1. Introduction

All large statin trials excluded patients with New York Heart Association class III and IV heart failure such that long term safety of statins in patients with heart failure has not been established.

HMG CoA-reductase inhibitors or statins are an effective class of drugs for lowering LDL cholesterol. These drugs have been associated with some beneficial impact on cardiovascular morbidity and mortality. As such, statins have become some of the most widely prescribed drugs in the United States with many millions of patients taking them on a regular basis. According to the most recent NCEP (National Cholesterol Education Program) guidelines, the indications for the use of statins have been broadened such that patients with even low normal LDL cholesterol levels are now being treated in hopes of favorably altering the incidence of stroke and myocardial infarction. Statins are frequently used in the

elderly and have gained very broad acceptance in the medical community. Statins have been noted to have significant anti-inflammatory and plaque-stabilizing effects which has added to their broader usage.

It is well established that the mevalonate pathway is involved not only in the biosynthesis of cholesterol but also in the biosynthesis of the essential co-factor required for energy production, coenzyme Q 10 (CoQ10, ubiquinone). As such, HMG CoA reductase inhibitors block the cellular production of both cholesterol and of coenzyme Q10 [23,59]. This drug-nutrient interaction has been reviewed [7,8].

2. Background

Coenzyme Q10 is the coenzyme for mitochondrial enzyme complexes involved in oxidative phospho­rylation in the production of ATP [38,46,47]. This bioenergetic effect of CoQ10 is believed to be of fundamental importance in its clinical application, particularly as relates to cells with exceedingly high metabolic demands such as cardiac myocytes. The second fundamental property of CoQ 10 involves its antioxidant (free radical scavenging) functions [5,67]. CoQ10 is the only known naturally occurring lipid soluble antioxidant for which the body has enzyme systems capable of regenerating the active reduced ubiquinol form [16]. CoQ10 is carried in the blood with low density lipoprotein and serves to diminish the oxidation of LDL cholesterol in settings of oxidative stress [1]. CoQ10 is known to be closely linked to vitamin E and serves to regenerate the reduced (active) alpha-tocopherol form of vitamin E [10] as well as the reduced form of ascorbate [24]. Other more recently discovered aspects of CoQ 10 function include its involvement in extramitochondrial electron transfer, e.g. plasma membrane oxidoreductase activity [67], involvement in cytosolic glycolysis [36], and potential activity in both Golgi apparatus and lysosomes [22,53]. CoQ10 also plays a role in improvement in membrane fluidity [37]. The multiple biochemical functions of CoQ10 have been reviewed by Crane [11].

Coenzyme Q10 is clearly necessary for cellular ATP production and is of particular importance in heart muscle function given this tissue’s extreme energy requirements. A deficiency of CoQ 10 in the blood and the heart muscle has been documented in congestive heart failure [19,28]. An Australian group of cardiovascular surgeons has recently documented impairment in myocardial function secondary to age-related CoQ10 deficiency in patients undergoing coronary artery bypass surgery (CABG). That impairment was completely eliminated with incubation of the atrial myocardium with CoQ10 [57]. Later these researchers performed a trial of preoperative supplemental CoQ10 therapy and found improved outcomes in coronary artery bypass surgery [58]. The clinical experience with supplemental CoQ 10 in cardiovascular disease, including congestive heart failure, ischemic heart disease, hypertensive heart disease and heart surgery has been reviewed [33,34].

In the US we are presently in the midst of a congestive heart failure (CHF) epidemic, with a significant increase in the incidence of CHF over the past decade. The annual number of deaths directly from CHF increased from 10,000 in 1968 to 42,000 in 1993. The rate of hospitalizations for heart failure increased more than three times between 1970 and 1994. In the largest health system study of its kind, researchers at the Henry Ford Heart and Vascular Institute in Detroit found that the annual number of heart failure cases more than doubled from 1989 to 1997. Over that nine-year period, 26,442 cases were identified in the Henry Ford Health System in Detroit. Strikingly, the annual prevalence rose from 9 to 20 cases per 1000 health system patients . These results were compiled in the Resource Utilization Among Congestive Heart Failure (REACH) study [44].

