Review article: hyperlipidaemia and cardiovascular risk
Dr M. Bertolotti, Medicina III, Policlinico, Via Del Pozzo 71, 41100 Modena, Italy.
Hyperlipidaemia represents a determinant for the development of atherosclerosis and an important risk factor for cardiovascular disease, particularly in the context of the insulin resistance syndrome. This is characterized by alterations in the profile of plasma lipoprotein including high triglyceride levels, low high-density lipoprotein cholesterol concentrations and the appearance of qualitatively modified, small-dense low-density lipoproteins. Many charts and algorithms have been developed to estimate the entity of coronary and cardiovascular risk as related to dyslipidaemia, on the basis of additional individual risk factors and conditions: most include age and gender, smoking status, hypertension and diabetes. They should preferably be utilized in consistent patient populations, in terms of geographical areas and general risk profile. Pharmacological treatment of dyslipidaemia, in particular with statin drugs, was shown to greatly improve cardiovascular morbidity and mortality. A body of evidence also underlines the need for a multidisciplinary approach, integrating non-pharmacological lifestyle and diet interventions, as well as treatment of concomitant diseases (hypertension and diabetes).
Cardiovascular diseases, in particular coronary heart disease (CHD) and stroke, are the leading cause of death and permanent disability in the Western world.
Hyperlipidaemia represents a determinant for the development of atherosclerosis and an important risk factor for cardiovascular disease. When hyperlipidaemia is present in the context of the insulin resistance syndrome (or metabolic syndrome), it reflects a particular high-risk condition. Alterations in the lipid profile are both qualitative and quantitative and usually include high levels of plasma triglyceride, low levels of high-density lipoprotein (HDL) cholesterol and the appearance of modified, small-dense low-density lipoproteins (LDL).1 This constellation, often referred to as the ‘lipid triad’, is particularly prone to induce atherogenic changes in the arterial wall and to promote plaque instability, thus predisposing to acute cardiovascular events.
Estimation of cardiovascular risk
Many charts and algorithms have been developed in the attempt to accurately estimate the entity of coronary and cardiovascular risk on the basis of individual risk factors and conditions; most charts include, as determinants of cardiovascular morbidity or mortality, age and gender, smoking status, hypertension and diabetes, in addition to plasma cholesterol. The adult treatment panel-III (ATP-III) of the National Cholesterol Education Program,2 stratifies three different risk levels with regard to LDL cholesterol goals for treatment (160 mg/dL for low-risk, 130 mg/dL for medium-risk and 100 mg/dL for high-risk patients); this is based on a categorical evaluation of risk conditions, the presence or absence of CHD or diabetes and, in borderline cases, on an estimation of absolute cardiovascular risk according to the Framingham score. The presence of the metabolic syndrome is also underscored as a high-risk condition. A more recent revision of the ATP-III panel places even greater emphasis on the association of CHD and diabetes, identifying a ‘very high-risk’ population with an LDL cholesterol target of 70 mg/dL.3
As the guidelines and charts based on the Framingham database are supposed to overestimate cardiovascular risk in non-US populations, the adoption of charts and algorithms from different geographical areas would be recommended in countries outside the USA.
Indeed, the European risk charts derived from local population data have recently been devised, where the risk scores can be calculated in both high-risk and low-risk countries.4 This score brings the estimates of cardiovascular mortality, rather than morbidity, applies only for primary prevention (i.e. for non-CHD subjects) and does not include diabetes among its parameters, implying that the presence of diabetes automatically allocates affected subjects into a high-risk group.
With regard to our country, finally, risk charts have been developed using epidemiological databases from the Italian cohorts.5, 6 This will probably represent in future, when such evidence is validated, an ideal approach on a national basis.
All risk charts either include diabetes as a very important determinant of risk calculation or consider diabetes per se as a high-risk condition, independently of other factors. This largely derives from the widely accepted concept that diabetes brings the same risk for a cardiovascular event as previous CHD.7 Diabetes, however, is always considered as a dichotomous (i.e. ‘yes or no’) variable regardless of its severity. A model for the calculation of cardiovascular risk specifically in diabetic patients has been recently developed from the United Kingdom Prospective Diabetes Study (UKPDS) cohort, which takes into account several markers of diabetes severity.8 In our opinion, this approach would be highly recommendable from both an epidemiological and a pathophysiological point of view. Indeed preliminary data from our group, obtained in a local diabetic population database of about 1000 subjects, have shown large variability in the cardiovascular risk estimation, comparing the US-based Framingham score, the Italian Riscard score and the UKPDS algorithm. This evidence highly encourages the development of locally based risk charts for the diabetic population; such project is currently underway in our unit.
Non-pharmacological measures are seen as a landmark in the treatment of hyperlipidaemia, particularly when the stigmata of the metabolic syndrome are also present. Adherence to proper lifestyle and dietary habits can counteract most of the components of the syndrome (weight excess, dyslipidaemia, diabetes, hypertension) in the absence of any side effect; furthermore, diet bears a favourable impact on plasma cholesterol even when superimposed to pharmacological therapy.9
Nonetheless the pharmacological approach, often necessary in order to achieve optimal lipid profile, has shown important benefits. A body of evidence comes from large trials with hydroxymethyl-glutaryl (HMG)-CoA reductase inhibitors or statin drugs. In most trials where a subpopulation of diabetic patients were present, both in primary and secondary prevention, the protective effects of statin treatment were impressive, often being more marked than in the non-diabetic population.10–12 Such evidence was confirmed by a recent large trial, specifically conducted in a diabetic population, where statin treatment induced a 37% relative risk reduction of cardiovascular events compared with placebo.13 On the basis of their pharmacological action, fibric acid derivatives (fibrates), being particularly active in lowering plasma triglycerides, raising HDL cholesterol and reducing the levels of small-dense LDL, should be very useful in the treatment of dyslipidaemia in the metabolic syndrome. Recent evidence has indeed shown a benefit of fibrate treatment on coronary diameter, determined by angiography, in diabetic patients.14
In general, convincing evidence in the literature strongly supports the need for a multidisciplinary integrated approach in the management of the metabolic syndrome. Intensive treatment of dyslipidaemia, diabetes and hypertension has a significant impact on cardiovascular morbidity,15 and therefore needs to be actively pursued, by both non-pharmacological and pharmacological means; this obviously implies strong motivation by both the patients and their physicians.
This work was partly sponsored by grant COFIN-PRIN 2004067491 of the Italian Ministry of Education, University and Research.