Professor Philip Calder – Lowering LDL cholesterol levels: the earlier, the better

Article highlights:

• Early identification of CVD risk can have significant long term benefits.
• Even modest decreases in LDL-C are beneficial.
• Risk management strategies should be holistic, incorporating diet and lifestyle first and foremost.

Lowering LDL-cholesterol: the earlier, the better

Cardiovascular disease remains a significant health burden

Cardiovascular disease (CVD), which includes coronary heart disease, stroke, peripheral artery disease and vascular dementia, remains a major source of morbidity and mortality(1,2). Even though mortality rates have declined over the last five decades, CVD still accounts for about one-in-three deaths among both men and women and CVD is the biggest single cause of mortality globally and in the UK^1,2. The root cause of most CVD is atherosclerosis – the build-up of fatty plaque within the blood vessel walls. Plaques can grow sufficiently large to cause hypertension and to partially occlude blood flow to organs such as the heart, the brain and the lower limbs. Unstable plaques can rupture causing thrombosis that can precipitate cardiovascular events like myocardial infarction or stoke.

Current approaches to identification of CVD risk

Current approaches for primary prevention of CVD rely upon assessment of risk factors and their subsequent integration through algorithms such as QRISK in order to identify those individuals who are at high risk who can then be managed mainly through pharmacological interventions³. However, earlier identification of risk can have significant benefits in the long term and it has been argued that there should be a focus on lower risk individuals for long-term gain.^4,5
One risk factor that is commonly targeted is low-density lipoprotein (LDL) cholesterol (LDL-C). LDL is small enough to permeate the blood vessel wall where it can oxidise if is trapped, ultimately contributing to growth of atherosclerotic plaques. Hence, elevated LDL-C concentration in the bloodstream (“high cholesterol”) is a known risk factor for development of CVD, and high LDL-C is associated with about one quarter of CVD deaths in the UK¹. It is estimated that almost half of UK adults are living with a total blood cholesterol concentration above the national guidelines, currently 5 millimoles per litre(1) (this typically corresponds to an LDL-C concentration of 3 millimoles per litre).

The role of earlier LDL-C reduction

Lowering LDL-C level in the blood reduces risk of CVD. There is a linear relationship between LDL-C concentration and risk of CVD which means that even modest decreases in LDL-C are beneficial to disease risk. For example, it is estimated that a 10% reduction in blood total cholesterol in middle-aged men will result in the 50% reduction in heart disease within 5 years⁵. In men aged 70 years, this reduction in blood cholesterol will achieve a 20% reduction in heart disease within 5 years⁵. Hence, bigger effects are achieved, and are achieved earlier in life, by lowering cholesterol sooner rather than later. This is really important because many middle-aged people not yet exhibiting elevations in recognised risk factors for CVD have already developed significant atherosclerosis. Linked to this, it is now recognised that the increased risk of CVD with age begins much earlier than previously thought, for example with increases in LDL-C in early adulthood in both men and women(6). This suggests that management of risk factors should begin early. This is especially important in families with early onset of atherosclerotic cardiovascular disease⁷. Also because of the linear relationship between LDL-C and CVD risk, benefits are still seen at concentrations below those currently considered as the recommended upper concentration (3 millimoles per litre). Indeed, early lowering of LDL-C in apparently low-risk individuals has long-term benefits⁵.

Strategies to lower LDL-C, including diet and lifestyle modification

Statins inhibit hepatic HMGCoA-reductase, the rate-limiting step in hepatic biosynthesis of cholesterol. This inhibition results in increased hepatic expression of LDL receptors thus increasing hepatic clearance of LDL from the bloodstream. The ability of statins to lower blood LDL-C concentration reduces risk of CVD mortality and thus statins have become a mainstay of the medical management of CVD risk. However, many patients have adverse responses to statin therapy and consequently adherence can be poor⁸. Thus, other approaches to reducing blood cholesterol, and CVD risk in general, should be considered as part of a more holistic management strategy. In fact, NICE advises that patients should be offered an opportunity to change their lifestyle BEFORE lipid modification therapy is offered³. Lifestyle modifications should include weight management, smoking cessation, control of alcohol intake, increased physical activity and dietary change. For most patients, making such lifestyle modifications is not easy, so support is necessary to enable these changes.

Dietary changes that are important in reducing LDL-C concentration include increasing intake of non-digestible fibre from wholegrains, vegetables and legumes(9) and altering the sources of different types of fat in the diet, particularly lowering intake of saturated fats and increasing intake of omega-6 polyunsaturated fats^10,11. These dietary strategies work through different mechanisms. Non-digestible fibres lower cholesterol through a combination of decreasing uptake of cholesterol from the gut and decreasing uptake of bile acids from the gut, thereby promoting increased hepatic use of cholesterol for bile acid synthesis. Exchanging saturated for omega-6 polyunsaturated fats modifies hepatic metabolism to favour LDL clearance from the bloodstream.

