|Year : 2016 | Volume
| Issue : 4 | Page : 125-129
Low density lipoprotein cholesterol reduction for the prevention of cardiovascular disease: Newer concepts
Shamanna S Iyengar DM, FRCP (E)
Department of Cardiology, Manipal Hospital, Bengaluru, Karnataka, India
|Date of Web Publication||20-Oct-2016|
Shamanna S Iyengar
Manipal Hospital, Bengaluru, Karnataka
Source of Support: None, Conflict of Interest: None
Low density lipoprotein cholesterol (LDL-C) is the target of lipid lowering therapy in subjects who have atherosclerotic cardiovascular disease (ASCVD) or who are at risk of developing it. There have been many debatable issues in this field. Should lifelong statins be prescribed for subjects at low risk of ASCVD in primary prevention? How low one can go in LDL-C lowering and is it safe? Should we "treat to target" or just administer high or moderate or low intensity statins based on the risk category? What is the role of nonstatin drugs in lipid lowering therapy? Are proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9 inhibitors) going to be the game changers? There is an abundance of literature looking at these matters. Statins continue to be the first choice in dyslipidemia management. PCSK9 inhibitors would be a welcome addition to the armamentarium or an attractive alternative in certain situations.
Keywords: Atherosclerotic vascular disease, low density lipoprotein cholesterol, nonstatins, proprotein convertase subtilisin/kexin type 9 inhibitors, statins
|How to cite this article:|
Iyengar SS. Low density lipoprotein cholesterol reduction for the prevention of cardiovascular disease: Newer concepts. J Clin Prev Cardiol 2016;5:125-9
|How to cite this URL:|
Iyengar SS. Low density lipoprotein cholesterol reduction for the prevention of cardiovascular disease: Newer concepts. J Clin Prev Cardiol [serial online] 2016 [cited 2019 May 23];5:125-9. Available from: http://www.jcpconline.org/text.asp?2016/5/4/125/192689
"Is statin monotherapy the perfect polypill?"
-Paul M Ridkar (2016)
| Introduction|| |
Low density lipoprotein cholesterol (LDL-C) is highly atherogenic and is the target of lipid lowering therapy (first on the hit-list!) in subjects and patients at high risk of atherosclerotic cardiovascular disease (ASCVD). There is enough evidence about LDL-C, to say "lower is better" and "earlier is better." The concerns about adverse effects such as cancer, cerebral bleed, and neurocognitive defects largely seem to have been cleared.
Statins are superbly safe and extremely effective in lowering LDL-C and improving cardiovascular (CV) outcome. Statins seem to exert a "legacy effect." Nonstatin drugs such as ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been added to the armamentarium. Genetic studies have strengthened the "LDL-C hypothesis" (probably it is no longer a hypothesis).
There is some noise from statin skeptics and misinformed media. But, LDL-C as a target and statins as lipid lowering therapeutic agents stand firm highly substantiated by scientific data, and there is an exciting field of PCSK9 inhibitors awaiting outcome data with optimism.
| Low Density Lipoprotein Cholesterol|| |
Low density lipoprotein has its origin from intermediate density lipoprotein, its density is 1.019-1.063 g/ml, size is 20-25 nm, 25% of it is protein, triglycerides constituting 4-8%. In humans, it is a major cholesterol carrier. 
LDL-C is a key player in the process of atherogenesis. LDL-C meets all the criteria of modified Koch's postulates as one of the causative factors for atherosclerotic vascular disease. Animal experiments, genetic studies, and clinical studies have shown the relationship of high LDL-C with ASCVD. Clinical trials and imaging studies have clearly shown reduction of ASCVD events and regression of atherosclerosis with LDL-C lowering therapy. 
