Management of dyslipidaemia

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Sedentary lifestyle is a major risk factor for CHD which increases lipid and non-lipid risk factors seen in obesity, metabolic syndrome and type 2 diabetes. Weight loss and exercise can reduce TG, increase HDLc and, in some persons, lower LDLc levels (Wood et al., 1988; Goldstein, 1992). Regular physical activity should be a standard part on any lipid management programme. The American Diabetes Association (ADA) suggests a reduction in the proportion of dietary saturated fats with increase in carbohydrate or monounsaturated fat or both. The ATP III recommends therapeutic lifestyle changes including dietary changes combined with regular exercise and weight management as the first line treatment for all risk factors associated with metabolic syndrome (National Cholesterol Education Program, 2002). Diets high in trans fatty acids, like margarine, biscuits and white bread, that can raise LDLc as well as lower HDLc should be avoided. National Cholesterol Education Program and ADA recommend drug therapy only after lifestyle interventions has been tried except for those patients with clinical evidence of CHD or with very high LDLc levels. Several studies have shown that aggressive dietary therapy alone or in combination with exercise has beneficial effects on lipid levels and CHD.

The St. Thomas' Atherosclerosis Regression Study (STARS) randomized men with CHD and TC above 6.0 mmol/l to conventional care or a low-fat diet. Weight reduction measures and exercise programmes were provided for overweight subjects. After 3 years, the progression rate of coronary atherosclerosis slowed in the diet-treated group (Watts et al., 1992). The clinical trials involving omega 3 fatty acids also showed significant benefit on cardiovascular end points. In the Diet and Reinfarction Trial (DART), men recovering from myocar-dial infarction, who were randomized to dietary advice consisting of increased fatty fish consumption had a 29 per cent reduction on all cause mortality at 2-year follow up (Burr et al., 1989).

In the GISSI Prevention Trial, patients randomized to receive omega 3 fatty acid supplementation (1 g/day) had a significant 10-15 per cent reduction in combined primary endpoints of death, and fatal/non-fatal stroke (GISSI Pre-venzione Investigators, 1999). In the Lyon Diet Heart Study, patients on a Mediterranean diet instead of a western diet had a reduction in death from cardiovascular causes; non-fatal acute myocardial infarction of 73 per cent, cardiovascular mortality of 76 per cent and all cause mortality of 70 per cent (De Lorgeril et al., 1996, 1999).

Several large-scale, controlled, randomized clinical trials have established that intervention with statins reduces CHD risks. This is seen in both the primary and secondary prevention settings and it is mediated mainly by reducing the LDL cholesterol (Table 9.2).

The landmark Scandinavian Simvastatin Survival Study (4S) convincingly demonstrated that coronary events and total mortality were decreased by 30

MANAGEMENT OF DYSLIPIDAEMIA 187 Table 9.2 CHD prevention trials with statins in patients with diabetes - subgroup analysis


Baseline LDLc CHD risk reduction (%)

LDLc lowering -

Primary prevention


Lovastatin 155 3.9 Simvastatin 2982 3.4

37 24

Secondary prevention



Pravastatin 586 3.6

Simvastatin 202 4.8

Pravastatin 782 3.9

Simvastatin 1978 3.3

27 36 25 30

23 32

24 24

NS, not significant.

per cent with LDLc reduction of 36 per cent. The Cholesterol and Recurrent Events (CARE) and Long Term Intervention with Pravastatin in Ischemic Disease (LIPID) demonstrated similar benefits in patients with relatively average TC and LDLc (Sacks et al., 1996; LIPID, 1998).

The link between increasing LDL and CHD is well established in statin trials. There is a roughly linear relationship between CHD events rates and LDLc levels on treatment with statins. Those at the highest CHD risk experience the greatest benefit from the decrease in LDLc and tends to plateau at lower LDLc level. The lowest event rate is in the CARE pravastatin group, who achieved a mean LDLc of less than 2.6 mmol/l, which is in accordance with the NCEP guideline of LDLc target <2.6 mmol/l. The baseline LDLc level in 4S was 4.88 mmol/l, in CARE 3.6 mmol/l, and 3.88 mmol/l in LIPID. In all these trials, statins approximately reduced LDLc level by about one third. In the recent Heart Protection Study, (HPS) 33 per cent of the total 20 536 subjects had baseline LDLc <3 mmol/l, 25 per cent between 3 and 3.5 mmol/l and 42 per cent had levels >3.5 mmol/l. The simvastatin (40 mg) group, when compared to placebo, had significant reduction in all cause mortality, CHD deaths and major cardiovascular events. The benefit in reduction of events was similar in all the three tertiles of baseline LDLc (MRC/BHF, 2002).

