ATHEROSCLEROSIS

What is atherosclerosis?

Also called arteriosclerosis, this is an inflammatory process leading to a degeneration of the artery wall. In its early stages, fatty deposits (plaques) form just under the surface layer of cells lining the artery wall, causing thickening of the walls and restricting blood flow (Figure 1). Later, blood clots can form, further reducing blood flow and increasing the risk of embolism.

Plaque in the coronary artery will predispose people to angina pains and heart attack (see Ischaemic Heart Disease), while plaque in the neck and head increases the risk of dementia and ischaemic stroke (see Stroke). Plaque can also form in the arteries supplying the limbs (see Peripheral Vascular Disease). Plaques increase resistance to blood flow, forcing the heart to work harder, contributing to hypertension (raised blood pressure) and heart failure. They also reduce delivery of oxygen to vital organs, causing angina or pain on walking (see Peripheral Vascular Disease), and act as sites for blood clots which may detach and cause acute embolism (see Thrombosis). Atherosclerosis may thus be seen as a central feature of many of the main circulatory diseases (Figure 2), and treating it can be expected to reduce the risks of these diseases.

Many factors contribute to the formation of atherosclerotic plaque. It is known that age and family history (inheritance) are important risk factors, as is obesity. In addition, plaque formation is most probably a response to injury to the arterial wall by excess cholesterol, chemicals in cigarette smoke, raised blood pressure
and chemical changes induced by diabetes.

Who does atherosclerosis affect?

The blockage of blood vessels by plaque or blood clots is a major cause of illness and death in the UK, where cardiovascular disease accounts for a large number of deaths. Plaque formation starts very early in life. Signs of it (called 'fatty streaks') are found even in the main arteries of three-year-olds, and 77 per cent of soldiers killed in battle (at an average age of 22) had extensive plaques. So it would appear that plaque occurs in all of us, but it is the degree and rate of formation that are important.

Present treatments and shortcomings

A healthy lifestyle will help control plaque formation - as will the treatment of related conditions (see Hypertension and Diabetes). Cholesterol and triglyceride levels can be controlled by dietary measures, but some people have difficulty keeping to such diets, or have an inherited tendency towards high levels of blood cholesterol, and require active therapy. The main classes of medication to control cholesterol level are bile acid sequestrants, fibrates, nicotinic acid derivatives and statins. In addition, omega-3 triglycerides (e.g. Omacor, Solvay) reduce cholesterol and triglyceride levels, as do nicotinic acid derivatives. More recently, a selective cholesterol absorption inhibitor, ezetimibe, (Ezetrol, Merck Sharp & Dohme and Schering-Plough) has been introduced that reduces cholesterol absorption from the intestine. Ezetimibe can be used alone, but is more often taken together with a statin, when it has an additive effect on lowering cholesterol, and a fixed combination product that combines it with simvastatin (Inegy, Merck Sharp & Dohme and Schering-Plough) is also available.

Bile acid sequestrants have been available for almost 30 years. They work by binding to and removing bile acids (which are made from cholesterol) from the gut during digestion. As the body produces more bile acids, cholesterol in the blood is consumed and a fall of 15-30 per cent may be achieved. However, absorption of fat-soluble vitamins (A, D, K) is also reduced and circulating levels of many other medicines given at the same time can be affected.

Nicotinic acid is a water soluble vitamin B complex which may work by decreasing free fatty acid release from adipose tissue. Nicotinic acid increases HDL by 30 per cent and reduces triglycerides by 27 per cent. It is used in conjunction with statins to treat dyslipidaemia, particularly in patients with elevated LDL and triglycerides and low HDL. Nicotinic acid derivatives can induce flushing that may limit their use. A prolonged release version of nicotinic acid (Niaspan, Merck Pharmaceuticals) has been introduced that reduces these flushing events.

The fibrates (e.g. fenofibrate, bezafibrate, gemfibrozil) appear to act by altering the lipid balance in the blood. Over a period of time, a 5-15 per cent reduction in cholesterol level has been demonstrated. Fibrates are used to treat at-risk men whose hyperlipidaemia - an abnormally high level of fat in the blood or tissues - is resistant to diet and other medication. They can cause a muscle-wasting condition called rhabdomyelitis, and people using this medicine need to be regularly monitored to detect its onset.

The most-used medicines are the statins. These block a key step in the formation of cholesterol, reducing its level by 30 per cent or more and helping to improve triglyceride levels as well. They include atorvastatin (Lipitor, Pfizer), fluvastatin (Lescol, Novartis), pravastatin (Lipostat, Bristol-Myers Squibb), simvastatin (Zocor, Merck Sharp & Dohme) and rosuvastatin (Crestor, AstraZeneca). Statins confer significant benefits beyond their main indications, such as reducing the risks of dementia, strokes or a second heart attack. It has been demonstrated that, in high dose, rosuvastatin is even able to reverse the build-up of atherosclerotic plaque in the coronary arteries. However, this highly desirable result was seen at a dose above that normally used and no statin is currently available for the reversal of established atherosclerosis. Statins are generally well tolerated, but rare cases of rhabdomyelitis have been reported, as with fibrates.

