Visiting Professor Patrick Holford of Teesside University and Head of Science and Education at Biocare has an odd relationship with statins. Who can forget his straight-to-camera overview of Big Pharma’s “full spectrum dominance” and the industrial complex that enforces mass-medication with prescription drugs such as statins. Or his shocked (and incorrect) assertion that “almost 20,000 people have to take a statin for 5 years for 1 less heart attack”. It could never have made sense to anyone who gave the matter half a second’s thought, far less someone who styles himself as leading health expert, but there you have it: Visiting Professor at the University of Teesside and able to make that statement with a rather unnerving (and misplaced) sincerity. Regular readers will not be surprised to learn that Holford sees the just announced and updated NICE Clinical Guidelines as yet another opportunity to decry Big Pharma’s profits relating to statins and to promote niacin: you may, however, be interested in an upcoming plot twist.
Now, there is a lot of disagreement about the need for mass-medication of particular demographics with statins; this is not one of the areas of faux controversy where 98% of researchers, health policy wonks and doctors share one point of view and 2% think otherwise. Business Week Jan 2008 offers a good overview of some of the issues: Do Cholesterol Drugs Do Any Good?
HolfordWatch expressed some of our own mixed feelings in our recent item about polypills of which statins are a component. However, the associated research issues continue to be intriguing.
Some of the areas of research interest lie in whether statins are effective in people who have existing heart disease because of their cholesterol-lowering effect in combination with the reduction in rho-kinase and upregulation of enodothelial Nitric Oxide Synthase expression which is possibly additionally protective of the cardiovascular system. If this latter is confirmed, then it may prove that statins are more effective for prevention in, e.g., smokers or people with high systemic inflammation.
Unsurprisingly, Holford doesn’t have anything to contribute to such interesting areas of research but, undaunted, he has pluckily issued a press release that outlines his disagreement with the new NICE Guidelines on management of lipid levels, cardiovascular risk assessment and primary and secondary prevention. All of which he seems to consider boils down to the prescription of statins. The press release is as muddled as his usual thinking on the matter but can be reduced to the following:
- Holford refers to a paper that can’t be identified to support his assertion that “statins are far from harmless”
- he reprises his Co-enzyme Q10 horror
storiesstudies involving tiny numbers of participants
- he attempts to have his cake and eat it by highlighting disagreement about the relationship between cholesterol levels and heart disease, using that to deprecate the use of statins, yet advocate the supplementation of niacin to modify cholesterol levels (Dr Aust provides a good account of Holford’s mentor Abram Hoffer who is responsible for much of the early work on niacin). If you haven’t taken that part of his advice, then he would like you to take 90mg of CoQ10 a day alongside your statin. Either way, it seems he would like you to spend your money on supplements.
Other issues aside, it is particularly irritating that Holford produces an un-nuanced account of the NICE Guidelines.
The new guidelines issued by Nice yesterday say all adults aged 40 to 75 should be assessed for risks, including smoking, weight and blood pressure and those with at least a 20 per cent increased chance of a heart attack over the next 10 years should be offered treatment.
I completely disagree. Statins work by blocking the production of cholesterol, which is a perfectly normal substance, and in the process, stops the body producing Co-Q10, a vital heart nutrient, causing harmful side effects.
It initially reads as if he disagrees that adults should be assessed for their risk of cardiovascular disease which is quite novel given his usual recommendation for tests for everything. However, even Holford can’t mean that, so we will overlook that and the fact that he does not mention that the guidelines concern both primary and secondary prevention of cardiovascular disease (CVD) and concentrate on the segue from ‘treatment’ to the discussion of statins.
NICE has provided extensive documentation in support of the new Clinical Guidelines for Lipid Modification: Cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease. They have taken considerable care to state that, aside from age and sex, there are modifiable risk factors such as smoking, raised blood pressure and raised cholesterol that make a contribution to heart disease, particularly in combination. They highlight the need to identify people at higher risk of CVD such as those with heart disease in the family or men with a South Asian (for example, Indian, Pakistani or Bangladeshi) background. They also include social deprivation as a proxy indicator for an increased risk of CVD.
