In view of the strong relationship between elevated plasma triglycerides and the small dense LDL phenotype, triglyceride lowering therapies could be expected to have a greater impact on LDL size and density than predominantly cholesterol lowering therapies. The HMG CoA reductase inhibitors (statins) lower LDL cholesterol substantially and their value in reducing CAD mortality and morbidity has been demonstrated conclusively [2–4]. These drugs have little effect on particle size when tested in patients with the small dense LDL phenotype. Simvastatin caused a decrease in both large and small LDL particles in combined hyperlipidaemic patients, with no overall improvement in the subclass phenotype [57]. Pravastatin reduced total and LDL cholesterol in combined hyperlipidaemic patients but LDL particle size was either unchanged or became even smaller [58, [59]. In familial hypercholesterolaemia, lovastatin and simvastatin decrease cholesterol more in the light LDL than in dense particles [60]. These statins cause little or no decrease in plasma triglycerides in the combined and familial hyperlipidaemic patients, which may explain why there is generally no reduction of small, dense LDL particles. Any apparent worsening of LDL phenotype by statins may be due to up-regulation of LDL receptors, preferentially increasing clearance of larger LDL particles which have a higher affinity for LDL receptors. As a result, small LDL particles come to dominate the plasma LDL subfraction profile. Potentially adverse effects of statins on LDL density profiles are clearly more than offset by the beneficial effects of reducing the total plasma LDL cholesterol pool, as evidenced by the reduction of CAD events which has been demonstrated in recent clinical trials [2–4]. A new member of the HMG CoA reductase inhibitor, atorvastatin, lowers plasma triglycerides more than other marketed statins at licensed doses [61]. As a result it may have greater beneficial effects on LDL density profiles than other currently licensed statins.
The impact of aggressive lipid lowering on CAD progression and the relationship to small dense LDL was evaluated in a retrospective analysis of data from the Familial Atherosclerosis Treatment Study, FATS [62]. Patients treated with nicotinic acid plus cholestyramine or lovastatin plus cholestyramine experienced a significant reduction in coronary stenosis severity compared to controls. There was a strong inverse relationship between the changes in LDL density and coronary stenosis. The reduction of small, dense LDL was a stronger predictor of decreased disease progression than was reduction of LDL cholesterol. Combinations of nicotinic acid plus cholestyramine and lovastatin plus cholestyramine decreased plasma triglycerides [63, [64], which probably contributed to the improvement in the small dense LDL phenotype. Cholestyramine alone tended to increase the level of small, dense LDL [63, [64]. This is probably due to up-regulation of LDL receptors. These preferentially bind (and hence clear) larger more buoyant LDL particles. Nicotinic acid alone reduces the concentration of small dense LDL [63, 65]. Nicotinic acid is more effective at lowering plasma triglycerides than cholesterol and in hypertriglyceridaemic patients the change in LDL phenotype caused by nicotinic acid is both correlated with baseline triglyceride levels and the reduction in triglycerides after treatment [65]. It causes only a modest reduction of LDL particle diameter in individuals with normal plasma triglycerides but a more marked reduction in particle size in subjects with hypertriglyceridaemia [63, 65].
Currently, the most widely used triglyceride lowering agents are fibrates. Several of these agents, including gemfibrozil, fenofibrate, bezafibrate and ciprofibrate, decrease small dense LDL in patients with combined hyperlipidaemia [66–68]. Gemfibrozil increased LDL particle size and decreased particle density in patients with triglycerides in the approximate range of 3.5–9.0 mmol l−1 [68]. The effect was strongly correlated with the reduction of triglycerides. Gemfibrozil had no effect on LDL density profile in hypercholesterolaemic patients with normal triglyceride levels (1.3 mmol l−1), in whom LDL particles were larger and less dense [68]. In hypercholesterolaemic patients with somewhat higher triglycerides (2.0 mmol l−1), gemfibrozil shifted LDL to the larger and less dense phenotype in association with reduced triglycerides [66]. Thus, the effect of gemfibrozil and the other fibrates on LDL size and density depends on the baseline triglyceride levels. Elevated plasma triglycerides favor the transfer of VLDL triglycerides to LDL by CETP. The subsequent hydrolysis of LDL triglyceride generates small dense LDL [69]. By reducing plasma triglycerides, fibrates limit the amount of substrate available for CETP-mediated transfer to LDL and thereby decrease the formation of small dense LDL. In addition, fenofibrate was found to decrease CETP mass and transfer activity, which further limits the formation of small dense LDL [70].