Statins were first released in 1987 and are considered the most effective medications for managing elevated concentrations of low-density lipoprotein cholesterol. Although it is believed that they are generally well tolerated by most patients they can produce a variety of muscle-related complaints or

myopathies, of which rabdomyolysis is the most serious one. The issue was recently discussed in an article by Thompson et al. [66] where the following are indicated as the possible mechanisms of statin-induced muscle injury:

                        reduction of the cholesterol content of skeletal muscle membranes

                        reduction of the levels of ubiquinone

                        reduction in farnesyl pyrophosphate, an intermediary for the production of ubiquinone, which is required for the activation of small GTP-binding regulatory proteins.

In the present article we will examine the existing literature on animal studies and human trials evaluating the effect of statins on coenzyme Q blood and/or tissue levels. Statin-induced depletion of CoQ10 must be considered in the above mentioned epidemic of heart failure. The coenzyme Q 10 ­lowering effect of statin medications has clinical relevance and must be considered by all physicians when prescribing this class of medication.

3. Animal studies

From 1990 through 2001 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 ischemia/reperfusion, increased mortality in cardiomyopathy, and skeletal muscle injury and dysfunction. Some of the animals use coenzyme Q9 as their native ubiquinone which is a shorter chain homologue of coenzyme Q10 and in those cases the term coenzyme Q or CoQ is used.

The first animal data was published in 1990 by Willis et al. and documented statistically significant decreases in CoQ concentration in blood, heart and liver in 45 adult male Holtzman rats when treated with lovastatin. This statin-induced blood and tissue CoQ deficiency could be completely prevented by supplementing the lovastatin treated animals with coenzyme Q10 [70]. 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 al. [42].

In 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 [20]. The simvastatin treated rabbits were noted to have significantly reduced liver and cardiac muscle CoQ content as compared to the control group. Interestingly, skeletal muscle ubiquinone content in this study was not affected. Also in 1993, Belichard et al. studied lovastatin in cardiomyopathic hamsters and found a 33% decrease in ubiquinone content in heart muscle as compared to control [4]. Cholesterol lowering in cardiomyopathic hamsters with fenofibrate did not lower coenzyme Q10 levels. Statins are the only class of lipid-lowering drugs that are known to block the synthesis of mevalonate.

In 1994, Diebold et al. documented a depletion in CoQ10 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 CoQ10 content in heart muscle in the guinea pigs in the younger age group (2 to 4 months of age) [14]. 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 CoQ10 depletion is of concern in humans as older patients are treated with statin medications and are observed to be more fragile and more susceptible to side effects. Also in 1994, Loop et al. documented again that lovastatin decreased CoQ content in rat liver that could be completely prevented with supplemental coenzyme Q [41].

In 1995, Satoh et al. evaluated ischemic reperfusion in dog hearts and documented that simvastatin significantly decreased myocardial CoQ10 levels and worsened ischemia reperfusion injury [61]. 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 CoQ10 levels. It is believed that the lipid soluble simvastatin may be more detrimental in this model due to better membrane penetration of this fat soluble drug.

In 1997, Morand et al. studied hamsters, squirrel monkeys, and mini pigs, and documented CoQ 10 depletion in heart and liver with simvastatin treatment [48]. The investigators saw no decrease in CoQ10 in heart and liver using the experimental cholesterol lowering drug 2,3-oxidosqualene:lanosterol cyclase, which blocks the synthesis of cholesterol below the mevalonate level and thus does not impair the biosynthesis of coenzyme Q10.

In 1998, Nakahara et al. evaluated simvastatin (a lipophilic inhibitor of HMG CoA-reductase) or pravastatin (a hydrophilic inhibitor) [52]. 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 II rabbits were treated with pravastatin at 100 mg/kg per day for four weeks, which did not cause skeletal muscle injury and reduced CoQ10 in skeletal muscle by 18% to 52%. In group III, treated with high dose pravastatin at 200 mg/kg per day for three weeks followed by 300 mg/kg per day for another three weeks, there was a greater reduction in CoQ10 skeletal muscle content from 49% to 72% depletion and evidence of skeletal muscle necrosis and CK elevation. In 1998, Sugiyama observed that pravastatin caused a significant decrease in the activity of mitochondrial complex I in diaphragm skeletal muscle in rats age 35–55 weeks [65]. 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 al. 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 [25]. In 2000, Satoh et al. further observed a detrimental effect from 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 [60].