For primary prevention, NICE recommends that people should be prioritised on the basis of an estimate of their CVD risk before a full formal risk assessment. Their CVD risk should be estimated using CVD risk factors already recorded in primary care electronic medical records. NICE emphasises that before offering drugs to reduce cholesterol levels, all other modifiable risk factors should be considered and support given to manage them: this includes support for smoking cessation and advice for dietary modification, weight loss (if necessary), lifestyle changes, increasing physical activity levels etc. It also details the additional tests and assessments that should be performed to identify and manage secondary causes that dysregulate cholesterol levels such as thyroid issues.[a]
NICE recommends statin therapy for primary prevention when the individualised risk of CVD is more than 20% over the next 10 years. However, they emphasise that the decision to initiate statin therapy should follow an informed discussion of all an individual’s risks and benefits and should be arrived at jointly between the responsible clinician and the individual.[b]
All of the above is rather more nuanced than Holford’s bald summary would indicate. NICE emphasises that the decision to embark on statin therapy for primary prevention should not be taken lightly and is to be advised only for those at higher risk, and to be used in conjuction with other risk-management strategies such as smoking cessation etc..
Holford has some unobjectionable and unoriginal dietary recommendations for a healthy heart that sound very like the mediterranean diet and strongly resembles the dietary advice that most people would receive from their health advisers. Being able to argue both sides of the fence at the same time, having deprecated the relevance of cholesterol levels to heart disease, Holford recommends niacin for cholesterol management.
A low glycemic load (GL) diet is the best way to lower both cholesterol and heart disease risk. The most effective substance to raise ‘good’ HDL cholesterol and lower ‘bad’ LDL cholesterol is not a statin – it is niacin (vitamin B3), but this nutrient in not patentable or profitable, and hence is rarely prescribed. In addition for prevention of cardiovascular disease and if taking statins, take CoQ10 90mg a day.
Unfortunately, Holford neglects to give any references that would support the usefulness of a low GL diet for these purposes in the general population, far less one that it at increased risk of CVD.
As for the by-the-numbers assertions about niacin, here, we have an interesting plot twist. You can see Holford’s face, beaming at you, with a ker-ching in his eye on his own formulation of NoBlush Niacin: this costs £14.95 for a 30 day supply. For those people who meet the criteria for statin therapy and agree to it, NICE recommends a daily dose of 40mg of simvastatin, which costs 4p per day or £1.20 to the NHS for a 30 day supply. Crudely, it does rather look as if Holford’s preferred formulation is considerably more expensive than the solution recommended by NICE.
But, then again, what is cost if one considers benefit? And, it is clear that Holford somehow believes that cardiovascular specialists, GPs and other relevant clinicians disdain to prescribe niacin because of some (rather unclear) personal profit motive. Which is rather at odds with sparse but interesting sections of the NICE Guidelines that specifically address nicotinic acid and the primary or secondary prevention of CVD. In a nutshell, there is a dearth of clinical evidence to support the usefulness of nicotinic acid (niacin) for primary prevention,[e] so NICE advises against it, either individually[f] or in combination with other therapies.[g] However, although there is a small corpus of clinical evidence to support niacin for secondary prevention,[h] NICE advises it in cases where individuals have been unable to tolerate statin therapy.[i]
NICE considered the issue of niacin. If Holford disagrees with the NICE interpretation of the literature on the benefits of nicotinic acid for primary or secondary prevention of CVD among people at high risk, then it would be tremendously useful if he were to carry out a well-specified systematic review of the literature to support his stance. Likewise, if he could supply a reason why his preferred supplement for cholesterol management represents better value for money than NICE’s recommendations.
