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Statins and HDL Cholesterol
Abstract & Commentary
By Michael H. Crawford, MD, Professor of Medicine, and Chief of Clinical Cardiology, at the University of California, San Francisco. Dr. Crawford is on the speaker's bureau for Pfizer.
Source: Asztalos BF, et al. Comparison of the Effects of High Doses of Rosuvastatin Versus Atorvastatin on the Subpopulations of High-Density Lipoproteins. Am J Cardiol. 2007;99:681-685.
Synopsis: Rosuvastatin and atorvastatin at their maximal doses, favorably change HDL subpopulation levels, but rosuvastatin is significantly more potent than atorvastatin for this purpose.
The failure of new drugs that raise HDL cholesterol to change outcomes has renewed interest in HDL subpopulations. Thus, Asztalos and colleagues analyzed HDL subpopulations in the Statin Therapies for Elevated Lipid Levels compared Across doses to Rosuvastatin (STELLAR) trial. This study showed that 40 mg/day of rosuvastatin exhibited the greatest increase in HDL (+10%) versus (+2%) for atorvastatin 80 mg/day (Clin Ther 2004;26:1388 and Am J Cardiol 2003;92:152). This was a multi-centered open-label randomized study conducted in the U.S. that compared the effects of 4 statins on various lipoprotein values. The current analysis involved serum samples from baseline and after 6 weeks of therapy, plus diet in over 300 patients in the rosuvastatin 40 mg/day group and the atorvastatin 80 mg/day group. They assayed Apo A-1 levels and 8 subpopulations of HDL. About half the subjects were men and the average age of the two groups were 56 and 58 years. Baseline lipid, lipoprotein and HDL subpopulation values were well matched between the 2 treatment groups. Apo-1 increased 5% on rosuvastatin and decreased 1% on atorvastatin (p < .001). Both drugs decreased total cholesterol, triglycerides and LDL cholesterol to a similar degree. HDL was increased more on rosuvastatin (10% vs 3%), as was Apo-1 (5% vs 1, p < .001). Increases in α-1 and α-2 HDL have been previously shown to decrease the risk of coronary heart disease (CHD) and CHD events; both of these subpopulations were increased significantly by statin treatment (24% rosuvastatin and 12% atorvastatin for α-1 and 13 vs 4% for α-2, both p < .001 for the difference between treatment groups). The pre α-1 subpopulation was decreased similarly by both drugs suggesting a shift of cholesterol to the larger α particles (reversed cholesterol transport). Individuals with baseline low HDLs (< 40 mg/dl men, < 50 mg/dl women) showed an even greater difference between the effects of rosuvastatin vs atorvastatin (α-1 32% vs 11% and α-2, 21% vs 5%). The authors concluded that both rosuvastatin and atorvastatin at their maximal doses, favorably change HDL subpopulation levels, but rosuvastatin is significantly more potent than atorvastatin for this purpose.
There are several interesting aspects to this study. First, changes in total cholesterol, LDL, HDL and triglycerides were nearly identical between rosuvastatin and atorvastatin at their maximum recommended doses. So claims that rosuvastatin is more potent does not hold up when maximum doses are considered. This is reminiscent of what happened when atorvastatin was released with claims of increased potency over simvastatin. Suddenly the maximum dose of simvastatin was increased from 40 to 80 mg to minimize these differences. Was the impending release of rosuvastatin the driving force behind atorvastatin 80 mg? If one believes adverse events are more likely with higher doses of a drug, then rosuvastatin 40 may be preferable to atorvastatin 80. Second, although both drugs at maximum doses favorably altered the HDL subpopulations, the effect of rosuvastatin was of a much greater magnitude, especially in those with low HDL at baseline, but also in those with high triglycerides at baseline. Although observational studies suggest that the particular HDL subpopulation profile achieved with these drugs is associated with less CHD, only prospective treatment trials focusing on outcomes can establish this. Whether the differences between the 2 drugs will affect outcomes is unknown. However, this data suggests that rosuvastatin is more potent at favorably altering HDL subpopulations, which could be an advantage of this agent.
Third, the decrease in pre α-1 HDL and the increase in the cholesterol rich α particles suggest that reverse cholesterol transport may be enhanced by these statins. Pre α-1 particles avidly take up cholesterol from the periphery and deliver it to the liver. This pathway is not enhanced by the new direct cholesterol ester transport protein inhibitors, which may explain their failure to reduce atherosclerosis despite markedly raising HDL levels. Both statins showed about a 40% decrease in pre α-1 particles.
Baseline characteristics of the patients studied are worth noting to see if you can expect similar results in the patients you are treating. They had relatively normal HDL levels on average (about 50 mg/dl), but very high LDL levels (about 190 mg/dl) and moderately high triglyceride levels (about 180 mg/dl). Only about 20% had known vascular disease and < 10% were diabetic. Whether the results observed would be found in a population with more comorbidity is not known.