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| The pill for every ill |
28-Sep-2005 |
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Just when it seemed statins couldn
’
t get any bigger, studies are suggesting they may have a role to play in conditions ranging from Alzheimer
’
s disease to cancer.
By Bianca Nogrady
WHEN a drug taken by tens of millions of people around the world for one condition starts to show possibilities for a host of other illnesses, experts understandably get excited.
The cholesterol-lowering properties of statins have already made them the epitome of the blockbuster drug, but now research is pointing to possible benefits extending far beyond the cardiovascular system — from osteoporosis and arthritis to Alzheimer’s disease and cancer.
One expert who is excited about the possibilities is Professor Henry Krum, head of clinical pharmacology at Melbourne’s Monash University.
“They are quite fascinating drugs because they do seem to have these pleiotropic effects ... that seem to be occurring above and beyond [those] one would observe merely with the lowering of cholesterol,”he says.
Laboratory and clinical studies — most of them epidemiological — suggest statins have anti-inflammatory, immunomodulatory and anti-cancer properties. There is some evidence they may reduce risk of Alzheimer’s disease, hip fractures and renal failure, and reduce the risk of death in people with pneumonia.
Statins’ cholesterol-lowering properties probably have little to do with any beneficial effects they may have in this wide range of conditions, Professor Krum says.
“If you take the view that inflammation is critical to a number of disease processes, and also the knowledge now that — at least in test tubes — statins are very potent anti-inflammatories, they might be beneficial in conditions we haven’t even thought about, like arthritis,” he says.
“The very fact that we’re talking about a drug with a pretty robust safety track record, and given that other anti-inflammatories have been getting a very hard time of late … if you can come up with a safe, potent anti-inflammatory then you’re on a winner.”
Statins’ anti-inflammatory effects may also have contributed to their spectacular success in cardiovascular medicine.
“Statins are to cardiovascular disease what penicillin was to infectious disease,” says lipid expert Professor Leon Simons, head of the cholesterol clinic at Sydney’s St Vincent’s Hospital. “They are one of the most important, if not the most important, advances in cardiovascular medicine.”
Since the drugs were first launched in the late 1980s, landmark clinical trials have been published on an almost annual basis showing their efficacy in heart disease prevention and improved survival, Professor Simons says.
“Before, we took the worth of cholesterol lowering on faith, but it took powerful drugs like statins to demonstrate what we knew would be true.”
Statins are so effective they have forced a rethink of what defines ‘healthy’ cholesterol levels. A recent study into intensive lipid lowering with statins in patients with stable heart disease found the risk of major cardiovascular events continued to drop even when their LDL cholesterol was as low as 2mmol/L.1
“That was the first real proof of ‘the lower, the better’,” Professor Simons says. Current Australian guidelines recommend a cholesterol target of 2.5mmol/L, but Professor Simons says the US has now adopted a provisional target of 1.7mmol/L.
For most of the other possible benefits of statins the evidence is not yet so clear, although experts are eagerly waiting to see if the postulated effects in Alzheimer’s disease will be confirmed in clinical trials.
A Cochrane review in 2001 found a growing body of biological, epidemiological and some non-randomised, clinical evidence that statins’ actions could slow the progression of the disease.2 The authors concluded that, while there was not at this point enough evidence to recommend taking statins to reduce risk of Alzheimer’s, further clinical studies should be a priority.
Psychogeriatrician Professor Henry Brodaty is involved in one such study and says statins may inhibit formation of the beta-amyloid plaques that are a key feature of Alzheimer’s disease. The international research effort he is part of is attempting to disentangle such possible effects from the drugs’ better known cholesterol-lowering properties. Patients with Alzheimer’s disease and normal cholesterol levels are being treated with either donepezil (Aricept) combined with atorvastatin, or donepezil alone, to see if the addition of statins improves outcomes.
However, Professor Brodaty, of Sydney’s Prince of Wales Hospital, is not placing any bets yet.
“We were burnt with the HRT story where we had similar epidemiological evidence that looked overwhelmingly positive, then the [Women’s Health Initiative study] came out that had the opposite results,” he says.
“Until we see some double-blind data I think the jury’s still out.”
It’s a similar scenario in oncology, where research is pointing to a possible reduction in risk of some cancers among patients taking statins.
Oncologist Professor Alan Coates, chairman of the Cancer Council of Australia, says it is early days, but the outlook is positive.
“Epidemiology suggests that those who are taking them [statins] have a lower-than-expected risk of some cancer, particularly bowel cancers and perhaps skin,”he says.
One recent population study suggested the drugs’ use almost halved the risk of colorectal cancer, independent of factors such as age, history, diet and use of aspirin and other NSAIDs.3 Other studies have reported reductions in risk of pancreatic, prostate and breast cancer. The possible anti-cancer effect could relate back to the drugs’ inhibition of HMG-CoA reductase, which is fundamental to many biochemical cell processes, Professor Coates says.
It may be a long time before these additional effects are confirmed beyond reasonable doubt, but Professor Krum says for people already on statins, that’s beside the point.
“If two million adults are already taking statins for other reasons then it’s a nice bonus.”
