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Return of the great cholesterol debate

Tony Winder
Emeritus Professor in Chemical Pathology
Royal Free and University College Medical School London

Consultant in Clinical Biochemistry and the Cardiovascular Lipid Clinics
Royal Free Hospital NHS Trust

Chairman of Trustees
Family Heart Association Maidenhead

Tackling cholesterol has been an uphill struggle for years. It is interesting that things now appear to be going downhill, to the extent that caution, particularly in the rush to medication, is seen as heresy. 
Pharmaceutical and food-supplement marketing has much to answer for, particularly in promoting cholesterol levels of 5.0 or 5.2mmol/l as universal targets, even in primary prevention, and for which widespread use of medication is then recommended. Around 80% of UK adults have cholesterol levels above 5.2 mmol/l, and prescribing to this target for fit patients with no other risk factors is good business but dubious medicine; these days, new products are promoted on the stock market, not in clinical practice. 
The trouble with primary prevention is that large trials have shown that clinical events are marginally less frequent against placebo when patients with mildly adverse (not average) lipids are given statins (or fibrates with triglyceridaemic patients), but that the targeting of individuals later found to be at risk or to benefit is wildly inexact and depends on much more than cholesterol.(2) 
The global whole-patient approach is absolutely central to management in primary prevention, family history being one undervalued component of risk assessment for which information is available in practice records. The epidemiology of lifestyle is deeply convincing, but implementation of maintained change remains difficult, except for low-risk professional classes.(3) Most doctors and practice staff are also wholly untrained in motivating behavioural change; courses are now being introduced. 
The EXERT (Exercise Evaluation Randomisation Trial) study is an interesting NHS-funded initiative in Barnet, which is reviewing the measurable benefits of prescribed supervised attendance at a sports and leisure centre. 
The emerging nutriceuticals industry is a grey area; they certainly work - plant-based margarines have been shown to reduce cholesterol on average by 15%.(4) Population change through awareness may come, as in Finland, although our genetics may also be significant, but this involves education, also favoured by the government above a nanny-state approach. 
The need for education of both physicians and patients on heart disease risks also came out in the REACT (Reassessing European Attitudes to Cardiovascular Treatment) survey of patients and physicians.(5) For patients, awareness of blood pressure as a heart risk was far ahead of smoking and cholesterol. Physicians were not confident that they understood and could implement available guidelines, and recommended further education initiatives for themselves as well as patients. 
Given the inexact information, the best approaches to primary prevention are community-based awareness initiatives and the continual development of, and familiarisation with, widely based guidelines for risk calculation for individual patients, which can often also give reassurance.(2) This particularly applies to the asymptomatic and otherwise fit elderly for whom above-mean cholesterol levels without recent fall are generally good news, excluding major debilitating disease. 
The cardiovascular risks associated with type 2 diabetes are high, with almost half of patients dead within a year of their first infarct. The outcome benefits associated with both statins and fibrates as well as with antihypertensives are also high, and the guidelines for secondary prevention are applied before any cardiovascular event.(2) Individual risk of developing diabetes within families with diabetes is also massively increased by obesity, yet awareness of this effect seems low.
Targets in secondary prevention
Patients with occlusive arterial disease of any sort are extremely likely to die of a coronary. Therefore the power of secondary prevention is that it targets the most likely cause of death. Current targets as summarised in the NSF specify cholesterol at or below 5.0mmol/l and low-density lipoprotein (LDL) cholesterol Trials already underway will clarify the lower-is-better argument, and the move to flat pricing has also blunted cost concerns. Superstatins and generic products are also on the way, and the NSF specifies that drug costs to meet lipid and blood pressure targets will be met. Post-hoc trial analysis convincingly supports the idea that early prescribing, within 48 hours of a clinical event, improves outcome. The underlying science is not clear and all sorts of additional effects of the predominantly statin medication involved are proposed. But the benefits are persuasive, and early prescribing greatly improves recorded compliance at one year from around 10%, where initiated in primary care, to about 50%. 
Patient rather than practice attitudes may be involved here, but partnership with acute units and maintenance of compliance on return to primary care are key NSF targets. Statins may also have unexpected additional benefits, reducing stroke rates, onset of dementia and osteoporosis, and possibly colon carcinoma in patients who were overwhelmingly prescribed statins for cardiovascular disease. 
The WOSCOPS (West of Scotland Coronary Prevention Study) and HOPE (Heart Outcomes Prevention Evaluation) trials also suggested that intervention with a statin or ACE inhibitor reduced the later expression of diabetes.(6) Any such benefits may directly relate to cholesterol lowering - the stroke effect is probably through plaque stabilisation in the aortic arch - or unforeseen cellular effects now under intensive investigation. Involvement of statins in primary prevention of these events in patients without cardiovascular disease is not yet known, and their use is not yet supported. 
Patients meeting lipid and other guidelines in secondary prevention still have high event rates, including death. This awkward consequence has raised interest in the composition of lipoprotein fractions - the lipoprotein complex - and not just their gross amount. Statins can lower LDL cholesterol and fibrates can modify LDL composition, reducing the triglyceride enrichment which is characteristic of type 2 diabetes and may arise generally when triglyceride levels exceed 1.5mmol/l. This enriched, small, dense LDL seems particularly atherogenic and, as well as below-average levels of high-density lipoprotein, may be the predominant cardiovascular risk association of moderate hypertriglyceridaemia. The risk of pancreatitis at triglyceride levels around, and often well above, 20mmol/l is well known but rare. Combination statin/fibrate use is expected to increase; major trials are in hand.

