lipid

Lipid management in cardiovascular disease: an update

د. حسين محمد جمعه
اختصاصي الامراض الباطنة
البورد العربي
كلية طب الموصل
2012

Key points

Cardiovascular disease kills more people per year in the UK than any other disease .There is a direct link between cardiovascular disease and elevated LDL cholesterol levels
HMG CoA reductase inhibitors (statins) decrease the incidence of cardiovascular events in patients with known cardiovascular disease by reducing LDL cholesterol levels.

Statins may also reduce cardiovascular events by mechanisms unrelated to reducing cholesterol levels (such as anti-inflammatory, antithrombogenesis, and improved vasomotor properties), collectively termed pleiotropic effects
Statins reduce the incidence of cardiovascular events in patients without established coronary heart disease.

Clinical tip

Giving advice about cholesterol is vital. But you should always do this in the context of the patient's overall risk.
So you should also remember to modify the following core risk factors if they are present:
Smoking
Hypertension
Diabetes mellitus.


Statins for secondary prevention
Early major statin trials testing simvastatin and pravastatin in people with established cardiovascular disease (4S, CARE, and LIPID) demonstrated significant reductions in coronary events and coronary mortality.
Recent trials with simvastatin (Heart Protection Study, A to Z, and IDEAL), pravastatin (ALLHAT and PROSPER), atorvastatin (IDEAL, GREACE, ASCOT, CARDS, PROVE-IT, and TNT), and fluvastatin (LIPS and ALERT) have expanded the population that can benefit from this class of drugs.

Recommendations have now been extended to include:

Women
Elderly people
People with acute coronary syndrome
People with diabetes
People with a renal transplant
People previously considered to have normal total cholesterol and LDL cholesterol levels (the Heart Protection Study showed convincing evidence of benefit in people with total cholesterol levels as low as 3.5 mmol/l).

A recent meta-analysis of data from more than 90 000 participants from 14 randomised trials of statins concluded that
statin therapy can safely reduce the five year incidence of major coronary events, coronary revascularisation, and stroke by 20% per mmol reduction in LDL cholesterol level.

Statins for primary prevention

Issues concerning safety and cost effectiveness have made the use of statins in primary prevention controversial. But findings of many primary prevention trials have now expanded the populations shown to benefit from statins to include patients without coronary heart disease.
Early statin trials in asymptomatic people at risk of developing cardiovascular disease using pravastatin and lovastatin (WOSCOPS and AFCAPS/TexCAPS) showed significant reductions in coronary events and coronary mortality.

Further, the lipid lowering arm of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT-LLA), involving hypertensive, normocholesterolaemic patients ended two years earlier than expected because there was a significant 3.4% absolute risk reduction
(p = 0.0005) in the primary endpoint of combined non-fatal myocardial infarction and fatal coronary heart disease in the group treated with atorvastatin, compared with the group taking placebo.


More recently the results of the JUPITER trial
astudy of apparently healthy persons without hyperlipidaemia but with elevated high sensitivity C reactive protein levels – showed that rosuvastatin significantly reduced the incidence of major cardiovascular events.

Role of statins for people with diabetes

Subgroup analyses in early secondary prevention trials showed that patients with diabetes had fewer cardiovascular events following statin therapy. Recent trials support the use of lipid lowering therapy in many patients with diabetes.
For example, in the Heart Protection Study, patients with diabetes but without cardiovascular disease experienced a 1.5% absolute risk reduction in the incidence of a first major vascular event (p <0.0001), identical to that of the overall population.

In ASCOT-LLA, patients with hypertension and diabetes experienced a significant 2.9% absolute risk reduction in the incidence of total cardiovascular events and coronary procedures following treatment with atorvastatin versus placebo.19

Recently published NICE guidelines for diabetes mellitus acknowledged the above findings and recommended a statin for every patient with diabetes above 40 years of age with at least a low risk of coronary heart disease. Further they also advocated statins in people with diabetes under 40 years of age with a poor coronary risk profile.
In contrast, a study of patients with diabetes and end stage renal disease reported no benefit of atorvastatin, compared with placebo (for less understood reasons).

Evidence for statins for elderly people

Initially excluded from statin trials, elderly people may experience similar cardiovascular benefits with statins to their younger counterparts.

The Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) trial randomised more than 5000 patients aged 70-82 years to 40 mg pravastatin or placebo. It reported a significant relative reduction in the primary composite endpoints of death due to coronary heart disease, non-fatal myocardial infarction, and stroke (15%, p = 0.014), and in the secondary endpoint of coronary heart disease death plus non-fatal myocardial infarction (19%, p = 0.006). The absolute risk reductions for primary and secondary endpoints were between 2% and 4%.

The recently reported Study Assessing Goals in the Elderly (SAGE) study was the first large international trial to look at the efficacy of lipid lowering therapy in reducing duration of myocardial ischaemia in elderly people - a surrogate endpoint. Some 893 patients aged 65-85 years with coronary heart disease were randomised to atorvastatin 80 mg/day or pravastatin 40 mg/day. At 12 months there was a significant reduction in duration of myocardial ischaemia in each treatment group (p <0.0001), but no difference in the number of episodes of ischaemia. Proportions of patients experiencing side effects were similar in the two treatment groups, as were withdrawal rates.

When should you start statins?

Existing guidelines recommend starting a statin within three to six months of hospitalisation for patients with an acute coronary syndrome.
However, the PROVE-IT TIMI 22 trial, comparing standard therapy (40 mg pravastatin) with intensive therapy (80 mg atorvastatin) started within days of hospitalisation for acute coronary syndrome in more than 4000 patients, reported a 2.6% absolute risk reduction in death, myocardial infarction, stroke, unstable angina, and revascularisation in patients receiving intensive therapy.


In contrast, the A to Z trial, comparing early simvastatin therapy (within 2-5 days post event) with low dose statin therapy initiated three to six months after the index event in more than 4500 patients, did not show a significant benefit for early, aggressive statin therapy. In addition, patients in the aggressive treatment group experienced a slightly higher incidence of liver transaminitis and myopathy and, as a result, a higher discontinuation rate.
Similarly, other studies (such as MIRACL and FLORIDA) comparing early with late statin therapy have not shown any significant difference between the two groups.

How should you prescribe statins?

Randomised control trials comparing the differences between different dosing strategies have not been conducted. Dosing strategies can be inferred from existing trials.

Fixed dose strategy

A fixed dose strategy based on trials would employ the daily dose used:
Atorvastatin 10 mg
Fluvastatin 80 mg
Pravastatin 40 mg
Simvastatin 40 mg.
The advantage is that this strategy is based on evidence and that little or no cholesterol testing is needed. The drawback is that a fixed dose may be insufficient for some people and excessive for others.

LDL target strategy

In the 4S trial the target was a total cholesterol level of <5.2 mmol/l (LDL <3.8 mmol/l). In AFCAPS the target was an LDL cholesterol level of <2.8 mmol/l. In GREACE the target was an LDL cholesterol level of <2.6 mmol/l.
A dosing strategy based on these trials would titrate the dose to an LDL cholesterol level target and may prevent excessive LDL cholesterol level lowering if the dose is minimised to just achieve the target. The disadvantage is that patients may needs lots of tests.

Average cholesterol reduction strategy

The average reduction from baseline in total cholesterol level for the different statins was between 18% and 25%. Daily doses of statin required to achieve the middle of this range, a 22% reduction in total cholesterol level, are approximately:
Fluvastatin 40 mg
Pravastatin 20 mg
Lovastatin 20 mg
Simvastatin 10 mg
Atorvastatin 5 mg
Rosuvastatin 2.5 mg.
The advantages of this strategy are reduced statin doses and costs and a possible reduced risk of dose related toxicity. The disadvantage is frequent blood tests.


What harms can statins cause?
Statins are well tolerated by most patients. The two most important side effects of statins are:
Myopathy (which includes a range of muscle symptoms and elevated serum markers of muscle injury, such as creatine kinase)
Hepatotoxicity (reflected by increased levels of alanine aminotransferase and aspartate aminotransferase).
Cerivastatin was withdrawn from the market in 2001 because of frequent reports of serious myopathy. A common complaint is non-specific muscle aches or joint pains that are generally not associated with significant increases in creatine kinase.

