The British Journal of Diabetes & Vascular Disease

The role of cholesterol in cardiovascular disease (CVD) and especially coronary heart disease (CHD) is well established. Epidemiological studies show consistent relationships between total cholesterol, low-density lipoprotein cholesterol (LDL-C) and CHD risk. These same studies show a strong inverse relationship for levels of high-density lipoprotein cholesterol (HDL-C) and CHD risk and a possible relationship for triglycerides.

The metabolic syndrome is a common syndrome affecting 20—25% of the population whose features include abdominal obesity, low-HDL-C, elevated triglycerides, hypertension, hyperglycaemia, hyperinsulinaemia, elevated inflammatory markers, renal dysfunction and microalbuminuria. In the UKPDS study in type 2 diabetes that compared the effects of improved glycaemic and blood pressure control, though some benefit was seen on cardiovascular end points with tighter control, the critical factors predisposing to later macrovascular disease were LDL-C and HDL-C.

There is extensive trial evidence for the benefits of statins in secondary and primary prevention. All guidelines state these are first-line agents for the treatment of cardiovascular risk. Statins have undoubted benefits in the treatment of patients with type 2 diabetes. Statins are also effective in reducing CVD in patients with metabolic syndrome. However, the focus on the benefits of statin therapy has limited discussion of their limitations. In all statin trials to date they reduce CVD events by 25—30% with the largest reduction in the GREACE study being 50%. Only high-dose statin therapy prevents progression of atherosclerosis. Thus, a single minded concentration on LDL-C may underestimate the benefits of a more integrated approach to the management of hyperlipidaemia.

High-density lipoprotein (HDL) removes excess cholesterol from macrophages in the artery wall, thereby reducing the rate of development of the cholesterol from macrophages in the artery wall, thereby reducing the rate of development of the atherosclerotic plaque. Other anti-atherogenic actions of HDL include preservation of endothelial function, inhibition of the recruitment of inflammatory cells to the developing plaque, antioxidant effects, and antithrombotic effects. Not surprisingly, large epidemiological cohort studies have identified low HDL-cholesterol (HDL-C) as a risk factor for coronary heart disease independently of levels of low-density lipoprotein cholesterol (LDL-C). Low HDL-C frequently occurs together with elevated triglycerides and the appearance of small, dense LDL, as a direct result of the metabolic changes associated with insulin resistance in conditions such as type 2 diabetes and the metabolic syndrome. The worldwide increase in these conditions and the associated increase in prevalence of low HDL-C have resulted in HDL being considered as a target for therapeutic intervention. Correction of low HDL-C should be an important target for therapy, especially in patients with type 2 diabetes and the metabolic syndrome.

Reduction of low-density lipoprotein cholesterol (LDL-C) is central to the management of cardiovascular risk associated with dyslipidaemia. Yet, at best, this strategy is only capable of a reduction of about 50% in ischaemic vascular disease. Therefore, there is still a need for interventive strategies to improve the situation. Triglyceride lowering and high-density lipoprotein cholesterol (HDL-C) elevation feature prominently in this context, a viewpoint increasingly adopted by international treatment guidelines. This article reviews current thinking on the subject and offers additional treatment strategies for the dyslipidaemic patient.

steady decline in cardiovascular mortality has occurred in recent decades, but a substantial burden of cardiovascular mortality remains. Intervention with statins, for example, has resulted in significant reductions in cardiovascular event rates in a broad range of patient populations, but these agents reduce cardiovascular event rates by only about 20—40%, despite profound reductions in low-density lipoprotein cholesterol (LDL-C) in some trials. Low high-density lipoprotein cholesterol (HDL-C) is a risk factor for adverse cardiovascular outcomes independent of levels of LDL-C. Well designed intervention trials have demonstrated marked improvements in cardiovascular outcomes with agents that raise levels of HDL-C. Combinations of statins with nicotinic acid, the most potent agent for increasing levels of HDL-C currently available, appear to be the most effective strategy for managing cardiovascular risk. Indeed, reductions in the risk of cardiovascular events of up to 90% relative to placebo with a nicotinic acid-statin combination were observed in the double-blind, randomised HDL Atherosclerosis Treatment Study (HATS). A once-daily, prolonged-release formulation of nicotinic acid, Niaspan® is as effective as immediate-release nicotinic acid with superior tolerability and safety. A randomised, double-blind placebo-controlled evaluation of Niaspan® added to a statin, the Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER 2) study, demonstrated significant inhibition of atherosclerosis in men with low HDL-C over only one year of treatment. Patients with low HDL-C are at elevated cardiovascular risk and combination treatment with nicotinic acid and a statin represents a rational and evidence-based treatment for this population.