Statins still lead the way

High cholesterol levels are a factor in heart disease. Dr Sarah Houlton discusses the use of statins to combat the disease, as well as investigating other alternatives

Heart disease is the scourge of modern living, with unhealthy diets and insufficient exercise being major contributory causes of coronary problems. Globally, the death toll directly attributable to cardiovascular disease is estimated at 15m a year, and heart disease is responsible for maybe half of these deaths.

One of the major risk factors implicated in heart disease is high cholesterol levels. The steroid cholesterol (1) is involved in many essential bodily functions, including hormone, vitamin D and bile salt production. Around 80% of the cholesterol present in the human body is produced in the liver, and the remainder comes from foods such as dairy products in the diet. High cholesterol levels in the blood can lead to atherosclerosis, where cholesterol builds up in plaques on the walls of the arteries, narrowing and hardening them. The plaques can also break and cause blood clots. If either of these situations leads to blood flow to the heart being blocked, a heart attack or stroke results.

Cholesterol exists in the blood in various forms, including low density lipoproteins (LDL) and high density lipoproteins (HDL). Excessive levels of the former are implicated in atherosclerosis.

desirable cholesterol levels

The US National Institutes of Health's guidelines are that desirable cholesterol levels are below 200mg/dl for total cholesterol, and below 130mg/dl for LDL cholesterol, or under 100mg/dl for patients with existing heart disease.

Estimates indicate that 30% of all US adults have an LDL cholesterol level that is too high, and only around a third of these are aware of the problem. Less than 15% of patients with recognised heart disease have an LDL cholesterol level below the recommended threshold.

The initial treatment for high cholesterol is to modify the diet, reducing the intake of foods containing high levels of saturated fat like butter, eggs, whole milk and some meats. Regular exercise can also help. In severe cases, this may not be enough, and a major advance in the treatment of high cholesterol levels came with the introduction of statins. Sales of these medicines have escalated rapidly as patients and doctors realised the potential for them being an 'easy fix' for cholesterol levels. But prospects for the drug class took a big knock in August, however, when Bayer withdrew cerivastatin (Baycol/Lipobay) from the market, following reports of adverse effects.

Before the problems with cerivastatin surfaced, the market for lipid lowering drugs was estimated to rise sharply. IMS Health's figures showed that in 1999 the market increased by nearly a quarter to almost US$10.5bn, and it was estimated that this could reach US$16bn by 2003.

Statins are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA, 2) reductase inhibitors. This enzyme is responsible for the conversion of HMG-CoA to mevalonate, which is a biochemical precursor of the sterols, and this process is the rate limiting step in cholesterol biosynthesis. The inhibition of HMG-CoA reductase-dependent cholesterol biosynthesis leads to lower levels of cholesterol in the liver. It also increases the synthesis of hepatic LDL cholesterol receptors, as the liver compensates for the reduced cholesterol synthesis. This increases the uptake of LDL cholesterol from the blood by the liver, as it is needed by the liver to make more cholesterol. Both of these actions contribute to the reduction of LDL cholesterol within the bloodstream, typically 20–40%. Additionally, statins increase HDL cholesterol levels, and most lower triglyceride levels, both of which should also reduce the risk of cardiovascular problems.

benefits of using statins

Large-scale clinical trials have shown the benefits of using statins in both primary and secondary prevention of heart disease, as well as long-term prevention.¹

Two studies looked at primary prevention,^2,3 the first in middle-aged men with extremely high LDL cholesterol levels, and the second in both men and women with average levels. Both trials showed significant reductions in coronary events, with non-fatal myocardial infarction and mortality from heart disease reduced by 31% in the high cholesterol trial, and the risk of a first coronary event cut by 37% in the patients with average cholesterol.

One of the secondary prevention trials,⁴ the Scandinavian simvastatin survival study, proved that lowering cholesterol levels is a safe way of going about reducing heart disease. It showed a 30% cut in all-round mortality in addition to reducing deaths from coronary artery disease in high-risk patients.