The benefit of aggressive lipid lowering is also extended to the Regression Growth Evaluation Statin Study (REGRESS) where pravastatin delayed the progression of atherosclerosis on angiography and reduction in clinical events at 24 months in the 885 men who took part. These benefits occurred at all lipid levels, including those in the lowest quintile with LDLc concentration between 2.2 and 3.8 mmol/l (Jukema et al., 1995) The Atorvastatin Versus Revascularisation Treatment Study (AVERT) compared the outcome of aggressive lipid lowering with atorvastatin (80 mg/day) to that of angioplasty in 341 stable CHD patients with coronary vessel disease. The atorvastatin group (n = 164) achieved a greater reduction of LDLc to 2.0mmol/l, as opposed to 3.0mmol/l in angioplasty group followed by usual care. The incidence of ischaemic events was 36 per cent lower in the atorvastatin group over 18 months, although not statistically significant, there was lower rate of coronary artery bypass graft and percutaneous transluminal coronary angioplasty as well as hospitalization for worsening angina (Pitt et al., 1999).

This raises the point 'the lower the LDLc, the better?' and the issue as to whether there is a threshold LDLc below which no benefit occurs. It has been postulated that the cardiovascular benefits of lowering LDLc may be due, at least in part, to improvement in endothelial dysfunction and the anti-inflammatory properties of statins rather than lipid lowering. In the substudy of CARE, it was shown that pravastatin was associated with improved endothelium dependent vasodilatation and reduction of CRP. Studies in 4S and WOSCOP demonstrated benefit within 6 months of randomization, too soon for the benefit to be explained by regression of atherosclerosis. Acute coronary syndromes arise as a result of rupture of unstable plaque which poses a greater threat than the plaque size or severity of stenosis. The vulnerability of the atherogenic plaque is related to the size of the lipid-rich core, foam cells, inflammatory cells and the thickness of the fibrous cap which is contributed by the vascular smooth muscle cells. Statins reduce the lipid rich core and inflammatory cells especially macrophages and T lymphocytes and directly inhibits metalloproteinase secretion by macrophages that digest collagen in the plaque (Jukema et al., 1995; Aronow et al., 2001; Corti et al., 2001).

The clinical equivalent to this effect was shown in the Myocardial Ischaemia Reduction with Aggressive Cholesterol Lowering study (MIRACL) in which 3086 patients with unstable angina or non-Q wave myocardial infarction received either atorvastatin 80 mg/day or placebo within 4 days of hospital admission. The primary endpoint (recurring infarction, cardiac arrest with resuscitation, worsening angina requiring hospitalization) was less frequent with atorvastatin at 16 weeks compared to placebo with a relative risk reduction of 16 per cent, but the benefit was primarily due to a 26 per cent reduction in hospitalization for worsening angina (Schwartz et al., 2001).

The beneficial effect of statins was not seen in the recent lipid arm of ALLHAT study. One possible explanation is that a relatively large proportion of patients taking pravastatin (22.6 per cent) stopped the medication and around 26 per cent of people in the 'usual care' have been started on a statin (ALLHAT Collaborative Group, 2002).

The role of statins in diabetic dyslipidaemia is based on subgroup analyses from the major statin studies. Patients with diabetes benefit as much or more than non-diabetics from statin treatment, but the majority of the outcomes did not reach statistical significance due to the small number of diabetic patients compared to non-diabetic subjects (Table 9.2).


Table 9.3 CHD prevention trials with fibrates in patient with diabetes


Table 9.3 CHD prevention trials with fibrates in patient with diabetes

CHD risk reduction

Secondary prevention











23 (NS)

NS, not significant; VA-HIT, Veterans Affairs HDL Intervention Trial; DIAS, Diabetes Atherosclerosis Intervention Study.

NS, not significant; VA-HIT, Veterans Affairs HDL Intervention Trial; DIAS, Diabetes Atherosclerosis Intervention Study.

In fact, statins reduce CHD events by only approximately 30 per cent with a residual risk of 70 per cent, which may be related to suboptimal LDLc lowering or due to the presence of other untreated lipid abnormalities. In a retrospective analysis, low baseline HDLc was found to be a strong inverse risk factor for both placebo and pravastatin groups in the CARE and LIPID trials. The conclusion was that low HDLc is a powerful negative risk factor for coronary events despite treatment with statin and the risks associated with a low HDLc is not altered by statin therapy. There is evidence that fibrates which increases HDLc may be effective for secondary prevention of CHD as observed in the Veterans Affairs HDL Intervention Trial (VA-HIT) (Table 9.3; Rubins et al., 1999; Bloomfield et al., 2001). The DIAS (the Diabetes Atherosclerosis Intervention Study) demonstrated that the progression of focal, localized atherosclerosis was reduced by 40 per cent on two measurements in the fenofibrate group compared with the control group. There was a non significant trend towards reduction in combined coronary events, fewer deaths, MI and coronary intervention in the treatment arm (Table 9.3; DIAS, 2001).

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