Diabetic dyslipidemia: extending the target beyond LDL cholesterol

Lipids in diabetes

A number of patterns of lipid abnormalities are encountered in patients with diabetes. Given the common presence of both diabetes and hypercholesterolemia in patients with coronary artery disease many patients are found to have elevated levels of low-density lipoprotein (LDL) cholesterol [4]. However, in many other patients with diabetes LDL cholesterol seems to be in ‘normal’ limits. In these patients the predominant lipid abnormalities include hypertriglyceridemia, low levels of high-density lipoprotein (HDL) cholesterol and the presence of small, dense LDL particles [4]. This atherogenic dyslipidemia phenotype is likely to have a particularly detrimental effect at the level of the arterial wall, given the atherogenicity of triglyceride-rich particles and protective role of HDL. In addition, the activation of plasma lipase activity and inflammation in association with diabetes and abdominal adiposity are likely to promote increasing generation of smaller, dense LDL particles. Given that small, dense LDL particles are more likely to undergo oxidative modification there is increasing susceptibility to foam cell formation and propagation of atherosclerotic plaque.

Lowering low-density lipoprotein cholesterol

Over the last century, the role of LDL cholesterol in atherosclerotic cardiovascular disease has become well established. A curvilinear relationship between levels of LDL cholesterol and prospective risk of coronary heart disease has been consistently demonstrated in population studies [5]. The finding that lowering LDL cholesterol with statins in large placebo-controlled trials of both primary and secondary prevention [6–12] has promptedtheir increasing use in treatment algorithms for risk reduction. Subgroup analysis showed no evidence of heterogeneity with regard to treatment benefit in diabetic patients [13]. The Collaborative Atorvastatin Diabetes Study [14] directly investigated the impact of statin therapy in 2838 patients with type 2 diabetes and one other risk factor, LDL cholesterol less than 160 mg/dl (4.2mmol/l) and no clinical evidence of cardiovascular disease. Treatment with atorvastatin 10 mg daily was associated with a 37% reduction in vascular events over 4 years compared with placebo. In a recent meta-analysis of lipid-lowering trials involving 18 686 diabetic patients, it was reported that each mmol/l reduction in LDL cholesterol was associated with a 9% reduction in allcause mortality and 21% reduction in major vascular events [15]. Given these findings LDL cholesterol remains a major target for the therapeutic intervention for cardiovascular prevention in diabetics. The classification of diabetes as a coronary risk equivalent has prompted treatment guidelines to endorse a treatment goal of less than 100 mg/dl (2.6 mmol/l) for all patients with diabetes and less than 70 mg/dl (1.8mmol/l) for those deemed to be at particularly high risk of an adverse cardiovascular outcome [2,16].

Fibrates

Fibric acid derivatives (fibrates) are relatively weak agonists of peroxisome proliferator-activated receptor (PPAR-α). Fibrates lower triglycerides by 20-50% and raise HDL cholesterol by 5-20%. These lipid effects are likely to result from transcriptional expression of HDLassociated apolipoproteins (A-I and A-II), lipoprotein lipase and factors involved in the facilitation of cholesterol mobilization from peripheral tissues to the liver (ATP-binding cassette A1 and scavenger receptor-BI) [19]. The finding that PPAR-α agonists have a favorable impact on inflammatory pathways is likely to contribute to a potential beneficial influence on the artery wall [19].

Early studies demonstrated that gemfibrozil administration reduces cardiovascular events in trials of both primary and secondary prevention [20,21]. Of interest, modest elevations in HDL cholesterol, but not lowering triglycerides, independently predicted the clinical benefit in these studies [22]. Subsequent studies showed that this benefit was largely attributed to the generation of smaller forms of HDL [23], which have been reported to possess potent cholesterol efflux and anti-inflammatory activities [24]. The observation that the greatest event reduction with fibrates was observed in those patients with an elevated body mass index, low HDL cholesterol and high triglyceride at baseline supports their potential for benefit in patients with diabetes [25,26].

Given the difficulty in administering gemfibrozil in combination with statins there has been considerable interest in the potential to use alternative fibrates for risk reduction. Early use of micronized fenofibrate was demonstrated to slow progression of obstructive disease on coronary angiography in the Diabetes Atherosclerosis Intervention Study [27]. However, when directly evaluated in a cohort of 9795 type 2 diabetics in the Fenofibrate Intervention and Event Lowering in Diabetes study [28] the impact on cardiovascular outcomes was disappointing. Despite no reduction in the composite endpoint of coronary death or nonfatal myocardial infarction, fenofibrate administration was associated with a 24% reduction in nonfatal myocardial infarction and 21% reduction in need for coronary revascularization. This was balanced by the finding of a nonsignificant greater rate of cardiovascular mortality in fenofibrate-treated patients. The higher rate of statin initiation in the placebo group and minimal rise in HDL cholesterol with fenofibrate may have contributed to the lack of overall benefit in the study. The Action to Control Cardiovascular Risk in Diabetes study [29] is currently testing the clinical impact of fenofibrate versus control, in addition to background statin therapy.