In the meantime, the statin market is expanding into another lucrative arena —the so-called ‘polypill’. The concept of a polypill — multiple drugs combined in one tablet — gained credibility through research predicting a six-in-one cardiovascular polypill could slash ischaemic heart disease events and stroke by more than 80% in patients with pre-existing cardiovascular disease.4
In Australia, several companies have already jumped on the polypill wagon, releasing a simvastatin/ezetemibe combination (Vytorin), a pravastatin/aspirin combination (Pravigard) and the most recent, an atorvastatin/amlodipine combination (Caduet).
The key advantage of a polypill is that it can reduce medication costs and improve compliance, particularly in patients taking multiple drugs for various risk factors. And, despite their efficacy, statins do have a problem with compliance. Some 30% of patients stop taking the drugs within six months of starting therapy, Professor Simons says. “Because you’re treating a disease without symptoms, the retention rate in people on medication is poor.”
Statin manufacturers have also been eyeing the over-the-counter market. In the UK, patients can get a 10mg dose of simvastatin over the counter after assessment by a pharmacist. Professor Simons says the measure was an attempt by the UK Government to cut health costs.
“There’s one little problem,” he says. “There’s not a shred of evidence that it [the low dose] will reduce the risk of heart disease.” All clinical trials of simvastatin use a dose of 40mg so, even in people at low risk of cardiovascular events, there is no evidence of benefit with a 10mg dose.
Australia’s decision not to follow the UK in licensing OTC statins has been welcomed by expert groups, such as the AMA, which argue lowering cholesterol is just one part of managing patients at risk of cardiovascular disease.
Cardiologist Professor Andrew Tonkin, chairman of the National Heart Foundation of Australia, agrees. He thinks we are at risk of relying on statins a little too much.
“I think it’s going to be imperative that we … don’t see statins as in any way replacing lifestyle measures, including recommended diets,” he says. “They must be seen as complementary.”
Although at least one expert has jokingly suggested statins should be put into the water supply, Professor Tonkin says the decision to treat should be based on a person’s estimated absolute cardiovascular risk.
“Because of the costs which are being spent on statins — close to 15% of total PBS expenditure — it’s going to be imperative that we really target their use to the highest-risk groups,” he says. l
References
1. New England Journal of
Medicine 2005; 352:1425-35.
2. The Cochrane Database
Systematic Reviews 2001; 3.
3. NEJM 2005; 352:2184-92.
4. BMJ 2003; 326:1419-23.
PBS
SPENDING ON STATINS IN
2004
Name
Volume
Cost
1. Atorvastatin 6,629,408 $427,030,219
2. Simvastatin 5,526,791 $373,139,090
6. Pravastatin 1,949,376 $128,718,054
STATINS AND SAFETY
Statins have an enviable, but not perfect, safety profile. Their pristine image recently took a battering with the withdrawal of the ‘super statin’ cerivastatin from the US market after 31 reports of fatal rhabdomyolysis, mostly in patients taking higher doses or in combination with another lipid-lowering drug, gemfibrozil. Recent media coverage has also focused on reports of transient global amnesia, although no causal link has been proved and experts say the condition is very rare and fully reversible.
THE EVIDENCE
Cardiovascular disease
: Statins reduce coronary events by an estimated 25-30% over five years of treatment and stroke risk by 10-15%, according to several meta-analyses.1 One review concluded a reduction in LDL cholesterol of 1.8mmol/L after several years of statin therapy reduced coronary heart disease events by as much as 61%.2
Colorectal cancer
: A recent population-based, case-control study of almost 2000 patients with colorectal cancer found five years of statin use was associated with a 47% relative reduction in the risk of colorectal cancer, after adjustment for other known risk factors.3
Alzheimer
’
s disease and dementia
: A Cochrane review in 2001 acknowledged a growing body of biological, epidemiological and some, non-randomised, clinical evidence that statins could slow progression of the disease.4 Since then, a pilot placebo-controlled study of the impact of atorvastatin in 63 patients with moderate Alzheimer’s disease found one year of therapy had positive effects on several clinical and cognitive scales.5 However, a larger cohort study found statins had no effect on risk of Alzheimer’s disease or dementia, although the authors suggested “methodological differences” could explain the contradictory findings.6
Osteoporosis
: Early scientific studies suggested statins stimulated osteoblast activity by increasing production of bone growth factors, and suppressed bone resorption. Several observational studies have found people taking statins had higher bone mineral densities and in some cases a decreased incidence of fractures, while others have shown no benefits.
Arthritis
: A placebo-controlled trial of 166 patients with rheumatoid arthritis found the addition of atorvastatin to their anti-rheumatic therapy reduced symptoms such as joint swelling and pain.7
Pneumonia
: Prior statin use may improve pneumonia outcomes, according to one retrospective cohort study of 787 patients admitted with pneumonia. Patients taking statins were almost three times less likely to die within 30 days of admission.8
References
1. Medical Journal of Australia 2005; 182:286-89.
2. BMJ 2003; 326:1423-29.
3. NEJM 2005; 352:2184-92.
4. The Cochrane Database Systematic Reviews 2001; 3.
5. Archives of Neurology 2005; 62:753-57.
6. Archives of Neurology 2005; 62:873-82.
7. Lancet 2005; 363:2015-21.
8. Respiratory Research 2005; 6:82.
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