In 2000, Caliskan et al. studied rats treated with simvastatin and found significant reductions in plasma cholesterol and ATP concentrations, indicating an impairment in bioenergetics related to CoQ depletion [9]. In 2000, Marz et al. studied hamsters with inherited cardiomyopathy and concluded that lovastatin but not pravastatin at a dose of 10 mg/kg body weight significantly increased the mortality of cardiomyopathic hamsters, as a result of inhibition of myocardial ubiquinone [43]. Finally, in 2001 study by Pisarenko et al. in rats treated with simvastatin at 24 mg/kg for 30 days showed a significant decrease in ATP and creatinine phosphate in myocardium, again indicating that statin-induced CoQ 10 depletion has a detrimental impact on energy production in the heart muscle [56].

3.1. Summary of animal studies

Animal studies to date uniformly document varying degrees of coenzyme Q depletion in blood and in tissue with statin therapy, and that the coenzyme Q deficiency is associated with adverse effects in cardiomyopathic hamster models, in the ischemia reperfusion injury in dog models, as well as in liver and cardiac coenzyme Q content in rabbits causing skeletal muscle damage. A decrease in cardiac CoQ content and in ATP production has been documented in two years old (elderly) guinea pigs. Significant CoQ depletion was documented in the heart and liver in hamsters, squirrel monkeys, and mini pigs. It is also noteworthy that the lipid soluble statins appear to show more animal toxicity, particularly in the ischemia reperfusion dog models. One can surmise from these animal studies that statins have the potential to produce clinically meaningful coenzyme Q depletion in several animal species and that the depletion is dose related. In all animal studies where supplemental coenzyme Q was given to the animals prior to the institution of statins, the coenzyme Q blood and tissue depletion was completely prevented.

4. Human trials

From 1990 to date there have been 15 published studies in humans evaluating the effects of statins on CoQ10. Nine of those were controlled trials and eight of those nine studies demonstrated significant CoQ10 depletions secondary to statin therapy.

Human observations on the interaction between statins and coenzyme Q 10 were first published in 1990 by Folkers et al., that observed five patients with pre-existing cardiomyopathy that exhibited a significant decline in blood CoQ10 level and clinical deterioration after having been started on lovastatin [17]. That decrease in CoQ10 blood level and decline in clinical status was reversed through an increase in supplemental CoQ10.

In 1993, Watts et al. 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 [68]. Patients treated with simvastatin had significantly lower plasma coenzyme Q10 levels and a lower coenzyme Q10 to cholesterol ratio than either patients on diet alone or normal controls. The depletion of plasma CoQ10 was significantly associated with the dose of simvastatin. It was concluded that simvastatin may lower plasma CoQ10 concentration and that that reduction may be proportionally greater than the reduction in cholesterol. The authors felt that that adverse effect of simvastatin on the biosynthesis of coenzyme Q10 may be clinically important and requires further study. Also in 1993, Ghirlanda et al. 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 [21]. These HMG CoA-reductase inhibitors showed significant reduction in both total cholesterol and plasma CoQ10 levels, not only in hypercholesterolemic patients but also in the normal healthy volunteers.

In 1994, Bargossi et al. 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 CoQ10 [3]. The study demonstrated that simvastatin lowered both LDL cholesterol and plasma and platelet CoQ10 levels. The depletion of CoQ10 in both plasma and platelets was prevented in the supplemental CoQ10 group without affecting the cholesterol lowering effect of simvastatin.

In 1995, Laaksonen et al. documented a significant decrease in serum CoQ 10 levels in hyperc­holesterolemic patients treated for four weeks with simvastatin, with no reduction in skeletal muscle CoQ10 [29]. In 1996, Laaksonen et al. evaluated skeletal muscle biopsy specimens in 19 hypercholes­terolemic patients treated with simvastatin at 20 mg per day and found no depletion of skeletal muscle CoQ10 concentration as compared to control subjects [30].

In 1996, De Pinieux et al. evaluated 80 hypercholesterolemic patients – 40 patients treated with statins, 20 patients treated with fibrates, and 20 untreated controls [13]. Further, they evaluated 20 non-hyperlipidemic health controlled patients. Serum CoQ10 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 [54]. 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. [one of 4 reasons why statins don’t prolong life.  Oxidation of LDL is the starting point for plaque buildup--jk.]

