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STATINS AND HEART FAILURE. A TREATMENT PARADOXby William R. Ware, PhD
INTRODUCTION
HF is an enormous social and medical problem affecting more than 2% of the U.S. population or almost 5 million people. The mortality is high and 30-40% die within 1 year of diagnosis. It can also be disabling and severely impact the quality of life.2 This Research Review will look at one aspect, statin therapy, since there appears to be an interesting paradox associated with the current guidelines. The 2005 and 2009 American Heart Association (AHA) guidelines for the treatment of heart failure (HF) recommend that for patients at high risk of HF and those with various stages of established HF, part of the standard treatment protocol should include "treat lipid disorders" which presumably translates into establishing and attempting to reach low LDL targets.3 The only drug in common use is the statin. However, statins reduce levels of a critical enzyme, coenzyme Q-10 (CoQ-10), and there is a fairly extensive literature concerning the adverse effect of low CoQ-10 on muscle function (including heart muscle) related in part to the role of this enzyme in mitochondrial energy production. Statins inhibit the mevalonate pathway involved in CoQ-10 synthesis. Furthermore, several small but significant studies indicate that there is an inverse association among individuals with HF between total cholesterol, LDL cholesterol and mortality. The effect is in fact rather strong and would suggest cholesterol elevation, not reduction, as an appropriate therapeutic target in this context. Also, it has been suggested on a number of occasions that there is a distinct possibility that in some patients, statins may actually contribute to the severity of HF. It has been repeatedly pointed out that HF has increased in lock-step with the use of statins. As will be discussed below, statin treatment of HF patients appears to provide no benefit in terms of overall mortality or fatal cardiovascular events. Thus it appears that, paradoxically, there is evidence that one of the treatments recommended for HF may in fact provide no benefit. This may perhaps be due to the balance between adverse effects and non-lipid-lowering beneficial effects. Under some circumstances, statin therapy may aggravate HF. This is just part of a larger subject related to the consequences of inhibiting a major biological pathway and thus reducing the levels of a number of important endogenous biochemicals just in order to reduce the synthesis of one target molecule, in this case cholesterol. It is interesting that one of the major statin manufacturers actually acquired patents for a combination of CoQ-10 and their statin but never marketed the combined medication. Instead, the industry appears to be in a state of denial regarding potential problems associated with the inhibition of the mevalonate pathway. The mevalonate pathway directly involves over 13 biochemicals, only one of which is cholesterol. These chemicals are each involved in a number of other processes and pathways leading to additional biochemicals. There is considerable variation in the extent of understanding of the role of each of these molecules and in many cases research is ongoing. Inhibiting this pathway with a statin inhibits the synthesis of these biochemicals from mevalonic acid and as well those further down the line from it. The effects of this inhibition are thus profoundly complex, not as yet fully understood by any means, and may have serious long term adverse effects, either not as yet identified or attributed to other causes. Nevertheless, it is widely believed that aside from what are termed minor side effects, the interruption of this pathway presents no risk. The safety of statins is "evidence based" we are told. Critics point out that studies of side effects have frequently involved too few subjects and that the post-introduction reporting is notorious for its inadequacy, with the typical estimate that only 1% of side effects are reported and officially recorded, and that in fact the rate of adverse effects is large and significant.4,5 The widespread belief that statins are safe also leads to a failure to associate observed problems with the drug. Rather, they are easily attributed to the effects of aging and other disorders. When Dr. Duane Graveline had his two disabling episodes of transient global amnesia he was simply told by cardiologists that "statins did not do that." In fact the evidence is now compelling that they do.4 Given this background, we will briefly examine the apparent paradox outlined above.
