The Discovery Of Cholesterol Lowering Agents

Published Date: 02 Nov 2017

statins, ushered in a series of large cholesterol reduction trials. The first of these studies was the

Scandinavian Simvastatin Survival Study (4S) in which hypercholesterolemic men with CHD who were

treated with simvastatin had a reduction in major coronary events of 44% and a reduction in total

mortality of 30%. Many more secondary prevention trials followed to establish unequivocally the

benefit of cholesterol reduction. Strategies that aim to improve primary prevention are important for

managing the overall burden of disease. Recently therefore, the role of statin in primary prevention is

being debated. The JUPITER trial, a recent primary prevention trial proved that statins reduced the

rate of first major cardiovascular events among apparently healthy individuals. Statins have also been

discussed to be having certain pleotropic effects on other diseases like diabetes, cancer, osteoporosis

and Alzheimer's. However, issues of cost effectiveness and adverse effects like myositis,and

transaminitis still loom large. The medical community needs to debate and evolve a possible consensus

on the path breaking subject.

Key Words - Statins, Primary Prevention, heart disease

STATINS: CAN WE ADVOCATE THEM FOR PRIMARY PREVENTION OF HEART

DISEASE?

Cardiovascular disease (CVD) remains the leading cause of morbidity and

mortality worldwide. Reducing high blood cholesterol is an important goal of medical

treatment and statins had been the first-choice agents. Since the early statin trials were

reported, several reviews of the effects of statins have been published highlighting their

use in primary and secondary prevention of CVD. Strategies that aim to improve

primary prevention are important for managing the overall burden of disease. In case, it

is established that statins can prevent or delay CVS disorders in healthy individuals, it

would not only reduce human misery but also reduce costs of healthcare as treating

heart disease is expensive, and in a developing country like ours often out of reach of

the majority of the populace. Several studies have been carried out to evaluate the cost

effectiveness of low cost generic statins available in the market for primary prevention.

In a study carried out to by Lawrence D et al to evaluate the cost effectiveness of statins

in primary prevention in different LDL cholesterol prescribing thresholds (ã160, ã130,

and ã100 mg/dL) and in different levels of cardiovascular risks, they found that primary

prevention with statins was projected to be cost-saving in persons with LDL ã100 mg/dL

and moderately high risk, with LDL ã130 mg/dL and moderate risk, and with LDL ã160

mg/dL and lower or lowest risk (1). With wide availability of low-cost generics, primary

prevention with statins has become less expensive and low-cost statins have been

found to be cost-effective for most persons with even modestly elevated cholesterol or

any coronary heart disease risk factors (2). In this mini review, we have attempted to

analyse the cost effectiveness of using statins as a primary prevention pharmacological

agent vis a vis its use in secondary prevention, as cited by contemporary systematic

reviews.

Statins in Secondary Prevention. The role of statins in secondary prevention is well

known. The first major secondary prevention statin trial (3) was the Scandinavian

Simvastatin Survival Study (4S Trial). 4444 patients with angina pectoris or previous

myocardial infarction and serum cholesterol 5.5-8.0 mmol/L on a lipid-lowering diet were

randomised to double-blind treatment with simvastatin or placebo. Over the 5.4 years

median follow-up period, simvastatin produced mean changes in total cholesterol, lowdensity-

lipoprotein cholesterol, and high-density-lipoprotein cholesterol of -25%, -35%,

and +8%, respectively, with few adverse effects. Statins have since been found to be

significantly decreasing cardiovascular morbidity and mortality and total mortality as

demonstrated in several secondary prevention trials like 4S, CARE, LIPID,

AFCAPS,, GREACE and HPS with different lipid lowering agents like atorvastatin,

pravastatin, lovastatin and rosuvastatin. In recent times however, rosuvastatin has been

found to be more effective for reducing LDL-C levels and attaining NCEP ATP III LDL-C

goals than other statins (4).

