COMMENTARIES

Effects of Statins on the Atherogenic Lipid Subclasses Commonly Associated With Hypertriglyceridemia

Dean G. Karalis, M.D., FACC, Drexel University College of Medicine, Department of Cardiology, Philadelphia, PA, United States
Please address correspondence to:
Dean G. Karalis, M.D.
Drexel University College of Medicine
Hahnemann University Hospital
227 North Broad Street, Suite 200
Philadelphia, PA, 19107
Tel: (215) 762-8272
Fax: (215) 564-3398
E-mail: dgk25@drexel.edu

Dean G. Karalis

Recent studies have shown that elevated levels of serum triglycerides (TG) are an independent risk factor for coronary heart disease (CHD) [1]. The atherogenicity associated with high levels of TG is thought to be due to the atherogenic lipoprotein subclasses commonly associated with hypertriglyceridemia [2,3] Statins have been shown to reduce cardiovascular events in both individuals with or at risk for CHD [4-6]. These benefits are thought to be due to the statin’s effects in lowering low density lipoprotein (LDL) cholesterol. However, statins have effects on other lipoproteins as well. This discussion will review the effects of statins on the lipid subclasses commonly associated with hypertriglyceridemia.

 
Triglyceride-rich Remnant Lipoproteins

High levels of TG lead to the production of large very-low density lipoprotein (VLDL) particles. Degradation of these large TG-rich VLDL particles by lipoprotein lipase results in small VLDL and intermediate density lipoprotein (IDL) remnants which are particularly atherogenic. Statins not only lower TG levels but also lower the levels of these TG-rich remnant lipoproteins. Schaefer and colleagues examined the effects of atorvastatin on remnant lipoproteins in 103 patients with CHD and normal levels of TG, and reported a significant reduction in cholesterol and TG levels in remnant-like particles [7]. Other statins have also been shown to reduce levels of TG-rich lipoproteins [8,9]. The more potent the statin and the higher the dose, the greater is the reduction in the levels of these remnant lipoproteins. In 151 patients with type 2 diabetes and hypertriglyceridemia both 40 and 80 mg of simvastatin lowered levels of small VLDL (VLDL3) and IDL more than placebo, with the higher dose of simvastatin lowering VLDL3 levels more than the lower dose (35 versus 30%; p < 0.05) [9]. In comparator trials, atorvastatin has been shown to lower the levels of TG-rich remnant lipoproteins more than lovastatin, fluvastatin, pravastatin, or simvastatin [10]. We evaluated the effects of differing doses of atorvastatin in 191 men and women with baseline TG levels > 200 mg/dL and demonstrated that higher doses of atorvastatin not only lowered TG but also significantly lowered the levels of the TG-rich remnant lipoproteins VLDL3 and IDL more than did lower doses [11]. The greatest benefit was seen at the 80 mg dose, at which VLDL3 and IDL were both lowered by 55%. At the 80 mg dose, over 83% of patients achieved normal levels of VLDL3 and IDL compared to 55% with the 10 mg dose of atorvastatin. The reduction in the levels of these TG-rich lipoproteins correlated significantly with the reduction in total TG levels. It would be expected that the higher the baseline TG level the greater the reduction in TG-rich remnant lipoproteins that would occur with statin therapy. In a small study, rosuvastatin at a dose of 40mg a day significantly lowered the cholesterol in remnant like particles in those patients with hypertriglyceridemia, but not in those with normal baseline TG levels [12].

Reducing levels of these TG-rich remnant lipoproteins is clinically important because of their atherogenic potential. Small VLDL (VLDL3) and IDL are remnants derived from the metabolism of large, TG-rich VLDL particles and in clinical studies both of these remnant particles have been shown to be associated with atherosclerotic progression and increased cardiovascular risk, independent of total levels of fasting TG [13,14].

 
Small Dense LDL Cholesterol

In individuals with hypertriglyceridemia, LDL cholesterol particles are predominately small and dense. The production of small and dense LDL particles is linked metabolically to an overproduction of the large subclass of VLDL. TG in the large VLDL subclass are exchanged for cholesteryl esters on the large LDL particles by cholesteryl ester transfer protein (CETP) enriching these LDL particles with TG. The TG in LDL are hydrolyzed by hepatic lipase producing a small and dense cholesteryl ester depleted LDL particle [15]. Small dense LDL particles are more likely to enter the arterial wall and be oxidized, and are thought to be the most atherogenic LDL subclass [15].

