Managing diabetic dyslipidaemia—beyond LDL-C:HDL-C and triglycerides

Abstract

Treatment with statins reduces coronary risk In all people but do not remove the risk associated with a low HDL-C or with other features of the metabolic syndrome such as an elevated level of plasma triglyceride or with a high BMI. Treatment with a fibrate such as gemfibrozil (a PPAR alpha agonist) has been shown to be especially effective in people with low HDL-C and other features of the metabolic syndrome. Potential beneficial effects of the combination of a statin and an agent with PPAR alpha activity in patients with type2 diabetes is currently being addressed in the ongoing Action to Control Cardiovascular Risk in Diabetes (ACCORD) study.

Introduction

Atherogenic dyslipidaemia in type 2 diabetes manifests mainly as an increase in plasma triglycerides. In addition, there is increased Apo B, increased small dense low-density lipoprotein cholesterol (LDL-C) particles and decreased high-density lipoprotein cholesterol (HDL-C). A similar pattern is seen in insulin resistance and metabolic syndrome. It is well known from Framingham data that HDL-C and LDL-C are independent risk factors [1]. A low HDL-C increases coronary heart disease (CHD) risk regardless of the LDL-C level.

In the Prospective Cardiovascular Munster study (PROCAM), 4559 male participants were examined for cardiovascular risk factors and then kept under observation to record mortality and cardiovascular events including myocardial infarction and stroke [2]. Interestingly, the results showed that a high triglyceride level in the absence of high LDL-C/low HDL-C does not increase risk of CHD. However, if the LDL-C/HDL-C ratio is greater than 5, then an increased triglyceride level confers an additional risk [2] (Fig. 1).

According to the results of the PROCAM study, the prediction of risk for myocardial infarction or coronary artery disease cannot be based on LDL cholesterol determination alone. At moderately (160–189 mg/dL) and severely (≥190 mg/dL) elevated LDL cholesterol concentrations, the risk of atherosclerotic CAD increased approximately 2.5-fold in hypertriglyceridemic persons. The importance of the triad of high triglycerides, low HDL cholesterol and elevated LDL cholesterol is provided by recent analysis of the Helsinki Heart Study [3].

Taken together, the data from the PROCAM and the Helsinki Heart studies suggest that the hypertriglyceridemia/low HDL cholesterol syndrome constitutes a powerful risk factor for non-fatal myocardial infarction or CAD death that would escape attention if LDL cholesterol levels alone were determined. For practical purposes it appears advisable to base risk prediction of atherosclerotic CAD and treatment decision on a full lipid profile (cholesterol, triglycerides, LDL cholesterol, HDL cholesterol) rather than cholesterol or LDL cholesterol determination alone [2].

In order to understand the role of lipids in the development of CHD disease, it is important to examine what is happening at the endothelial level. As LDL-C passes across the endothelium it is modified and stimulates macrophage chemoattractant protein-1 (MCP-1) to recruit monocytes, and also stimulates differentiation into macrophages, which express scavenger receptors that take up lipid to make foam cells. These foam cells produce growth factors and proteinases. They also release cytokines to stimulate the endothelium to make adhesion proteins that recruit more monocytes and, in this way, a vicious cycle is initiated [4]. It is also known that the triglyceride-rich remnants of either chylomicrons or very low density lipoproteins (VLDL) not only act the same as LDL-C at the level of the endothelium, but act at much lower concentrations. These remnants are perhaps even more atherogenic. Moreover, the remnants are much more likely to be increased in diabetics and metabolic syndrome than is LDL-C [5].

HDL has multiple effects on the endothelium and can block the atherogenic process at several levels. The best known is the ability of HDL to promote efflux of cholesterol from foam cells and thereby prevent the formation of foam cells. HDL can also prevent the oxidising modification of LDL within the intima. In addition, HDL has been shown to inhibit the cytokine-induced expression of adhesion proteins and to inhibit MCP-1. It is also anti-thrombotic and anti-apoptotic [6] (Fig. 2).

Many studies have shown that an approximate 1% increase in HDL-C equates to an approximate 1% decrease in coronary risk. For example, in the Scandinavian Simvastatin Survival Study (4S) trial with simvastatin, each 1% increase in HDL-C predicted a 1% reduction in coronary events, independent of changes in LDL-C [7]. Also in the Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT) study, which used cholestyramine as the therapeutic intervention, each 1% increase in HDL-C predicted a 1% reduction in coronary events, again independent of changes in LDL-C [8]. In the Cholesterol and Recurrent Events (CARE) and Long-term Prevention with Pravastatin in Ischaemic Disease (LIPID) studies, it was found that for both the placebo group and the group receiving treatment with pravastatin, the higher the baseline HDL-C, the lower the risk of a cardiac event [9]. Importantly, while statin treatment reduced risk whether the baseline HDL-C was high or low, it did not eliminate the risk associated with a low baseline level of HDL-C [9]. Similarly in the West of Scotland Coronary Prevention Study (WOSCOPS) study, the risk of having an event in the placebo group reduces as the baseline HDL-C increases [10]. While everyone in the treatment group benefited from receiving pravastatin, again the risk associated with a low HDL-C was not eliminated (Fig. 3). This finding is also supported by the results from 4S and Heart Protection Study (HPS) [11], [12]. It can be concluded from all these studies that while statins reduce coronary events in subjects with high and low HDL-C, a low baseline HDL-C remains predictive of cardiac events, even in subjects treated with statins.

In contrast to the statin trials, the Helsinki Heart Study, with gemfibrozil (a fibrate) as the intervention, found that for each 1% increase in HDL-C, a 3% reduction in coronary event was predicted and this was independent of changes in LDL-C [13]. In fact, fibrates (PPAR alpha agonists) almost eliminate the risk associated with a low baseline HDL-C. In the VA-HIT study, concentrations of HDL-C achieved with gemfibrozil treatment predicted a significant reduction in CHD events in patients with low HDL-C levels. However, the change in HDL-C levels only partially explained the beneficial effect of gemfibrozil [14] (Fig. 4).

Following these impressive results, there has been much interest in identifying which patients would benefit most from treatment with fibrates. From these studies, it appears that the benefits of fibrates are greatest in people with features of the metabolic syndrome, not just in those with a low HDL-C. Attention has focused on examining the individual components of the metabolic syndrome to predict risk reduction in people treated with lipid-lowering drugs. Four typical features of the metabolic syndrome have been examined: weight, plasma triglyceride, low HDL-C and insulin resistance as indicated by plasma insulin level.