We all know that food is an important part of our life; be it fast food or gourmet it is one of our guilty pleasures. However, the way we relate to it can lead to serious problems such as obesity, hypertension, diabetes, cardiovascular disease, etc. 

Cholesterol (Greek chole = bile and stereos = solid) is an essential molecule for human homeostasis and its pathophysiology has been extensively studied, with no less then 13 Nobel prize winners receiving recognition for research and discoveries in this field.¹ All this extensive research found that there is a major correlation between lipoproteins and the pathogenesis of cardiovascular disease, further promoting clinical trials and eventually leading to the development of new lipid lowering drugs. One of those are HMG-CoA (3-hydroxy-3-methyl-glutaryl-coenzime A) reductase inhibitors, more commonly known as statins, which have been the mainstay in lipid lowering therapy for almost 30 years since lovastatin was first discovered in 1978 by Akira Endo.¹

Pathophysiology

There are three major classes of lipoproteins circulating in plasma: cholesterol and its esters, triglycerides and phospholipids. As they are not soluble in water (blood’s major constituent) they are transported in the form of chilomicrons from the intestine to the liver where they are degraded in smaller particles and further transported into the circulation. Out of these smaller particles, the ones that sparked most interest are LDLc and HDLc. 

LDLc is the main carrier of circulating cholesterol within the body, with the majority of LDLc particles taken up by LDLc receptors in the liver and the rest of LDLc being removed at the cellular level. As LDLc is taken up by receptors, free cholesterol is released and accumulates within the cells. Plasma LDLc concentrations are regulated by LDLc receptor activity and uptake of LDLc, through such mechanisms as decreasing the synthesis of hydroxy-3-methyglutaryl coenzyme A (HMG-CoA) reductase (which controls the rate of cholesterol synthesis), suppressing the synthesis of new LDLc receptors in the cells, and activating the enzyme acyl-coenzyme A cholesterol acyltransferase, which esterifies free cholesterol into cholesterol ester, storing cholesterol in the cell.²

HDLc is a lipoprotein involved in reverse cholesterol transport and the transfer of cholesterol esters between lipoproteins. HDLc is formed through a maturation process whereby precursor particles (nascent HDL) secreted by the liver and intestine proceed through a series of conversions (known as the ‘HDL cycle’) to attract cholesterol from cell membranes and free cholesterol to the core of the HDL particle. The exact mechanism by which the HDL delivers cholesterol esters to the liver is not well understood, but possible mechanisms include the action of cholesteryl ester transfer protein, that transforms HDL into a TG-rich particle that interacts with hepatic-triglyceride lipase. Another mechanism may be that cholesterol esters are delivered directly to the liver for uptake without catabolism of the HDL cholesterol particle.

Regarding cardiovascular disease risk, the higher that HDLc levels are, the lesser the risk of heart disease, therefore higher levels of HDLc are considered to be protective. This leads to the appreciation that the other ‘non-HDL’ particles (LDL, VDLC) are highly atherogenic.³

Statins act by competitively inhibiting the enzyme HMG Co-A reductase leading to a fall in hepatocellular cholesterol, which results in an upregulation of hepatic LDL receptors that bind circulating LDLc. The increased uptake of LDLc reduces plasma cholesterol levels and increases the HDLc levels. Cholesterol levels are reduced by 25-30% under statin therapy. Statins also slow the rate of progression of athersclerosis, promote plaque regression and stabilise atherosclerotic plaques prone to rupture (pleiotropic effects).

As with all homeostasis abnormalities, there is usually an imbalance between production and clearance of lipoproteins and, as well an enzymatic deficiency, that can lead to what we know as dyslipidaemia which plays a major role in cardiovascular disease (CVD). CVD describes disease of the heart and vascular system causes by the process of aterosclerosis. 