The NSF for coronary heart disease and the primary care agenda
This first NSF includes a number of specific directives relating to lipid management in primary care as well as to smoking, other lifestyle effects and hypertension (see Tables 1 and 2). Lipids will also arise in further service frameworks on diabetes and care of the elderly. The main organisational task will not be management of the occasional new cases discharged from acute units, but a catching-up exercise to find and effectively treat with follow-up the many undertreated patients with existing disease(7) for whom nurse-led cooperative clinics are proposed.



New cases are now much more likely to be discharged on specific evidence-based medication(8) with advice to continue, and there is urgent need for settled agreements on prescribing policies between acute care trusts and the community services, so that appropriate treatments are not casually changed. Practices will also be involved in the community drive for enhanced awareness of cardiovascular risks and the opportunities for primary prevention. Local initiatives, as with prescribed lifestyle support in Barnet, are also welcome. 
Other initiatives in partnership with the Family Heart Association include finding more of the 100,000 or so currently unidentified patients with familial hypercholesterolaemia by working from recognised cases back through generations and the family tree  - the procedure of close family tracking.(9) 
Practice and community care performance in meeting NSF objectives is also to be subjected to detailed audit through procedures to be developed. 
This may all seem overwhelming, but the NSF proposals offer great potential to raise performance in cardiovascular care by rounding up, and some resource and educational support is assured. Record systems and arrangements to ensure flowing partnership between acute and community units will require early attention, and one interesting possibility is that the specialised lipid clinic may decline, as has mostly happened with hypertension and diabetes. 
However, there is a downside to treatment by numbers, such as recognising familial disorders and ensuring wider attention to the family as well as introducing radical new treatment. We live in interesting times.



  1. Department of Health. National Service Framework for coronary heart disease. Modern standards and service models. London: HMSO; 2000. ( nsf/ coronary.htm)
  2. Wood D, Durrington P, Poulter N, McInnes G, Rees A, Wray R. Joint British recommendations on prevention of coronary heart disease in clinical practice. Heart 1998;80:S1-S29.
  3. Lifestyle measures to tackle atherosclerotic disease. Drug Ther Bull 2001;39(3):21-4.
  4. Law M. Plant sterol and stanol margarines and health. BMJ 2000;320:861-4.
  5. Hobbs FDR, Erhardt L. Reassessing European Attitudes about Cardiovascular Treatment (REACT) - general population and physicians surveys (abstract supplements).Eur Heart J 2000;21:2562-3.
  6. Haffner SM. Do interventions to reduce coronary heart disease reduce the incidence of type-2 diabetes? A possible role for inflammatory factors. Circulation 2001;103:346-7.
  7. Primatesta P, Poulter NR. Lipid concentrations and the use of lipid-lowering drugs: evidence from a national cross-sectional survey.BMJ 2000;321:1322-5.
  8. Statin therapy - what now? Drug Ther Bull 2001;39(3):17-21.
  9. Neil HAW, Hammond T, Huxley R, Mathews DR, Humphries SE. Extent of under-diagnosis of familial hypercholesterolaemia in routine practice. BMJ 2000;321:148.

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