I read a book by Dr, Whitaker that mentioned this issue.
At the FDA site there is a petition that has been submitted by some Doctors requesting statins include the suggestion to also take CoQ10 when taking statins to avoid possible lowering of CoQ10 levels. In reading the petition it is interesting that a pharmaceutical company has apparently gotten a patent on a combo statin and CoQ10 medicine perhaps anticipating that some Doctors might recommend taking CoQ10 with the statins.
The petition is at :
http://www.fda.gov/ohrms/dockets/dailys/02/May02/052902/02p-0244-cp00001-01-vol1.pdf
>>>>>[excerpt about the patent issue-]
In apparent recognition of the dangers associated with statin-induced CoQ 10 depletion,
Merck has obtained patents to combine CoQlO with its statin drugs. See Exhibit B (the Merck
patents). Merck describes the risks of CoQlO depletion as follows: ?The most serious reported
adverse effects of lovastatin, a commercially available HMG-CoA reductase inhibitor, are
myopathy and asymptomatic but marked and persistent increases in liver transaminases.. .
[CoQl 01 is.. . an essential co-factor in the generation of metabolic energy and may be important
in liver hnction.? Exhibit By Patent No. 4,929,437, at 2. A second Merck patent states:
?[CoQ 10 supplementation] would be of considerable benefit to counteract the myopathy
observed in a small percent of patients. Since CoQlO is of benefit in congestive heart failure
patients, the combination with [statins] should be of value in such patients who also have the
added risk of high cholesterol levels.? Exhibit B, Patent No. 4,933,165, at 2. Merck?s patents
would preclude other companies from combining CoQ 10 with statins in a single-dose form.
That fact underscores the critical need for FDA to add the requested Warning statement to alert
physicians of the need for CoQ 10 supplementation to offset statin-induced CoQlO depletion
arising from use of those statins that are not combined with CoQ 10 in a single-dose form.
>>>>>
This is along summary of some studies cited in the petition -
re: statins and Coq10
at:
http://www.fda.gov/ohrms/dockets/dailys/02/May02/052802/02p-0243-cp00001-02-Exhibit_A-vol1.pdf
>>>> [excerpts]- [the Journal citations are at pages 13 to 18 of this article]
From 1990 to date there have been 15 published studies in humans evaluating the effects of
statins on CoQlo. Nine were controlled trials and eight of those demonstrated significant CoQlo
depletions secondary to statin therapy.
Human observations on the interaction between statins and coenzyme Q1o were first
published in 1990 by Folkers et al, who observed that five patients with pre-existing
cardiomyopathy exhibited a significant decline in blood coenzyme Ql0 level and clinical
deterioration following lovastatin (Folkers 1990) treatment. That decrease in coenzyme Q 10
blood level and decline in clinical status was reversed through an increase in supplemental
coenzyme Qlo.
In 1993, Watts et a1 studied 20 hyperlipidemic patients treated with a low cholesterol diet and
simvastatin and compared them to 20 hyperlipidemic patients treated with diet alone and 20
normal controls (Watts 1993). Patients treated with simvastatin had significantly lower
plasma coenzyme Qlo levels and a lower coenzyme Qlo to cholesterol ratio than either
patients on diet alone or normal controls. The depletion of plasma CoQlo was significantly
inversely associated with the dose of simvastatin. It was concluded that simvastatin may
lower plasma coenzyme Qlo concentration and that the reduction may be proportionally
greater than the reduction in cholesterol. The authors felt that the adverse effect of
simvastatin on the biosynthesis of coenzyme Qlo may be clinically important and requires
hrther study.
In 1993, Ghirlanda et a1 studied 30 hypercholesterolemic patients and 10 healthy volunteers
in a double-blind controlled trial, comparing placebo with either pravastatin or simvastatin
for a three-month treatment period (Ghirlanda 1993). Both of those HMG CoA-reductase
inhibitors showed significant reduction in total cholesterol and plasma CoQlo levels, not only
in hypercholesterolemic patients but also in the normal healthy volunteers.
In 1994, Bargossi et a1 performed a randomized controlled trial evaluating 34
hypercholesterolemic patients treated with either 20 mg of simvastatin for six months or 20
mg of simvastatin plus 100 mg of supplemental coenzyme Qlo (Bargossi 1994). The study
demonstrated that simvastatin lowered LDL cholesterol and lowered plasma and platelet
coenzyme Qlo levels. The depletion of CoQlo in both plasma and platelets was prevented in
the supplemental Coenzyme Q 10 group without affecting cholesterol lowering caused by
simvastatin.
