Current Medical Research & Opinion 0300-7995 doi:10.1185/03007995.2014.924488

2014, 1–5

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Editorial The 2013 American College of Cardiology/ American Heart Association guidelines for the treatment of dyslipidemia: mind the gaps!

Vasilios G. Athyros Niki Katsiki Asterios Karagiannis Dimitri P. Mikhailidis Second Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, Hippokration Hospital, Thessaloniki, Greece Department of Clinical Biochemistry (Vascular Prevention Clinic), Royal Free Campus, University College London Medical School, University College London (UCL), London, UK Address for correspondence: Vasilios G. Athyros MD FESC FRSPH FASA FACS, Head of Atherosclerosis and Metabolic Disease Units, 2nd Propedeutic Department of Internal Medicine, Medical School, Aristotle University, 15 Marmara St, Thessaloniki, 55132, Greece. Tel.: +30 2313 312606. Fax: +30 2310 835955; [email protected] Keywords: ACC/AHA guidelines – Cardiovascular disease – dyslipidemia – Statins Accepted: 12 May 2014; published online: 4 June 2014 Citation: Curr Med Res Opin 2014; 1–5

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Abstract The ACC/AHA lipid guidelines need to be reconsidered before full implementation. A new cardiovascular disease (CVD) risk estimation, preferably based in interventional multiethnic studies, will be ideal. Specific LDL-C targets may also be necessary because there are data pointing out that they are useful and pragmatic. The risk/benefit ratio should be a key issue because medicine is all about this concept (Hippocrates 460 – c. 370 BC: ‘‘first do not harm’’; and then in the Hippocratic Oath: ‘‘I will follow that system of regimen which, according to my ability and judgment, I consider for the benefit of my patients, and abstain from whatever is deleterious and mischievous’’).

A recent publication1 used data from a representative sample of 3800 adults (age range: 40–75 years) from the 2005–2010 National Health and Nutrition Examination Surveys (NHANES), and extrapolated from this sample to the US population (115.4 million) in this age range. They used this model to calculate the number of people eligible for statin treatment according to the recent 2013 American College of Cardiology/American Heart Association (ACC/AHA) lipid guidelines compared with the previous National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) guidelines, updated in 20042. The extrapolation of the ACC/AHA guidelines to 115.4 million US adults (aged 40–75 years) predicts that 12.8 million more people would become eligible for statin treatment compared with if the ATP III guidelines are used1. From those 10.4 million would be from the primary prevention pool. The total number of subjects on statins would rise from 43.2 million (37.5%) to 56.0 million (48.6%)1, while the percentage of older adults (60–75 years old), who do not have overt CVD, that would be eligible for statin treatment would increase from 30.4 to 87.4% in men and from 21.2 to 53.6% in women in this age group1. The authors conclude that the full implementation of the new ACC/AHA lipid guidelines would substantially increase the net number of new statin recipients by almost 13 million, mainly among primary CVD prevention adults, aged between 60 and 75 years1. The 2013 ACC/AHA lipid guidelines3 identify four high-risk groups who could benefit from statins: (1) Patients with atherosclerotic cardiovascular disease (CVD). (2) People with a low density lipoprotein cholesterol (LDL-C) 190 mg/dl (4.9 mmol/l), usually due to familial (heterozygous) hypercholesterolemia. (3) Those aged 40 to 75 years who have diabetes mellitus (DM). In patients with type 2 DM (T2DM), high-intensity statin therapy is recommended for those with an estimated 10 year CVD risk 7.5% and moderate-intensity statin therapy for those at 57.5% risk. 2013 ACC/AHA guidelines on dyslipidemia: mind the gaps! Athyros et al.