Epidemiology

CVD is the most common cause of morbidity and mortality in the world, accounting for more than 17.3 million deaths per year, a figure which is estimated will increase to more than 23.6 million deaths by 2030 according to a World Health Organization (WHO) statement. More than three-quarters of CVD deaths take place in low and middle income countries. Out of the 16 million deaths under the age of 70 due to non-communicable diseases, 82% are in low and middle income countries and 37% are caused by CVDs.⁴ Can this be prevented? According to the same WHO statement, by treating modifiable risk factors (responsible for > 90% CVD) such as sedentarism, poor diet, smoking, hypertension, diabetes mellitus and dyslipidaemia, up to 80% of CVD is preventable.⁴

In this article we focus on why statins have become the mainstay of treatment in primary and secondary prevention for CVD.⁵

Statins in primary prevention 

Let us start with primary prevention of CVD. Statin treatment reduces the relative cardiovascular risk by 20-30% regardless of the LDLc baseline value.⁶

The 1995 West of Scotland Coronary Prevention Study (WOSCOPS)⁷ enrolled 6,595 hyperlipidaemic men aged 45-64, with 92% of participants free of known CVD at the beginning of the study. It showed that cholesterol lowering with pravastatin 40mg versus placebo, reduced the number of non-fatal myocardial infarction and CHD (coronary heart disease) mortality. 

Long-term follow up after completion of the trial showed sustained benefits and that reduction of mortality increased over five to 10 years. Similar results were observed in the Anglo-Scandinavian Cardiac Outcomes Trial – Lipid Lowering Arm (ASCOT-LLA)⁸ with atorvastatin 10mg in both men and women with hypertension and three other CVD risk factors. 

The Justification for the Use of Statins in Prevention trial (JUPITER)⁹ showed that rosuvastatin 20mg reduced LDLc values by more than 50% and hs-CRP by 37%, and showed a 44% decrease in the composite primary endpoint of MI, stroke, arterial revascularisation, hospitalisation for unstable angina (UA or death from any cardiovascular causes).

Target population for primary prevention

The issues is then who to treat? In recent years a number of risk scores predicting a 10 year risk of CVD (coronary artery disease, myocardial infarction, sudden cardiac death, stroke and peripheral vascular disease), tried to answer that question. These include the Framingham Risk Score, D’Agostino Score¹⁰ and the European Society of Cardiology (ESC) SCORE (Systematic COronary Risk Evaluation).¹¹ The patients who have documented CVD, diabetes type 1 and 2, chronic kidney disease (CKD) and very high individual risk factors are consider to already have very high cardiovascular (CV) risk and they need active management for all risk factors. 

Age has always been an issue as most of the risk model exclude young patients (< 40 years). The American College of Cardiology/American Heart Association (ACC/AHA) for example makes the following recommendations for adults aged 40-75 without known CVD and LDLc from 1.81mmmol/L-4.9mmol/L: “Without diabetes and an estimated 10 year CVD risk ≥ 7.5%, treat with moderate to high intensity statins”; “it is reasonable to treat those with a 10 year CVD between 5-7.5% with moderate statin therapy” and for those with diabetes “high intensity statins for those with a 10 year CVD risk ≥ 7.5%”.¹²

Regarding the group with a LDLc > 4.92mmmol/L, they recommend high intensity statins with the use of non-statin lipid lowering drugs to further reduce LDLc. Similar recommendation are made by the UK’s National Institute for Health and Clinical Excellence (NICE).¹³

Regarding LDLc targets, those are tailored according to risk score calculators. In 2016 the Task Force for Management of Dyslipidaemia of the European Cardiology Society and European Atherosclerosis Society issued new guidelines for management of dyslipidaemias as follows: 

• Very high risk patients should have a LDLc < 1.8mmmol/L or a 50% reduction from baseline value
• High risk patients should have a LDLc <2.6mmmol/L or a 50 % reduction from baseline value
• Low risk patients should have a LDLc <3mmmol/L.¹⁴
• Non-statin therapy showed no benefit in primary prevention of CVD, but instead showed an increase of non-cardiovascular mortality and as such it is not recommended.¹⁵

As we discussed age involvement in risk calculators, we also need to discuss familial hypercholesterolaemias (FH) as they can present in much younger age groups. The ESC/EAS recommend that a patient with FH should have an LDLc < 2.6mmmol/L and if CVD is present < 1.8mmmol/L. If targets are not achieved they suggest adding a non-statin lipid lowering drug to achieve maximal reduction in LDLc levels.¹⁴

Statins in secondary prevention 

Patients with a prior history of CHD (myocardial infarction, angina, prior myocardial revascularisation) and CVD (including, stroke, transient ischaemic attacks, peripheral vascular disease) need lipid lowering treatment as well. Patients with known myocardial infarction have a risk of death from CHD 20 times higher then those without CVD and as such they are the ones that benefit most from lowering LDLc values.¹⁶

There are large trials and meta-analysis that have shown a major benefit of statin therapy in patients with CVD.

