Comparison of the effects of maximal dose atorvastatin and rosuvastatin therapy on cholesterol synthesis and absorption markers

Abstract

We measured plasma markers of cholesterol synthesis (lathosterol) and absorption (campesterol, sitosterol, and cholestanol) in order to compare the effects of maximal doses of rosuvastatin with atorvastatin and investigate the basis for the significant individual variation in lipid lowering response to statin therapy. Measurements were performed in participants (n = 135) at baseline and after 6 weeks on either rosuvastatin (40 mg/day) or atorvastatin (80 mg/day) therapy. Plasma sterols were measured using gas-liquid chromatography. Rosuvastatin and atorvastatin significantly (P < 0.001) altered plasma total cholesterol (C) levels by −40%, and the ratios of lathosterol/C by −64% and −68%, and campesterol/C by +52% and +72%, respectively, with significant differences (P < 0.001) between the treatment groups for the latter parameter. When using absolute values of these markers, subjects with the greatest reductions in both synthesis (lathosterol) and absorption (campesterol) had significantly greater reductions in total C than subjects in whom the converse was true (−46% versus −34%, P = 0.001), with similar effects for LDL-C. Rosuvastatin and atorvastatin decreased markers of cholesterol synthesis and increased markers of fractional cholesterol absorption, with rosuvastatin having significantly less effect on the latter parameter than atorvastatin. In addition, alterations in absolute values of plasma sterols correlated with the cholesterol lowering response. We measured plasma markers of cholesterol synthesis (lathosterol) and absorption (campesterol, sitosterol, and cholestanol) in order to compare the effects of maximal doses of rosuvastatin with atorvastatin and investigate the basis for the significant individual variation in lipid lowering response to statin therapy. Measurements were performed in participants (n = 135) at baseline and after 6 weeks on either rosuvastatin (40 mg/day) or atorvastatin (80 mg/day) therapy. Plasma sterols were measured using gas-liquid chromatography. Rosuvastatin and atorvastatin significantly (P < 0.001) altered plasma total cholesterol (C) levels by −40%, and the ratios of lathosterol/C by −64% and −68%, and campesterol/C by +52% and +72%, respectively, with significant differences (P < 0.001) between the treatment groups for the latter parameter. When using absolute values of these markers, subjects with the greatest reductions in both synthesis (lathosterol) and absorption (campesterol) had significantly greater reductions in total C than subjects in whom the converse was true (−46% versus −34%, P = 0.001), with similar effects for LDL-C. Rosuvastatin and atorvastatin decreased markers of cholesterol synthesis and increased markers of fractional cholesterol absorption, with rosuvastatin having significantly less effect on the latter parameter than atorvastatin. In addition, alterations in absolute values of plasma sterols correlated with the cholesterol lowering response. There is extensive evidence that HMG-CoA reductase inhibitors (statins) significantly lower total cholesterol and LDL cholesterol (C) levels and reduce coronary heart disease (CHD) risk (1Baigent C. Keech A. Kearney P.M. Blackwell L. Buck G. Pollicino C. Kirby A. Sourjina T. Peto R. Collins R. et al.Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins.Lancet. 2005; 366: 1267-1278Abstract Full Text Full Text PDF PubMed Scopus (5820) Google Scholar). Although reductions of up to 60% in LDL-C levels have been reported (2Schachter M. Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update.Fundam. Clin. Pharmacol. 2005; 19: 117-125Crossref PubMed Scopus (901) Google Scholar), there is large variation in the lipid-lowering response between individuals (3Pedro-Botet J. Schaefer E.J. Bakker-Arkema R.G. Black D.M. Stein E.M. Corella D. Ordovas J.M. Apolipoprotein E genotype affects plasma lipid response to atorvastatin in a gender specific manner.Atherosclerosis. 2001; 158: 183-193Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar). These variations have been attributed to intrinsic factors, such as genetic variation, as well as extrinsic factors, such as compliance, time of administration, concomitant drug therapy, and dietary intake (4Thompson G.R. O'Neill F. Seed M. Why some patients respond poorly to statins and how this might be remedied.Eur. Heart J. 2002; 23: 200-206Crossref PubMed Scopus (58) Google Scholar). Total body cholesterol pools represent a balance between endogenous synthesis and dietary absorption (5Matthan N.R. Lichtenstein A.H. Approaches to measuring cholesterol absorption in humans.Atherosclerosis. 