A meeting to discuss statins took place in Paris, on September 9, organised by an International Task Force for Prevention of Coronary Heart Disease. In addition to lipid lowering properties, other effects of statins were described
The introduction of a number of statins since the first drug, simvastatin, was launched in the UK in 1989 has resulted in a debate over the benefits of one statin over another. An International Task Force for Prevention of Coronary Heart Disease met in Paris to develop a consensus on their use. The meeting concluded that statins have a class effect in terms of lipid lowering (see p438) but that differences did exist between the drugs.
Effects on LDL
It was likely that target low density lipoprotein (LDL) cholesterol levels should
be lower than those that were currently striven for, said Dr JOHN KASTELEIN
(academic medical centre, University of Amsterdam, Netherlands).
There had been a gradual decrease in what was considered a “normal”
cholesterol level, from 10mmol/L in the 1950s through to 6.5mmol/L in the ’70s
and 5.0mmol/L in the 1990s. The desired level in the future may be lower still,
he said. Newborn babies had cholesterol levels of 1.3mmol/L and this was at
the time in life when cholesterol was needed most for development, so perhaps
1.5mmol/L was sufficient, he suggested.
Dr Kastelein plotted the percentage of people with coronary heart disease (CHD)
events against LDL levels using results from each of the major statin trials
and found that the points formed a straight line — low CHD event rates
correlated with the low LDL levels. The lowest LDL level achieved by trials
had been 2.6mmol/L so a question mark remained over what happened to the CHD
event rate when LDL was reduced to below that level. This was currently being
investigated, he said, although data suggested that there was no threshold level
below which lowering LDL had no further benefit.
Evidence from the Scandinavian simvastatin survival study (4S) also showed that
long-term treatment was better than short-term in terms of preventing coronary
deaths. Therefore, prescribing a statin was a life-long decision, he said.
Pharmacokinetics of statins
Statins shared a common function in their inhibition of HMG coA reductase but
there were many differences in their pharmacokinetics, said Professor RADOLFO
PAOLETTI (institute of pharmacology, University of Milan, Italy).
Bioavailability differed between the statins; simvastatin had a low bioavailablity
whereas that of cerivastatin was much higher, with atorvastatin and pravastatin
in between. There were also differences in other pharmacokinetic parameters
including the fraction of drug absorbed, which varied from 30 per cent for atorvastatin
to 60 per cent for simvastatin and 98 per cent for fluvastatin and cerivastatin.
Plasma levels of pravastatin were 10-15 times higher than those of other statins
which had higher fractions bound to plasma proteins. This meant that pravastatin
had a shorter half life. All currently available statins, except pravastatin,
were lipophilic and there were also differences in the degree of lipophilicity.
Bile acid sequestrants might modify patterns of absorption and maximum concentrations
of statins, said Professor Paoletti. Again, statins interacted in different
ways with these drugs. They reduced area under the curve for fluvastatin and
pravastatin by 50 per cent but no change in clinical efficacy was found. However,
when given in combination with bile acid sequestrants, the maximum concentration
of cerivastatin was reduced by 41 per cent. Cimetidine changed the half life
of atorvastatin but did not change the drug’s effect on lipids.
In terms of metabolism, fluvastatin and pravastatin had inactive metabolites
but simvastatin and atorvastatin had active metabolites which might be of clinical
relevance, he said. Different metabolites might also account for differences
in the duration of activity. Atorvastatin had hydroxylated metabolites which
might prolong its activity to practically 24 hours, he added. Many statins were
metabolised by the cytochrome P450 family. Individual statins were metabolised
by different enzyme fractions, which could have implications for drug interactions.
Professor Paoletti concluded that, when prescribing statins, care should be
taken in selecting both the compound and the dose.
Pleiotropic effects
Statins were developed to lower cholesterol but had been found to have many
other
effects (pleiotropic effects), said Dr JEAN DAVIGNON (hyperlipidemia and atherosclerosis
research group, Clinical Research Institute of Montreal, Canada).
Some of these additional effects, such as anti-inflammatory effects and plaque
stabilisation, could help to explain how statins prevented heart attacks (PJ,
February 12, p245). Statins might also improve endothelial dysfunction by enhancing
nitric oxide production and they might have antioxidant and anticoagulant properties.
The drugs also appeared to have effects that were not related to the cardiovascular
system. The most promising findings so far had been in osteoporosis and cancer.
In both cases, only lipophilic statins demonstrated effects.
Trials had found that statins enhanced the activity of bone morphogenetic protein
2 (BMP-2), said Dr Davignon. BMP-2 increased activity of osteoblasts which were
involved in bone formation. Comparing the statins, a progressive increase in
BMP-2 activity was observed with simvastatin, fluva-statin and lovastatin. Pravastatin
(a hydrophilic drug) had no effect on BMP-2. Cerivastatin produced the fastest
effect. It had also been suggested that statins acted on the same pathway as
bisphosphonates. Trials in rats had shown that the statins increased trabecular
bone volume. The drugs appeared to reduce activity of osteoclasts (which caused
bone resorption), said Dr Davignon. The in vitro data was backed by clinical
studies, including data from the UK general practice research database (PJ,
July 8, p43), which showed that statins reduced the risk of bone fracture.
Another pleiotropic effect of statins was in cancer. Lovastatin had been shown
to inhibit attachment, motility and invasion of highly metastatic mice melanoma
cells, said Dr Davignon. Statins had also been shown to enhance the effect of
chemotherapeutic agents, for example, combining lovastatin with cisplatin had
resulted in a dose-dependent increase in activity. Recent eight-year follow-up
data from the 4S trial had shown that the incidence of cancer was 2.3 per cent
in the simvastatin group and 3.1 per cent in the placebo group, suggesting that
statins may have a long-term anticancer effect, said Dr Davignon. The anticarcinogenic
effect of statins was probably multi-faceted, he said. Statins could be antiproliferative,
pro-apoptotic and anti-inflammatory.