measure?Total cholesterol has a log linear relationship with CAD with no apparent threshold below which risk diminishes. However, total cho-lesterol incorporates both the atherogenic components–low-density lipoprotein (LDL), intermediate-density lipoprotein (IDL) and very-low-density lipoprotein (VLDL) cho-lesterol (collectively known as non-high-density lipoprotein cholesterol [non-HDL-C] – and the protective factor high-density lipoprotein (HDL) and its measure HDL-C. Therefore, measurements of either apolipo-proteins (apo) (one apo B per LDL, IDL and VLDL particle, or apo A as a measure of the number of HDL particles) or cholesterol content (non-HDL-C and HDL-C) are more informative. Collective evidence demon-strates that CAD risk per 1 standard devia-tion (SD) is identical for apo B and non-HDL-C and 30% stronger than for LDL-C; apo A and HDL-C offer similar magnitudes of protection.2 As measurement of LDL-C requires a fasting sample, is calculated (TC-HDL-C – (TG/5), where TC-HDL-C is total cholesterol HDL-C and TG is triglyc-eride) rather than directly measured and incompletely captures atherogenic risk, non-CMJ1306_CME_Ray.indd   618 11/19/13   8:04:31 PMCME Cardiology© Royal College of Physicians, 2013. All rights reserved. 619for statin-intolerant subjects, but the evi-dence base is unclear. Niacin, which lowers LDL-C by 20%, raises HDL-C by 30% and lowers Lp(a) by 25%, has recently been withdrawn in several European countries because of a lack of contemporary out-comes data. Therapeutic options being licenced for rare conditions such as homozygous familial hypercholesterol-aemia include mipomersen which is an antisense inhibitor of apo B, which reduces transcription of the protein scaffold, pro-viding 30% lowering of LDL-C and the microsomal triglyceride transfer protein (MTP) inhibitor lomitapide, which reduces LDL-C by about 50% but does lead to an increase in hepatic fat. More exciting are the monoclonal PCSK9 anti-bodies given by subcutaneous injection every 2–4 weeks that increase LDL receptor survival time and reduce LDL-C by a fur-ther 70% in patients on optimal statin therapy. ReferencesRosamond W, Flegal K, Furie K et al; 1 American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics – 2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2008;117:e25–146.Emerging Risk Factors Collaboration, Di 2 Angelantonio E, Sarwar N et al. Major lipids, apolipoproteins, and risk of vascular disease. JAMA 2009;302:1993–2000. may be dose-related but, in general, statins are safe and well tolerated even at high doses (except simvastatin) and side effects are usu-ally fully reversible with cessation of therapy.10,11 Myopathy and rhabdomyolysis are rare at standard doses (about 0.1% per year)5 but the rates of myalgia are higher (about 4%).12 Conditions that increase the likelihood of statin-induced myalgia or myopathy, such as alcohol excess, hypothy-roidism, vitamin D deficiency and acute viral illness, should be ruled out. Medications may affect statin metabolism (eg gemfibrozil, cyclosporine, amiodarone, macrolides, anti-biotics, verapamil, warfarin and protease inhibitors), and a high intake of grapefruit juice may have an impact on CYP3A4 in the liver. Asymptomatic increases in hepatic transaminases are dose dependent and revers-ible with down-titration or discontinuation. Hepatitis attributable to drugs is rare (0.001%).13 As the evidence base for statins far exceeds any other LMT, intolerant patients should try at least one other statin at a lower dose. If this fails, suggest a weekly or twice weekly dose of a statin with a longer half-life, such as rosuvastatin 5 mg or atorvastatin 10 mg, before trying monotherapy with ezetimibe or bile acid sequestrants such as colesevalam. In the JUPITER trial, it was observed that rosuvastatin increased the risk of developing diabetes mellitus (DM) compared with pla-cebo.14 In two large-scale meta-analyses of all randomised controlled trials, this obser-vation was established as a class and dose effect, where statins increased the relative risk of DM by 9% at a standard dose and by 12% when comparing high with standard doses. In absolute terms, the risk is low and offset by the greater number of CVD events prevented, approximately five per case of DM (for statin vs placebo) or three CVD events per case of DM (for high vs standard dose). Therefore, in patients with high or existing cardiovascular risk, current clinical practice should not change, but initiation of therapy in low-risk subjects should be con-sidered on a case by case basis, with annual blood glucose monitoring.15 Maximising cardiac risk reductionOptimising evidence-based treatments remains a challenge; for example, data from EuroASPIRE III showed that although 80% of patients with CVD were treated with LMT, only 34% achieved lipid targets.16 This represents a significant burden of residual but modifiable risk correctable by optimising the statin dose. Absolute risk depends on both the number of uncon-trolled modifiable risk factors and the pres-ence of non-modifiable risk factors such as DM