2004; 174: 197-205Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar). It has been documented using formal cholesterol balance studies, which measure cholesterol synthesis and intestinal cholesterol absorption, that the plasma sterols lathosterol and desmosterol serve as markers of cholesterol synthesis, while campesterol, sitosterol, and cholestanol are markers of fractional cholesterol absorption (6Miettinen T.A. Tilvis R.S. Kesaniemi Y.A. Serum plant sterols and cholesterol precursors reflect cholesterol absorption and synthesis in volunteers of a randomly selected male population.Am. J. Epidemiol. 1990; 131: 20-31Crossref PubMed Scopus (561) Google Scholar). The benefit of statins has largely been linked to total cholesterol and LDL-C lowering, and it has been suggested that the degree of lowering may relate to reductions in synthesis markers, which may be offset by increases in markers of absorption. In small-scale cholesterol balance studies, Miettinen et al. (7Miettinen T.A. Gylling H. Synthesis and absorption markers of cholesterol in serum and lipoproteins during a large of statin J. Clin. PubMed Scopus Google H. Kesaniemi Y.A. Miettinen T.A. serum and cholesterol absorption in Full Text PDF PubMed Scopus Google Miettinen T.A. absorption and synthesis during and Full Text PDF PubMed Scopus Google have documented that statins lower cholesterol synthesis and significantly fractional intestinal cholesterol absorption. of and dietary cholesterol on in Clin. PubMed Scopus Google reported similar and Gylling T.A. Gylling H. sterols and cholesterol lowering by treatment in coronary to serum PubMed Scopus Google have reported in a of patients in the that in the of the of cholesterol while on had in as with the with the converse the and Gylling T.A. Gylling H. sterols and cholesterol lowering by treatment in coronary to serum PubMed Scopus Google have reported that plasma sterols serve as markers of LDL-C lowering response to these there has been some in the as to statins intestinal cholesterol absorption. to for the in and sitosterol, markers of fractional cholesterol absorption, may be that statins are in the of cholesterol and In addition, there is data on between statins and effects on cholesterol The is a of a of patients in the for to Rosuvastatin which the effects of rosuvastatin in the of LDL-C with statins Stein A. of rosuvastatin versus and on and lipid ratios in patients with from the 2004; Full Text PDF PubMed Scopus Google Stein J.M. of the and safety of rosuvastatin versus and doses J. Full Text Full Text PDF PubMed Scopus Google Scholar). The of the was to investigate the effects of maximal rosuvastatin and atorvastatin treatment on markers of cholesterol synthesis and absorption. In addition, in synthesis and absorption markers correlated with in total and LDL-C. The of the is that it the effects of the statin of rosuvastatin and of on plasma lipid and from The was performed in a of patients in the the was the of both a and a plasma for the of the synthesis and absorption The of the and of the and of the have been Stein A. of rosuvastatin versus and on and lipid ratios in patients with from the 2004; Full Text PDF PubMed Scopus Google Stein J.M. of the and safety of rosuvastatin versus and doses J. Full Text Full Text PDF PubMed Scopus Google Scholar). the was an in patients in The was to compare the of rosuvastatin in the of LDL-C with statins a of the effects of the statins on such as and and lipid ratios Stein A. of rosuvastatin versus and on and lipid ratios in patients with from the 2004; Full Text PDF PubMed Scopus Google Stein J.M. of the and safety of rosuvastatin versus and doses J. Full Text Full Text PDF PubMed Scopus Google Scholar). and or with were to a for 6 were with the and had LDL-C levels between and and < were to the statin doses as Stein A. of rosuvastatin versus and on and lipid ratios in patients with from the 2004; Full Text PDF PubMed Scopus Google Stein J.M. of the and safety of rosuvastatin versus and doses J. Full Text Full Text PDF PubMed Scopus Google Scholar). The the and participants were on at and after and 6 weeks of treatment and to a for the of lipid and that and as Stein A. of rosuvastatin versus and on and lipid ratios in patients with from the 2004; Full Text PDF PubMed Scopus Google Stein J.M. of the and safety of rosuvastatin versus and doses J. Full Text Full Text PDF PubMed Scopus Google Scholar). Plasma were at at the serum were on to the in In the rosuvastatin and atorvastatin of the and respectively, were and had data at baseline