Low density lipoprotein cholesterol target
American College of Cardiology/American Heart Association (ACC/AHA) guidelines  have deviated from the standard "treat to target" principle to what many believe to "fire and forget" practice. It was a risk-based approach to manage ASCVD, focusing on statin therapy. They identified the following four groups where statin therapy is beneficial:
- Patients with clinical ASCVD
- Subjects with a LDL-C of 190 mg/dL or more
- Diabetes 40-75 years of age and LDL-C 70-189 mg/dL
- No diabetes, 40-75 years of age and LDL-C 70-189 mg/dL, and if 10 year ASCVD risk is 7.5% or more.
In subjects with 5 to <7.5% 10-year ASCVD risk, they recommend considering additional risk factors, tests, and life time risk and a detailed discussion with the subject before starting statins.
They also brought in the concept of high intensity statins (reducing serum LDL-C by 50% or more), and moderate intensity statins (reducing LDL-C by 30-50%). No specific LDL-C goals are recommended. LDL-C measurements are also not recommended other than to assess response and adherence.
This is not appealing to many clinicians as most of us are used to practice target-based therapies, and it could motivate the patients too to have a goal. Moreover, there are scores of studies convincing us that lower LDL-C is better. Hence, it is probably prudent to follow a hybrid approach to LDL-C lowering therapy as described in two recent Indian guidelines on lipid management. ,, 2016 European Guidelines on CV disease prevention in clinical practice also recommend such an approach as shown below [Table 1]. 
Low density lipoprotein cholesterol lowering in subjects at low risk of atherosclerotic cardiovascular disease
There continues to be a debate in some quarters about use of statins in subjects at low risk of ASCVD.
Recommendations from the American College of Cardiology/ American Heart Association guidelines
The lipid guidelines from the American College of Cardiology/ American Heart Association  recommend the following:
Those with ASCVD risk of 5-7.5%: This population does derive benefit from moderate intensity statin therapy, but the risk-benefit trade-off is not distinct. Here, the patient/subject engagement is crucial in taking a decision on drug therapy. The potential benefits, risks, drug interactions, and subject preferences should be discussed at length.
Those with an ASCVD risk of <5% or there is uncertainty about statin therapy, additional factors should be assessed, i.e. LDL-C 160 mg/dL or more, family history of premature ASCVD, high-sensitivity C-reactive protein 2.0 mg/L, coronary calcium score >300 Agatston units, ankle brachial index <0.9, or lifetime ASCVD risk, to take decision.
Meta-analysis of 27 randomized trials
This meta-analysis reports the effects of lowering LDL-C with statins in subjects at low CV risk. 
Out of 27 trials, 22 were trials of statin vs control, including 134,537 participants where the mean LDL-C difference between the groups was 1.08 mmol/L and they were followed up to 4.8 years. The other 5 trials were of high dose versus standard dose of statins and had 39,612 participants; the mean difference in LDL-C achieved was 0.51 mmol/L with a follow up of 5.1 years.
Major vascular events (nonfatal myocardial infarction, coronary death, stroke, coronary revascularization) among individuals who had a 5 year risk of <10% were analyzed. This population, i.e., vascular risk of <10% would not be eligible to receive statin as per the Adult Treatment Panel III,  European Society of Cardiology Task Force,  and National Institute for Health and Care Excellence guidelines. 
The analysis showed clearly a benefit in this low risk population with statin therapy. Each 1 mmol/L reduction in LDL-C produced an absolute reduction in major vascular events of 11/1000 over 5 years. There was no increase in cancer incidence, cancer mortality, or nonvascular mortality. This makes a strong case for statin therapy in low ASCVD risk population.
Lower low density lipoprotein cholesterol is better
In LDL hypothesis, the theme is that reduction in LDL-C by whatever means, should lead to corresponding reduction in CV events. Cholesterol treatment trialists' collaboration  found from their meta-analysis of nearly 90,000 participants of 14 randomized trials that each 38.7 mg% reduction of LDL-C results in 23% reduction in major coronary events over a period of 5 years.
Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT)
This study supports two concepts: 
- "LDL hypothesis" and
- "Lower LDL-C is better."
In this study, there were 18,144 patients of acute coronary syndrome randomized to simvastatin plus ezetimibe or simvastatin plus placebo. The primary end point was a composite of CV death, nonfatal myocardial infarction, unstable angina, or coronary revascularization. The primary endpoint was significantly lower in the statin/ezetimibe combination arm, without significant difference in rate of adverse events.
The mean LDL-C at the end of 1 year was 53.2 mg% in simvastatin-plus-ezetimibe arm and 69.9 mg% per deciliter in the simvastatin-monotherapy arm.
Some authors now would like to change the term "LDL hypothesis" to "LDL principle." 
Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER)
In this study of 17,802 participants, those attaining LDL-C <50 mg/dl had a lower risk of CV events without an increase in adverse events.  Those who achieved LDL-C <50 mg/dL had 65% reduction in the risk of major CV events and 46% reduction in total mortality. Approximately, 23% of the subjects reached LDL-C level of <40 mg/dL. In a post hoc analysis, no adverse effects were seen in this group.
The cardiology community is looking for a lower cut off value of LDL-C below which further lowering is no longer beneficial. The JUPITER authors suggest that this threshold, if it exists, may be <50 mg/dl or 50% LDL-C reduction.
Meta-analysis of 8 trials
A meta-analysis of individual patient data from 8 landmark randomized controlled trials (including AFCAPS/TexCAPS [Air Force/Texas Coronary Atherosclerosis Prevention study], LIPID [Long-Term Intervention with Pravastatin in Ischaemic Disease], JUPITER, TNT [Treating to New Targets], IDEAL [Incremental Decrease in Endpoints Through aggressive Lipid Lowering], SPARCL [Stroke Prevention by Aggressive Reduction in Cholesterol Levels]), at 1-year follow-up, revealed 54% reduction in major CV events among individuals who achieved LDL-C level <50 mg/dL. 
There is a linear and continuous relationship between cholesterol levels and ASCVD events,  and randomized controlled trials have shown that lower LDL-C results in greater risk reduction.
Various imaging studies have confirmed regression of atherosclerotic process with aggressive reduction of LDL-C to 50 mg% or less. ,
Based on the data available, it is reasonable to lower the LDL-C target. Indian guidelines  recommend an LDL-C goal of 50 mg% for subjects/patients at a very high risk of ASCVD. 2013 ACC/AHA guidelines, though recommend a fixed dose strategy, indirectly endorse lower LDL-C when they state that "if LDL-C is <40 mg/dl on two consecutive measurements, decreasing the dose of statin therapy may be considered, and that no data have been identified to suggest that adverse events occurred when LDL-C was <40 mg/dl." 
Legacy effect of statins
West of Scotland Coronary Prevention Study  had randomized 6595 men to receive pravastatin or placebo for nearly 5 years. When followed up for 20 years, men who received pravastatin had significantly reduced all-cause mortality, whereas non-CV and cancer death did not show difference. Cumulative hospitalization event rates were lower in the pravastatin group. It was 18% for any coronary event (P = 0.002), 24% for myocardial infarction (P = 0.01), and 35% for heart failure (P = 0.002).
This long-term legacy effect of statins supports the role of statins for wider application in primary prevention.
However, this raises an important question. Does it mean that lifelong treatment with statins is not required? One should note that in this study there was a diminution in the treatment effect in the post-trial period compared with the in-trial phases. It may mean that there is a possibility of reducing the dose, but not stopping the drug.
Proprotein convertase subtilisin/kexin type 9 inhibitors
Statins remain the drug of first choice in the management of subjects and patients with dyslipidemia and high risk ASCVD. However, there are situations where additional lipid lowering drug is required to meet the LDL-C targets, or an alternative drug is needed when there is statin intolerance. Ezetimibe fills the role partly. But the game changer seems to be PCSK9 inhibitors.