It is rare for patients to develop severe myositis (muscle aches or weakness associated with raised creatine kinase levels, generally greater than 10 times the upper limit of normal).
In this setting, failure to stop the drug can lead to rhabdomyolysis, myoglobinuria, and acute renal necrosis.

Myositis is most likely to occur in people with coexisting medical problems or who are taking multiple medications, or both. It may rarely happen with statin monotherapy, but it occurs more frequently when statins are used in combination with a variety of medications, including ciclosporin, fibrates, macrolide antibiotics, certain antifungal drugs, and niacin.

Elevated hepatic transaminases generally occur in 0.5-2.0% of patients and are dose dependent.
It has not been determined whether transaminase elevation with statin therapy constitutes true hepatotoxicity. Progression to liver failure specifically due to statins is exceedingly rare.
Reversal of transaminase elevation is frequently noted with a reduction in dose, and elevations do not often recur with either rechallenge or selection of another statin.

Table. Factors increasing the risk of myopathy associated with statins

Age >70 years (women are at higher risk than men)
Frailty and small body frame
Multisystem disease (for example chronic renal insufficiency, heart failure)
Hypothyroidism
Solid organ transplant recipients
Polypharmacy
Perioperative period
Specific concomitant medications or substances, such as:
Fibrates (especially gemfibrosil)
Nicotinic acid (rarely)
Ciclosporin
Azole antifungals (itraconazole and ketoconazole)
Macrolide antibiotics (erythromycin and clarithromycin)
Protease inhibitors (for HIV infection)
Nefazodone
Verapamil
Amiodarone
Large quantities of grapefruit juice (usually more than 1 quart (1.14 l) per day)
Alcohol abuse


What other measures are there for reducing lipid levels?
There are other pharmacological methods and nonpharmacological methods for reducing serum lipid levels. Although compelling evidence suggests that patients with established coronary heart disease should be treated with a statin, those at high risk of developing coronary heart disease can benefit from a six month trial of nonpharmacological measures.
Dietary and lifestyle measures include37:
Restricting saturated fat intake
Choosing mono-unsaturated fats
Eating more fruit and vegetables, as well as oats, beans, and pulses,Taking regular physical activity and losing excess weight.

Are there other lipid regulating drugs?

Other agents can be used to regulate lipid levels.
Anion exchange resins include colestyramine and colestipol. They work by binding to bile acids, which are passed into the gut from the liver and gallbladder. This stops bile acids being reabsorbed into the bloodstream, which has a knock on effect of lowering cholesterol levels.

Fibrates include bezafibrate, ciprofibrate, fenofibrate, and gemfibrozil. A fibrate is generally used for patients with a high triglyceride level with or without a high cholesterol level.
Nicotinic acid may be tried if other medicines do not work. It is not used often because it has a high rate of side effects such as facial flushing, nausea, vomiting, and headache.
Ezetimibe is used in certain situations in combination with a statin, or on its own. It prevents the absorption of cholesterol from the gut.

Statins in people of South Asian origin

People from South Asia tend to have:
Higher levels of triglycerides
Lower levels of high density lipoprotein (HDL) cholesterol
Higher levels of lipoprotein(a).
In addition, the higher risk of coronary heart disease in this population may be related to a higher prevalence of the metabolic syndrome, insulin resistance, and diabetes.


The Framingham model may also underestimate the risk of coronary heart disease in people from South Asia. Total cholesterol levels and LDL cholesterol levels are correlated with extent and severity of coronary heart disease in South Asians, as in white people. However, at any given total cholesterol or LDL cholesterol level, people from South Asia have a greater risk of coronary heart disease than do white people.

But the point of starting treatment and the therapeutic goals in this population remain to be established.
Furthermore, emerging data suggest that smaller and lighter South Asians may require only low dose statin therapy. However, this subject is contentious because studies conducted with cerivastatin and simvastatin suggest that pharmacokinetic differences between different ethnic groups do not require dosage modification.

Ethnic differences in treatment response is an area of research that governmental bodies must explore.
Finally, although statins are the therapeutic cornerstone for reducing major coronary events, they primarily act on LDL cholesterol. Triglyceride levels are only modestly decreased, and HDL cholesterol levels are only modestly elevated. Statins have little or no effect on lipoprotein(a).

