This week saw the publication of another large clinical trial investigating the effects of dietary supplementation with omega-3 containing fish oil to prevent cardiovascular disease. The use of fish oil to promote good health goes back many hundreds of years however interest grew in the 1960's when there were reports of very low levels of coronary heart disease in Greenland Eskimos. This was attributed to a diet that was rich in marine omega–3 fats and led to the hypothesis that omega-3 supplementation would prevent cardiovascular disease. Today omega-3 is synonymous with good health and supplements are taken widely in the belief that they will prevent heart disease. There has been a large amount of clinical research but much controversy remains as to the effectiveness of these supplements. So what is the evidence that supplementing the diet with fish oils prevents heart disease and are we overlooking other important aspects of the Eskimo diet which might be responsible for their good health? Does fish oil prevent high risk people getting heart disease? A recent study published in NEJM randomised 12,513 patients to take either omega-3 supplements or placebo. The trial subjects had multiple cardiovascular risk factors or clinical evidence of vascular disease. After 5 years 11% of subjects had experienced cardiovascular events but there was no effect of omega-3 treatment. Does fish oil prevent recurrent heart disease after heart attack? In the GISSI-P study diet was supplemented with omega-3 rich fish oil in people who had recently had a heart attack. Over 3.5 years there was a difference of just 1.3% in favour of fish oil in the combined end point of death, non-fatal MI and non-fatal stroke. This study was conducted about 20 years ago and the treatment of patients post MI is now very different. Only 40% of patients were on beta-blockers or ACE inhibitors and only a 25% underwent stenting or had coronary bypass surgery. Clopidogrel, now almost always used after an MI, was not available at that time and the statin mega trials had not been published so at the start of the trial only a few patients were treated with these drugs. The overall effect of omega-3 supplementation was small and of low clinical significance. This was further confirmed in a the more contemporary Alpha-Omega Study published in 2010 which again showed no benefit with omega-3 fatty acid rich margarines. A Cochrane systematic review of trials included 36,913 participants and 41 cohort analyses. Pooled trial results did not show a reduction in the risk of total mortality or combined cardiovascular events in those taking additional omega-3 fats no significant effect of omega-3 fats. Although omega-3 supplementation was originally recommended by NICE most local cardiac networks and guidelines groups have strongly indicated that omega-3 is not a high priority to be prescribed for patients Why doesn't omega-3 prevent heart disease? Whilst there is biochemical and observational research to suggest that omega-3 fatty acids are beneficial to prevent cardiovascular disease the large controlled clinical trials have been very disappointing. The original fish oil hypothesis was formed following the observation of a very low level of cardiovascular disease in Inuit Eskimos. The diet of an Eskimo would be regarded, at first glance, as extremely unhealthy. It contains a large amount of animal protein and fat. The amount of carbohydrate and sugar is very low. The Eskimo diet is like that of a carnivorous animal and very rich in omega-3 fatty acid. Most researchers have focused on the high omega-3 content of the diet forgetting the high fat and protein content. Because of the link between cholesterol and fat to coronary artery disease, the lack of carbohydrate and sugar in the diet were quietly forgotten. So to pick on one component, albeit present at high level in the diet, and expect that supplementing it into a completely different high carbohydrate Western diet would lower heart disease is not particularly credible. Recently the book by Dr John Yudkin - "Pure, White and Deadly has been republished. The thesis of this book was that the rise in coronary heart disease is due to the increased consumption of sugar in the Western diet rather than the traditional belief that it is related to the consumption of saturate fat. It is interesting that the Eskimo diet was very rich in fat and meat but low in sugar. Perhaps if we want to obtain the same low risk of heart disease of the Eskimos we need to follow their marine diet more closely. References: n–3 Fatty Acids in Patients with Multiple Cardiovascular Risk Factors: The Risk and Prevention Study Collaborative Group N Engl J Med 2013; 368:1800-1808 May 9, 2013 DOI:10.1056/NEJMoa1205409 n–3 Fatty Acids and Cardiovascular Events after Myocardial Infarction Daan Kromhout, M.P.H., Ph.D., Erik J. Giltay, M.D., Ph.D., and Johanna M. Geleijnse, Ph.D. for the Alpha Omega Trial Group N Engl J Med 2010; 363:2015-2026 November 18, 2010 DOI: 10.1056/NEJMoa1003603
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Today MSD announced that it will be withdrawing its nicotinic acid preparation called Tredaptive following announcement of results from the long awaitied HPS2-Thrive trial. Tredaptive is a combination of nicotinic acid with laropiprant which reduces flushing, the major side effect of the drug. HPS2-Thrive investigated whether, in patients already treated with statins, addition of tredaptive reduced major vascular events. The trial which followed patients for 4 years did not reach its primary endpoint. This result also follows the early termination of the AIM-HIGH trial in 2011 which investigated another nicotinic acid preparation called Niaspan. This trial was also negative. There is epidemiological data from the Framingham Study which showed that risk of cardiovascular disease increases by about 1% for every 1% increase in LDL cholesterol. Clinical trials with statins, which potently lower LDL, have consistently demonstrated reduction in cardiovascular endpoints when compared to placebo. However despite widespread treatment with statins some people still go on to have a heart attack or require coronary stents or bypass surgery leaving cardiologist to look for additional treatments to try and reduce risk and targetting patients with a low HDL has always been an attractive for cardiologists. We recognise that patients with recurrent cardiac events often have low levels of HDL (<1.1mmol/L). This is often seen in patients with type 2 diabetes and in South Indian Asians. People wiht low HDL often have raised triglycerides and small dense LDL particles which are highly atherogenic. There is good evidence from the Framingham Study that for a 1% increase in HDL there is a 3% reduction in the risk of cardiovascular disease. This led pharmaceutical companies to look search for new drugs which increase HDL also to re-examine old drugs (e.g. nicotinic acid) which also raising HDL. But there is a catch, we need to remember that Framingham was an epidemiological study which only looks at associations between risk factors. An association of increased HDL with reduced cardiovascular risk does not prove causality and raising HDL may not translate into reduced atherosclerosis and cardiovascular events. Nicotinic acid also known as vitamin B3 or niacin has been used for 50 years to raise levels of HDL. Early research in the Coronary Drug Project published in the 1970's suggested it might be effective but careful analysis of the study demonstrated only a very modest benefit in decreasing definite non-fatal recurrent myocardial infarction and did not decrease mortality. It was only in a long-term follow up study over 15 years (9 years after medication stopped) that a significant 11% difference in mortality was demonstrated. These results have not been repeated and were performed in non-statin treated patients so the results are not relevant for today's clinical practice. The results of the AIM-HIGH and HPS2-thrive trials are long awaited but clearly demonstrate no benefit of nicotinic acid. Perhaps its time for us to move on from regarding HDL as a target for pharmacological modification and simply use it as a marker of small dense LDL and increased cardiovascular disease risk. |
Dr Richard BogleThe opinions expressed in this blog are strictly those of the author and should not be construed as the opinion or policy of my employers nor recommendations for your care or anyone else's. Always seek professional guidance instead. Archives
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