PCSK9 is abundantly expressed in liver, gastrointestinal tract, kidney, and nervous system. It degrades LDL receptors leading to increased levels of LDL-C. PCSK9 inhibitors block this action, increase LDL receptors which clear LDL-C from the circulation, thus lowering LDL-C.
A gain-of-function mutation in PCSK9 gene results in elevated LDL-C levels in blood, in turn, leading to high risk of CV disease in these subjects. This mutation is responsible for 10-25% of autosomal dominant form of familial hypercholesterolemia (FH).
Loss of function mutation in PCSK9 is associated with low levels of LDL-C and low risk of ASCVD.
There are several PCSK9 inhibitors available now. Evolocumab and alirocumab have already been approved for the use in patients with FH and in those with ASCVD where LDL-C targets are not met.
Exploratory analyses of ODYSSEY LONG-TRM (Long-term Safety and Tolerability of Alirocumab in High Cardiovascular Risk Patients with Hypercholesterolemia Not Adequately Controlled with Their Lipid Modifying Therapy; alirocumab, n = 2341) and OSLER (Open-Label Study of Long-Term Evaluation against LDL Cholesterol; evolocumab, n = 4465) indicate the reduction in CV outcomes of 50-55% over a period of up to 78 weeks. ,
A meta-analysis of 24 trials of PCSK9 antibody therapy, involving >10,000 patients, showed a 55% reduction in all-cause mortality (P < 0.015), with similar decline in CV mortality and myocardial infarction.  Outcome data with PCSK9 inhibitors are eagerly awaited.
These have to be administered by subcutaneous injections, and they are well tolerated. Their safety profile is reassuring. The possibility of neurocognitive effects is being objectively evaluated. It is heartening to note that there was no evidence of an effect of alirocumab on development of new-onset diabetes in 3448 individuals without diabetes at baseline with a follow-up period of 6-18 months, compared to either placebo or ezetimibe.  Similar encouraging reports came from Blom et al. in their study 901 participants followed up for 52 weeks with evolocumab. 
Genetic studies and familial hypercholesterolemia
Genetic epidemiology adds a different perspective to persons having a lifetime of low cholesterol levels as they manifest a particularly low prevalence of ASCVD.  Similarly, those having FH have a lifelong exposure to high LDL-C and thus a high risk of ASCVD. This finding indicates that "the longer, the better" is true for cholesterol. Longer the exposure to low cholesterol, higher is the CV protection. Longer the exposure to high levels of cholesterol, higher is the risk of ASCVD, and earlier the onset of ASCVD.
It has been rightly remarked that for smokers, we talk about "pack-years." Similarly, we need to consider "cholesterol years" for prevention of ASCVD.
Heterozygous FH is a common genetic disease (prevalence 1/200-1/500) and characterized by extremely high LDL-C concentrations. This results in premature atherosclerosis and CV disease. Homozygous FH is a more severe form of FH, and these patients develop CV disease at a mean age of 20 years.  The treatment goal for adult patients with FH a LDL-C of 70 mg/dL or 50% reduction in LDL-C. However, achieving this goal is difficult, and PCSK9 inhibitors are useful.
In FH, the important fact is the absolute duration of exposure to high cholesterol levels. Earlier the treatment is started, better it is.
Fasting lipids or nonfasting lipids
It has been found after analyzing extensive observational data that changes in maximal mean lipid values 1-6 h after meals are not clinically significant. Hence it is recommended that: 
- Nonfasting blood samples be routinely used for the assessment of plasma lipid profiles
- Nonfasting and fasting measurements should be complementary but not mutually exclusive.
This will also improve patient compliance with lipid testing. The following is the guide for using fasting or nonfasting samples for lipid testing.
