You may have experienced déjà vu over the last few days if you’ve been reading excited accounts about polypills for the over-55s (there was a lot of Oh Brave New World about the potential for polypills in 2003). The claims are that polypills will prevent 100,000 premature deaths a year and also prevent up to 80% of heart attacks and strokes. The polypills will contain a cholesterol-reducing statin; three types of medicine to lower blood pressure (thiazide, aspirin and beta-blockers); and folic acid to reduce levels of homocysteine (Hcy).
Visiting Professor Patrick Holford of Teesside University is a frequent advocate of Hcy testing and recommends that people with high levels (as defined by him) should lower it by taking various supplements (see related reading). According to Holford and Dr James Braly, homocysteine is:
[l]ike a chemical crystal ball, it reveals exactly what we should be doing to guarantee our future health…your H score predicts your risk of more than 100 diseases and medical conditions-including increased risk of premature death from all common causes.
HolfordWatch has covered the extravagant claims relating to the clinical benefits of reducing homocysteine levels with supplements on several occasions. Recent trials emphasise that there is still no substantial evidence to support such recommendations for the general, asymptomatic population.
The polypills were written up in The Times and The Telegraph. Giving credit where it is due, the Daily Mail provided a good, nuanced overview of the pros and cons of polypills (I don’t agree with all of it but that is to be expected – plus, we don’t know why the deaths prevented here are 200,000).
If given to everyone in the UK over 50 it would cost the NHS about £6bn a year — but save £14bn treating the victims of cardiovascular disease (which cause a third of all deaths in the UK) and prevent 200,000 deaths a year.
The truth is that, in cost-benefit terms, there is little doubt that the polypill would be worth it.
It could create another leap forward in life expectancy for the over-50s, which is already increasing at an unprecedented rate…
Yes, if you were to give this pill to everyone over 50, say, then you would save lives.
But some people would also die as a result.
No drugs are entirely free of side-effects and the chemicals in the polypill are no exception. Some statins have been linked to psychological disturbances.
Even aspirin, the almost magical wonder- drug, can cause severe gastrointestinal problems in a minority of people.
By courtesy of the Wolfson Institute of Preventive Medicine you can read some of the 2003 polypill papers. In all of the extensive coverage, there is some excitment about the projected 11 years of extra lifespan. One slightly disturbing claim that has been repeated without much critical examination in the newspapers is that clinical trials have established that the individual ingredients prevent heart attacks and strokes. The corollary of this is supposedly that a polypill that combines these would only require small-scale trials to validate that it behaves in the same way so this product may come to market quite quickly.
Well, we’re not overly-confident that trials have established that all of the individual ingredients are effective for primary prevention across all demographics. Nonetheless, these are the sort of issues that mainstream media and other blogs have covered in some depth.
However, we’re more interested in the claims for clinical outcomes for lowering Hcy levels with B vitamins, including folic acid. Although the accruing evidence does not support his claims, Holford has not as yet rescinded his claims for the clinical relevance of Hcy testing or the value of lowering it by taking various supplements (see related reading).
Currently, it seems like there is no clear clinical evidence to support the notion that lowering raised homocysteine levels actually results in a significant clinical outcome. Even at a recent homocysteine conference, the general consensus was:
The results of ongoing randomized controlled intervention trials must be available before screening for and treatment of hyperhomocysteinemia can be recommended for the apparently healthy general population.
Eva Lonn’s editorial in JAMA addresses the implications of a newly-published trial that looked at the clinical outcomes for women who took B vitamins to reduce their Hcy levels (full text currently available): Effect of Folic Acid and B Vitamins on Risk of Cardiovascular Events and Total Mortality Among Women at High Risk for Cardiovascular Disease. The women were US health professionals aged 42 years or older. Participants had either a history of cardiovascular disease or 3 or more coronary risk factors; the trial follow-up extended for 7.3 years, which is substantially longer than many previous trials. They were randomised to a combination pill of B vitamins recommended for lowering Hcy levels or a placebo. Although the pill was successful in reducing Hcy levels there was no significant clinical benefit such as a reduction in major cardiovascular events.
In summary…a combination pill of 2.5 mg of folic acid, 50 mg of vitamin B6, and 1 mg vitamin B12 had no beneficial or adverse effects on a combined outcome of total major cardiovascular events in a high-risk population of women with prior cardiovascular disease or 3 or more coronary risk factors over 7.3 years of follow-up. Our results are consistent with prior randomized trials performed primarily among men with established vascular disease3 and do not support the use of folic acid and B vitamin supplements as preventive interventions for CVD in these high-risk–fortified populations.