In 1997, Mortensen et al. studied 45 hypercholesterolemic patients in a randomized double-blind trial with either lovastatin or pravastatin for 18 weeks [50]. A dose-related significant decline in total serum CoQ10 was found in the pravastatin group from 1.27 ± 0.34 to 1.02 ± 0.31 mmol/L, p<0.01. In the lovastatin group, there was a more pronounced decrease in serum CoQ 10 level from 1.18 ± 0.36 to 0.84 ± 0.17 mmol/L p<0.001. The authors concluded that although HMG CoA-reductase inhibitors are safe and effective within a limited time horizon, continued vigilance of a possible adverse consequence from coenzyme Q10 lowering seems important during long-term therapy.

In 1998, Palomaki et al. evaluated 19 men with hypercholesterolemia and coronary artery disease treated with lovastatin with or without CoQ10 supplementation [55]. In statin treated patients supple­mented with ubiquinone the lag time in copper mediated oxidation of LDL increased by 5% (p= 0.02). Upon AMVN (2,2-azobis (2,4-dimethylvaleronitrile)) oxidation the faster depletion of LDL ubiquinol and shortened lag time in conjugated diene formation during lovastatin therapy was significantly ame­liorated with CoQ10 supplementation.

In 1999, Miyake et al. studied 97 non-insulin-dependent diabetic patients treated with simvastatin and observed a significant decrease in serum CoQ10 concentrations along with the decrease in serum cholesterol [45]. Oral CoQ10 supplementation in diabetic patients receiving simvastatin significantly increased serum coenzyme Q10 level without affecting the cholesterol levels. Furthermore, the supple­mental coenzyme Q10 significantly decreased cardiothoracic ratios from 51.4 ± 5.1 to 49.2 ± 4.7% (p< 0.03). The authors concluded that serum coenzyme Q10 levels in diabetic patients are decreased by statin therapy and may be associated with subclinical diabetic cardiomyopathy, reversible by coenzyme Q 10 supplementation.

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 [12]. Serum CoQ10 levels were significantly reduced after treatment with simvastatin but 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 dysfunction 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 CoQ10 in 12 young, healthy volunteers with normal cholesterol levels treated with either pravastatin or atorvastatin for four weeks [6]. Also in 2001, Wong et al. documented that the beneficial anti-inflammatory effect of simvastatin on human monocytes was completely reversible with supplemental mevalonate but not with CoQ10, indicating that supplemental CoQ10 would not interfere with this important statin-mediated anti-inflammatory effect [71]. The most recent statin/CoQ study was a randomized controlled trial by Jula et al., published in JAMA [26]. Simvastatin at 20 mg per day caused a reduction in serum short term trial.

In human trials evaluating coenzyme Q10 in statin therapy there appears to be frequent and significant depletion in blood CoQ10 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 Q 10 levels was associated with a drop in ejection fraction and clinical deterioration. Supplemental CoQ10 has been found to prevent the depletion of CoQ10 in blood and in one study also to prevent the depletion measured in platelet CoQ10 levels. The serum depletion of CoQ10 was associated with an elevation in lactate to pyruvate ratio, suggesting an impairment in mitochondrial bioenergetics, secondary to statin-induced CoQ10 depletion. Furthermore, two trials demonstrated enhanced oxidizability of LDL cholesterol related to the lowering of serum CoQ10 by statins. Supplemental CoQ10 has been shown to increase the CoQ10 content in low density lipoproteins and to decrease significantly LDL cholesterol oxidizability. One trial demonstrated no significant CoQ10 depletion in 12 young normolipidemic volunteers treated with statins and one trial found no skeletal muscle depletion of CoQ10 in statin treated hypercholesterolemic patients. In diabetic patients, the CoQ10 depletion with statin therapy appears to be associated with subclinical cardiomyopathy, with significant improvement in cardiothoracic ratios upon CoQ10 supplementation.

From these studies, one can conclude that supplemental CoQ10 prevents the statin induced CoQ10 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. [PhARMA doesn’t disseminate this side effect of statins; their mantra is safe and effective--jk.]