and after 6 weeks In have measured as M. Stein Schaefer E.J. of maximal doses of atorvastatin versus rosuvastatin on cholesterol J. Full Text Full Text PDF PubMed Scopus (49) Google Scholar). of variations and between for were less than was measured to the by et al. T. T. of for an 2004; PubMed Scopus Google Scholar). Plasma of campesterol, sitosterol, and cholestanol were in subjects using gas-liquid to N.R. A. Schaefer E.J. Lichtenstein A.H. of on cholesterol in patients with Full Text Full Text PDF PubMed Scopus Google Scholar). these plasma sterols are in the LDL (7Miettinen T.A. Gylling H. Synthesis and absorption markers of cholesterol in serum and lipoproteins during a large of statin J. Clin. PubMed Scopus Google Scholar), it is to for the total plasma cholesterol by as a to In the plasma sterols were for plasma cholesterol levels as well as in absolute significant differences the from plasma were with values after at and The of variations between for plasma sterols were from and were less than were for and as were in of as and were on the and the were between baseline plasma lipid and levels and after 6 weeks of treatment were on a or a for between the statin were on an or a for subjects were groups on having or with statin treatment in the absolute values of lathosterol and either an or a in absolute levels and Total cholesterol were synthesis and absorption using a with for were to the with in campesterol, and cholestanol during In in campesterol, and as while statin baseline total and in total cholesterol as In addition, on the baseline levels of campesterol, and cholestanol were as were to investigate the of baseline levels of plasma sterols with in total cholesterol and LDL-C levels and in lathosterol and with in total cholesterol and LDL-C. In these in total cholesterol and LDL-C as while statin and baseline levels of plasma sterols and in plasma as P than was significant and were performed using were similar the treatment groups and P = The was in the atorvastatin the versus P = on lipid and plasma levels at baseline and after 6 weeks of treatment with maximal doses of either rosuvastatin or atorvastatin are in significantly decreased the levels of total LDL-C and (P < for both These were significant the statin treatment the a significant in was in the rosuvastatin treatment (P < 0.001), while a of was for the In both levels decreased significantly (P < for both the was in the rosuvastatin with the patients P = There was a individual response to for and levels and levels of plasma sterols and after treatment with rosuvastatin or (n = (n = of the plasma sterols to of of the plasma sterols to of of the plasma sterols to of of the plasma sterols to of are as or of the plasma sterols to of in a are as or with both statins decreased the of cholesterol synthesis, in both absolute and The absolute values of the absorption markers, and significantly in the while a significant was in the rosuvastatin P = and P = The absolute of the absorption significantly in both groups P = and atorvastatin P = The treatment effects were significant for and (P treatment = for both for cholestanol (P treatment = When the effects the to of the statin on campesterol, sitosterol, and the absorption markers increased significantly both treatment groups (P < there was a greater for the ratios of and to cholesterol in the patients with the rosuvastatin (P treatment < for both The in the to be in the this between treatment statins had a significant on the a of than (P < for both There was a individual response for the plasma sterols campesterol, and cholestanol in absolute as well as to total cholesterol the The response of and to the as the absorption markers, and cholestanol The baseline of and lipoproteins with the plasma sterols are in The of cholesterol synthesis, correlated with total cholesterol levels = P < LDL-C = P < = P < and = P < the lathosterol/C with total cholesterol levels = a with was = P < and the with and significant = P < and = P < The of and correlated significantly with total cholesterol and LDL-C = P < and = P < and = P < and = P < In addition, of correlated significantly with = P < while the correlated with and = P < and = P < of cholestanol correlated with = P < 0.001), and there was a with and = P < and = P < The correlated with total and = P < = P < = P < and = P < The lathosterol/C with total or there was a significant with = P < (n = 135) of plasma and lipoproteins with plasma < < < < The were for the < < < < < < The were for the < < of the plasma sterols to of < < < of the plasma sterols to of of the plasma sterols to of < < of the plasma sterols to of < < < < < < of