Learning bite

You may find evidence of hyperlipidaemia on the skin of some patients.
For example a xanthelasma is a yellow swelling in the skin of the lower eyelid resulting from deposition of fat. Xanthelasmata are common in elderly people. This lesion may be a localised phenomenon or may suggest a systemic hyperlipidaemia and be associated with elevation of LDL cholesterol levels as in familial hypercholesterolaemia or type III hyperlipoproteinaemia.
Xanthomas are yellow fat deposits under the skin. They are also associated with hyperlipidaemia.Patients affected with any of these lesions need a lipid profile.

• Waist-to-hip ratio

• Waist measured around the narrowest point between ribs and hips when viewed from the front after exhaling (usually around the belly-button or just above it).
• Measure hips at the widest part around buttocks when viewed from the side.
•

acceptable

unacceptable

excellent

good
average
high
extreme
male
< 0.85
0.85 - 0.90
0.90 - 0.95
0.95 - 1.00
> 1.00
female
< 0.75
0.75 - 0.80
0.80 - 0.85
0.85 - 0.90
> 0.90


April 10, 2012 (Baltimore, Maryland and San Francisco, California) — Differing opinions on the use of statins in primary prevention make the pages of one of the leading medical journals this week, with the Journal of the American Medical Association (JAMA) the latest in a line of professional and mainstream media outlets getting in on the contentious topic .
Should Statins Be Used in Primary Prevention? JAMA Gets in on the Debate
2012 Medscape

Introduced by the JAMA editors to encourage discussion and debate [3], the inaugural "dueling viewpoints" kicks off its new series by considering the clinical question of whether or not a healthy 55-year-old male with elevated cholesterol levels should begin taking the lipid-lowering medication.

The two "combatants" in the clinical duel will also be familiar, having previously debated the topic in the pages of the Wall Street Journal, as well as on theheart.org. For Drs Rita Redberg and William Katz (University of San Francisco, California), who argue that healthy men should not take statins, there are other effective means to reduce cardiovascular risk, including dietary changes, weight loss, and increased exercise.

"These strategies are effective in increasing longevity and also result in other positive benefits, including improved mood and sexual function and fewer fractures," they write. "Although these strategies are challenging, prescribing a statin may undermine them. For example, some patients derive a false sense of security that because they are taking a statin they can eat whatever they want and do not have to exercise."

In their counterpoint, Drs Michael Blaha, Khurram Nasir, and Roger Blumenthal (Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, Baltimore, MD) agree that the cornerstone of treatment for patients with elevated cholesterol levels will always be diet and exercise but that statins can be a "critical adjunct for those identified to be at increased coronary heart disease risk."

The Johns Hopkins physicians argue that there is no logic in waiting for an MI to occur before starting statin therapy and that if clinicians are unsure of the risk of seemingly healthy patients with elevated cholesterol levels, the use of coronary artery calcium (CAC) screening can help.
"The CAC scan is a helpful tool that enables clinicians to direct statin treatment at the disease (coronary atherosclerosis) that they propose to treat and illustrates the concept of risk-based, individualized decision making," write Blaha, Nasir, and Blumenthal. "Statin therapy would not be recommended if a CAC scan revealed a score of 0."

In their viewpoint, they point to data from WOSCOPS and AFCAPS/TexCAPS showing reductions in MI and other coronary events in the primary-prevention setting. However, they argue that the debate over cholesterol therapy needs to be rephrased, because doctors should never treat elevated cholesterol levels in isolation but instead aim to provide therapy to the highest-risk patients most likely to benefit.

For Redberg and Katz, however, the data simply do not support the use of statins in the 55-year male patient with normal blood pressure and no family history of disease but with elevated cholesterol levels. They point to a recent meta-analysis in healthy but high-risk men and women showing no reduction in mortality with statin therapy, as well as a recent Cochrane review showing similar results.

Moreover, Redberg and Katz highlight the adverse effects associated with statins, including cognitive defects and diabetes.
"For every 100 patients with elevated cholesterol levels who take statins for five years, a myocardial infarction will be prevented in one or two patients," they write. "Preventing a heart attack is a meaningful outcome. However, by taking statins, one or more patients will develop diabetes and 20% or more will experience disabling symptoms, including muscle weakness, fatigue, and memory loss."