Despite having only a modest effect on LDL-cholesterol, bezafibrate may reduce progression of coronary atherosclerosis and coronary events in young men following myocardial infarction [71]. Likewise, a subgroup analysis of patients in the Helsinki Heart study demonstrated a reduced number of ischaemic events in patients randomised to gemfibrozil [72]. Their pharmacological effects suggest that combination therapy with a statin and fibrate could be of particular benefit in dyslipidaemic patients with a preponderance of small dense LDL, a hypothesis that needs to be tested by clinical trials.
As discussed above, small dense LDL profile is associated with insulin resistance. Interventions that improve insulin sensitivity include exercise [73], thioziodolinediones [74] and possibly imidazoline receptor agonists [75] while reports on fibrates remain controversial. Insulin resistance, hypertension, hypertriglyceridaemia and small dense LDL particles coexist and together form the metabolic syndrome which is strongly associated with atherosclerosis (‘syndrome X’). Interventions on these factors could increase LDL particle size. The thiazoledinedione, troglitazone, causes a small increase in LDL cholesterol in obese individuals [76] due to an increase in large, less dense LDL. This may explain the observation that troglitazone increases the resistance of LDL particles to oxidation [77, [78]. It is possible that troglitazone is protective against atherosclerosis. The shift in the LDL particle density is associated with a statistically insignificant decrease in plasma triglycerides, although larger effects on triglycerides are generally observed in patients treated with troglitazone [79]. Since the small, dense LDL profile is associated with insulin resistance, the improvement caused by troglitazone may be related to its ability to improve insulin sensitivity. Further studies will be required to determine the relative roles of enhanced insulin sensitivity and of reducing plasma triglyceride in the effects of troglitazone on LDL density.
Troglitazone and other thiazolidinediones exert their pharmacological effects by binding to the peroxisome proliferator activated receptor (PPAR) type γ found predominantly in adipocytes [80]. The precise mechanism by which they improve insulin sensitivity is not fully known, but is at least partially attributable to increased expression of a variety adipocyte genes involved in fatty acid metabolism [81]. The triglyceride lowering effects of thiazolidinediones also seems to involve PPARγ-mediated effects on adipocyte gene expression. Interestingly, triglyceride lowering fibrates exert their major pharmacologic activity by binding to a PPAR, in this case PPARα, which is expressed primarily in the liver [82]. Both the PPARγ (troglitazone) and PPARα ligands (fibrates) decrease plasma concentrations of small dense LDL. Their mechanisms overlap at the level of plasma triglycerides but there may be additional means by which they affect LDL density including effects on CETP. Recently, compounds were described that bind both PPAR and PPARα [83, [84]. These compounds decrease plasma triglycerides and increase insulin sensitivity in animal models. It is conceivable that such compounds may have greater effects on small dense LDL than thiazolidinediones or fibrates.
Additional therapeutic approaches that decrease plasma concentrations of triglycerides or transfer triglycerides between lipoprotein classes may influence the formation of small dense LDL. Thus, inhibitors of CETP and microsomal triglyceride transfer protein (MTP) which are currently under development may decrease small dense LDL. The value of these or other therapeutic approaches to modulate LDL size and density profiles still must be determined. Finally, studies in patients with differing degrees of insulin resistance and hypertriglyceridaemia should allow effects on particle size to be differentiated from effects on other factors. Such studies are needed to determine whether LDL particle size plays a direct role in atherogenicity. If so, evaluating the effects of different drug classes on particle size will play an increasing part in clinical cardiovascular pharmacology, influencing choice of therapy not only in dyslipidaemic states but in hypertension and diabetes.
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