Two further studies,^5,6 in patients with mild to moderate hypercholesterolaemia, both resulted in substantial reductions in heart disease and mortality. And, although high cholesterol levels have not definitely been shown to be a risk factor for strokes, all three of these trials showed a reduced incidence of stroke.

subject of debate

While the benefits of lipid lowering in patients with high cholesterol levels is pretty clear cut, its advantage in patients with low to moderately raised cholesterol has been the subject of much debate. The combined results of several studies indicate that the treatment of such patients with statins gave a reduction in fatal and non-fatal myocardial infarction of 62%.⁷

Statin therapy also compares favourably with patients receiving angioplasty, with a long-term comparison trial showing a 36% lower incidence of ischaemic events in those treated with statins rather than surgery.⁸

There is also evidence that statins may have cardioprotective properties unrelated to their cholesterol reducing ability. For example, a recent study indicates that cerivastatin has an effect on angiotensin II induced inflammation.⁹

Statins are believed to decrease LDL oxidation and inflammation, inhibit platelet aggregation and the stimulation of fibrinolytic factors, hence reducing clotting potential, and improve blood flow and viscosity. They are also thought to have positive effects on vessel endothelial tissue.

statin discovery

The earliest statin to be discovered, mevastatin, was isolated from Penicillium mould, but did not reach the market. Lovastatin, from Merck & Co (Mevacor, 3), was the first to be approved for clinical use, and has just lost its patent protection in the US. Simvastatin (Zocor, 4), also a Merck & Co drug, is structurally very similar. Both of these agents are prodrugs. Bristol-Myers Squibb's statin drug, pravastatin (Pravachol, 5), is again structurally similar, but it is metabolised in a very different way by the body. And Novartis markets fluvastatin (Lescol, 6) which, unlike its fungally-derived predecessors, is entirely synthetic.10 Fluvastatin itself is active, and most of the circulating metabolites are inactive. It is absorbed rapidly and completely following oral administration.

The current biggest seller of the six members of the class that have reached the market is atorvastatin (Lipitor, 7) from Pfizer/Parke Davis. It had sales of nearly US$3bn, over a quarter of the total market, in 1999, according to IMS Health. It lowers LDL cholesterol by up to 60%, and around 70% of its activity is derived from metabolites.

Cerivastatin (Baycol/Lipobay, 8) was the most important new drug Bayer had introduced for years and, like fluvastatin, is fully synthetic. It was the most potent of the marketed statins. Its withdrawal has hit the company hard, and may even lead to Bayer selling its healthcare business. The company estimates that it will lower its operating results by up to €800m (US$707m) this year; the drug had been predicted to have a peak annual sales potential of €2.5bn (US$2.2bn).

muscle weakness

The withdrawal followed reports of several incidences of the condition rhabdomyolysis, a form of muscle weakness, in patients co-prescribed with the unrelated cholesterol lowering drug gemfibrozil (Lopid, Pfizer). This problem is known to occur with all statins when administered with gemfibrozil, and their concurrent use is contraindicated. However, despite this advice, some physicians, particularly in the US, have continued to prescribe both drugs to the same patient. It is thought that around 1.5% of cerivastatin patients in the US were also taking gemfibrozil, despite the warnings to the contrary. A significant number of doctors were disregarding the prescribing advice for patients to be started off at the lowest dose, and not the highest licensed dose of 0.8mg, and there have been some reports of fatalities when this advice was ignored.

It is difficult to prove that cerivastatin was the direct cause of the problem, because of lack of availability of further information such as which other medicines the patients concerned were taking. But the incidence of rhabdomyolysis appears to be higher in patients where the prescribed statin is cerivastatin than it is with the alternatives, which led to Bayer voluntarily withdrawing the drug from the market in August. Initially, it was withdrawn from sale in all markets other than Japan, where gemfibrozil is not currently available. However, it transpired that gemfibrozil is likely to be licensed there in the near future, so Bayer withdrew cerivastatin in Japan, too.

Several lawsuits claiming damages have been launched in the US, which Bayer says it will 'defend rigorously', citing the lack of proven causal connection, and the clear warnings of side-effects and contraindications that had been given to doctors and inside drug packets.