The secondary prevention theory of statins has been proved by several meta

analyses hitherto. Three meta-analyses, one a 164 short term randomised placebo

controlled trials of six statins and LDL cholesterol reduction; second one, 58 randomised

trials of cholesterol lowering by any means and IHD events; and thirdly, nine cohort

studies and the same 58 trials on stroke, were analysed by M R Law et al and they

observed that statins can lower LDL cholesterol concentration by an average of 1.8

mmol/l which reduces the risk of IHD events by about 60% and stroke by 17% (5). In

another meta analyses, eleven trials representing 43,193 patients were included in

2012. Overall, statin therapy was associated with a reduced risk of cardiovascular

events in all outcomes for women (relative risk [RR], 0.81 [95% CI, 0.74-0.89]) and men

(RR, 0.82 [95% CI, 0.78-0.85]). However, they did not reduce all-cause mortality in

women vs men (RR, 0.92 [95% CI, 0.76-1.13] vs RR, 0.79 [95% CI, 0.720.87]) or stroke

(RR, 0.92 [95% CI, 0.76-1.10] vs RR, 0.81 [95% CI, 0.72-0.92]). (6)

Statins in Primary Prevention. Though statins are still approved for use in subjects

with established coronary artery disease or at high risk for coronary events, several

studies show that the limits of treatment are subsequently been expanded to include

persons at progressively lower risk. The breakthrough was in 2008, when the results of

the JUPITER (Justification for the Use of Statins in Primary Prevention: an Intervention

Trial Evaluating Rosuvastatin) trial showed that patients with high C reactive proteins

might benefit from preventive statin therapy regardless of their LDL-C level. Therapy

with Rosuvastatin 20 mg/d reduced the rate of first major cardiovascular events

(myocardial infarction, stroke, arterial revascularization, hospitalization for unstable

angina, or death from cardiovascular causes) among apparently healthy individuals with

low-density lipoprotein cholesterol (LDL-C) levels below 130 mg/dL, but with hs-CRP

levels of 2 mg/L or higher by 44% as compared with placebo. The study was closed

after a median follow up of 1.9 years (maximum 5 years) (7). In a meta analysis in 2011,

for efficacy of statins in primary prevention, comprising of 29 eligible trials involving a

total of 80,711 participants, Tonelli M et al, found that the all-cause mortality was

significantly lower among patients receiving a statin than among controls (RR 0.90, 95%

confidence interval CI 0.84-0.97) for trials with a 10-year risk of cardiovascular disease

< 20% [primary analysis] and 0.83, 95% CI 0.73-0.94, for trials with 10-year risk < 10%

[sensitivity analysis]). Patients in the statin group were also significantly less likely than

controls to have nonfatal myocardial infarction (RR 0.64, 95% CI 0.49-0.84) and

nonfatal stroke (RR 0.81, 95% CI 0.68-0.96). Neither metaregression nor stratified

analyses suggested statistically significant differences in efficacy between high-and lowpotency

statins, or larger reductions in cholesterol (8). A Cochrane review (9) during the same time (2011) on the use of cholesterollowering

statin drugs sparked some controversy. The authors found that out of fourteen

randomised control trials (16 trial arms; 34,272 participants), eleven trials recruited

patients with specific conditions (raised lipids, diabetes, hypertension, microalbuminuria)

and all-cause mortality was reduced by statins (RR 0.84, 95% CI 0.73 to 0.96) as was

combined fatal and non-fatal CVD endpoints (RR 0.70, 95% CI 0.61 to 0.79) and also

there was no clear evidence of any significant harm caused by statin. Also, Kaushik Ray

et al (10) undertook a meta-analysis of published clinical trials to assess whether statins

reduce all-cause mortality in the setting of high-risk primary prevention populations and

provided combined information from 11 randomized controlled trials (like JUPITER,

ALLHAT, WOSCOPS, etc) involving a total of 65 229 participants. The authors

observed that use of statins in this high-risk primary prevention setting was not

associated with a statistically significant reduction (risk ratio, 0.91; 95% confidence

interval, 0.83-1.01) in the risk of all-cause mortality.

