Yet another clinical trial of folic acid and heart disease has been published – an extremely well designed trial where the results suggest true adherence to the vitamins vs. placebo regime. The conclusions are:
First of all this is very good news regarding cancer especially as this would be considered a high risk group (where the majority were over 60 yrs old and therefore more likely to have precancerous lesions which excess folate could in theory accelerate the growth of see Ulrich, CEBP, 2008). This is important and the authors are right to highlight it – it is often used as a headline argument to oppose B vitamins but the details don’t support there being a real significant risk compared to the benefits, and this large study helps to confirm that.
Not so good news though for preventing heart disease, but what does it really tell us? They also mention osteoporosis, see below. This is a problem with trying to squeeze nutrition into a pharma type clinical research study. We are not dealing with a novel molecule with a precisely defined target but a common vitamin involved in complex biochemical pathways (inc. DNA synthesis and methylation) and it’s not surprising that perturbations to these pathways have multiple effects.
Homocysteine is a risk-marker for CVD, whether it is cause or effect is not established although there is reasonable evidence for it being involved (Wald et al, BMJ, 2002). It has been reported to have damaging effects on genome stability (Fenech, AJCN, 2010) and high levels have been linked to a host of diseases from osteoporosis to dementia (Selhub, 2006). The evidence strongly suggests that it is a good thing to keep it low. So why have all these trials shown more or less no effect of homocysteine on heart disease? Quite possibly because all of them are looking at secondary prevention, i.e. the study patients in all the trials are exactly that, patients, already ill with heart disease. Maybe it’s to late to start lowering homocysteine if the damage has been done – just like no-one really expects calcium and vitamin D to have much positive benefit in people who already suffer from osteoporosis (incidentally in the paper the authors say “Low folate status and increased homocysteine levels have been associated with osteoporosis and fracture risk but fracture incidence was similar in the 2 groups” – not at all surprising, osteoporosis prevention does not start at >60 yrs old).
Post infarct reduction of cholesterol levels have been shown to be effective in secondary prevention (indeed all patients in the SEARCH trial were on simvastatin) but the mechanisms are different. Cholesterol clogs a pipe whereas homocysteine, if it is indeed involved, is likely to do so via damaging blood vessel walls. So we can talk about plumbing. If a pipe becomes blocked following years of calcium deposits in a high calcium water area, once the blockage is treated, recurrence can be prevented by reducing the calcium content. If the pipe develops a leak due to years of erosion due to acidic water, even after repairing the leak the pipe walls will still be weak and neutralising the water is not going to make much difference, the damage is done.
The SEARCH study was well done and they make good points about cancer, but the final sentence was disappointing:
As discussed in the past, clinical trials of nutrients for primary prevention are pretty much impossible, we have to rely on the best evidence we have to give nutrition advice – the evidence is strongly in favour of homocysteine lowering with levels of folic acid much lower than 2mg per day (RDA of 400µg is enough for most, those with polymorphism in MTHFR will need more, of course it goes without saying that there was not genetic component to this study…). SEARCH and all the other trials have often been misused in the folic acid/homocysteine debate, they have often been cited as proof that the homocysteine theory is wrong – but they do no such thing and it would help if the authors of these studies made it clear that all conclusions are relevant (and useful) only as far as secondary prevention is concerned.
Taken together with the previous homocysteine-lowering trials, the results of SEARCH indicate that folic acid supplementation has no significant adverse effects on cancer or other major health outcomes, even if it also produces no beneficial effects on cardiovascular disease. In addition, these results highlight the importance of focusing on drug treatments (eg, aspirin, statins, and antihypertensive therapy) and lifestyle changes (in particular, stopping smoking and avoiding excessive weight gain) that are of proven benefit, rather than lowering homocysteine with folic acid–based vitamin supplements, for the prevention of cardiovascular disease.JAMA: Effects of Homocysteine-Lowering With Folic Acid Plus Vitamin B12 vs Placebo on Mortality and Major Morbidity in Myocardial Infarction Survivors: A Randomized Trial, June 23/30, 2010, Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group 303 (24): 2486 http://bit.ly/azza0X
First of all this is very good news regarding cancer especially as this would be considered a high risk group (where the majority were over 60 yrs old and therefore more likely to have precancerous lesions which excess folate could in theory accelerate the growth of see Ulrich, CEBP, 2008). This is important and the authors are right to highlight it – it is often used as a headline argument to oppose B vitamins but the details don’t support there being a real significant risk compared to the benefits, and this large study helps to confirm that.