STATINS DECREASE CoQ-10 IN CIRCULATION AND MUSCLE TISSUE In a review in 2007, Littarru and Langsjoen6 list a large number of studies from 1990 to 2005 which demonstrate that there is significant circulating CoQ-10 depletion secondary to statin therapy. The effect is particularly important at high doses and most notable among the elderly. Blood markers suggest impairment of mitochondrial bioenergetics which impacts muscle energetics. In addition, they cite evidence of enhanced LDL oxidizability associated with lower CoQ-10 levels. The review also discusses the impact of statins on muscle levels of CoQ-10. While the data is somewhat less consistent, the weight of the evidence favors a statin induced decrease of CoQ-10 in muscle tissue. In a review available online,7 Peter Langsjoen puts this decline of CoQ-10 and its relation to HF in perspective. CoQ-10 is essential for all cellular ATP production and is of particular importance in heart muscle function given that this tissue has extreme energy requirements. He points out that already in 1984 and 1985 a deficiency in CoQ-10 both in the blood and heart muscle was documented in cases of congestive HF, and age-related CoQ-10 deficiency was associated with myocardial dysfunction in patients undergoing coronary bypass surgery in Australia. In addition, preoperative supplementation with CoQ-10 was found to improve outcomes in bypass surgery. He also points out that that the steady increase in the prevalence of HF coincides with the advent and increased use of statin drugs. CoQ-10 BLOOD LEVELS ARE AN INDEPENDENT PREDICTOR OF HF MORTALITY A study reported in 2008 in the Journal of the American College of Cardiology examined the association between blood levels of CoQ-10 and mortality in chronic heart failure. Blood samples were obtained from 236 patients admitted to hospital with chronic heart failure with a median follow up of about 2.7 years. A detailed statistical analysis (multivariate) allowed for the standard predictors of survival - age, gender, previous heart attack, a peptide marker, and a measure of kidney function. It was found that low CoQ-10 was an independent predictor of survival which persisted in a model that also included statin treatment. Thus the depletion of CoQ-10 appears associated with worse outcomes in chronic heart failure.8 STATINS MAY INCREASE RISK OF HF BY INHIBITING THE SELENOPROTEIN PATHWAY The element selenium, acting through selenium containing proteins called selenoproteins, plays an important role in development, metabolism and antioxidant defence. There are over 25 selenoproteins including the highly critical glutathione peroxidase which provides protection from oxidative damage, and a class of selenoproteins which govern thyroid metabolism. The synthesis of these proteins depends on a special RNA molecule containing selenocysteine, an amino acid where the sulphur atom in cysteine has been replaced by selenium. For this RNA to function it must be modified by a chemical reaction that involves a molecule which is a direct metabolite of mevalonate, the production of which is inhibited by statins. This is one view of the connection between statins and the inhibition of the synthesis of essential selenium containing proteins.9 In a recent review, de Lorgeril and Salen present evidence supporting the role of selenium in the prevention and treatment of HF.10 Unfortunately, there do not appear to be clinical studies published to date that examine the effect of selenium supplementation on the risk of coronary heart disease, heart disease mortality or overall mortality. The authors mention a few epidemiologic studies which document associations between serum glutathione peroxidase activity and cardiovascular disease, but none provide data specifically about HF. Recently, however, a case history describes a 55-year-old woman with documented heart failure who presented with a significant selenium deficiency. Her symptoms resolved in 3 weeks with daily IV selenium treatments of 100 micrograms. Beta-blockers and ACE inhibitors, two standard treatments, were not tolerated because of very low blood pressure. Her ejection fraction measured by an echocardiogram went from 30% to 65% over the treatment period.11 Thus it can be argued on general principles that it is not a good idea to mess with the pathway involved with such an important class of biochemical as the selenoproteins, and that there is some indirect evidence that inhibiting the selenoprotein pathway may adversely impact heart failure. Selenium status appears to be rarely measured in patients presenting with HF.