What's in the development pipeline?

Compounds in development exploit a very wide range of approaches to regulating lipid levels and preventing atherosclerosis, reflecting the numerous processes involved. Some seek to improve existing approaches, such as Takeda's TAK-475, currently in Phase 3 trial, which inhibits a later stage from statins in the production of cholesterol. Others, such sanofi-aventis's rimonabant, also in Phase 3 trial, seek to exploit quite new pathways.

1. Combination products
Increasingly, treatments are aimed at bringing about three key changes in blood lipids: reducing 'bad' low-density lipoprotein (LDL)-bound cholesterol, increasing 'good' high-density lipoprotein (HDL)-cholesterol, and normalising circulating triglycerides. This may often mean combining two or more agents, or developing compounds with multiple activities. Thus, Merck Sharp & Dohme is developing a combination (MK-0524B) of simvastatin, niacin and a third agent designed to prevent the blushing often provoked by niacin.

2. Intestinal cholesterol blockers
Inhibitors of the enzyme acyl-CoA:cholesterol acyltransferase (ACAT inhibitors) reduce absorption of cholesterol from the intestine, but work in a different way from that of ezetimibe. Kowa has the compound K-604 in Phase 1 and also has a new 'superstatin' compound, pitavastatin (NK104), in Phase 3 trial. Sanofi-aventis has the cholesterol absorption inhibitor AVE 5530 at Phase 2.

3. Inhibitors of plaque formation
GlaxoSmithKline's compound SB 480848 (darapladib), currently in Phase 3 trial, is an example of a new approach that tries to block plaque formation. The company has two other inhibitors (GSK 659032, rilapladib and GSK 568859) at Phase 1, as a back-up to darapladib.

Blocking inflammatory cell recruitment, and thus plaque formation, is also thought to explain the activity of AGI-1067, a compound in Phase 3 trial being developed by AstraZeneca and AtheroGenics.

4. Agents that affect HDL-cholesterol levels
Research is especially active into agents that can raise the level of 'good' HDL-cholesterol, which has a protective effect against the progression of atherosclerosis. These make up three distinct groups: cholesteryl ester transfer protein (CETP) inhibitors, so-called PPAR modulators, and substances similar to an HDL component known as apolipoprotein A-1.

Several companies have CETP inhibitors in development. Roche's R1658 has reached Phase 2, as has MK-0859 from Merck Sharp & Dohme, while Bayer's BAY 60-5521 and Japan Tobacco's JTT-302 are at Phase 1.

Peroxisome Proliferator-Activated Receptors (PPARs) are 'master switches' that regulate a variety of important processes in the body, including the formation and breakdown of lipids. Three types are known: PPAR alpha, gamma and delta. PPAR-gamma activators (glitazones) are used to treat diabetes, and it was noted that lipid imbalances often seen in diabetes were improved by this treatment. Further interest was aroused by the discovery that fibrates, which have long been known to raise HDL-cholesterol levels, are PPAR-alpha activators. This has encouraged several companies to develop new medicines from this area of research.

Those in Phase 2 study are:

• PPAR-alpha activators from Kyorin (KRP 101) and sanofi-aventis (AVE 8134)
• Dual PPAR-alpha/gamma activators, including: LBM 642 (Novartis), AVE 0847 (sanofi-aventis) and AZD 6610 (AstraZeneca)
• A PPAR-delta activator (GSK 501516) from GlaxoSmithKline.

The other major new line of research into ways of preventing atherosclerosis explores variants of apolipoprotein A-1, a normal constituent of HDL. A genetic study found that a small number of people living by Lake Garda in northern Italy had very low levels of HDL-cholesterol but also a very low risk of having cardiovascular disease. Investigations showed that these people had inherited a variant form of apolipoprotein A-1 that was very effective at clearing cholesterol from artery walls and other tissues (thus shrinking atherosclerotic plaques) and transporting it back to the liver for elimination. This finding encouraged development of a form of the protein combined with phospholipid to mimic natural HDL and Pfizer now has this agent (ETC-216), which is given by injection, in Phase 2 trial. Data have shown that this synthetic form of HDL is able to reduce plaque size in coronary arteries. Novartis is also exploring this approach and the company is developing an oral form of an Apo A-1 'mimic' (APP 018) that is in Phase 1 trial.

The longer-term future

The processes behind atherosclerosis are so closely linked with those of other major diseases that advances in treating this condition will have enormous health benefits. Many other projects than those above have promise in this area, and other pathways may eventually turn out to be important too. However, such is the intensity of research in this area that the outlook for new treatments becoming available over the next ten years is surely bright.

FOR FURTHER INFORMATION CONTACT:

British Heart Foundation
14 Fitzhardinge Street
London, W1H 4DH
Phone: 0870 600 6566 (Helpline)
Website: www.bhf.org.uk