In 1995, Laaksonen et al. documented a significant decrease in serurn Coenzyme Qlo levels
in hypercholesterolemic patients treated with four weeks of simvastatin, with no reduction in
skeletal muscle ubiquinone (Laaksonen 1995).
In 1996, Laaksonen et a1 evaluated skeletal muscle biopsy specimens in 19
hypercholesterolemic patients treated with simvastatin at 20 mg per day and found no
4
depletion of skeletal muscle ubiquinone concentration as compared to control subjects
(Laaksonen 1996).
In 1996, De Pinieux et a1 evaluated 80 hypercholesterolemic patients (40 patients treated with
statins, 20 patients treated with fibrates, and 20 untreated controls) (De Pinieux 1996).
Further, they evaluated 20 non-hyperlipidemic health controlled patients. Serum ubiquinone
levels were significantly lower in statin treated patients and were not depleted in fibrate
treated patients or in untreated controls. Lactate to pyruvate ratios were significantly higher
in statin treated patients, indicating mitochondrial dysfunction in patients treated with statins,
which was not observed in untreated hypercholesterolemic patients or in healthy controls.
In 1997, Palomaki et al. studied 27 hypercholesterolemic men in a double-blind placebo
controlled crossover trial with six weeks of lovastatin at 60 mg per day (Palomaki 1997).
Lovastatin therapy was associated with a significant decline in serum ubiquinol content as
measured per LDL phosphorus, and there was an increased oxidizability of LDL in the
lovastatin treated patients.
In 1997, Mortensen et a1 studied 45 hypercholesterolemic patients in a randomized double-
blind trial with either lovastatin or pravastatin for 18 weeks (Mortensen 1997). A dose-
related significant decline in total serum coenzyme Qlo was found in the pravastatin group
from 1.27 +/- 0.34 to 1.02 +/- 0.31 mmol/L. In the lovastatin group, there was a more
pronounced decrease in serum CoQlo level from 1.18 +/- 0.36 to 0.84 +/- 0.17 mmol/L
p<O.OOl. The authors concluded that although HMG CoA-reductase inhibitors are safe and
effective within a limited time horizon, possible adverse consequences fiom coenzyme Qlo
lowering was an important factor in long-term therapy.
In 1998, Palomaki et a1 evaluated 19 men with hypercholesterolemia and coronary artery
disease treated with lovastatin with or without ubiquinone supplementation (Palomaki 1 998).
The lag time in copper mediated oxidation of LDL increased by 5% (p=0.02). It was
observed that the faster depletion of LDL ubiquinol and shortened lag time in conjugated
diene formation during lovastatin therapy may partially be restored with ubiquinone
supplementation.
In 1999, Miyake et a1 studied 97 non-insulin-dependent diabetic patients treated with
simvastatin and observed a significant decrease in serum CoQlo concentrations along with
the decrease in serum cholesterol (Miyake 1999). Oral CoQlo supplementation in diabetic
patients receiving simvastatin significantly increased serum coenzyme Q 10 levels without
affecting cholesterol levels. Furthermore, the supplemental coenzyme Q 10 significantly
decreased cardiothoracic ratios from 51.4 +/- 5.1 to 49.2 +/- 4.7% (pC0.03). The authors
concluded that serum coenzyme Qlo levels in diabetic patients are decreased by statin therapy
and may be associated with subclinical diabetic cardiomyopathy, reversible by coenzyme Q 10
supplement ation.
In 1999, De Lorgeril et al. studied in a double-blind fashion 32 patients treated with 20 mg of
simvastatin compared to 32 patients treated with 200 mg of fenofibrate (De Lorgeril 1999).
Serum coenzyme Qlo levels were significantly reduced after treatment with simvastatin but
5
not with fenofibrate. No significant change in left ventricular ejection fraction could be
determined after 12 weeks of therapy. They observed a loss of myocardial reserve with a
flattening of the ejection fraction response to exercise, which could be explained by the
statin-induced diastolic dyshnction in those patients. Unfortunately, only systolic
measurements of ejection fraction were obtained in this study.
In 2001, Bleske et al. failed to show a depletion in whole blood CoQlo in 12 young, healthy
volunteers with normal cholesterol levels treated with either pravastatin or atorvastatin for
four weeks (Bleske 2001).