Although it is clear that Holford ‘completely disagrees’ with the NICE guidelines and is calling for them to be “reconsidered”, the grounds for his disagreement are not clear. Particularly so when one considers the nuance and detail of the recommendations. HolfordWatch wonders if Holford had perused the whole of the 238 page guidelines plus other supporting documents before he commented in such disparaging terms. If he failed to read the recommendations in full before he commented, then what sort of example is this for the students of the Visiting Professor of Teesside University?
Clinical Guidelines and Evidence Review for Lipid Modification:
cardiovascular risk assessment and the primary and secondary prevention of
cardiovascular disease (pdf) is the source of the following quotations from the guidelines throughout the notes.
[a] pp. 134-5; Section 6.1.2.
Baseline blood tests and clinical assessment should be performed, and comorbidities and secondary causes of dyslipidaemia should be treated. Assessment should include:
- smoking status
- alcohol consumption
- blood pressure (see ‘Hypertension’, NICE clinical guideline 34)
- body mass index or other measure of obesity (see ‘Obesity’,
NICE clinical guideline 43)
- fasting total cholesterol, LDL cholesterol, HDL cholesterol and triglycerides (if fasting levels are not already available)
- fasting blood glucose
- renal function
- liver function(transaminases)
- thyroid-stimulating hormone (TSH) if dyslipidaemia is present.
[b] pg. 135; Section 6.1.4.
The decision whether to initiate stain therapy should be made after an informed discussion between the responsible clinician and the person about the risks and benefits of statin treatment, taking into account additional factors such as comorbidities and life expectancy.
[c] The Energy Equation and Co-enzyme Q10: Holford the Pioneer. Holford also seems to be labouring under the illusion that “Co-Q10…is found in all cells”. That is rather a shock as I seemed to have missed noticing them in (say) red blood cells or eye lens cells.
For people with a burning interest to know how humans synthesise their own CoQ10, we recommend this flowchart of the process. We should also mention there are dietary sources of CoQ10: organ meats, beef, nuts, seeds, sardines, herrings and mackerel have some CoQ10 as do oils such as canola.
[d] Coracle has written some good overviews on statins, myopathy and CoQ10. In particular, with respect to the issue of muscle pain, statins and the putative protective role of CoQ10:
we need to ask a big question; does CoQ10 supplementation help those with statin-associated myopathy? At the time of press of the Markoff and Thompson paper, two trials had not been published. One has now been published (Caso et al, 2007), finding benefit for 100 mg/day CoQ10 compared to Vitamin E in a study of 32 subjects for 30 days. The other remains in abstract form but found no benefit for a 200 mg daily supplementation in a randomised, placebo controlled, double-blind trial.
Clearly, there is a lot left to unravel in terms of the clinical applications of CoQ10 for statin-associated myopathy. So, future trials are need to determine the possible efficacy of CoQ10 in preventing myopathy. I’ve only been able to locate one study and that is another small trial, with only forty subjects.
[e] pp. 155-6; Section 6.5.
Evidence statements for nicotinic acids 18.104.22.168 No randomised controlled trials in people at high risk of CVD were identified that compared nicotinic acid therapy with placebo and reported cardiovascular event outcomes.
6.5.2 Clinical effectiveness of nicotinic acids
No randomised controlled trials in people at high risk of CVD were identified that compared nicotinic acid therapy with placebo and reported cardiovascular
[f] pg. 137; Section 6.1.12. “Nicotinic acid should not be offered for the primary prevention of CVD.”
[g] pg. 137; Section 6.1.15. “The combination of an anion exchange resin, fibrate or nicotinic acid with a statin should not be offered for the primary prevention of CVD.” And, pg. 160; Section 6.8.2.
Evidence to recommendations – combination drug therapy
The GDG considered that there was insufficient evidence to recommend combining a statin with a fibrate, anion exchange resin, or nicotinic acid in primary prevention.
[h] The following quotations all relate to secondary prevention.
