Could a product sold as a dietary supplement really be delivering the benefits that advocates have claimed for decades? That’s what you might be wondering about coenzyme Q10, following recent stories like:
- The energy-boosting supplement that could HALVE the number of deaths from heart failure screamed The Daily Mail.
- It’s Official: Coenzyme Q10 Improves Heart Failure Survival from the “orthomolecular” advocates AOR.
- Could Antioxidant Supplement Cut Heart Failure Risk? asked eMaxHealth.
- First Drug to Significantly Improve Heart Failure Mortality in Over a Decade from Live Science.
- Could supplements be the key to boosting survival from heart failure? asked WebMD.
What’s caused all the excitement about CoQ10 is the Q-SYMBIO trial, more properly called “The effect of coenzyme Q10 on morbidity and mortality in chronic heart failure”, presented at the European Society of Cardiology conference last month. I’d normally wait for the full article to come out, and will review it if possible at that time, but the results are too interesting to ignore so I’ll dive into the study and the reaction – which is equally as interesting for advocates of science-based medicine.
Coenzyme Q10 (CoQ10) has a long and mixed history filled with both promise and disappointment. Also known as vitamin Q10, ubiquinone, or ubidecarenone, CoQ10 isn’t actually vitamin, as the body produces its own supply. CoQ10 is found in most cells of the body, with high concentrations in the heart, liver, kidney, and pancreas. Its function seems to include antioxidant effects as well as acting as a cofactor in multiple metabolic pathways. Supplementation can push blood levels much higher than anything the body can produce on its own. While trials with supplements have been small and somewhat equivocal, CoQ10 seems to effectively treat rare cases of coenzyme Q-10 deficiency, as well as conditions resulting in mitochondrial deficiencies. At least one formulation of CoQ10 has been FDA-approved as an orphan drug for the treatment of these rare disorders. The majority of the CoQ10 research (and it’s considerable) has focused on cardiovascular disease such as congestive heart failure and angina, but there is also some limited study of its use in diabetes, hypertension, chronic fatigue, and a long list of other conditions. Finally there’s the question of whether it’s useful for preventing “statin”-drug-induced muscle pain, where the bottom line seems to be “maybe”. In general, most of the studies have been poorly designed and had small sample sizes, giving lots of results which are promising but little that is unambiguously positive. This hasn’t stopped advocates, particularly supplement vendors, from recommending it as a panacea for just about anything, and even adding it to products like cosmetics. Given what appears to be a reasonably good safety profile, CoQ10 is a supplement advocate’s dream: a “natural” product that seems safe and may actually work.
But is CoQ10 actually a supplement at all? The line between supplements and therapeutic drugs isn’t an easy one to define. Vitamins can be treated like drugs (e.g., niacin) and some drugs are rebranded as supplements if they can’t pass the evidence standards to be approved drug products. Natural substances can be marketed as both supplements and drugs (e.g., magnesium) or as drugs alone (e.g., epinephrine). There is not always a clear line, and the variations between countries can be striking. It generally seems to be based more on evaluations of safety than that of efficacy. This may in part explain the varying use of CoQ10 around the world. It’s probably most widely used in Japan, which coincidentally is also the world’s biggest supplier. There it’s apparently used as a routine treatment for congestive heart failure, where it was approved for this purpose almost 40 years ago. It’s also used Europe and Russia, though the U.S. and Japanese markets make up 85% of the world’s consumption. Supplement or drug, what matters is whether it works when it’s evaluated using objective standards. So describing a supplement like CoQ10 as an “alternative” or “complementary” treatment for heart failure is using misleading terminology. As has been said before, there is no such thing as alternative medicine: There is medicine, which are treatments shown to work, and treatments which are unproven to work, or proven not to work. Medicine does not fail to work in a conventional sense and yet work in some “alternative” sense.
The study
It has not been established that CoQ10 helps in heart failure, but smaller studies have shown improvements in exercise tolerance and other measures, though not consistently. Observed benefits may be due to the prevention of oxidative damage (antioxidant) or to some other mechanism that has not yet been determined. The evidence to date suggests that at best, CoQ10 may offer some benefit to patients already taking other drugs for heart failure but still experiencing significant disease effects. The current study was quite simple by design, with what appears to be a meaningful and unambiguous endpoint: major adverse cardiac event (MACE) including hospitalization due to worsening CHF, cardiovascular death, and cardiac transplantation. The Q-SYMBIO trial included 17 centres across 8 countries, and randomized 420 people with moderate-to-severe heart failure into two groups: One which took 100mg of CoQ10 three times daily, the other a placebo. All continued their regular medications. Patients had an average ejection fraction of 31% (that’s not good) and they were, on average, 62 years of age. After two years:
- 14% on CoQ10 experienced a major adverse cardiac event, versus 25% in the placebo group (p=0.003).