Nonfasting sample should be used in most patients, including the following:
- Initial lipid profile testing in any patient
- For CV risk assessment
- Patients admitted with acute coronary syndrome
- In children
- If preferred by the patient
- In diabetic patients (due to hypoglycemic risk)
- In the elderly
- Patients on stable drug therapy.
Fasting can sometimes be required if:
- Nonfasting triglycerides 5 mmol/L (440 mg/dL)
- Known hypertriglyceridemia followed in lipid clinic
- Recovering from hypertriglyceridemic pancreatitis
- Starting medications that cause severe hypertriglyceridemia
- Additional laboratory tests are requested that require fasting or morning samples (e.g. fasting glucose, therapeutic drug monitoring).
| Conclusion|| |
LDL hypothesis is no longer a hypothesis and is a principle since it fulfills modified Koch's postulate. Fasting state is not necessary to take samples for lipid values routinely. Cardiology community is searching for a safe and a low LDL-C target. Ezetimibe and PCSK9 inhibitors have joined the lipid lowering armamentarium. Statin continues to be a key player in lipidology and in prevention of ASCVD and it has exhibited a legacy effect.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Genest J, Libby P. Lipoprotein disorders and cardiovascular disease. In: Braunwald′s Heart Disease, A Text Book of Cardiovascular Medicine. 10 th
ed., Ch. 45. South Asia: Publisher Elsevier Saunders; 2015.
Ridker PM, Libby P, Buring JE. Risk markers and the primary prevention of cardiovascular disease. In: Braunwald′s Heart Disease, A Text Book of Cardiovascular Medicine. 10 th
ed., Ch. 42. South Asia: Publisher Elsevier Saunders; 2015.
Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, et al
. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults : a0 report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63(25 Pt B):2889-934.
Chandra KS, Bansal M, Nair T, Iyengar SS, Gupta R, Manchanda SC, et al
. Consensus statement on management of dyslipidemia in Indian subjects. Indian Heart J 2014;66 Suppl 3:S1-51.
Iyengar SS, Puri R, Narasingan SN, Wangnoo SK, Mohan V, Mohan JC, et al
. Lipid association of India expert consensus statement on management of dyslipidemia in Indians 2016: Part 1. J Assoc Physicians India 2016;64 Suppl: 1-54.
Iyengar SS, Puri R, Narasingan SN. Lipid Association of India Expert Consensus Statement on Management of Dyslipidemia in Indians 2016: Part 1 - Executive summary. J Clin Prev Cardiol 2016;5:51-61.
Authors/Task Force Members, Piepoli MF, Hoes AW, Agewall S, Albus C, Brotons C, et al
. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The sixth joint task force of the European Society of cardiology and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of 10 societies and by invited experts): Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur J Prev Cardiol 2016;23:NP1-96.
Cholesterol Treatment Trialists′ (CTT) Collaborators, Mihaylova B, Emberson J, Blackwell L, Keech A, Simes J, et al
. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease : m0 eta-analysis of individual data from 27 randomised trials. Lancet 2012;380:581-90.
Grundy SM, Cleeman JI, Merz CN, Brewer HB Jr., Clark LT, Hunninghake DB, et al.
Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110:227-39.
European Association for Cardiovascular Prevention & Rehabilitation, Reiner Z, Catapano AL, De Backer G, Graham I, Taskinen MR, et al
. ESC/EAS Guidelines for the management of dyslipidaemias : t0 he Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2011;32:1769-818.
Cooper A, Nherera L, Calvert N, O′Flynn N, Turnbull N, Robson J, et al
. Clinical Guidelines and Evidence Review for Lipid Modification: Cardiovascular Risk Assessment and the Primary and Secondary Prevention of Cardiovascular Disease. London: National Collaborating Centre for Primary Care and Royal College of General Practitioners; 2008.
Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, et al
. Efficacy and safety of cholesterol-lowering treatment : p0 rospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005;366:1267-78.
Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, et al
. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015;372:2387-97.
