Many thanks to everyone (from all parts of the northern hemisphere) for
their views on stain resistence, CK and compliance. This list is one of the
best educational resources we have and as some respondents sent messages
privately, I append a summary. Names have been omitted as I have not been
able to check whether everyone would be happy for comments to be attributed:
The original query:
Dear All,
We have been discussing a young (my age - upper 40s) patient with a
cholesterol greater than 10mmol/l who is prescribed 80mg simvastatin but
his cholesterol is not falling by the expected amount. We will be seeing him
to ascertain whether he is compliant but a question that was raised concerns
"resistance" to a statin formulation.
At 80mg, we would expect a raised total CK. The question is: does the
magnitude of a raised CK correlate with the magnitude of the effect of the
treatment on cholesterol levels? ie, is a higher CK associated with a
diminished cholesterol-lowering effect
I've had a look at PubMed but its difficult to phrase the search
adequately.
Has anyone come across any published studies?
Many thanks.
The Responses:
The manufacturers quoted responses to statin treatment are always an
average, and it is usually very difficult to get a straight answer about the
range of response. We all have experience of people who have responded
extraordinarily well to treatment (we tend not to complain about them!) and
those who respond poorly. I am sure concomitant drug treatment is a reason
in some but by no means all of these patients.
Anecdotally, I have also seen several patients who have had a poor response
to a reputedly potent statin e.g. atorvastatin, but had a far better
response to simvastatin, despite them both being metabolised by similar
pathways. Is it tachyphylaxis for some patients but not others?
>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>
The other thing to consider in this situation is microsomal induction of
simvastatin to less active metabolites. I came across a case a couple of
years ago of a patient on simvastatin where the introduction of phenytoin
led to a dramatic rise in the total cholesterol (Postgrad Med J
1999;75:359-60). Gamma GT acted as a marker of the microsomal induction.
Pravastatin is the only statin which is not metabolised by this enzyme
system.
>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>
I do not know of any published studies but in a patient of mine who had
CK of over 5000 on statins, he was also sensitive to them and got a good
response, eventually.
Also the effects have completely different biological explanations. It
is possible that the reduction in isoprenoids is involved but this would
suggest that raised CK only occurs in those whose HMGCoA has been
effectively antagonised - the opposite of what you are suggesting.
>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>
Most patients on statins do not have a raised CK. I had thought that this
was an idiosyncratic, rather than a dose-related, effect.
If compliance is not an issue, I am sure that he will have been screened
for hypothyroidism. Some patients respond poorly to statins - I have
wondered whether this is related to their intestinal cholesterol absorption
- and it would certainly be worth his clinician prescribing him a bile acid
sequestrant.
>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>
Agreed. most recommendations do not even include CK for
regular
monitoring.
>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>
I also agree that it is important to exclude all of the
secondary causes of hyperlipidaemia in the face of a poor
response to treatment (hypothyroidism, nephrotic syndrome
etc).
Assuming secondary causes are absent, with a cholesterol
level
this high familial hypercholesterolaemia must be a distinct
possibie. Response to statins in FH may be partly
influenced by
the nature of the LDL receptor mutation if this is the
case.
>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>
Statin resistance is known - there were those who didn't have any
decrease in WOSCOPs on 40 mg pravastatin. I have never heard of
a dose related increase in CK, just idiopathic large increases with
increased frequency (a doubling) for every doubling of the dose.
One issue is biological variation - it is very large for total
cholesterol. have you considered this for both pre-treatment and
post treatment values, i.e. have you got a mean of several values?
>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>
I am not aware of any published studies but I do have experience of a
number ofpatientts who failed to respond completely to full doses of
simvastatin who did respond to either pravastatin or atorvastatin. I think
it is well worth trying another statin. Perhaps a formal review has been
published somewhere but I have not come across it.
>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>
what was his initial cholesterol, triglycerides and HDL? Has diabetes,
hypothyroidism (very unlikely if normal CK and on statin), and alcohol been
excluded. His he compliant with diet?
Is he taking simvastatin at night? What job does he do (shift work)?
I do not use 80 mg of Simvastatin, but certainly at 40 mg, CK not always
elevated, nor is it always elevated with 40mg atorvastatin, and you do have
to watch relationship between exercise and blood sample.
>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>
After the demise of cerivastatin I converted 75 patients to other statins
using dose-equivalents from published data: It seemed that [I have yet to do
formal audit] about 1/3 responded as expected, 1/3 did better than expected
and 1/3 did worse...
The other possibility in this case is that the patient is
hypertriglyceridemic - and therefore would respond to a fibrate and not a
statin.
>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>
Isn't Simvastatin is very prone to pharmacokinetic interactions with other
drugs, (apparently more so than some other statins) as it is metabolised by
the CYP450 system?. ? could there be enhanced metabolism.
>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>
The Atorva reps claim that it works with high trigs but their claims only
extend to levels of about 4mmol/L. If his trigs were too high to assay, then
he will _never_ respond to a statin. A further likely cause is excess
alcohol. In one of my alcoholics (one whose blood alcohol was 3x drink drive
limit at 10am despite only having a pint of shandy the night before), trigs
were 160mmol/L and chol 25mmol/L, which went down to 4.5 and 5.1
respectively on a statin with no change in alcohol intake.
Alternatively as the patient is diabetic and hypothyroid (?effect of lipids
on TSH??) there is also the probebility that obesity contributes. At the
very least he should have the atorva stopped to be replaced by a fibrate [I
usually use Supralip - the low dose formulation of fenofibrate). This will
reduce his cholesterol somewhat and then add a statin if further control is
needed [with careful monitoring in view of the cerivastatin combination
therapy and renal failure debacle).
>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>
What are his triglycerides. Patients with high trig don't necessarily
respond to statins but do well on a fibrate.
>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>
Particular thnks to those who obviously went away and thought about the
matter and came back with additional information.
Gareth
Gareth Davies
Senior Clinical Biochemist
Wrexham Maelor Hospital
Wrexham LL13 7TD
UK
01978 725345
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