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MARKED INCREASE IN HF MORTALITY ASSOCIATED WITH LOW CHOLESTEROL
Two studies provide evidence for the hypothesis that low total cholesterol is associated with an increase in mortality from HF. Horwich et al12 studied 1,134 patients with advanced HF who presented at a single center for HF management. Survival was observed over 5 years. Total cholesterol, LDL, HDL and triglyceride levels all predicted survival with improved survival at higher levels. When other risk factors were taken into account, those in the lowest quintile of total cholesterol had twice the mortality risk as those in the highest. These results were confirmed in a study by Rauchhaus et al13. They found that the chance of survival increased 25% with each increase of one mmol/L (approximately 40 mg/dL) of total cholesterol. It was concluded that patients with lower serum total cholesterol had a worse prognosis in the context of HF. Thus a treatment protocol which includes aggressively lowering cholesterol may be counterproductive in this context. STUDIES REGARDING STATINS AND HEART FAILURE It might seem that one approach to resolving the problem of statins and heart failure would be to do clinical studies. But there immediately arises the question of appropriate endpoints. Some studies use hospitalization for a cardiovascular indication, but the reasons associated with the admission may not be directly or even indirectly related to heart failure. Death from coronary heart disease has also been used, but this is too general and includes a heart attack, not necessarily the first, or sudden cardiac death which may be directly related to an arrhythmia problem, not a failure of the heart due to a chronic inability to pump enough blood. Thus studies that look at large databases of causes of hospitalization and mortality can be fatally confounded if one is trying to directly relate events to heart failure. Furthermore, coronary heart disease and heart failure are closely coupled and any treatment that impacts the former can impact the latter if it is related to muscle damage or weakness due to ischemia. Overall mortality is not informative because it does not zero in on heart failure as the cause. Also statins have an amazing number of non-lipid lowering effects which might impact heart failure favourably, and in fact, statins are given immediately post MI with almost instantaneous beneficial results that can not be explained by lipid lowering. Also, in studies the expectation is that there will be benefit, and when there is harm it may be ignored. Thus while statins have the potential to increase the risk of heart failure or mortality directly related to heart failure and there is considerable evidence to back up this belief, they also have the potential to provide beneficial effects. These beneficial effects may vary considerably with the type of statin and in addition have a dose dependence which would lead the unwary to conclude that it was lipid lowering that was providing the benefit whereas it is merely the increase in the dose of a drug that is acting independent of lipid lowering. This in fact is a fundamental problem with the position of those who believe that statins provide benefit because they lower cholesterol, especially in the case of individuals with coronary heart disease, This belief is so widespread that is has all the characteristics of a dogma, and yet the logic is fatally flawed. Thus studies that result in null results, or sets of studies that are inconsistent, may reflect both endpoint problems and a balance between benefit and harm which results in a wash. If the latter is true, then a more sensible approach would be to use different drugs that might have the beneficial actions without the adverts effects of the enzyme inhibition caused by statins. The resistance to this approach is in part based on the belief that statins are good for the heart, period. STATINS IN RANDOMIZED CLINICAL TRIALS DO NOT DECREASE HF MORTALITY While observational studies suggest that statin therapy is beneficial for individuals with HF with and without prior heart attack, some medical scientists, as a matter of principle, have suspended judgment pending randomized placebo-controlled trials. Two such trials have recently reported which do not support the observational studies. The first (CORONA) randomized about 5000 patients with HF to either 10 mg/day of rosuvastatin (Crestor) or a placebo. The primary endpoint was death for cardiovascular causes, non-fatal heart attack or non-fatal stroke. Secondary outcomes included death from any causes, any coronary event and the number of hospitalizations. Statin treatment did not reduce the primary outcome or the number of deaths from any cause although the drug did slightly reduce the number of cardiovascular hospitalizations (2.1% absolute difference). The second study (GISSI-HF) randomized approximately 4600 patients with CHF to the same protocol as CORONA. The primary endpoints were time to death, admission to hospital for cardiovascular reasons. It was found that 10 mg daily of rosuvastatin did not affect clinical outcomes in patients with CHF of any cause. For those who believe that in the hierarchy of trials and studies, the randomized placebo controlled trial provides the strongest evidence, then the use of statins for the treatment of HF does not appear to be evidence-based. Many of the investigators in both studies had ties to the maker of rosuvastatin, a fact that some would say in this case strengthens the credibility of the study and the validity of the negative results. The GISSI-HF investigators took the position that the prescription of rosuvastatin, or in fact any statin, to patients with heart failure should be discouraged. EVIDENCE THAT CoQ-10 SUPPLEMENTATION IMPROVES CARDIAC FUNCTION From the above discussion it appears that age related decline in CoQ-10 leads to the impairment of cardiac function and perhaps HF. It also appears that statins potentially exacerbate this disorder. Evidence appeared as early as 1990 when Folkers et al14 described a few cases of cardiac patients supplemented with CoQ-10 where HF worsened when lovastatin was added to their therapy. This deterioration was reversed upon increasing the daily dose of CoQ-10. More recent evidence that there is the potential for benefit from supplementing with CoQ-10 mainly derives from the work of cardiologist Peter Langsjoen and coworkers in Texas. Four studies are of interest. The studies suggest that the impact of CoQ-10 depletion is multi-factorial.
