Focus on LDL Cholesterol Targets With Statin Therapy, New ESC-EAS Cholesterol Guidelines Say

ROME, Italy—A new consensus statement from the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) on the management of dyslipidemias highlights the different approaches taken by European and American physicians, with the new European guidelines focusing on treating patients to a specific LDL cholesterol target. 

Published today in the European Heart Journal to coincide with the start of the ESC Congress 2016 in Rome, Italy, the ESC/EAS guideline experts reiterate their position that LDL cholesterol is the primary target for treatment. They recommended treating patients at very high risk for cardiovascular events to an LDL cholesterol target of less than 70 mg/dL, or to achieve at least a 50% reduction in LDL cholesterol if baseline levels range between 70 and 135 mg/dL (class 1, level of evidence B).

For those at high risk for cardiovascular events, the LDL cholesterol target is less than 100 mg/dL, or with the aim of achieving at least a 50% reduction in LDL cholesterol if baseline levels range between 100 and 200 mg/dL (class I, level of evidence B). For those at low or moderate risk for cardiovascular events, a goal of less than 115 mg/dL can be considered (class IIa, level of evidence C). 

Some of the guidance in today’s document echoes the lipid-lowering recommendations already incorporated in the ESC prevention guidelines released earlier this year, as reported by TCTMD. 

In the ESC/EAS guidelines, very high risk is defined as patients who have documented cardiovascular disease, such as prior MI, and a 10-year risk of fatal cardiovascular disease ≥ 10%. In high-risk patients, individuals have a markedly elevated single risk factor, diabetes mellitus, moderate chronic kidney disease, or a calculated 10-year risk score of ≥ 5% to less than 10%.  

In contrast with the European approach, the American College of Cardiology/American Heart Association (ACC/AHA) 2013 guidelines do not recommend treating to specific LDL goals, instead advising either a moderate- or high-dose statin to patients that fall within four primary- and secondary-prevention groups. For example, in patients with atherosclerotic cardiovascular disease, high-intensity statin therapy—such as rosuvastatin 20 to 40 mg or atorvastatin 80 mg—should be used to achieve at least a 50% reduction in LDL cholesterol. 

Explaining their rationale in opting to treat to specific LDL cholesterol targets, the ESC/EAS expert panel, which was chaired by Alberico Catapano, MD (University of Milan, Italy) and Ian Graham, MD (Hermitage Medical Clinic, Dublin, Ireland), noted they considered a wider range of available studies than the US guidance, including data from basic science, clinical observations, genetics, epidemiology, and randomized controlled trials, to understand the causes of cardiovascular disease and potential for prevention. 

“The task force is aware of the limitations of some of the sources of evidence and accepts that randomized, controlled trials have not examined different LDL-cholesterol goals systematically, but felt that it was appropriate to look at the totality of the evidence,” states the ESC/EAS expert panel. “Indeed, the task force accepts that the choice of any given target goal for LDL-C may be open to debate given the continuous nature of the relationship between LDL-C reduction and reduction in risk.”

Speaking with TCTMD, François Schiele, MD (University Hospital of Besançon, France), a spokesperson for the ESC, said physicians in Europe “love targets” associated with the lipid guidelines, noting that there was surprise on this side of the pond when the US released their lipid recommendations nearly 3 years ago. That said, he understood the position taken by the US writing committee given the lack of randomized controlled trials showing a clinical benefit of treating to a specific LDL cholesterol target. The true science, he added, supports treating by statin intensity and not to specific LDL thresholds. 

Since the publication of the US guidelines, however, subgroup analyses from IMPROVE-IT—a study that showed a modest benefit with the addition of ezetimibe to statin therapy in post-ACS patients—suggested that lower LDL was better for reducing clinical events, said Schiele. Although he was not involved in drafting the ESC/EAS dyslipidemia guidelines, Schiele argued that physicians “don’t really know where they are at” with a patient if LDL cholesterol targets are not used. 

“Physicians need the targets, but [so do] the patients,” he said. “You tell a patient, ‘This is the line and please don’t go over it.’ If you’re treating them with high-intensity statins, and you’d like them to be below 70 mg/dL, you can ask the patient to take care of their diet and so on. Without the 70 mg/dL, the message might be, ‘You have the high-intensity statin, you can do what you want or eat what you want.’”  

Importantly, Schiele noted that guidelines play an important role in unknown clinical situations. Where the evidence is less than rock solid, IIa and IIb recommendations provide guidance on how to manage patients. “We love IIa and IIb recommendations because it’s true advice,” he said. “The Ia recommendation is something you should know. It’s something you can teach. If you’re a practitioner, IIa and IIb tells you what to do.” 

Statins Remain the Gold Standard for Treatment

Importantly, and not unlike the ACC/AHA guidelines, statin therapy is the go-to treatment for elevated cholesterol, with the ESC/EAS recommending the highest dose tolerable to achieve treatment goals (class I, level of evidence A). For patients who are statin intolerant, ezetimibe (Zetia, Merck/Schering-Plough) or a bile-acid sequestrant should be considered (class IIa, level of evidence C), while statins and ezetimibe can be considered for patients not at goal (class IIa, level of evidence B). 