the plasma sterols to of P < P < P < The were for the in a the between in plasma and sterols treatment in lathosterol levels significantly correlated with in total and in both treatment groups = P < = P < and = P < respectively, and = P < = P < and = and P < in correlated with in total cholesterol and LDL-C in both treatment while in the atorvastatin = P < and = P < of cholestanol correlated with LDL-C = P < in the while a was in the When the in cholestanol were for total cholesterol the with LDL-C to a in the while the with total and LDL-C and significant in the patients = P < and = P < between in plasma and lipoproteins and plasma sterols statin (n = = < < < < < < < < < < < of the plasma sterols to of total < < of the plasma sterols to of total of the plasma sterols to of total of the plasma sterols to of total < < < of the plasma sterols to of total P < P < P < in a were using campesterol, and respectively, as and statin baseline levels of plasma and total cholesterol and in total cholesterol as the in campesterol, and the baseline values of these sterols were the for the in these sterols during treatment and P < for levels of and cholestanol decreased significantly both treatment were the in total cholesterol was the of in lathosterol and and P < and P = for the in cholestanol P = There were data in on dietary intake of plant the of variations in dietary plant on levels of plant sterols is less than J. Plasma of plant and with coronary heart PubMed Google variations in dietary sterols have a effect on in and cholestanol in for with in campesterol, and cholestanol levels during statin = rosuvastatin total in total = rosuvastatin campesterol, total in total = rosuvastatin total in total the in total campesterol, and cholestanol as while statin baseline total total cholesterol and on the baseline campesterol, and cholestanol as = = = in a In the in total campesterol, and cholestanol as while statin baseline total total cholesterol and on the baseline campesterol, and cholestanol as In the of the participants reported a of Miettinen T.A. absorption and synthesis during and Full Text PDF PubMed Scopus Google Scholar). In the was as a for correlated with lathosterol levels and lathosterol/C at baseline = P = and = and P = with the was a significant of lathosterol as a of statin treatment In order to the between in synthesis and absorption markers and treatment groups were and in total lathosterol and were groups and in the synthesis and the or in the absorption campesterol, The greatest of total cholesterol was in the in absorption while the reductions of total cholesterol was in the in absorption P = effects were for LDL-C for in or In addition, of the synthesis and absorption markers that alterations in both of in absolute levels of lathosterol and in absolute levels of were significantly with in total cholesterol and LDL-C levels values of plasma were of total cholesterol or LDL-C in for statin and baseline of total cholesterol or of lathosterol and in to in total cholesterol and LDL cholesterol during statin in total in = = = = = = = = are in lathosterol is as a greater than The significant from for were using the for P = P = P = P = in a are in lathosterol is as a greater than The significant from for were using the for In order to the effects of statin on in markers of cholesterol synthesis and absorption, measured plasma sterols in a of participants of the It is well that the effect of HMG-CoA reductase or is to cholesterol synthesis a in cholesterol a there is an of LDL and fractional of lipoproteins from the plasma effect to in and LDL-C in in the levels of plasma sterols on these plasma sterols are in Miettinen and Gylling (7Miettinen T.A. Gylling H. Synthesis and absorption markers of cholesterol in serum and lipoproteins during a large of statin J. Clin. PubMed Scopus Google plasma sterols as a with total The the of is that plasma sterols be for total cholesterol in plasma by levels as a to It has been on the that using values is in statin studies, as the in total cholesterol the to cholesterol there is in the J. Plasma of plant and with coronary heart PubMed Google Scholar). the of using ratios is that are to in and and to or and the of the R. Google Scholar). was the for the in data We the with total cholesterol at baseline the synthesis and absorption markers were in absolute and in the synthesis and absorption markers be in absolute or In the in which plasma sterols are on the When synthesis and absorption differences to be that these effects are of the cholesterol and values be to cholesterol cholesterol the between absorption markers, synthesis markers, and