Nicotinic acid for secondary prevention
7.1.12 Nicotinic acid may be considered for secondary prevention in people with CVD who are not able to tolerate statins…
[pg. 165] ]For people with established CVD] [n]icotinic acid and anion-exchange resins have also shown evidence of cardiovascular benefit…
[pg. 167] The same strength of evidence that exists for statins does not exist for other classes of lipid lowering drugs (fibrates, anion exchange resins, nicotinic acid) where the trials are fewer in number, the total patient population studied can be small, and trials have shown variable benefits on cardiovascular events despite reduction in cholesterol.
pp. 216-7; Section 7.5.2.
7.5.2 Clinical effectiveness of nicotinic acids
No randomised controlled trials were identified that compared nicotinic acid therapy with placebo in patients with angina, peripheral arterial disease or following stroke. Due to the lack of trial evidence, it was decided by the GDG to consider evidence used in the NICE Myocardial Infarction guidance (Myocardial infarction – Secondary prevention in primary and secondary care for patients following a myocardial infarction, CG48, 2007)
One paper was identified that compared niacin treatment with placebo in patients after an MI (Wilkins, R. W., Bearman, J. E., Boyle, E. et al , 1975). The Coronary Drug Project Research Group randomly assigned post MI patients to six treatment groups: low and high conjugated oestrogen therapy, clofibrate, dextrothyroxine sodium, niacin and a placebo…Patients were followed for 5 years.
Compared with placebo, niacin was not associated with a reduction in the incidence of the following outcomes: all cause mortality, the individual components of all cause mortality, definite pulmonary embolism (fatal or nonfatal), fatal or nonfatal stroke or intermittent cerebral ischaemic attack, definite or suspected fatal or nonfatal pulmonary embolism or thrombophlebitis and also any definite or suspected fatal or nonfatal cardiovascular event. Niacin therapy reduced the incidence of nonfatal MI and also the combination of coronary death or nonfatal MI, compared with placebo. Cholesterol and triglycerides levels decreased in the niacin group compared with the placebo group.
Patients in the niacin group had a greater incidence of the following side effects compared with the placebo group: the combination of diarrhea, nausea, vomiting, black tarry stools, stomach pain, flushing, itching of skin, urticaria, other type of rash, pain or burning when urinating, decrease in appetite, unexpected weight loss, and excessive sweating (Wilkins, R. W., Bearman, J. E., Boyle, E. et al , 1975).
[i] pg. 218.
7.5.4 Evidence into recommendations
The GDG considered that there was insufficient evidence to routinely recommend the use of nicotinic acids as a first line treatment for patients with CVD. It was decided however, that they may be offered as an alternative for those who are intolerant of statin therapy.
 Cooper A, Nherera L, Calvert N, O’Flynn N, Turnbull N, Robson J, Camosso-Stefinovic J, Rule C, Browne N, Ritchie G, Stokes T, Mannan R, Brindle P, Gill P, Gujral R, Hogg M, Marshall T, Minhas R, Pavitt L, Reckless J, Rutherford A, Thorogood M, Wood D (2007) Clinical Guidelines and Evidence Review for Lipid Modification: cardiovascular risk assessment and the primary and secondary prevention of cardiovascular disease (pdf). London: National Collaborating Centre for Primary Care and Royal College of General Practitioners.
 Rikitake Y, Liao JK. Rho GTPases, statins, and nitric oxide. Circ Res. 2005 Dec 9;97(12):1232-5.
 Reidenberg MM. Statins, lack of energy and ubiquinone. Br J Clin Pharmacol. 2005 May;59(5):606-7.
 Marcoff L, Thompson PD. The role of coenzyme Q10 in statin-associated myopathy: a systematic review. J Am Coll Cardiol. 2007 Jun 12;49(23):2231-7. Review.
 Caso G, Kelly P, McNurlan MA, Lawson WE. Effect of coenzyme q10 on myopathic symptoms in patients treated with statins. Am J Cardiol. 2007 May 15;99(10):1409-12.