Also in 200 1, Wong et al. documented that the beneficial anti-inflammatory effect of
simvastatin on human monocytes was completely reversible with supplemental mevalonate
but not with coenzyme Qlo, indicating that supplemental coenzyme Qlo would not interfere
with this important statin-mediated anti-inflammatory effect (Wong 200 1).
The most recent statidCoQ study was a randomized controlled trial by Jula et al., published
in JAMA (Jula 2002). Simvastatin at 20 mg per day caused a reduction in serum CoQlo of
22% @<0.001). The clinical consequences of this significant CoQlo deficiency were not
evaluated in this short term trial.
In summary, in human trials evaluating coenzyme Qlo in statin therapy, there appears to be
frequent and significant depletion in blood CoQlo levels, particularly when statins are taken at
higher doses and most notably in the elderly. In one study involving patients with preexisting
CHF, the depletion in blood coenzyme Qlo levels was associated with a drop in ejection fraction
and clinical deterioration. Supplemental coenzyme Qlo has been found to prevent the depletion
of CoQlo in blood and in one study also to prevent the depletion measured in platelet CoQlo. The
serum depletion of CoQlo was associated with an elevation in lactate to pyruvate ratio,
suggesting an impairment in mitochondrial bioenergetics, secondary to statin-induced CoQ 10
depletion. Furthermore, two trials demonstrated enhanced oxidizability of LDL cholesterol
related to the lowering of serum CoQlo by statins. Supplemental CoQlo has been shown to
increase the CoQlo content in low density lipoproteins and to decrease significantly LDL
cholesterol oxidizability (Alleva 1997). One trial demonstrated no significant CoQ 10 depletion in
12 young normolipidemic volunteers treated with statins and one trial found no skeletal muscle
depletion of CoQlo in statin treated hypercholesterolemic patients. In diabetic patients, the CoQ 10
depletion with statin therapy appears to be associated with subclinical cardiomyopathy, with
significant improvement in cardiothoracic ratios upon CoQ 10 supplementation.
From these studies, one can conclude that supplemental coenzyme Qlo prevents the statin
induced CoQlo deficiency state without altering the cholesterol-lowering ability of these drugs
and appears to have benefit both in terms of decreasing the oxidizability of low density
lipoprotein cholesterol, as well as preventing or reversing observed detrimental clinical changes.
6
Animal Studies
From 1990 through 200 1 there have been 15 published animal studies involving six different
animal species (six rat studies, three hampster studies, three dog studies, one rabbit study, one
guinea pig study and one study looking at squirrel monkeys, mini pigs and hampsters) evaluating
the effect of statins on coenzyme Q blood and/or tissue levels. Nine of these 15 studies looked
specifically at the adverse consequences of this statin-induced CoQ depletion: decreased ATP
production, increased injury after ischemidreperfusion, increased mortality in cardiomyopathy,
and skeletal muscle injury and dysfunction. Some of the animals use coenzyme Qg which is a
shorter chain homologue of coenzyme Q ~o and in those cases the term coenzyme Q or CoQ is
used.
Some of the first animal data was published in 1990 by Willis et al. and documented
statistically significant decreases in coenzyme Q (CoQ) concentration in blood, heart and
liver in 45 adult male Holtzrnan rats. This blood and tissue CoQ deficiency could be
completely prevented by supplementing the lovastatin treated animals with coenzyme Q 10
(Willis 1990).
In 1992, Low et al. found similar decreases in ubiquinone in liver and heart in rats treated
with lovastatin (mevinolin), confirming observations by Willis et a1 (Low 1992).
1993, Fukami et al. studied simvastatin treated rabbits and specifically looked at those
animals with elevations in creatinine kinase, lactate dehydrogenase, and skeletal muscle
necrosis (Fukami 1993). The simvastatin treated rabbits were noted to have significantly
reduced liver and cardiac muscle coenzyme Q content as compared to the control group.
Interestingly, skeletal muscle ubiquinone content in this study was not affected.
In 1993, Belichard et a1 studied lovastatin in cardiomyopathic hamsters and found a 33%
decrease in ubiquinone content in heart muscle as compared to control (Belichard 1993).
Cholesterol lowering in cardiomyopathic hamsters with fenofibrate did not lower coenzyme
Qlo levels. Statins are the only class of lipid-lowering drugs that axe known to block the
synthesis of mevalonate.