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(4) People 40 to 75 years old with 7.5% risk of developing CVD in the next 10 years, according to a new risk equation described in the guidelines. To estimate 10 year CVD risk, a new Pooled Cohort Equation was derived from data from five large epidemiological studies (n ¼ 24,626) conducted in the US (Atherosclerosis Risk in Communities, Cardiovascular Health Study, Coronary Artery Risk Development in Young Adults, and the Framingham and Framingham Offspring studies)4,5. In contrast with previous guidelines for the management of dyslipidemia, the 2013 ACC/AHA guidelines do not recommend specific low density lipoprotein cholesterol (LDL-C) targets; this is a conceptual change2,3,6. Instead, they propose a 50% reduction in LDL-C in high CVD risk patients by administering high-intensity statin therapy (high doses of rosuvastatin or atorvastatin) or a 30–50% reduction in LDL-C in subjects with moderate CVD risk with moderate-intensity statins (low doses of rosuvastatin or atorvastatin and all doses of other statins)2. Moreover, the new ACC/AHA guidelines do not suggest follow-up visits after statin initiation for establishing the efficacy and safety of this treatment3. Other estimates7,8 of the new ACC/AHA risk prediction algorithm report that this is overestimating CVD risk by 75–150%, more or less doubling the actual observed risk7,8. A recent commentary on the new ACC/AHA lipid guidelines is in favor of them. However, it reports that previous guidelines were immediately and widely accepted and incorporated in clinical practice9, while the new guidelines have been the subject of debate, based on statements that some parts of the recommendations are not evidence based7,8 and on the fact that practically all men 466 years and all women 470 years have a CVD 10 year risk47.5%, even with optimal values of CVD risk factors8. However, the increased number of individuals recommended to receive statin treatment is not the only problem with the implementation of the 2013 ACC/AHA lipid guidelines. The epidemiological studies used to derive the ACC/AHA risk equation were conducted in the US. Thus, these guidelines might be applicable in the US, but not elsewhere. These guidelines practically ignore all other hypolipidemic agents; thus, they are ‘statin’ and not ‘lipid’ guidelines (unlike previous guidelines). This underestimation of other drugs may not help overcome residual CVD risk reduction10. Residual CVD risk may be related with high triglyceride levels as shown in many trials including the Pravastatin or Atorvastatin Evaluation and Infection Therapy – Thrombolysis In Myocardial Infarction (PROVE-IT TIMI) 22 trial11. Moreover in the Action to Control Cardiovascular Risk in Diabetes Lipid (ACCORD) Trial the addition of fenofibrate to simvastatin in a pre-specified subgroup (patients with combined 2

2013 ACC/AHA guidelines on dyslipidemia: mind the gaps! Athyros et al.

hyperlipidemia) was associated with a 31% reduction in the primary endpoint (first occurrence of nonfatal myocardial infarction, nonfatal stroke or death from CVD)12. Thus, any guidelines dealing only with statins might deliver suboptimal treatment. There is practically no mention in the 2013 ACC/ AHA lipid guidelines about coronary heart disease (CHD) equivalents, such as chronic kidney disease (CKD), present in the Canadian13, and the European Atherosclerosis Society/European Society of Cardiology (EAS/ESC) guidelines14. The ACC/AHA guidelines also differentiate the intensity of statin treatment between patients with T2DM (another CHD equivalent in previous guidelines2,13,14), i.e. high- and moderate-intensity statin therapy is recommended for those with an estimated 10 year CVD risk 7.5% and 57.5%, respectively3. However, patients with T2DM have (or will eventually achieve) a similar CVD risk compared with patients with established CVD15,16; therefore it can be argued that they should managed as aggressively as the latter. Accordingly, the ESC/EAS recommendation of LDL-C levels570 mg/dl (1.8 mmol/l) in patients with T2DM appears sounder14. Data from a registry of 1,120,295 adults aged 420 years followed up for 2.84 years showed that patients with CKD stage 3 or above (i.e. glomerular filtration rate (GFR) 59–30 or 530 ml/min/1.72 m2, respectively) have an annual mortality rate, mainly due to CVD, just below 10%17. Moreover, the combination of T2DM and CKD (diabetic nephropathy) has an annual CVD morbidity rate of 49% and an annual CVD mortality rate of 20%18, similar to that of cancer. At a time when we probably should consider expanding the concept of CHD equivalents including rheumatoid arthritis19, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) and metabolic syndrome20,21,22 these disease states and their combination are essentially ignored by the 2013 ACC/AHA lipid guidelines. The lack of specific LDL-C targets3 is another potential problem. For example, let us consider a patient with heterozygous familial hypercholesterolemia with an LDL-C of 300–350 mg/dl (7.8–9.1 mmol/l). According to the ACC/AHA guidelines a 50% reduction is enough. However, should we accept an LDL-C of 150–175 mg/dl (3.9–4.6 mmol/l) as a target for this patient? This suggests that some patients that need intensive hypolipidemic treatment (mainly with drug combinations) will be deprived of it, while others that do not need it (primary prevention patients with optimal CVD profile) are considered eligible for statin treatment. Moreover, these guidelines will at least delay the use of upcoming hypolipidemic drugs, such as antibodies against PCSK9 (evolocumab and alirocumab). These drugs will eventually become commercially available and are expected to be expensive. The same will apply in the case of mipomersen and lomitapide if they will be approved for general use in www.cmrojournal.com ! 2014 Informa UK Ltd

