NO Lower Limit- Follow " the lower the better" Strategy for managing LDL Cholesterol: ESC Guidelines

Paris: There is no lower limit of LDL cholesterol that is known to be unsafe and hence the lower the LDL cholesterol the better, were the key recommendations of the guidelines released today at the ESC Congress 2019 being held in Paris

The lower the LDL cholesterol levels, the better it is for people at a very high risk of heart attack or stroke, recommended new guideline released by the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) for dyslipidaemias released at the ESC Congress 2019 and published online today in European Heart Journal

The guideline suggests that low-density lipoprotein (LDL) cholesterol levels should be lowered as much as possible to prevent cardiovascular disease, especially in high and very high-risk patients.

“There is now overwhelming evidence from experimental, epidemiological, genetic studies, and randomised clinical trials, that higher LDL cholesterol is a potent cause of heart attack and stroke,” said Professor Colin Baigent, Chairperson of the guidelines Task Force and director of the MRC Population Health Research Unit, University of Oxford, UK. “Lowering LDL cholesterol reduces risk irrespective of the baseline concentration. It means that in people at very high risk of heart attack or stroke, reducing LDL cholesterol is effective even if they have below-average starting levels.”

The guideline proposes that there is no lower limit of LDL cholesterol that is known to be unsafe. The guidelines aim to ensure that the available drugs (statins, ezetimibe, PCSK9 inhibitors) are used as effectively as possible to lower levels in those most at risk. It is recommended that such patients should achieve both a target LDL cholesterol level and a minimum 50% relative reduction.

“This is to ensure that high- or very high-risk patients receive intensive LDL cholesterol-lowering therapy irrespective of their baseline level,” said Professor Alberico L. Catapano, Chairperson of the guidelines Task Force and professor of pharmacology at the Department of Pharmacological and Biomolecular Sciences, University of Milan, Italy. “Patients who are already close to their target on current treatment will be offered additional treatment that provides a further minimum 50% reduction.”

Cardiovascular disease (CVD) is responsible for more than four million deaths in Europe each year. Clogged arteries, known as atherosclerotic CVD, are the main type of disease. The guidelines provide recommendations on how to modify plasma lipid levels through lifestyle and medication to reduce the risk of atherosclerotic CVD.

The guidelines also speak extensively about the role of Statins

“Statins are very well tolerated, and true 'statin intolerance' is uncommon. Most patients can take a statin regimen,” noted Professor François Mach, Chairperson of the guidelines Task Force and head of the Cardiology Department, Geneva University Hospital, Switzerland. “Statins have very few side-effects. These include an increased risk of developing diabetes, and they may rarely cause myopathy. But the benefits of statins greatly outweigh their hazards, even among those at low risk of atherosclerotic CVD.”

However, statins are not recommended in pre-menopausal women considering pregnancy or not using adequate contraception. “Although these drugs have not been shown to cause fetal malformations when unintentionally used in the first trimester of pregnancy, women needing a statin should avoid them during any period when they might conceive, as no formal study to address this question has been performed,” said Prof Catapano.

The evidence for statin therapy is more limited in patients over 75, though is still consistent with a benefit. The guidelines advise taking the level of risk, baseline LDL cholesterol, health status, and the risk of drug interactions into account when deciding whether statins are appropriate in those aged 75 or over.

Revisions have been made to the risk stratification categories so that patients with atherosclerotic CVD, diabetes with target organ damage, familial hypercholesterolemia, and severe chronic kidney disease are all categorized as very high-risk (and so will be offered intensive LDL-lowering therapy). Treatment goals for a particular risk category apply regardless of whether or not patients have had a heart attack or stroke.

Evidence since the 2016 guidelines suggests that raised Lp(a) is a cause of atherosclerotic CVD, and patients with genetically elevated Lp(a) can have a similar lifetime risk of heart attack or stroke as those with familial hypercholesterolemia. Since Lp(a) is largely genetically determined, the guidelines recommend measuring it at least once in adulthood. “Assessment should be around 40 years of age to identify people before they have a heart attack or stroke,” said Prof Baigent.