Unsurprisingly for such a successful therapeutic class, further statins are in development, particularly because currently available statins do not enable all patients to achieve desired LDL cholesterol levels. The closest to the market of these is AstraZeneca's so-called superstatin, rosuvastatin (Crestor, 9), licensed from Shionogi of Japan in 1998. It is a potent, long-lasting HMG-CoA reductase inhibitor that is highly selective for hepatocytes. Once a day dosing is possible because of its pharmacokinetics, and the potential for drug–drug interactions is lower because it does not have an oxidative hepatic metabolism route. It gives rapid dose-related reductions in total cholesterol, LDL cholesterol, triglycerides and apolipoprotein B, which could well prove to be bigger than those with statins currently on the market. HDL cholesterol levels are also raised. AstraZeneca has recently submitted the drug for marketing approval to the US and European authorities. Phase II trials showed it to reduce LDL cholesterol by up to 65%.

The first long-term Phase III trial results have just been revealed at the European Society of Cardiology annual congress in Sweden. In two comparator titration to guideline 52 week studies, over 800 hypercholesterolaemic patients were initially dosed with 5mg or 10mg rosuvastatin, or 10mg atorvastatin, 20mg pravastatin or 20mg simvastatin, and after 12 weeks these were titrated up until the target LDL cholesterol level was reached. Rosuvastatin produced significantly better LDL cholesterol reductions.¹¹

well tolerated

With doses from 10mg, rising to 80mg if necessary, 98% of patients treated with rosuvastatin reached the US LDL cholesterol guideline level in one trial and 88% in the second, compared to 87% of those receiving atorvastatin, 60% of the pravastatin group and 73% of those who took simvastatin. A total of 82% of the rosuvastatin group reached the desired level at the starting dose in one trial and 79% in the other, compared with 59% of the patients on atorvastatin, 31% of those taking pravastatin and 50% of those in the simvastatin group.

All the drug therapies were found to be well tolerated, with no obvious differences in side-effect profiles between the drugs. The most commonly reported side-effects were those typically seen on occasion in patients undergoing statin therapy — headache, and gastrointestinal and upper respiratory symptoms. AstraZeneca says that the company does not believe the withdrawal of cerivastatin will have any effect on the prospects for rosuvastatin's approval or sales potential. 'We are very confident with the Crestor data,' she said. 'Cerivastatin's problem is its problem.'

Indeed, if approval goes to plan and the side-effect problems of cerivastatin do not spread to encompass the entire class, then rosuvastatin should do well, and prospects for AstraZeneca's future balance sheet look good.

Another developmental statin, NK-104 (variously also known as pitavastatin, itavastatin and nisvastatin), is being investigated by Kowa in Japan. Data reported thus far indicate that its activity is dose-dependent and comparable to atorvastatin. It is only minimally affected by the cytochrome P450 system, meaning that clinically-significant interactions with other drugs are likely to be few.¹²

Although statin drugs are not cheap, they are less costly than the surgical alternative. A study published by Pfizer¹³ on the relative costs of treatment with atorvastatin, cerivastatin, fluvastatin, pravastatin and simvastatin indicated that cerivastatin provided the cheapest option and pravastatin the most expensive.

They found that fluvastatin and pravastatin were more expensive yet less effective than the lowest cost treatment, and atorvastatin gave the lowest cost-effectiveness ratios.

A recent report on the structural mechanism by which these drugs work indicates that there could well be room for manoeuvre in the creation of still more potent statin drugs.14 X-ray crystallography was used to discover how the drugs fit into HMG-CoA reductase's active site. One specific part of the receptor is not bound by any of the statins, and if a more all-encompassing compound could be invented, then its anti-HMG-CoA reductase activity may be higher.

It remains to be seen if the health concerns will have a long-lasting effect on the class. But trials have indicated that aggressive cholesterol lowering in people at risk from heart disease has a dramatic effect on their prospects. Penetration of the drugs into the patients that could benefit is still relatively low, and the potential for further blockbuster drugs within the field should still be enormous.