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dyslipidemic patients. These drugs are aimed at high risk patients that cannot reach the 570 mg/dl (1.8 mmol/l) LDL-C goal with available treatments23. The full implementation of the new ACC/AHA guidelines will probably lead to statin treatment for several millions that do not actually need them7,8. This challenges the risk/benefit ratio principle. Statin administration to large numbers of people that will have little benefit from them could lead to an increase of the incidence of new onset diabetes (NOD) and cataracts related to statin treatment24,25. Existing and emerging data on statin therapy suggest that ‘one size does not fit all’ with regard to NOD26. Each statin is associated with a specific NOD risk profile and a tailored statin treatment based on CVD and metabolic risk profile seems to be the safest therapeutic approach26. Regarding NOD24,27, statin treatment in high CVD risk male Caucasians outweighs any potential increase in CVD risk related to NOD, suggesting that current clinical practice regarding statin treatment is justified24. However, the risk/benefit ratio of treatment might not be as favorable in subjects at low CVD risk and/or predisposition to develop NOD, such as the elderly, postmenopausal women, and South Asians, that have a risk for NOD higher than others26,27. The ACC/AHA risk equation overestimates the contribution of age as a CVD risk factor; this could cause problems with NOD and reduce or even eliminate the net clinical benefit of statin treatment in elderly people with optimal CVD risk profile24,26–29. Another consideration for statin treatment in low CVD risk patients is the early onset cataract25. In secondary adjusted analysis, the incidence of cataracts is higher in statin users of both genders by 27% compared with non-users25. In addition, there have been postmarketing reports of cognitive impairment (e.g. memory loss, memory impairment, confusion) associated with statin use, mainly in older women30–32. The above suggest that the dogma ‘statins for everybody’ might turn out not to be ideal. Finally, the suggestion of these guidelines is that there is no need for follow-up visits and follow-up lab tests in patients on statins; the ‘fire and forget’ dogma. This will bring down the total cost of statin treatment. However, factors may change with time (e.g. hypothyroidism and CKD) which may alter the risk of side effects due to statins33,34. We also need to consider whether adherence to treatment will be maintained. These ACC/AHA guidelines may be trying to protect the US population from CVD events (e.g. due to the increasing prevalence of obesity) with cheap statins (generic atorvastatin costs 5$5/month) for everybody. Obesity, hypertension, dyslipidemia, T2DM, and metabolic syndrome are driving the CVD risk in US; CVD morbidity and mortality is expected to explode within the next few years, if drastic measures are not taken. In terms of lifestyle changes the situation is disappointing. ! 2014 Informa UK Ltd www.cmrojournal.com