Thiazolidinediones

Thiazolidinediones are agonists of the PPAR-γ receptor with beneficial effects on insulin sensitivity, lipids, and inflammatory markers. The combination of improving glycemic control with raising HDL cholesterol by 15-20% and lowering of triglycerides by 30-50% and C-reactive protein by 40-50% with pioglitazone is associated with a beneficial impact on progression of carotid intimal-medial thickness (CIMT) [30] and coronary atherosclerosis [31]. Subsequent analyses showed that raising HDL cholesterol was the strongest independent predictor of the ability of pioglitazone to slow CIMT progression [32]. Despite these effects, pioglitazone did not reduce a composite of cardiovascular endpoints in the Prospective Pioglitazone Clinical Trial in Macrovascular Events [33]. The relative contribution of inclusion of lower limb surgical procedures in the endpoint to the lack of overall benefit remains uncertain, particularly given the finding of a lower rate of myocardial infarction and stroke in the pioglitazone group. The latter finding is supported by the demonstration of cardiovascular benefit in a metaanalysis of trials involving pioglitazone [34]. Although a number of small studies have reported potentially beneficial effects of rosiglitazone at the level of the vessel wall, a meta-analysis suggested a potential increase in myocardial infarction [35]. This observation has not been replicated in subsequent clinical trials [36] and requires ongoing investigation. There remains considerable interest in the development of more potent PPAR-α agonists or use of agents that target more than one PPAR-α subtype. However, this field has been challenged by a lack of incremental efficacy or toxicity with a large number of experimental agents.

Niacin

Niacin has a combination of effects on plasma lipid parameters including lowering levels of LDL cholesterol, triglycerides, and lipoprotein (a), in addition to the most prominent raising of HDL cholesterol with currently available therapies. The Coronary Drug Project [37] provided early evidence of benefit with niacin, with significant reductions in both nonfatal myocardial infarction and long-term mortality, in an era that preceded use of statins. This is supported by numerous observations that niacin administration has a beneficial influence on progression of CIMT [38–40] and atherosclerosis within the coronary [41] and carotid [42] territories. Although niacin administration can impair glycemic control in diabetic patients, there is currently no evidence that its use is not likely to be beneficial in diabetic subgroups. The major hurdle to its widespread use has been due to the inability of many patients to tolerate doses high enough to have a therapeutic effect on lipids. Attempts to minimize flushing, permitting patients to achieve higher doses, are currently under investigation in large clinical trials.

Fish oils

Fish oils have been reported to have a number of beneficial effects across the spectrum of cardiovascular disease from early formation of atherosclerotic plaque through to ventricular remodeling and electrical instability in the setting of myocardial damage. The observation that fish oils lower triglyceride levels, in addition to potentially favorable effects on systemic inflammatory markers and platelet activity, provide an additional lipidmodifying approach for patients with diabetes. The impact of fish oils on disease progression and clinical outcome remains to be determined in clinical trials [43].

Remodeling factors

Plasma lipoproteins are constantly remodeled by a number of factors that result in changes in size, shape, and lipid composition of circulating particles [44]. This results in considerable heterogeneity of the circulating lipoprotein pool, which may influence both the level of conventional lipid parameters and potentially their relative functionality at the level of the vessel wall. Accordingly, there has been increasing interest in the development of new therapeutic agents that directly target these factors. Cholesteryl ester transfer protein (CETP) facilitates the transfer of esterified cholesterol from HDL to very low-density lipoprotein (VLDL) and LDL, in exchange for triglyceride [45]. The observations that some populations with low levels of CETP activity seem to be protected from cardiovascular disease [46] and that CETP inhibitors substantially raise HDL cholesterol in humans [47] and are atheroprotective in animals [48,49] has prompted immense interest in development of pharmacologic inhibitors as a preventive strategy. Although the first CETP inhibitor to reach an advanced stage of clinical development, torcetrapib, was associated with an excessive rate of mortality [50] and did not slow progression of either CIMT [51,52] or coronary atherosclerosis [53], it has also become apparent that the agent had considerable off-target toxicity [54]. As a result, there remains considerable interest in the development of CETP inhibitors that lack such toxicity. Given that low HDL cholesterol levels are low in many patients with diabetes there would be considerable interest in the use of CETP inhibitors if they were ultimately demonstrated to be clinically effective in humans.

A large number of phospholipases also play an important role in lipoprotein remodeling. Considerable interest has focused on the potential to inhibit various members of the phospholipase family, given their influence on LDL particles and potential role in the promotion of inflammatory and oxidative pathways in the arterial wall [55]. Systemic levels of lipoprotein-associated phospholipase A2 have been demonstrated to predict cardiovascular risk in population studies [56]. A pharmacologic inhibitor of lipoprotein-associated phospholipase A2, darapladib, has been demonstrated to have a favorable impact on the size of the necrotic core in coronary atheroma [57] and is currently being evaluated in a large morbidity-mortality trial. An inhibitor of secretory phospholipase A₂ has also been evaluated in early clinical trials with favorable effects on systemic inflammatory biomarkers and levels of LDL cholesterol [58]. The impact of phospholipase inhibition in diabetics remains to be determined.