Dr Eva Lonn provides a thoughtful editorial that gives an overview of the history of the heady potential of the therapeutic manipulation of homocysteine levels: Homocysteine-Lowering B Vitamin Therapy in Cardiovascular Prevention—Wrong Again? However, as she points out, the optimism has not been justified for the general population.
While the experimental and epidemiological evidence does indeed support a plausible role for homocysteine lowering in CVD prevention in the population at large (as opposed to a limited role in rare genetic disorders), overzealous interpretations of such data have led to extrapolations and unjustified early enthusiasm…
Two obvious questions arise: why did the B vitamin homocysteine-lowering trials conducted to date not demonstrate clinical benefits and is there a role for additional trials or should researchers close yet another chapter, which seemed promising but failed to deliver. The answers to these questions are complex…However, it is possible that the treatment truly has no effect on vascular risk…
In conclusion, B vitamin supplements cannot currently be recommended for the prevention of CVD events (with the exception of rare genetic disorders) and there is no role for routine screening for elevated homocysteine levels. However, ongoing clinical research should provide further evidence on whether there may be any role for homocysteine-lowering B vitamin supplements in CVD prevention and for the overall importance of homocysteine as a CVD risk factor.
This latest trial involved a significant number of women without prior cardiovascular disease (n=1950) but it was comparatively underpowered to be confident about the outcome for primary prevention of major cardiovascular events. Lonn makes some thoughtful observations about the statistical power of the study and potential limitations. We should also mention that the outcomes might be different for a population that is not well-nourished or for countries where there is no fortification of common foodstuffs with folic acid.
On a side-note, we have seen frequent claims that Hcy levels are monitored routinely as part of healthcare in Germany, we would be grateful for any information or pointers to Eurostat analyses or similar that comment on whether this translates into improved clinical outcomes.
So, if the confidence in polypills is to be founded upon strong clinical evidence for each of the component ingredients, then it seems as if we need some clearer results that apply to all of the touted demographic. Folic acid supplements have clear benefits for some demographics such as women who may conceive or are pregnant. However, for other segments of the population, where there is routine fortification of foodstuffs, there are some concerns that excess supplementation with folic acid might be associated with an increase in colon cancer. Dr Steve Murphy advocates personalised medicine but as a Gene Sherpa argues that lowering homocysteine hasn’t had the expected clinical effects and that there are some groups for whom the recommended vitamin supplementation is contra-indicated.
It doesn’t look as if there is clinical validation for all of the proposed components of the polypill for the intended demographic. Nor does it seem as if Hcy testing and therapeutic intervention by supplementation is ready to go mainstream for the general population. The hype seems to run ahead of the evidence for both polypills and the clinical benefits of reducing Hcy levels.
Update 7 May: Just to emphasise that we are discussing polypills and Hcy testing etc. for primary prevention of CVD in the general population of over-55s. There may well be interesting pleiotropic effects for statins, particularly in specific populations, but that is a separate issue (interesting comment about research in progress). Similarly, there may be other populations or disorders for whom Hcy testing and management yield more interesting results. Again, as the JAMA papers mention, these are in progress.
 Albert CM, Cook NR, Gaziano JM, Zaharris E, MacFadyen J, Danielson E, Buring JE, and Manson JE. Effect of Folic Acid and B Vitamins on Risk of Cardiovascular Events and Total Mortality Among Women at High Risk for Cardiovascular Disease. Journal of the American Medical Association, May, 2008; vol 299(17): pp. 2027-2036.
 Lonn, E. Homocysteine-Lowering B Vitamin Therapy in Cardiovascular Prevention—Wrong Again? May, 2008; vol 299: pp. 2086-2087.
 Cole BF, Baron JA, Sandler RS, Haile RW, Ahnen DJ, Bresalier RS, McKeown-Eyssen G, Summers RW, Rothstein RI, Burke CA, Snover DC, Church TR, Allen JI, Robertson DJ, Beck GJ, Bond JH, Byers T, Mandel JS, Mott LA, Pearson LH, Barry EL, Rees JR, Marcon N, Saibil F, Ueland PM, Greenberg ER; Polyp Prevention Study Group. Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. JAMA. 2007 June; vol 297(21): pp. 2351-9.
 Ulrich, C.M. and Potter, J.D. Folate and Cancer—Timing Is Everything. JAMA. 2007 June; vol 297: pp 2408-2409.
Never Mind the Research Quality, Feel the Fear: Justifying Homocysteine Tests
Homocysteine: Helpful or Hoax Asks Patrick Holford
How Relevant Are Holford’s Claims About Homocysteine Levels? Part 1
How Relevant Are Holford’s Claims About Homocysteine Levels? Part 2
Patrick Holford, Alzheimer’s Disease, Homocysteine Tests and Supplements
Gene Sherpa on homocysteine