and stage 3 CKD, hence any approach to CVD risk reduction should aim to opti-mise lifestyle and control all risk factors. Treatments need to be tailored to indi-vidual patients and clinicians should target high-risk subjects (with multiple risk fac-tors) for more intensive therapies, lower lipid targets and, importantly, should rec-ognise that LDL-C is a suboptimal target for assessing efficacy of LMT when HDL is low (for example, in patients with obesity, DM, CKD and those with high triglycer-ides) and instead use non-HDL-C. Alternative lipid-modification strategiesThe evidence base for other LMTs is small and they are generally less effective. Nevertheless, there is consistent data that in addition to statins, fibrates reduce CVD risk by about one-third when TG is >1.7 mmol/l and HDL-C is <1 mmol/l. Non-fatal events and revascularisation may be reduced but generally not CVD death. Ezetimibe and colesevelam each lower LDL-C by around 20% and are often used in addition to statins or as monotherapy Key pointsLow-density lipoprotein cholesterol (LDL-C) has a log linear relationship to the risk of coronary artery disease (CAD) and there is extensive evidence from epidemiological, genetic and animal studies, and from trials of LDL-C modification, demonstrating an important link between LDL-C and CADLDL-C is the principal target for treatment of conditions associated with insulin resistance and/or the combination of high triglyceride (TG) and/or low high density lipoprotein cholesterol (HDL-C), but non-HDL-C or apolipoprotein B are better therapeutic targets and provide better pre-treatment risk predictionAssessing absolute risk is crucial in ensuring that patients are optimally treatedLifestyle adjustment and targeting of multiple risk factors is necessary to reduce residual risk among those with a high absolute risk of cardiovascular diseaseStatins are generally safe and well tolerated. Myopathy and rhabdomyolysis are rare at standard doses and usually reverse fully with cessation of therapyKEY WORDS: Low-density lipoprotein cholesterol (LDL-C), residual risk, side effect, statin, primary prevention, secondary preventionCMJ1306_CME_Ray.indd   619 11/19/13   8:04:31 PMCME Cardiology620 © Royal College of Physicians, 2013. All rights reserved.Riesen WF, Virgini V, Vogt B 3 et al. [New european guidelines for dyslipidemia]. Rev Med Suisse 2012;8:525–6, 528–30. Boekholdt SM, Arsenault BJ, Mora S 4 et al. Association of LDL cholesterol, non-HDL cholesterol, and apolipoprotein B levels with risk of cardiovascular events among patients treated with statins: a meta-analysis. JAMA 2012;307:1302–9. Lancet. Randomised trial of cholesterol low-5 ering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383–9. Heart Protection Study Collaborative Group. 6 MRC/BHF Heart Protection Study of choles-terol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo controlled trial. Lancet 2002;360:7–22.Cholesterol Treatment Trialists’ (CTT) 7 Collaboration, Baigent C, Blackwell L et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010;376:1670–81.Cannon CP, Braunwald E, McCabe CH 8 et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;350:1495–504.Study of the Effectiveness of Additional 9 Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group, Armitage J, Bowman L et al. Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvas-tatin daily in 12,064 survivors of myocardial infarction: a double-blind randomised trial. Lancet 2010;376:1658–69.10 Wiviott SD, Cannon CP, Morrow DA et al. Can low-density lipoprotein be too low? The safety and efficacy of achieving very low low-density lipoprotein with intensive statin therapy: a PROVE IT-TIMI 22 sub-study. J Am Coll Cardiol 2005;46:1411–6.11 Peto R, Emberson J, Landray M et al. Analyses of cancer data from three ezetimibe trials. N Engl J Med 2008;359:1357–66.12 Collins R, Armitage J, Parish S et al. Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20,536 people with cerebrovascular disease or other high-risk conditions. Lancet 2004;363:757–67.13 Armitage J. The safety of statins in clinical practice. Lancet 2007;370:1781–90.14 Ridker PM, Danielson E, Fonseca FA et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359:2195–207.15 Sattar N, Preiss D, Murray HM et al. Statins and risk of incident diabetes: a collabora-tive meta-analysis of randomised statin trials. Lancet 2010;375:735–42 16 Kotseva K, Wood D, De Backer G et al. EUROASPIRE III: a survey on the life-style, risk factors and use of cardiopro-tective drug therapies in coronary patients from 22 European countries. Eur J Cardiovasc Prev Rehabil 2009;16:121–37.Address for correspondence: Prof KK Ray, Cardiac and Vascular Sciences Research Centre, St George’s University of London, Cranmer Terrace, London SW17 0RE.Email: kray@sgul.ac.ukCMJ1306_CME_Ray.indd   620 11/19/13   8:04:31 PM

Lipid management: maximising reduction of cardiac risk

J Webb

H Gonna

KK Ray

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Lipid management: maximising reduction of cardiac risk

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