- 9% of patients on CoQ10 died, versus 17% in the placebo group (p=0.01).
These are remarkable results for any treatment, and are particularly impressive if patients were already optimized on medical treatments (which isn’t clear). And if they are validated, then CoQ10 offers a dramatic benefit to patients with heart failure. But is the effect real? Notwithstanding the fact that we don’t actually have the full paper to critique, criticisms and concerns have been raised:
- The trial took over 10 years to complete, which is long for a trial with a two year endpoint, suggesting difficulty recruiting patients. The trial was first described over a decade ago.
- We don’t know the medications the participants were taking, and if they would still be considered appropriate and optimal, based on today’s evidence.
- The mortality rate of about 9% per year seemed low for a population this ill.
- Reporting and documentation of harms is not well described.
- The benefit seems implausibly good, and similar benefits haven’t been observed in other endpoints, consistently, in other trials of CoQ10.
- What we know about how CoQ10 might work is inconsistent with what’s been seen with statin trials in patients with heart failure. Statins lower CoQ10 levels, but don’t worsen CHF.
- As cardiology studies go, this is a small trial. It’s not clear if it was powered to detect mortality differences. The small numbers of deaths leads to imprecise estimates of risk reductions.
Coenzyme Q10 manufactured by Pharma Nord
Interestingly (supplement proponents and conspiracy theorists, please note) this trial has Big Pharma’s fingers all over it. Sponsors included the International Coenzyme Q10 Association (the advocacy organization), Kaneka Corporation of Osaka (the manufacturer) and Pharma Nord (the marketer) which sells products containing coenzyme Q10. So much for the old trope that that pharma’s trying to suppress dietary supplements, or that pharma won’t study it because it’s not patentable. With the global market for the chemical estimated at $835 billion (in 2009), it’s not surprising that there’s a lot of interest in expanding the use of this compound. The sponsorship doesn’t invalidate the study, but it does make me more cautious about drawing any conclusion until the full publication is available and has been subjected to peer review.
Investigator spin
The study still hasn’t been subjected to peer review, but the lead investigator is already calling for widespread use:
Professor Mortensen said: “CoQ10 is the first new medication to improve survival in chronic heart failure and it should be added to standard therapy.”
and he went on, describing a mechanism of action:
“Other heart failure medications block rather than enhance cellular processes and may have side effects. Supplementation with CoQ10, which is a natural and safe substance, corrects a deficiency in the body and blocks the vicious metabolic cycle in chronic heart failure called the energy starved heart.”
Natural. Safe. Mortensen has clearly drunk deeply from the CoQ10 Kool-Aid. And I can understand (in part) his enthusiasm, given the results he’s reporting. But has he really found a holy grail for CHF patients? It’s rare that a single trial results in a major change in medical practice. If you’re a regular reader of this blog you’ll know that many of us are fans of the research of John Ioannidis, particularly his work showing that new and often exciting scientific results rarely hold up to scrutiny, and more importantly, replication. More simply, most published research findings are false. In particular, follow-up studies can invalidate highly-cited initial studies. So a strong, unexpected effect in a single trial should be a red flag for skepticism. Replication is absolutely essential, and cardiologists are unlikely to endorse CoQ10 as a validated treatment until that occurs. This isn’t a bias against supplements, it’s good science at work. In the case of cardiology and antioxidants, there is very good reason for caution. When hype outpaces the evidence, unanticipated harms can result. Millions took antioxidant vitamins for years thinking that they were heart healthy, when evidence eventually showed they are at best, useless, and at worst, harmful.
Risks and harms
Coenzyme appears to be a safe product with few harms documented. Trials consistently report no significant adverse effects. The most common manageable side effect is stomach upset, which can be reduced by dividing the dose throughout the day (as was done in this study). The other downside to the product is the cost, which can be considerable, although CoQ10 prices seem to vary dramatically between brands and there’s a lack of information to help sort out the products which provide the best value-for-money.
Conclusion
Whether CoQ10 becomes an routine treatment for heart failure remains to be seen. The Q-SYMBIO results are surprisingly good, and for that reason, there is good reason to be skeptical. The history of medicine is replete with stories of breakthrough studies that subsequently fail to be replicated. Yet despite knowing this, we continue to make the same mistake again and again. When something appears to be too good to be true, it almost always is. Until the Q-SYMBIO study is published and replicated, I’ll remain skeptical of CoQ10’s role in heart failure.