Lipids, lipoproteins, and atherogenesis

• Lipids and lipoproteins have a central role in the pathogenesis of atherosclerosis. • The concentration of low-density lipoprotein (LDL) is strongly and directly related to risk of atherosclerosis whereas high-density lipoprotein (HDL) is inversly related, low HDL being an independent risk factor. • The role of plasma triglycerides is less well defined. • The ratio of apolipoprotein B (the major apolipoprotein of LDL) to apolipoprotein A-1 (the major apolipoprotein of HDL) is emerging as the best predictor of atherosclerotic risk.

Recent lipid-lowering trials in perspective: implications for therapy

• Despite the clinical benefits of statin therapy in primary and secondary cardiovascular disease (CVD) prevention trials, considerable residual risk persists. • Meta-analysis of major randomized controlled trials (RCTs) suggests that greater low-density lipoprotein (LDL)-lowering is associated with greater reduction in events. • Recent RCTs in stable coronary disease and in acute coronary syndrome have demonstrated greater benefit with more intensive LDL-lowering. • The results of these trials have changed LDL goals of therapy for those at highest risk.

Primary dyslipidaemias

• Primary hyperlipidaemias are autosomal dominant or recessive inherited disturbances in lipid metabolism, which become manifest either from early childhood or later in life. • Clinical manifestations are premature ischaemic vascular disease, xanthomatosis and other lipid depositions in the body, and acute pancreatitis. • The molecular defect is explained by mutations in genes, which encode proteins that play a major role in the formation, secretion, transport, or uptake of lipoproteins. • The most common forms of primary dyslipidaemias are multifactorial heterogeneous disorders with several genetic, metabolic, and environmental factors interacting and contributing to the clinical phenotype. • Family investigation is usually crucial for proper diagnosis and case finding of persons at risk for vascular disease.

Vascular imaging

• Atherosclerosis is a dynamic process that affects most medium and large calibre arteries, particularly the coronary and carotid arteries. • Atherosclerotic changes in the arteries develop over many decades before clinical presentation. • First cardiac events are often either myocardial infarction or death, with most acute coronary events triggered by destabilization and rupture of lipid, rich, thin capped, usually only mildly obstructive plaques. • Early identification of subclinical atherosclerosis and high-risk plaque/preclinical disease is of value in assessing a patient's future risk of developing clinical disease. • Angiography remains the gold standard investigation but visualizes only stenoses, which are a late manifestation of the atherosclerotic process. • Newer modalities such as computed tomography (CT) angiography, B mode carotid ultrasound, and magnetic resonance imaging (MRI) can identify at-risk individuals without invasive investigations. • Functional and anatomical imaging together holds great promise in for accurate identification of patients with high-risk plaque.

Pharmacotherapy: non-statin drugs

• Non-statin drugs do not have a large volume of data from randomized clinical trials (RCTs) to guide therapy but reasonable evidence exists for the fibrates, gemfibrozil, nicotinic acid, and the resins. • Non-statin drugs may be indicated in patients intolerant of statins or in whom statins are contraindicated. • Non-statin drugs may be added to statin therapy to obtain further effects on low-density lipoprotein (LDL) if treatment goals are not achieved on maximum-tolerated statin dose. • Non-statin drugs may be added to statin therapy to obtain further effects in increasing high-density lipoprotein (HDL) and reducing triglyceride.

Diet and lifestyle

• Consume a healthy, balanced diet. • Aim for a healthy body weight and shape. • Reduce saturated and trans fats and substitute with non-hydrogenated, unsaturated fats. Choose whole grains as the main form of carbohydrates, and consume a diet high in fruit and vegetables. • Be physically active. • Avoid use of (and exposure to) tobacco products.

Secondary dyslipidaemias

• Secondary causes including concurrent drug therapy should be sought and excluded in patients presenting with dyslipidaemia. • Depending on the cause, treatment is of the underlying condition, for example, hypothyroidism. • Lipid lowering is required in addition to treatment of the underlying cause in some conditions such as diabetes, kidney disease, and HIV/AIDS. • Dyslipidaemia is commonly seen in type 2 diabetes and metabolic syndrome, and its treatment is an important component of overall management.

Common problems in lipid management

• Cholesterol and low-density lipoprotein (LDL)-cholesterol are causal factors for atheromatous cardiovascular disease (CVD), and moderate and higher levels are a near obligate for disease development. • Statin drugs have overwhelming evidence of benefit at low side effect risk. • Estimation of an individual's CVD risk is required from a number of factors, and CVD prevention requires attention to all abnormal modifiable factors in individuals at higher risk. • Identifying, counselling, and appropriate treatment of individuals at high CVD risk is a current challenge for health care professionals. • Guidelines have been produced to help, and Government has provided levers to encourage their application.

Combination therapy for the management of hyperlipidaemia

• Low doses of multiple drugs can be combined to treat patients intolerant to statin therapy • Combination therapy to reduce LDL-C is increasingly necessary to reduce LDL-C >; 50% as required in the highest risk patients • Statins have little effect on risk driven by low HDL-C and increasingly niacin (nicotinic acid) and fibrates are used in combination with statins to optimize the total lipid profile • Large-scale end point studies with statin-other drug combinations are underway.

Pharmacological therapy: statins

• Statins are potent, competitive inhibitors of the rate-determining step in cholesterol synthesis which leads to up-regulation of hepatic LDL-receptor activity and decrease in plasma LDL. • There is a huge database of information from RCTS in both primary and secondary CVD prevention and in a wide range of patient groups on which to base therapy. • Statins are the most potent agents for reducing LDL and are first-line therapy for the great majority of patients. • Statins are safe and well tolerated, and myositis and abnormal liver function are exceedingly rare.