Heneghan C (11) in an editorial commented on these trials that in majority cases

the power calculations were based on composite outcomes; in over one third of trials,

outcomes were reported selectively and in eight trials did not report any adverse events

at all. He also brought out that to date only one trial has been publicly funded, while the

authors of nine trials reported having been sponsored either fully or partially by

pharmaceutical companies. This has led to allegations that it is the pharmaceutical

industry that is pushing for this drug to be used for primary prevention, to improve their

fiscal health, rather than public health. The fear is definitely not unfounded considering

the high cost of statins. So is use of statins a savior or a spam?

The debate continues. To counter the above, a recent public funded metanalysis

(Lancet, May 2012) included individual participant data from 22 trials of statin versus

control (n=134537; mean LDL cholesterol difference 1.08 mmol/L; median follow-up 4.8

years) and five trials of more versus less statin (n=39612; difference 0.51 mmol/L; 5.1

years). Reduction of LDL cholesterol with a statin reduced the risk of major vascular

events (RR 0.79, 95% CI 0.77—0.81, per 1.0 mmol/L reduction), largely irrespective of

age, sex, baseline LDL cholesterol or previous vascular disease, and of vascular and

all-cause mortality. The authors interpreted that in individuals with a 5-year risk of major

vascular events lower than 10%, each 1 mmol/L reduction in LDL cholesterol produced

an absolute reduction in major vascular events of about 11 per 1000 over 5 years. This

benefit greatly exceeds any known hazards of statin therapy. (12).

Beneficence vs Harm

A multifaceted action in different physiological and pathological conditions has

been proposed for statins. They have been shown to act through both cholesteroldependent

and cholesterol-independent mechanisms and are able to affect several

tissue functions and modulate specific signal transduction pathways that could account

for the cholesterol-independent pleiotropic effects. Some of these effects involve

improving endothelial function, enhancing the stability of atherosclerotic plaques,

decreasing oxidative stress and inflammation, and inhibiting the thrombogenic response

(13) and are depicted in Table 1 (14,15). Pleiotropic effects have also been observed in

Alzheimer’s disease and osteoporosis (16,17,18) to name a few. Understanding the

pleiotropic effects of statins is important to optimize their use in treatment and

prevention of cardiovascular disease.

On the other hand, the concept of Coronary Artery Calcification (CAC)

quantification being used as a surrogate for coronary events and use of statin has

thrown some interesting facts. The enthusiasm promised by the results of early

retrospective and prospective studies did not bear fruit in randomized controlled trials

(RCTs). Despite a significant reduction in low-density lipoprotein cholesterol (LDL-C)

and CRP levels, there was a nonsignificant increase in percentage CAC progression in

most of these RCTs (19). Though the safety and tolerability of statins support their use

as first-line treatment for hypercholesterolemia, myopathy and its serious complication,

rhabdomyolysis, are a potential effect of therapy with the available statins (20).

Again, the dose dependent association of different statins and new onset

diabetes in a recent (21) meta analysis is a cause for concern and needs to be treated

with caution and further investigated.

Conclusion

A wealth of data thus demonstrates that reduction of cholesterol levels is

associated with reduction of coronary artery disease risk and the magnitude of the benefit, which acts primarily to reduce low-density lipoprotein cholesterol (LDL-C), is

greater than that observed with any other lipid-modifying intervention. The recent

Cochrane review of statin use for primary prevention supports the conclusion that

statins are safe and effective in reducing vascular events and overall mortality even in

primary prevention. The benefits were found to be statistically small, which is expected

for a preventive measure in a low risk population. It is thus still unclear where to draw

the line in terms of which patients should receive statins, but these data will help

practitioners and patients make individualized decisions about cholesterol management

and vascular prophylaxis.

Statin therapy for primary prevention thus will depend on the balance between

the benefits of treatment and its long-term safety and cost. With increasing number of

Indians in the younger age group and not necessarily from the higher income group

being diagnosed with heart disease, it is time that the medical community evolve a

consensus on the subject. The present guidelines on LDL lowering statin therapy needs

to be reconsidered in view of the fresh developments and recent studies till then lifestyle

counselling should remain the focus of primary prevention efforts.