Statins are the most effective drugs in lowering the concentration of small dense LDL particles. We have shown that atorvastatin at each dose significantly lowered the concentration of small dense LDL, with higher doses of atorvastatin having more favorable effects on the concentration of small dense LDL particles than lower doses [11]. LDL size was also favorably changed with each dose of atorvastatin, shifting LDL particle size from the more atherogenic small dense to the less atherogenic, larger, more buoyant LDL particle size. Although the shift in LDL size was not dose dependant, higher doses of atorvastatin lowered the concentration of small, dense LDL cholesterol more than lower doses. In total, therefore, LDL size and concentration were more favorably shifted with higher compared to lower doses of atorvastatin. The change in the concentration of small dense LDL cholesterol was predicted by the change in total LDL cholesterol, while the change in the size of LDL cholesterol particles was predicted by the change in TG levels. Statins decrease VLDL production and in hypertriglyceridemia this may shift small dense LDL to larger, more buoyant LDL particles. Our findings are consistent with other studies that evaluated the effects of other statins on LDL subclass distribution [16-19]. Both rosuvastatin [12] and simvastatin [9] have also been shown to significantly reduce the concentration of small dense LDL cholesterol.

The effects of statins on the size and concentration of small dense LDL particles may in part explain how they prevent cardiovascular events. In a post hoc analysis of the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study investigating the effects of high dose atorvastatin in patients with acute coronary syndromes, the investigators proposed that the beneficial effects of high dose statin therapy on ischemic events were due to changes in the size and composition of LDL, rather than in changes in the concentration of LDL cholesterol [19]. In a post hoc analysis from the Familial Atherosclerosis Treatment study the change in LDL size was the most important predictor of atherosclerotic regression, and was more important than the change in the level of LDL cholesterol itself [20].

 
HDL Subclasses

In the setting of hypertriglyceridemia, high density lipoprotein (HDL) particles become TG enriched by exchange of cholesteryl esters for TG by CETP. Hydrolysis of TG in the HDL core by hepatic lipase produces smaller HDL particles that are more avidly taken up and degraded by the kidney, lowering the concentration of HDL cholesterol. As with LDL cholesterol, HDL cholesterol particles vary in size and composition. HDL is categorized into 2 major subclasses: HDL2, which is larger and more enriched in cholesterol and HDL3, which is smaller and has lower cholesterol content. The levels of HDL2 are thought to be a measure of reverse cholesterol transport, with higher levels reflecting more efficient reverse cholesterol transport. Higher levels of HDL2 are associated with less atherosclerotic progression and a lower risk of cardiovascular events [21,22].

Treatment with statins results in a small increase in HDL cholesterol levels [23]. We have shown in patients with hypertriglyceridemia that both lower and higher doses of atorvastatin increase HDL cholesterol from baseline with the greatest increases seen in the larger HDL2 subclass [11]. Although, other studies [24] have demonstrated that at the maximal 80 mg dose of atorvastatin the rise in HDL cholesterol is less than that at the lower doses, we observed no significant difference in the increase in HDL cholesterol and its subclasses between the lower and higher doses of Atorvastatin [11]. This may be due to the greater reduction in TG levels seen with the higher dose of atorvastatin. As TG levels fall with high-dose statin therapy, the HDL particle contains more cholesteryl ester and less TG. Metabolism of these less TG-rich HDL particles produces larger HDL particles and higher HDL cholesterol levels [25].

 
Conclusions

Diabetic patients often have a dyslipidemia characterized by increased triglyceride levels, low levels of HDL cholesterol, and LDL particles that are predominately small and dense. In the Collaborative Atorvastatin Diabetes Study (CARDS), diabetic patients with normal levels of LDL cholesterol had a 37% reduction in major cardiovascular events with low dose atorvastatin [26]. The beneficial effects of atorvastatin on reducing TG-rich remnant lipoproteins and on LDL particle size may have contributed to the clinical benefits seen in this study. Furthermore, there have now been several studies which have demonstrated that high doses of more potent statins reduce cardiovascular events or lead to less atherosclerotic progression compared to lower doses of similar or less potent statins [4]. These benefits are thought to be due to the greater LDL cholesterol reduction seen with high dose statin therapy, but also may be in part due to other non-LDL cholesterol effects. The benefits of further reducing TG-rich remnant lipoproteins and more favorably changing the concentration and size of LDL cholesterol particles may help to explain the clinical benefits seen in the high dose statin trials.

          In conclusion statins not only lower LDL cholesterol and TG levels but also significantly lower levels of TG-rich remnant lipoproteins and favorably changed LDL particle size and concentration in patients with hypertriglyceridemia. Higher doses of more potent statins have more favorable effects on the lipid subclasses commonly associated with hypertriglyceridemia that do lower doses of less potent statins. These non-LDL cholesterol effects may explain in part the clinical benefits of high dose statins seen in the large outcome trials.

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