The new ESC/EAS guidelines also open door for the use of PCSK9 inhibitors, the expensive new class of monoclonal antibodies approved in Europe and the United States in 2015. In patients at very high risk of cardiovascular events and persistently high LDL cholesterol levels despite maximally tolerated statin therapy in combination with ezetimibe (or persistently high cholesterol levels in statin intolerant patients treated with ezetimibe), the use of alirocumab (Praluent, Sanofi/Regeneron Pharmaceuticals) or evolocumab (Repatha, Amgen) can be considered (class IIb, level of evidence C). 

Earlier this year, ACC also updated their recommendations for the management of elevated LDL cholesterol levels in high-risk patients, specifically recommending ezetimibe first in high-risk patients who require additional LDL-cholesterol lowering beyond that achieved with a statin. Only after ezetimibe has been tried should physicians consider adding or replacing ezetimibe with one of the PCSK9 inhibitors, according to the ACC consensus statement.

For Schiele, he said the evidence is not yet available supporting widespread use of PCSK9 inhibitors in clinical practice. Moreover, the high-risk patient most likely to benefit from the costly drugs is also not known. That evidence will come to light with the FOURIER and ODYSSEY cardiovascular outcome trials testing evolocumab and alirocumab, respectively. Those results are expected possibly as early as the AHA meeting in New Orleans, LA, in November. 

Schiele does see an immediate role for PCSK9 inhibitors in the treatment of patients with homozygous familial hypercholesterolemia (FH). In this setting, there is no need to wait for clinical trial data, he argued. He also speculated that heterozygous FH patients unable to achieve sufficient LDL cholesterol lowering, a group at high risk for recurrent event cardiovascular events, would also likely benefit from PCSK9 inhibitors. 

“The problem comes down to selection,” said Schiele. “We need the randomized trials to determine who is at risk.” To overcome the high cost of the drug, it is important to identify a high-risk population in whom the drug is very effective, he added. 

At present, the ESC/EAS committee recommends PCSK9 inhibitors for heterozygous FH patients with cardiovascular disease or other risk factors for coronary heart disease, such as family history, high lipoprotein(a), or statin intolerance (class IIa, level of evidence C).

Special Populations

As part of treatment, the ESC/EAS expert panel states that non-HDL cholesterol can be considered a secondary treatment target, as should apolipoprotein B (apoB), when it’s available. HDL cholesterol is a not a treatment target, nor should any of the lipid ratios, such as non-HDL cholesterol/HDL cholesterol, be used as a treatment goal. 

In addition to broad strokes, the European guidelines also make specific recommendations for the treatment of women, older patients, and those with diabetes. The ESC/EAS expert panel acknowledges that the benefit of statins in the primary prevention of cardiovascular disease is less established in women than in men, but it still recommends statin therapy for primary prevention in women at high risk for coronary artery disease. Statins are also recommended for secondary prevention in women, with the same indications and targets as men.

For patients with ACS and those undergoing PCI, physicians should start or continue high-dose statin therapy (class I, level of evidence A) and lipids should be evaluated 4 to 6 weeks after the ACS to determine if the target LDL cholesterol level—less than 70 mg/dL or a 50% reduction in baseline if levels are between 70 and 135 mg/dL—has been reached. Statins are also recommended in patients with peripheral artery disease and in patients at high or very high risk of stroke (class I, level of evidence A).   

The ESC guidelines on cardiovascular disease prevention are the domain for behavioral strategies to achieve and adhere to a healthy lifestyle, but the 2016 ESC/EAS dyslipidemia guidelines also promote heart healthy behavior. No smoking, healthy eating, and physical activity are the Holy Trinity of disease prevention, and the expert panel provides tips to help patients adapt and change. 


  • Catapano AL, Graham I, De Backer G, et al. 2016 ESC/EAS guidelines for the management of dyslipidemias. Eur Heart J. 2016;Epub ahead of print. 


  • Catapano reports direct personal payment in the form of speaker fees, honoraria, consulting fees, and advisory/committee board member fees from Amgen, Esteve, Merck, Sharp, & Dohne, Kowa, AstraZeneca, Pfizer, Sanofi Aventis, Recordati International, Aegerion; payment to institution from Amgen, Pfizer, Sanofi Aventis, and Aegerion; and research funding from Pfizer, Sanofi Aventis, and Merck, Sharpe, & Dohme.  
  • Graham reports direct personal payment in the form of speaker fees, honoraria, consulting fees, and advisory/committee board member fees from Sanofi Aventis, Merck, Sharp, & Dohne, and MSD; and research funding from Merck, Sharpe, & Dohme and the World Health Organization. 

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Michael O’Riordan is the Managing Editor for TCTMD. He completed his undergraduate degrees at Queen’s University in Kingston, ON, and…

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