Fish oil supplements (particularly icosapent ethyl) are recommended, in combination with a statin, for patients with hypertriglyceridemia despite statin treatment. In these patients, supplements reduce the risk of atherosclerotic CVD events, including heart attack and stroke, by about one quarter.

The guidelines advocate a lifetime approach to cardiovascular risk. This means that people of all ages and risk levels should be encouraged to adopt and sustain a healthy lifestyle. “The main requirements are a healthy diet, avoidance of cigarette smoking, and regular exercise,” said Prof Mach. “There is no evidence that fish oil supplements prevent first heart attacks and strokes, so we did not recommend them for healthy people.”

Key Recommendations

Cholesterol and risk- Throughout the range of LDL-C levels, ‘lower is better’ with no lower threshold, at least down to ∼1 mmol/L. Lowering LDL-C may yield worthwhile benefits in patients with average or below average LDL-C who are already receiving LDL-C-lowering treatment. The proportional reduction in ASCVD risk achieved by lowering LDL-C (e.g. with a statin, ezetimibe, or PCSK9-inhibitor) depends on the absolute reduction in LDL-C, with each 1 mmol/L reduction corresponding to a reduction of about one-fifth in ASCVD.

PCSK-9 inhibitors. Large trials have shown that PCSK9 inhibitors further reduce ASCVD risk when given on top of statin-based therapy and their use may need to be restricted to those at the highest risk for ASCVD.

Use of cardiac imaging for risk stratification. CAC score assessment with CT may be helpful in reaching decisions about treatment in people who are at moderate risk of ASCVD. Obtaining such a score may assist in discussions about treatment strategies in patients where the LDL-C goal is not achieved with lifestyle intervention alone and there is a question of whether to institute LDL-C-lowering treatment. Assessment of arterial (carotid or femoral) plaque burden on ultrasonography may also be informative in these circumstances.

Use of Lp(a) in risk stratification. A one-off measurement of Lp(a) may help to identify people with very high inherited Lp(a) levels who may have a substantial lifetime risk of ASCVD. It may also be helpful in further risk stratification of patients at high risk of ASCVD, in patients with a family history of premature CVD, and to determine treatment strategies in people whose estimated risk is on the border of risk categories.

Intensification of treatment goals. It is important to ensure that treatment of the highest-risk patients achieves the largest LDL-C reduction possible. These Guidelines aim to support this by setting both a minimum percentage LDL-C reduction (50%) and an absolute LDL-C treatment goal of <1.4 mmol/L (<55 mg/dL) for very-high-risk patients, and <1.8 mmol/L (<70 mg/dL) for high-risk patients. It is recommended that FH patients with ASCVD or who have another major risk factor are treated as very-high-risk, and those with no prior ASCVD or other risk factors as high-risk.

Treatment of patients with recent ACS. New randomized trials support a strategy of intensification of LDL-C-lowering therapy in very-high-risk patients with ACS (MI or unstable angina). If the specified LDL-C treatment goal is not achieved after 4–6 weeks with the highest tolerated statin dose and ezetimibe, it is appropriate to add a PCSK9 inhibitor.

Safety of low LDL cholesterol concentrations. There are no known adverse effects of very low LDL-C concentrations [e.g. <1 mmol/L (40 mg/dL)].

Management of statin ‘intolerance’. While statins rarely cause serious muscle damage (myopathy, or rhabdomyolysis in the most severe cases), there is much public concern that statins may commonly cause less serious muscle symptoms. Such statin ‘intolerance’ is frequently encountered by practitioners and may be difficult to manage. However, placebo-controlled randomized trials have shown very clearly that true statin intolerance is rare, and that it is generally possible to institute some form of statin therapy (e.g. by changing the statin or reducing the dose) in the overwhelming majority of patients at risk of ASCVD.

Statin treatment for older people. Statin therapy in older people should be considered according to the estimated level of risk and baseline LDL-C, albeit with due regard to an individual’s underlying health status and the risk of drug interactions. There is less certainty about the effects of statins in individuals aged >75 years, particularly in primary prevention. Statin therapy should be started at a low dose if there is significant renal impairment and/or the potential for drug interactions, and then titrated upwards to achieve LDL-C treatment goals.