In 1994, Diebold et a1 documented a depletion in Coenzyme Qlo content in heart muscle in
guinea pigs when treated with lovastatin in older age (2 years of age) animals, and further
observed no significant depletion in coenzyme Qlo content in heart muscle in the guinea pigs
in the younger age group (2 to 4 months of age) (Diebold 1994). The authors evaluated
mitochondrial function as measured by the potential to phosphorylate ADP to ATP, and
again documented a decrease by up to 45% in cardiac mitochondria in the 2-year-old animals
treated with lovastatin, and no significant decrease in phosphorylation in the younger age
group animals. This sensitivity for older animals to show clinically relevant heart muscle
CoQlo depletion is of concern in humans as older patients are treated with statin medications
and are observed to be more fiagile and more susceptible to side effects.
In 1994, Loop et al. documented again that lovastatin decreased coenzyme Q content in rat
liver that could be completely prevented with supplemental coenzyme Qlo (Loop 1994).
7
In 1995, Satoh et a1 evaluated ischemic reperfusion in dog hearts and documented that
simvastatin significantly decreased myocardial coenzyme Q 10 levels and worsened ischemia
reperfbsion injury (Satoh 1995). Water soluble pravastatin was also studied in this dog
model and did not appear to cause worsening of mitochondrial respiration in the dog heart
muscle, nor did the pravastatin reduce myocardial CoQlo levels. It is believed that the lipid
soluble simvastatin may be more detrimental in this model due to better membrane
penetration of that fat soluble drug.
In 1997, Morand et a1 studied hamsters, squirrel monkeys, and mini pigs, and documented
CoQlo depletion in heart and liver with simvastatin treatment (Morand 1997). They saw no
decrease in coenzyme Qlo in heart and liver using the experimental cholesterol lowering drug
23 -oxidosqualene:lanosterol cyclase, which blocks the synthesis of cholesterol below the
mevalonate level and thus does not impair the biosynthesis of coenzyme Qlo.
In 1998, Nakahara et al. evaluated simvastatin (a lipophilic inhibitor of HMG CoA-
reductase) or pravastatin (a hydrophilic inhibitor) (Nakahara 1998). In group I, rabbits were
treated with simvastatin at 50 mg/kg per day for four weeks. There was a 22% to 36%
reduction in ubiquinone content in skeletal muscle and the observation of skeletal muscle
necrosis and elevated CK levels. Group I1 rabbits were treated with pravastatin at 100 mg/kg
per day for four weeks, which did not cause skeletal muscle injury and reduced coenzyme
Qlo in skeletal muscle by 18% to 52%. In group 111, treated with high dose pravastatin at 200
mg/kg per day for three weeks followed by 300 mgkg per day for another three weeks, there
was a greater reduction in ubiquinone skeletal muscle content from 49% to 72% depletion
and evidence of skeletal muscle necrosis and CK elevation.
In 1998, Sugiyama observed that pravastatin caused significant decrease in the activity of
mitochondrial complex I in diaphragm skeletal muscle in rats age 35-55 weeks (Sugiyama
1998). The authors concluded that careful clinical examination of respiratory muscle
function is necessary in patients treated with pravastatin, particularly in the elderly.
. In 1999, Ichihara et a1 studied the effect of statins on ischemia reperfusion in dogs and
observed that pretreatment of the dogs with the lipophilic HMG CoA-reductase inhibitors
simvastatin, atorvastatin, fluvastatin, and cerivastatin all worsened recovery of myocardial
contraction after ischemia reperfusion, but the water soluble pravastatin had no detrimental
effect on myocardial contraction in this model (Ichihara 1999).
In 2000, Satoh et a1 further observed a detrimental effect fiom atorvastatin, fluvastatin, and
cerivastatin in dog ischemia reperfusion, confirming that lipophilic HMG CoA-reductase
inhibitors enhance myocardial stunning in association with ATP reduction after ischemia and
reperfusion (Satoh 2000).
In 2000, Caliskan et a1 studied rats treated with simvastatin and found significant reductions
in plasma cholesterol and ATP concentrations, indicating an impairment in bioenergetics
related to CoQ depletion (Caliskan 2000).
>>>>
pages 13 to 18 have the Journal citations for those articles at:
http://www.fda.gov/ohrms/dockets/dailys/02/May02/052802/02p-0243-cp00001-02-Exhibit_A-vol1.pdf