Not so good news though for preventing heart disease, but what does it really tell us? They also mention osteoporosis, see below. This is a problem with trying to squeeze nutrition into a pharma type clinical research study. We are not dealing with a novel molecule with a precisely defined target but a common vitamin involved in complex biochemical pathways (inc. DNA synthesis and methylation) and it’s not surprising that perturbations to these pathways have multiple effects.
Homocysteine is a risk-marker for CVD, whether it is cause or effect is not established although there is reasonable evidence for it being involved (Wald et al, BMJ, 2002). It has been reported to have damaging effects on genome stability (Fenech, AJCN, 2010) and high levels have been linked to a host of diseases from osteoporosis to dementia (Selhub, 2006). The evidence strongly suggests that it is a good thing to keep it low. So why have all these trials shown more or less no effect of homocysteine on heart disease? Quite possibly because all of them are looking at secondary prevention, i.e. the study patients in all the trials are exactly that, patients, already ill with heart disease. Maybe it’s to late to start lowering homocysteine if the damage has been done – just like no-one really expects calcium and vitamin D to have much positive benefit in people who already suffer from osteoporosis (incidentally in the paper the authors say “Low folate status and increased homocysteine levels have been associated with osteoporosis and fracture risk but fracture incidence was similar in the 2 groups” – not at all surprising, osteoporosis prevention does not start at >60 yrs old).
Post infarct reduction of cholesterol levels have been shown to be effective in secondary prevention (indeed all patients in the SEARCH trial were on simvastatin) but the mechanisms are different. Cholesterol clogs a pipe whereas homocysteine, if it is indeed involved, is likely to do so via damaging blood vessel walls. So we can talk about plumbing. If a pipe becomes blocked following years of calcium deposits in a high calcium water area, once the blockage is treated, recurrence can be prevented by reducing the calcium content. If the pipe develops a leak due to years of erosion due to acidic water, even after repairing the leak the pipe walls will still be weak and neutralising the water is not going to make much difference, the damage is done.
The SEARCH study was well done and they make good points about cancer, but the final sentence was disappointing:
In addition, these results highlight the importance of focusing on drug treatments (eg, aspirin, statins, and antihypertensive therapy) and lifestyle changes (in particular, stopping smoking and avoiding excessive weight gain) that are of proven benefit, rather than lowering homocysteine with folic acid–based vitamin supplements, for the prevention of cardiovascular disease.Drug treatments OK but talking about smoking and weight as of “proven benefit… for the prevention of cardiovascular disease” is misleading, it suggests that this study has something to say about primary prevention, which it certainly does not.
As discussed in the past, clinical trials of nutrients for primary prevention are pretty much impossible, we have to rely on the best evidence we have to give nutrition advice – the evidence is strongly in favour of homocysteine lowering with levels of folic acid much lower than 2mg per day (RDA of 400µg is enough for most, those with polymorphism in MTHFR will need more, of course it goes without saying that there was not genetic component to this study…). SEARCH and all the other trials have often been misused in the folic acid/homocysteine debate, they have often been cited as proof that the homocysteine theory is wrong – but they do no such thing and it would help if the authors of these studies made it clear that all conclusions are relevant (and useful) only as far as secondary prevention is concerned.
Good analysis, Keith. I have the MTHFR polymorphism. Couldn't agree with you more. I'm continuing to take high doses of Folgard Rx 2.2
ReplyDeleteThere was a comment from a young friend of mine on the facebook note of this post:
ReplyDeleteJibril Mohammed - How and why could it have failed?
Keith Grimaldi: It's OK - no big surprise, vitamins don't cure heart disease! They may prevent it in the first place though, but once the damage is done, no surprise. The real surprise is why there have been 8+ clinical trials on folic acid, all asking the same question (and getting the same answer). A real waste of time and money.
Really, WHY so many expensive clinical trials with folic acid (the JAMA paper refs 7 of them, very large, very long, very expensive)? It seems to me it's intellectual laziness to keep asking the same question over and over again. OK ask it once or twice because it's not really a very good question anyway - we don't see so many clinical trials on calcium and osteoporotic bone fractures do we? I hope we are at the end of this long stream going nowhere