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Despite the fact that 70% of US adults are overweight or obese, diet quality continues to deteriorate, leading to the majority of US adults displaying lipid abnormalities35. However, statins for everybody without balancing the risk/benefit ratio is potentially harmful. These guidelines, if fully implemented, will probably increase the prevalence of T2DM, a major risk factor for CVD. Therefore, with regard to the epidemic of obesity and T2DM, the ACC/ AHA guidelines clearly oversimplify dyslipidemia treatment as they do not consider the data from mechanistic and clinical studies for atherogenic dyslipidemia36. It follows that the Task Force of the EAS/ESC, the American Diabetes Association, the US National Lipid Association, the American Society of Clinical Endocrinologists, and other smaller Societies from South America or Asia declined to endorse these new lipid guidelines and suggest persisting with previous guidelines36–40. No other society seems to have adopted these guidelines. Furthermore, the EAS restates that the ESC/EAS guidelines for dyslipidemia treatment are more suitable for European populations36. The ACC/AHA lipid guidelines need to be reconsidered before full implementation. A new CVD risk estimation, preferably based in interventional multiethnic studies, will be ideal. Specific LDL-C targets may also be necessary because there are data pointing out that they are useful and pragmatic. The risk/benefit ratio should be a key issue because medicine is all about this concept (Hippocrates 460 – c. 370 BC: ‘‘first do not harm’’; and then in the Hippocratic Oath: ‘‘I will follow that system of regimen which, according to my ability and judgment, I consider for the benefit of my patients, and abstain from whatever is deleterious and mischievous’’). Therefore, it is for every physician to decide which guidelines he/she should follow.

Transparency Declaration of funding This editorial was written independently; no company or institution supported the authors financially or by providing a professional writer. Declaration of financial/other relationships D.P.M. has disclosed that he is Editor-in-Chief of CMRO but has no significant relationships with or financial interests in any commercial companies related to this study or article. V.G.A. has disclosed that he is a member of CMRO’s International Advisory Board but has no significant relationships with or financial interests in any commercial companies related to this study or article. N.K. and A.K. have disclosed that they have no significant relationships with or financial interests in any commercial companies related to this study or article. Some of the authors have given talks, attended conferences and participated in trials and advisory boards sponsored by various pharmaceutical companies. V.G.A. has nothing to declare.

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N.K. has disclosed that she has attended conferences and participated in trials sponsored by Novartis, Pfizer, MSD and WinMedica. A.K. has disclosed that he has given talks and attended conferences sponsored by Pfizer, Astra-Zeneca, Menarini and Novartis. D.P.M. has disclosed that he has given talks and attended conferences sponsored by Merck, Sharp & Dohme and Genzyme. CMRO peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

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38. American Diabetes Association. Treatment targets. Diabetes Care 2014;37(Suppl 1):S16-80 39. American Association of Clinical Endocrinologists. Available at: http:// www.aace.com. Last accessed 1 May 2014 40. The European Athersclerosis Society. New guidlines in USA: How do they compare with the EAS/ESC guidelines for the management of dyslipidaemia? Available at: http://www.eas-society.org/Newsletter-Archive.aspx?newsId= 316. Last accessed 1 May 2014

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36. Fruchart JC, Davignon J, Hermans MP, et al. Residual Risk Reduction Initiative (R3i). Residual macrovascular risk in 2013: what have we learned? Cardiovasc Diabetol 2014;13:26-42 37. Ray KK, Kastelein JJ, Matthijs Boekholdt S, et al. The ACC/AHA 2013 guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular disease risk in adults: the good the bad and the uncertain: a comparison with ESC/EAS guidelines for the management of dyslipidaemias 2011. Eur Heart J 2014;35:960-8

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2013 ACC/AHA guidelines on dyslipidemia: mind the gaps! Athyros et al.

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American Heart Association guidelines for the treatment of dyslipidemia: mind the gaps!

Abstract The ACC/AHA lipid guidelines need to be reconsidered before full implementation. A new cardiovascular disease (CVD) risk estimation, preferab...
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