Opinion Leader Editorial - Lipid disorders
(Publication Date 10 January 2005)

This Editorial has been written by the specialist opinion leader, Dr Graham Jackson, Consultant Cardiologist, Cardiothoracic Centre, St Thomas’ Hospital, London and published in the latest issue of the serial publication, Drugs in Context.

Cardiovascular disease is the leading cause of morbidity and mortality for men and women in the United Kingdom, and diabetes alone is associated with a two- to four-fold increased risk of coronary disease and stroke.1

Dyslipidaemia is a major independent risk factor for cardiovascular disease but should not be managed in isolation from the other major risk factors such as hypertension, obesity, cigarette smoking and lack of exercise.2 As diabetics are particularly vulnerable to vascular disease they should now be considered as secondary prevention cases even in the absence of a cardiovascular history - being recognised as ‘cardiovascular equivalents’.3

For more than 10 years lipid-lowering with statin therapy has been available, and well-conducted clinical trials have established clear and overwhelming evidence of benefits from treatment in terms of reducing cardiovascular events, including fatal and non-fatal myocardial infarction and stroke.4 Overall, statins reduce the risk of coronary disease by 31%, total mortality by 21% and stroke by 27%, with women and men benefiting similarly. Recent studies have highlighted the importance of a more aggressive lipid-lowering strategy following acute coronary syndromes and in reducing the progression of disease using ultrasound assessments of plaque burden.5,6 From initial guideline targets of 5.0 and 3.0 mmol/L or less for total cholesterol and low density lipoprotein cholesterol (LDL-C), respectively, we have now moved to targets of 4.0 and 2.0 mmol/L, respectively, in both acute and chronic settings.7 In addition, the primary prevention study of atorvastatin in type 2 diabetes (Collaborative Atorvastatin and Diabetes Study [CARDS]) reported such substantial cardiovascular benefits that the authors suggested no diabetic was at low enough risk not to be receiving a statin.3 We have evidence of safety with high- (80 mg) and low-dose atorvastatin in addition to clinical endpoint benefits, but unfortunately simvastatin at the present time has safety concerns regarding rhabdomyolysis at the 80 mg dose level.8

Statins, in addition to achieving reductions in total cholesterol and LDL-C, also lower triglycerides by up to 25% but only marginally increase the protective high density lipoprotein cholesterol (HDL-C). In addition, statins have been shown to reduce inflammatory markers, with once more the evidence of benefit favouring the higher dose, more aggressive strategy.5

The combination of raised triglycerides and low HDL-C levels represents additional cardiovascular risk and is frequently associated with the various manifestations and degrees of severity of the metabolic syndrome. If the statins do not achieve satisfactory levels (triglycerides under 2.0 mmol/L and ideally less than 1.6 mmol/L, and/or HDL >1.0 mmol/L), fenofibrate or nicotinic acid may be added to the treatment regimen, as both agents lower triglycerides by up to 35% and raise HDL-C by 26%.9,10 Side-effects may be increased, but in reality seldom are, although careful monitoring of the patient is essential. Ezetimibe, a selective cholesterol absorbtion inhibitor, added to a statin may further reduce both LDL-C and triglycerides by 15-20%, and increase HDL-C by 4-5%.11

The biochemical impact of any of the drugs and/or lifestyle changes must be set in a clinical context, with beneficial clinical endpoint data driving patient management. To define increased cardiovascular risk as a greater than 30% chance of an event in the next 10 years and to use this as a justification for therapy only at that risk level, is perhaps relevant to those aged over 80 years but is clearly not to younger age groups of patients.4 When economic arguments override evidence-based scientific evidence we need to resist vigorously rather than accept placidly. It is now time to adopt a general strategy of intervening at a 15% 10-year risk with a special focus on diabetic patients.3,7

The challenge of cardiovascular disease begins with prevention in the young, emphasising the importance of better diets, reduced obesity, smoking avoidance and more exercise. This can only be achieved with investment in education specifically tailored to the younger male and female. If at any age a high-risk individual is identified, multiple risk factor intervention should be initiated. If a cardiovascular event has occurred, all the evidence-based medicine should be deployed at optimum dosage (if well tolerated and with no contra-indications present). This should include a statin, aspirin or clopidogrel, a ß-blocker and an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor antagonist. In family and hospital practice such an intervention strategy requires regular audit.

We have come a long way in a short time in the management of cardiovascular risk. If we focus only on dyslipidaemia, it is evident that a less aggressive approach will have less benefit and a more vigorous approach has more benefit. Looking into the future, if we adopt the aggressive philosophy, cardiovascular disease could be reduced by 50% or more.12

References 1 Stamler J, Vaccaro O, Neaton JD, Wentworth D. Diabetes, other risk factors, and 12 year cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care 1993; 16: 434-44.

2 DeBacker G, Abrosioni E, Borch-Johnsen K et al. European guidelines on cardiovascular disease prevention in clinical practice. Third joint task force of the European and other societies on cardiovascular disease prevention in clinical practice. Eur Heart J 2003; 24: 1601-10.

3 Colhoun H, Betteridge DJ, Durrington PN et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet 2004; 364: 685-96.

4 Thompson GR. Management of dyslipidaemia. Heart 2004; 90: 949-55.

5 Cannon CP, Braunwald E, McCabe CH et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004; 350: 1495-500.

6 Nissen SE, Tuzcu EM, Schoenhagen P et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA 2004; 291: 1132-4.

7 Williams B, Poulter NR, Brown MJ et al. Guidelines for management of hypertension: report of the fourth working party of the British Hypertension Society, 2004 - BHS IV. J Hum Hypertens 2004; 18: 139-95.

8 Lemos JA, Blazing MA, Wiviott SD et al. Early intensive versus a delayed conservative simvastatin strategy in patients with acute coronary syndrome. JAMA 2004; 292: 1307-16.

9 Schuster H. Improving lipid management - to titrate, combine or switch. Int J Clin Pract 2004; 58: 689-94.

10 Wierzbicki AS, Mikhailidis DP, Wray R. Drug treatment of combined hyperlipidaemia. Am J Cardiovasc Drugs 2001; 1: 327-36.

11 Ballantyne CM, Lipka LJ, Sager PT et al.Long-term safety and tolerability profile of ezetimibe and atorvastatin co-administration therapy in patients with primary hypercholesterolaemia. Int J Clin Pract 2004; 58: 653-9.

12 Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ 2003; 326: 1419.

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