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Reducing LDL cholesterol: The unmet need

Reducing LDL cholesterol for improved cardiovascular outcomes

More people die from cardiovascular disease (CVD) worldwide than from any other cause.1 Coronary heart disease (CHD) is the biggest driver of these deaths,2 with a third of global CHD attributable to high cholesterol alone.3 High cholesterol is a modifiable risk factor for heart disease: it is well established that lowering low-density lipoprotein cholesterol (LDL-C) decreases the number and risk of coronary events.4–6

There are also other types of cholesterol which, together with LDL-C, are associated with long-term risk of atherosclerotic CVD (ASCVD).7 These are collectively known as non-high-density lipoprotein cholesterol (non-HDL-C). Assessment of non-­HDL-C (total cholesterol minus HDL-C) is recommended by current US and European guidelines for cardiovascular risk estimation independently of LDL-C.8,9

Plant stanol ester has been shown to reduce non-HDL-C at similar levels to LDL-C when consumed at a 2–3 g per day intake of plant stanols.10–14

A recent study by Gylling et al. showed that plant stanol ester reduces LDL-C dose-dependently and, based on surrogate estimates, such LDL-C lowering reduces the risk of ASCVD events dose-dependently (ASCVD events are major vascular events, comprising fatal or non-fatal coronary artery disease, coronary artery revascularisation, or stroke). These novel estimations demonstrated that a consumption of 2 g/day plant stanols reduced LDL-C concentrations by 0.33 mmol/L, which was expected to reduce the risk of ASCVD events by 6.9%. For consumption of 3 g/day plant stanol, the respective estimates were –0.42 mmol/L and –8.8% (see table below).15 Based on EU guidance, consumers are not recommended to have a >3 g/day intake of plant stanols.

Change in LDL-C concentrations by plant stanol ester consumption and its predicted impact on the risk of ASCVD events*15

*ASCVD events = major vascular events (fatal or non-fatal coronary artery disease, coronary artery revascularisation, or stroke).

Elevated blood cholesterol is a major modifiable risk factor for CHD

More people die from CVD worldwide than from any other cause.1 CHD is the biggest driver of these deaths and is due to the buildup of fatty deposits in the blood vessels (atherosclerosis), causing blockages and preventing blood supply to the heart or brain (heart attack or stroke).2

Having CHD is attributable to a combination of risk factors:16

These risk factors for CHD are non-modifiable

Increasing age
Male gender (at an earlier age)
Genetic factors

These risk factors for CHD are modifiable

80% of premature heart attacks are preventable with careful management of modifiable risk factors16

Smoking
Poor diet
Physical inactivity
Elevated blood cholesterol

Some of these risk factors can be managed, such as a poor diet or physical inactivity, while others are not modifiable, such as genetic factors and ageing. Fortunately, 80% of premature heart attacks and strokes are preventable with careful management of modifiable risk factors.16

Elevated blood cholesterol, or hyperlipidaemia, is a major modifiable risk factor for CHD and widely studied. LDL-C in particular has been directly implicated in the development of ASCVD.17

Millions of people around the world live with elevated cholesterol, and according to the World Health Organization, a third of global CHD is attributable to high cholesterol alone.3 It is estimated that raised cholesterol causes 2.6 million deaths and around 30 million disability-adjusted life years globally.3

It is well established that lowering LDL-C decreases the number and risk of coronary events.4–6

LDL cholesterol: the earlier the better, the lower the better

There is good evidence to indicate that the process of atherosclerosis can manifest before there are any apparent risk factors. A 2017 study of 1,779 subjects who did not exhibit CVD risk factors found that plaque or coronary calcification were present in 49.7% of these subjects.18

The findings suggest that many middle-aged people with an LDL-C concentration greater than 50–60 mg/dL (1.3–1.6 mmol/L) may already have clinically manifested atherosclerosis,18 even though these concentrations are currently considered as normal according to clinical thresholds. This supports the case for more effective LDL-C lowering, even in individuals without conventional cardiovascular risk factors.

A series of meta-analyses by Ference et al. have shown that a life-long low LDL-C level reduces the risk of CHD substantially more than lowering LDL-C later in life. Long-term exposure to lower blood LDL-C due to certain gene variants resulting in lower LDL-C levels was associated with a 54.5% reduction in the risk of CHD for each mmol/L lower LDL-C.19 The study provides strong evidence for a prophylactic approach to lower the risk of CHD by lowering LDL-C earlier in life, for example via lifestyle adjustment.

In addition, during the 85th European Atherosclerosis Society (EAS) congress, the EAS published a consensus statement which states that the effect of LDL-C is cumulative, meaning that the higher the LDL-C is and the longer a person has elevated LDL-C, the higher the risk of ASCVD.17 Thus, lowering LDL-C early in life provides a major opportunity to reduce the lifetime risk of a cardiovascular event.

Even small LDL cholesterol reductions can make a difference 

The well-established linear relationship between LDL-C and relative risk of CHD has been consistently supported by clinical, epidemiological and genetic studies.17,20,21 It suggests that even small LDL-C reductions are worthwhile to minimise risk of disease and that an additional reduction in CHD risk is obtained when LDL-C is reduced below the typically recommended upper LDL-C concentration of 110 mg/dL (3.0 mmol/L).

Linear association between LDL-C level and absolute CHD event rate based on the extensive clinical evidence. Trend lines for primary and secondary prevention associations are virtually superimposable.
Adapted from Ference et al. 2017.17
CHD=coronary heart disease; LDL-C=low-density lipoprotein cholesterol.

The data suggest that for every 10 mg/dL (0.26 mmol/L) decrease in LDL-C, the relative risk for CHD is reduced by approximately 10%.17

The IMPROVE-IT study provides strong evidence that lowering LDL-C through the reduction of cholesterol absorption from the digestive tract results in an expected reduction in the risk of major vascular events.6

Relationship between reduction in LDL-C and cardiovascular event rate.  IMPROVE-IT Trial Data – Letters from a to n denote the following trials: a: Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI Prevenzione); b: Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial–Lipid Lowering Trial (ALLHAT-LLT); c: Assessment of Lescol in Renal Transplantation (ALERT); d: Lescol Intervention Prevention Study (LIPS); e: Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS); f: Cholesterol and Recurrent Events (CARE); g: Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID); h: Prospective Study of Pravastatin in the Elderly at Risk (PROSPER); i: Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm (ASCOT-LLA); j: West of Scotland Coronary Prevention Study (WOSCOPS); k: Post–Coronary Artery Bypass Graft (Post CABG); l: Collaborative Atorvastatin Diabetes Study (CARDS); m: Heart Protection Study (HPS); n: Scandinavian Simvastatin Survival Study (4S). Adapted from Cannon et al. 2015.6 LDL-C=low-density lipoprotein cholesterol.

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