The Heart Protection Study (HPS) compared simvastatin 40mg daily with placebo in patients with diabetes or known CHD and showed a consistent and early benefit of statin therapy, including in those patients with LDL-C values below 116mg/dL (3.0mmol/L), and even below 100mg/dL (2.6mmol/L).¹⁷

Two meta-analysis of 25 respective 34 trials including close to 100,000 patients showed 13-16% reduction in mortality risk.^18,19

The Scandinavian Simvastatin Survival Study (4S)²⁰ found that simvastatin therapy versus placebo for 5.4 years resulted in statistically-significant reductions in total mortality, major coronary events, CHD deaths (42% reduction), revascularisation procedures (CABG or coronary angioplasty, 37% reduction), and fatal plus non-fatal cerebrovascular events.

Statins in acute myocardial ischaemia

Another specific group will be the patients who have presented recently with ACS as they are at high risk of experiencing further cardiovascular events. 

The PROVE IT-TIMI 22 trial showed that patients with an acute coronary syndrome (n = 4162) who were treated with intensive lipid-lowering therapy with atorvastatin 80mg daily had a reduction in clinical events as compared to patients treated with standard therapy with pravastatin 40mg daily. The benefit began within 30 days, and the absolute benefit increased over time, such that the rate of patients reaching a composite primary endpoint was significantly lower with atorvastatin after two years (22.4% versus 26.3%).²¹ The ESC/EAS taskforce recommends the use of high dose statins and initiation during the one to four days of hospitalisation for an acute coronary syndrome.¹⁴ Regarding patients undergoing percutaneous coronary intervention, the same taskforce recommends starting high dose statins as pre-treatment or a loading high dose for those taking chronic statins, as an individual patient meta-analysis of 13 randomised studies including 3,341 patients, found decreased peri-procedural MI and 30-day adverse events in patients undergoing percutaneous coronary intervention.¹⁴

Statins in CVD

It was mentioned above that statins are used for reducing mortality in both CHD and CVD. As such similar LDLc targets should be achieved for patients with ischaemic cerebrovascular disease or peripheral vascular disease. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial showed a benefit for secondary ischaemic stroke prevention with high dose atorvastatin 80mg independent of LDLc baseline values.²²

Long-term treatment with statins reduces the risk of ischaemic stroke, even though hypercholesterolaemia is not a strong risk factor for stroke. An explanation is that statins also have a role in plaque stabilisation, reducing inflammation, slowing carotid arterial disease,²³ progression improving endothelial function, and reducing embolic stroke by prevention of myocardial infarction and left ventricular dysfunction. These are generally known as pleiotropic effects and there is currently debate among experts if they are involved in the cardiovascular benefits, or if all the benefits are due to just lowering LDLc levels.

Specific populations

Elderly people: The risk of CVD and CHD is much higher in this age group and as such they are the ones that benefit the most from statin therapy. We need to remember though, that at this point in time we individualise treatment to a specific person not to an age group.

Diabetes: As mentioned above, patients with diabetes and dyslipidaemia have a very high risk of CHD and as such should be treated with high intensity statins to specific target levels for LDLc. Also it is important to control hypertension and proteinuria which can further increase the risk of death from CHD. 

Side-effects

As with most of the drugs that we currently use in clinical practice, statins have side effects that potentially can lead to severe complications, especially when associated with other drug classes (eg. CYP3A4 inhibitors).

The most common one is statin-induced myopathy, through a mechanism that is not fully understood as yet. Patients can develop muscular pain, cramps (myalgia), weakness (myopathy) and even leading to rhabdomyolysis (myonecrosis – an increase in CK levels of at least 10 times, myoglobinuria and acute renal failure).

Hepatic dysfunction is more commonly seen in the first three months after initiation of statin therapy and is usually dose dependent. Episodes of severe hepatic failure have been seen in patients taking statins but they are relatively uncommon and the incidence of hepatic failure in patients taking statins doesn’t seem to be different from the normal population.  

There were issues regarding liver cancer found in rats tested with statins but long-term follow up of statin studies such as the 4S trial,²⁰ the West of Scotland Coronary Prevention Study (WOSCOPS)¹¹ and the Heart Protection Study (HPS)¹⁷ showed no increase rates of deaths caused by cancer.