Strategies that decrease gut uptake of cholesterol can be an effective means to lower blood LDL-C level and reduce CVD risk¹². One such strategy is through increased consumption of plant sterols or stanols. At an intake of 2 grams per day, plant sterols and stanols can lower LDL-C by 7 to 10%^13,14 which would result in a reduction in CVD risk. Interestingly, plant sterols and stanols can lower LDL-C even in patients taking statins¹⁵, indicating that reducing cholesterol uptake is still important even when other strategies are used to target hepatic cholesterol metabolism. Hence, plant stanols and sterols would also work well alongside changes in the pattern of intake of dietary fats.

Dietary changes important in reducing LDL-C:

• Increasing intake of non-digestible fibre from wholegrains, vegetables and legumes.
• Altering the sources of different types of fat in the diet, particularly lowering intake of saturated fats and increasing intake of omega-6 polyunsaturated fats.
• Consumption of 2g plant stanols/sterols daily with a main meal.

It is now recognised that even fairly small reductions in LDL-C can have a significant impact on CVD risk. Furthermore, new research shows that reductions in LDL-C early in life can have long-term benefit and that lowering LDL-C, even when its level is below the current upper limit, has benefits. Given this, lifestyle modifications must be part of a life course approach to manage LDL-C and reduce CVD risk and should precede pharmacological intervention. These should include weight management, increased physical activity and dietary change, along with the relevant support for these modifications. Plant sterols and stanols have a place as part of an LDL-C lowering diet and lifestyle.

Philip Calder is Head of the School of Human Development and Health and Professor of Nutritional Immunology in the Faculty of Medicine, University of Southampton. He is an internationally recognized researcher in human nutrition. His research addresses both life course and translational considerations. Professor Calder was formerly President of the Nutrition Society and is currently President of the Federation of European Nutrition Societies. He was previously Editor-in-Chief of the British Journal of Nutrition and is currently an Associate Editor of several journals

References

British Heart Foundation. Available at https://www.bhf.org.uk/what-we-do/our-research/heart-statistics. Accessed 16 February 2021.

World Health Organisation. Available at https://www.who.int/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds). Accessed 16 February 2021.

NICE (2014) Cardiovascular disease: risk assessment and reduction, including lipid modification. CG181. Available at https://www.nice.org.uk/guidance/cg181/resources/cardiovascular-disease-risk-assessment-and-reduction-including-lipid-modification-pdf-35109807660997. Accessed 16 February 2021.

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Brunner FJ, Waldeyer C, Ojeda F, et al. (2019) Application of non-HDL cholesterol for population-based cardiovascular risk stratification: results from the Multinational Cardiovascular Risk Consortium. Lancet 394, 2173-2183.

Zhang P, Su Q, Ye X, et al. (2020) Trends in LDL-C and non-HDL-C levels with age. Ageing Dis. 11, 1046-1057.

Moonesinghe R, Yang Q, Zhang Z et al. (2019) Prevalence and cardiovascular health impact of family history of premature heart disease in the United States: analysis of the National Health and Nutrition Examination Survey, 2007-2014. J Am Heart Assoc, 8, e012364.

Vinogradova Y, Coupland C, Brindle P, Hippisley-Cox J (2016) Discontinuation and restarting in patients on statin treatment: prospective open cohort study using a primary care database. BMJ 353, i3305.

Hartley L, May MD, Loveman E, Colquitt JL, Rees K (2016) Dietary fibre for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev 2016(1):CD011472.

Mensink RP, Zock PL, Kester AD, Katan MB (2003) Effects of dietary fatty acids and carbohydrates on the ratio of serum total to HDL cholesterol and on serum lipids and apolipoproteins: a meta-analysis of 60 controlled trials. Am J Clin Nutr 77, 1146-1155.

Sundfør TM, Svendsen M, Heggen E, Dushanov S, Klemsdal TO, Tonstad S (2019) BMI modifies the effect of dietary fat on atherogenic lipids: a randomized clinical trial. Am J Clin Nutr 110, 832-841.

Cannon CP, Blazing MA, Giugliano RP, et al. (2015) Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 372, 2387-2397.

Law M (2000) Plant sterol and stanol margarines and health. BMJ 320, 861-864.

Musa-Veloso K, Poon TH, Elliot JA, Chung C (2011) A comparison of the LDL-cholesterol lowering efficacy of plant stanols and plant sterols over a continuous dose range: results of a meta-analysis of randomized, placebo-controlled trials. Prostaglandins Leukot Essent Fatty Acids 85, 9-28.