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In the book The Sinatra Solution. Metabolic Cardiology20 Stephen Sinatra comments that 85% of his patients with CHF found CoQ-10 alone to be effective. For the
remaining 15% he found that adding L-carnitine resulted in significant improvement. L-Carnitine is required in cells to facilitate the breakdown of lipids for
the generation of metabolic energy. The protocol he uses for HF consists of daily supplementation with a multivitamin and a gram of fish oil to which he adds
300-360 mg of highly absorbable CoQ-10, 2 to 2.5 g of L-carnitine, 10-15 g of the sugar D-ribose, and 400-800 mg of magnesium. This protocol is frequently
combined with conventional therapies such as diuretics and digitalis. His book, which provides the scientific background for this protocol, is highly recommended
for anyone with heart problems. It contains an entire chapter on CoQ-10. He has also reviewed this subject in a recent paper in Alternative Therapies which includes
a good discussion of CoQ-10 trials and in particular why some fail. He points out in this paper that in 23 controlled trials of supplemental CoQ-10 in CHF between
1972 and 2006, 20 showed benefit.21
One of the above studies highlights a problem with CoQ-10 supplementation, i.e. bioavailability or absorption. Over the past few years there has been a lot of effort put into developing preparations which result in higher blood levels. The use of ubiquinol is one result of this research and this reduced form is available without prescription at our on-line vitamin store. This is also something to keep in mind when purchasing supplements. It is also a factor to question when reading studies, especially those with null results. This may be one reason why data on the effect of CoQ-10 supplementation on myopathic symptoms are inconsistent, and why a recent review suggested that the routine use of CoQ-10 could not be recommended for patients treated with satins.22 This appears overly conservative given that the prevalence of just myopathy alone appears much greater than admitted by the industry and points directly at a mitochondrial mechanism.5 In the context of HF, the clinical experience of Dr. Stephen Sinatra and the literature cited would suggest that not addressing CoQ-10 depletion is a big mistake. CONCLUSIONS The above discussion clarifies the nature of the paradox represented by the use of statins to treat HF and the AHA recommendation of 2009 to treat lipid disorders in HF patients. While the GISSI-HF trial reported after the 2009 AHA guidelines were prepared, this is probably not true for the CORONA results which appeared in 2007. Nevertheless, research suggesting that statins are contraindicated in HF goes back a long way. However, it is fair to say that statins do not occupy a prominent position in the AHA guidelines which concentrate on diuretics, ACE inhibitors and beta-blockers as well as aldosterone antagonists, digitalis and hydralazine/nitrates. In addition, the guidelines encourage smoking cessation, regular exercise, and discourage alcohol intake, illicit drug use and control the metabolic syndrome. But there appears the potential for making the disorder worse if a HF patient is left on statins or prescribed this drug. At the very least, HF patients have enough problems without having to deal with the possible side effects of this class of drug, given that they appear to offer no significant therapeutic benefit in the context of either mortality or cardiovascular events. For individuals who have a history of heart attack and/or symptomatic ischemia along with HF, statins appear to decrease the risk of secondary acute events associated with coronary artery disease. But, to quote Sinatra, "We don't prescribe statin drugs to lower cholesterol. We selectively use statins to improve outcome in patients with risk markers known to respond well to this drug intervention."23 This brings us in full circle to the necessity of always combining statin therapy when indicated with doses of CoQ-10 sufficient to elevate serum levels to a protective level.
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REFERENCES
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