The future

Over the past few years there have been new trials involving high risk cardiovascular patients who were treated with a new class of lipid lowering drugs known as PCSK9 inhibitors (proprotein convertase subtilisin kexin 9 antibodies). Meta-analysis of these studies showed that PCSK9 decreases CV events and mortality.²⁴ They also showed reduction of LDLc levels of more than 50% and increase in HDLc levels and as such might be beneficial in patient that are hard to reach LDLc goals. Administration is fortnightly by subcutaneous injections. It remains to be seen if they will take the place of statins as the mainstay treatment for CVD or will be used in conjunction. 

Statins have proven their efficacy in recent decades and have surely influenced the lives of millions of people for the better. They are still used on a large scale today and probably will continue to be until new and improved treatments become available.

References

1. Akira Endo - A historical perspective on the discovery of statins Proc Jpn Acad Ser B Phys Biol Sci. 2010 May 11; 86(5): 484-493
2. Genest J Jr. Physician’s Guide to the Management of Lipoprotein Disorders. Montreal, Canada: QUE. STA Communications; 1990:30-31 
3. Genest J Jr. Physician’s Guide to the Management of Lipoprotein Disorders. Montreal,Canada: QUE. STA Communications; 1990:32
4. Mendis S, Puska P, Norrving B. World Health Organization. Global Atlas on Cardiovascular Disease Prevention and Control: Policies, Strategies, and Interventions. Geneva: World Health Organization;2011 Expert Panel on Detection, Evaluation, and Treatment of High 
5. Blood Cholesterol in Adults. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001; 285:2486-2497
6. Cholesterol Treatment Trialists’ (CTT) Collaborators: Mihaylova B,Emberson J, Blackwell L et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 2012; 380(9841):581-90. doi: 10.1016/S0140-6736(12)60367-5
7. Shepherd J, Cobbe SM, FordI et al for the West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995; 333:1301-1308
8. Sever PS, Dahlöf B, Poulter NR et al (ASCOT investigators). Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial – Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet 2003; 361(9364);1149-1158
9. Ridker PM, Danielson E, Francisco FAH et al for the JUPITER Study Group. Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein. N Engl J Med 2008; 359: 2195-2207
10. Wilson PW, D’Agostino RB, Levy D et al. Prediction of coronary heart disease using risk factor categories. Circulation 1998; 97:1837-1847 
11. http://www.escardio.org/Education/Practice-Tools/CVD-prevention-toolbox/SCORE-Risk-Charts
12. Stone NJ, Robinson J, Lichtenstein HC et al. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A 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
13. www.nice.org.uk/guidance,CG181/chapter/1-Recommendations
14. Catapano AL, Graham I, De Backer G et al for the Task Force for the Management of Dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS). Guidelines for the Management of Dyslipidaemias
15. WHO cooperative trial on primary prevention of ischaemic heart disease with clofibrate to lower serum cholesterol: final mortality follow-up. Report of the Committee of Principal Investigator. Lancet 1984; 2(8403):600-4
16. Pekkanen J, Linn S, Heiss PHG et al. Ten-year mortality from cardiovascular disease in relation to cholesterol level among men with and without preexisting cardiovascular disease. N Engl J Med 1990; 322:1700-1707
17. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial.Heart Protection Study Collaborative Group Lancet. 2002;360(9326):7. 
18. Marchioli R, Marfisi RM, Carinci F et al. Meta-analysis, clinical trials, and transferability of research results into practice. The case of cholesterol-lowering interventions in the secondary prevention of coronary heart disease. Arch Intern Med 1996; 156(11):1158
19. Wilt TJ, Bloomfield HE, MacDonald R et al. Effectiveness of statin therapy in adults with coronary heart disease. Arch Intern Med 2004; 164(13):1427
20. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344(8934):1383 
21. Cannon CP, Braunwald E, McCabe CH et al. Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004; 350(15):1495 
22. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med 2006; 355:549-559
23. Amarenco P, Labreuche J, Lavallée P, Touboul PJ. Statins in stroke prevention and carotid atherosclerosis: systematic review and up-to-date meta-analysis. Stroke 2004; 35(12):2902
24. Safety and efficacy of anti-PCSK9 antibodies: a meta-analysis of 25 randomized, controlled trials. Zhang X-L, Zhu Q-Q, Zhu L et al J BMC Medicine 2015; 13:123 doi:10.1186/s12916-015-0358-8