Intensive low-density lipoprotein cholesterol lowering in cardiovascular disease prevention: opportunities and challenges

Abstract

Elevated levels of low-density lipoprotein cholesterol (LDL-C) are associated with increased risk of coronary heart disease and stroke. Guidelines for the management of dyslipidaemia from the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) were updated in late 2019 in light of recent intervention trials involving the use of innovative lipid-lowering agents in combination with statins. The new guidelines advocate achieving very low LDL-C levels in individuals at highest risk, within the paradigm of 'lower is better'. With the advent of combination therapy using ezetimibe and/or proprotein convertase subtilisin/kexin type 9 inhibitors in addition to statins, the routine attainment of extremely low LDL-C levels in the clinic has become a reality. Moreover, clinical trials in this setting have shown that, over the 5-7 years of treatment experience to date, profound LDL-C lowering leads to further reduction in cardiovascular events compared with more moderate lipid lowering, with no associated safety concerns. These reassuring findings are bolstered by genetic studies showing lifelong very low LDL-C levels (<1.4 mmol/L; <55 mg/dL) are associated with lower cardiovascular risk than in the general population, with no known detrimental health effects. Nevertheless, long-term safety studies are required to consolidate the present evidence base. This review summarises key data supporting the ESC/EAS recommendation to reduce markedly LDL-C levels, with aggressive goals for LDL-C in patients at highest risk, and provides expert opinion on its significance for clinical practice.

Keywords: atherosclerosis; epidemiology; hyperlipidaemias.

Figure 1

LDL-C and risk of ASCVD. (A) The approximately log-linear relationship between non-HDL-C and cardiovascular disease (CVD) risk as reported in epidemiological studies. The regression line and the quoted increase in CVD risk (1.56 x) per population standard deviation change in non-HDL-C (1.1 mmol/L) are taken from Di Angelantonio et al . Also shown is the increase in non-HDL-C that gives rise to a doubling of risk. (B) the association of LDL-C with ASCVD risk in genetic studies; and (C) the relationship between achieved LDL-C and CHD event rate in lipid lowering trials. ASCVD, atherosclerotic cardiovascular disease; CHD, coronary heart disease; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; SE, standard error. Adapted with permission from (B) Ference et al and (C) Ference et al.

Figure 2

History of LDL-C lowering trials. This schematic depicts average baseline (top of orange arrow) and on-treatment LDL-C levels (bottom of orange arrow). Grey dotted lines represent previous recommended LDL-C ESC/EAS goals for intervention and the red dotted lines (2019 a, b) represent the current LDL-C ESC/EAS goals. ESC/EAS, European Society of Cardiology/European Atherosclerosis Society; LDL-C, low-density lipoprotein cholesterol.

Figure 3

Patient scenarios. Cases of patients at high ASCVD risk being ascribed to regimens of increasingly intensive LDL-C lowering. LDL-C and triglyceride levels are given in mmol/L (see online supplemental figure 1 for the mg/dL version). The predicted LDL-C reductions of 20% for ezetimibe and 60% for PCSK9i are based on average published responses. Case 1 is a patient with probable FH on the basis of his high LDL-C and sibling with diagnosed FH. Note, the additional 6% reduction on 40 mg rosuvastatin is based on the untreated LDL-C of 5.1 mmol/L; the 20% drop on ezetimibe is calculated from the LDL-C on 20 mg rosuvastatin. Case 2 is a woman with obesity, type 2 diabetes plus other risk factors (hypertension) with symptomatic ASCVD. Case 3 is a man with hypertension with repeat ASCVD events within a short time period (26 months). Note, when LDL-C levels are low—typically <1.8 mmol/L—laboratory measurement can be problematic especially if lipoprotein(a) or plasma triglyceride levels are high. The guidelines recommend the use of non-HDL-C or apolipoprotein B as secondary measures to assess the need for further lipid-lowering action when LDL-C is low, as discussed in more detail. ACEi, angiotensin-converting-enzyme inhibitor; ASCVD, atherosclerotic cardiovascular disease; BMI, body mass index; BP, blood pressure; CFX, coronary circumflex artery; CVD, cardiovascular disease; ESC/EAS, European Society of Cardiology/European Atherosclerosis Society; FH, familial hypercholesterolaemia; LAD, coronary left anterior descending artery; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction; NSTEMI, non-ST elevation MI; PCI, percutaneous coronary intervention; PCSK9i, proprotein convertase subtilisin/kexin type 9 inhibitor; RCA, right coronary artery; TG, plasma triglyceride.

Figure 4

Schematic showing rationale for intensive LDL-C lowering. The outer circle represents patients at ‘high risk’ with an LDL-C goal of below 1.8 mmol/L (70 mg/dL). Evidence of established disease, comorbidities, cardiometabolic disorders and multiple risk factors moves patients into the ‘very high’ risk middle circle, with a more ambitious target of below 1.4 mmol/L (55 mg/dL). The most stringent goal of below 1.0 mmol/L (40 mg/dL) is recommended for those with a particularly aggressive disease course (see online supplemental figure 2 for the mg/dL (mmol/L) version). Note, all patients should achieve an LDL-C reduction of ≥50% relative to a measured or predicted off-treatment LDL-C. ASCVD, atherosclerotic cardiovascular disease; BP, blood pressure; CKD, chronic kidney disease; CVD, cardiovascular disease; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; Het FH, heterozygous familial hypercholesterolaemia; LDL-C, low-density lipoprotein cholesterol; SCORE, Systematic COronary Risk Estimation.