Jarcho JA, Keaney JF Jr. Proof that lower is better - LDL cholesterol and IMPROVE-IT. N Engl J Med 2015;372:2448-50.
Hsia J, MacFadyen JG, Monyak J, Ridker PM. Cardiovascular event reduction and adverse events among subjects attaining low-density lipoprotein cholesterol<50 mg/dl with rosuvastatin. The JUPITER trial (Justification for the Use of Statins in Prevention : a0 n Intervention Trial Evaluating Rosuvastatin). J Am Coll Cardiol 2011;57:1666-75.
Boekholdt SM, Hovingh GK, Mora S, Arsenault BJ, Amarenco P, Pedersen TR, et al
. Very low levels of atherogenic lipoproteins and the risk for cardiovascular events : a0 meta-analysis of statin trials. J Am Coll Cardiol 2014;64:485-94.
Law MR, Wald NJ, Thompson SG. By how much and how quickly does reduction in serum cholesterol concentration lower risk of ischaemic heart disease? BMJ 1994;308:367-72.
Nissen SE, Nicholls SJ, Sipahi I, Libby P, Raichlen JS, Ballantyne CM, et al
. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis : t0 he ASTEROID trial. JAMA 2006;295:1556-65.
Tsujita K, Sugiyama S, Sumida H, Shimomura H, Yamashita T, Yamanaga K, et al
. Impact of dual lipid-lowering strategy with ezetimibe and atorvastatin on coronary plaque regression in patients with percutaneous coronary intervention: The multicenter randomized controlled PRECISE-IVUS Trial. J Am Coll Cardiol 2015;66:495-507.
Smith SC Jr., Grundy SM. 2013 ACC/AHA guideline recommends fixed-dose strategies instead of targeted goals to lower blood cholesterol. J Am Coll Cardiol 2014;64:601-12.
Ford I, Murray H, McCowan C, Packard CJ. Long-term safety and efficacy of lowering low-density lipoprotein cholesterol with statin therapy: 20-year follow-up of West of Scotland Coronary Prevention Study. Circulation 2016;133:1073-80.
Sabatine MS, Giugliano RP, Wiviott SD, Raal FJ, Blom DJ, Robinson J, et al
. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1500-9.
Robinson JG, Farnier M, Krempf M, Bergeron J, Luc G, Averna M, et al
. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1489-99.
Navarese EP, Kolodziejczak M, Schulze V, Gurbel PA, Tantry U, Lin Y, et al
. Effects of proprotein convertase subtilisin/kexin type 9 antibodies in adults with hypercholesterolemia: A systematic review and meta-analysis. Ann Intern Med 2015;163:40-51.
Colhoun HM, Ginsberg HN, Robinson JG, Leiter LA, Müller-Wieland D, Henry RR, et al
. No effect of PCSK9 inhibitor alirocumab on the incidence of diabetes in a pooled analysis from 10 ODYSSEY Phase 3 studies. Eur Heart J 2016. pii: ehw292.
Blom DJ, Hala T, Bolognese M, Lillestol MJ, Toth PD, Burgess L, et al
. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med 2014;370:1809-19.
Cohen JC, Boerwinkle E, Mosley TH Jr., Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 2006;354:1264-72.
Nordestgaard BG, Chapman MJ, Humphries SE, Ginsberg HN, Masana L, Descamps OS, et al
. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population : g0 uidance for clinicians to prevent coronary heart disease : c0 onsensus statement of the European Atherosclerosis Society. Eur Heart J 2013;34:3478-90a.
Nordestgaard BG, Langsted A, Mora S, Kolovou G, Baum H, Bruckert E, et al
. Fasting is not routinely required for determination of a lipid profile : c0 linical and laboratory implications including flagging at desirable concentration cut-points- a joint consensus statement from the European Atherosclerosis Society and European Federation of clinical chemistry and laboratory medicine. Eur Heart J 2016;37:1944-58.