4.2. Safety and drug interactions

Coenzyme Q10 is sold in the United States and abroad as an over-the-counter nutrient and is widely recognized as completely safe with no reported toxicity in over a thousand published human and animal trials. The most recent animal safety study was published in 1999 by Williams et al. [69]. Potential CoQ10 toxicity was assessed in rats administered CoQ10 by oral gavage for 1 year at 100, 300, 600, and 1200 mg per kg body weight per day. No adverse changes in mortality, clinical signs, body weight, food consumption, or clinical pathology results occurred.

In human clinical trials the highest doses used were 1200 mg/day in 23 patients with Parkinson disease [62] and up to 3,000 mg/day in case study in patients with familial cerebellar ataxia with primary muscle CoQ10 deficiency [51] with no adverse effects noted. To date, there have been at least 34 placebo controlled trials using CoQ10 in cardiovascular disease involving a total of 2152 patients with no toxicity or drug interactions reported in the CoQ10 group as compared to the placebo group. Most of these controlled trials have been reviewed [33,34]. In addition to these controlled trials there have been many open-label long term trials in cardiovascular disease using CoQ10 in doses up to 600 mg per day with up to eight year follow up, again with a complete lack of toxicity. In heart failure alone there have been at least 39 open trials with supplemental CoQ10 published involving a total of 4498 patients again with remarkable safety with the only reported side-effects being rare cases of mild nausea.

Long term safety and tolerability of CoQ10 was documented by Langsjoen in 1990 [http://www.pnas.org/content/87/22/8931.full.pdf] in a six year study of 126 heart failure patients [35]. Later, in 1993, Morisco published a double blind controlled trial on 641 heart failure patients treated with either placebo or CoQ10 for one year [49]. The investigators found a significant reduction of hospitalizations for worsening of heart failure in the CoQ10 group and no evidence of side effects. In 1994 Baggio published an open-label multi-center trial on 2664 patients with heart failure, treated with 150 mg CoQ10 per day for three months and reported good tolerability [2]. Also in 1994 Langsjoen published long term observations on 424 cardiac patients, treated with 75 to 600 mg of CoQ10 per day for up to eight years with no adverse effects or drug interactions [32]. One out of the 424 patients experienced transient nausea.

There have been two case reports published claiming potential interaction between CoQ 10 and coumadin (warfarin), suggesting that CoQ10 has a vitamin K-like effect [31,64]. This has not been corroborated by other investigators and was the subject of a prospective trial [15]. Physicians wisely and routinely follow prothrombin times very closely in patients on coumadin, particularly after any change in diet, medication or over-the-counter supplements. In this author’s 18 year experience with the use of CoQ10 in many thousands of cardiac patients we have yet to see a single case of CoQ 10-coumadin interaction at doses up to 600 mg of CoQ10 per day (unpublished observations).

5. Conclusions

The widely prescribed HMG CoA-reductase inhibitors block the endogenous biosynthesis both of cholesterol and of coenzyme Q10, and the decrease in both substances is related to the dose as well as the potency of these drugs. The depletion of coenzyme Q10 appears to be well tolerated in younger and healthier patients, particularly in the short term, but the data reveal detrimental cardiac effects in several animal models, particularly in older animals, and there is good evidence to support a detrimental effect in humans with pre-existing cardiac dysfunction when subjected to this statin-induced coenzyme Q 10 depletion. CoQ10 is known to be deficient in congestive heart failure, with the degree of deficiency in blood and cardiac tissue correlating with the severity of the CHF [19,28]. Normal whole blood levels of CoQ10 are about 1.0 ± 0.2 µg/ml with deficiency in the range of 0.6 ± 0.2 µg/ml. [40% less].  It is also known that CoQ10 levels steadily fall after the age of 40 [27,63]. Statin drugs produce a depletion in coenzyme Q 10, which in settings of pre-existing CoQ10 deficiency, such as in CHF [18,19,28,39,40] and ageing [27], has the ability to worsen myocardial function. As the potency of statin drugs increases and as the target LDL cholesterol level decreases, the severity of CoQ10 depletion will increase with an increasing likelihood of impairment in heart muscle function. This tragic scenario may very well be prevented by using supplemental CoQ10 with all HMG CoA reductase inhibitors.

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