cholesterol the absolute be to the that or for total cholesterol that are the are in the synthesis after treatment with statins in absolute or both statins decreased this parameter to a similar The effect of atorvastatin treatment on synthesis markers has been well (7Miettinen T.A. Gylling H. Synthesis and absorption markers of cholesterol in serum and lipoproteins during a large of statin J. Clin. PubMed Scopus Google G. J. F. H. Plasma are with an increased of coronary in of a of the Full Text Full Text PDF PubMed Scopus Google A. N.R. Lichtenstein A.H. et of doses of atorvastatin on and Full Text Full Text PDF PubMed Scopus Google T.A. Gylling H. Miettinen H. Serum sterols during of cholesterol synthesis by Clin. Full Text Full Text PDF PubMed Scopus Google A. R. T. A. of atorvastatin on sterols in patients with and 2005; PubMed Scopus Google O'Neill G.R. of a statin on and plasma levels in the J. PubMed Scopus Google Scholar). It be that et al. J. G.R. Plasma an of cholesterol synthesis in and to HMG-CoA reductase inhibitors in Full Text PDF PubMed Scopus Google were the to in subjects (n = that statins and decreased markers of cholesterol In measured plasma levels and reported significant reductions in absolute for atorvastatin J. G.R. Plasma an of cholesterol synthesis in and to HMG-CoA reductase inhibitors in Full Text PDF PubMed Scopus Google Scholar). We have documented in a with individuals that atorvastatin at a of the of lathosterol by A. N.R. Lichtenstein A.H. et of doses of atorvastatin on and Full Text Full Text PDF PubMed Scopus Google Scholar). In the that patients of atorvastatin decreased lathosterol levels in a similar versus baseline in and in absolute et al. E.M. effect of rosuvastatin on in the Full Text Full Text PDF PubMed Scopus Google have reported in of subjects that rosuvastatin at a of decreased the or levels of lathosterol by and the absolute by as with In with a of rosuvastatin lathosterol by in and by in absolute We significant treatment differences between the statins with to the reductions in the synthesis We significant differences between statins with to reductions in the synthesis desmosterol to markers of fractional cholesterol absorption, significant differences between rosuvastatin and atorvastatin. Rosuvastatin decreased and in absolute for while atorvastatin increased the absolute levels of these markers and When these markers were in both statins significantly increased the ratios of campesterol/C and and and to We a significant (P < 0.001) between these statins with rosuvastatin the of or as as atorvastatin. rosuvastatin less of an in markers of fractional cholesterol absorption than that this statin may have less of an effect on the than atorvastatin. may be that in to atorvastatin is in the of cholesterol and with the reported effects that have to cholesterol and in the and with to cholesterol and sterols either the intestinal or L. J. of and cholesterol and fractional absorption of dietary Clin. 2002; PubMed Scopus Google and are for both during the treatment with there are on the of rosuvastatin with an with atorvastatin has been reported C. Ordovas J.M. Schaefer E.J. and and plasma levels and after treatment with 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). it is to on the the In to rosuvastatin is to be a statin that is the (2Schachter M. Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update.Fundam. Clin. Pharmacol. 2005; 19: 117-125Crossref PubMed Scopus (901) Google Scholar). In addition, the of atorvastatin is by dietary intake in to rosuvastatin (2Schachter M. Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update.Fundam. Clin. Pharmacol. 2005; 19: 117-125Crossref PubMed Scopus (901) Google Scholar). with to the absorption markers, both statins have pharmacokinetic which may for the greater in LDL-C lowering and for rosuvastatin than atorvastatin. We were in how alterations in plasma levels to statins in of in reductions in total and and increases in the differences in alterations the statin treatment groups were these differences had effects on the in lipid in the absolute levels of significantly correlated with in total cholesterol and LDL-C in the atorvastatin with similar in the rosuvastatin in this were These the treatment groups in order to investigate effects of alterations in synthesis and absorption markers on plasma lipid data that the greatest total cholesterol and LDL-C reductions were in subjects with the greatest in and in cholesterol absorption markers, as with subjects in whom the converse was in with the that respond to treatment with that statin treatment is the individual was a of cholesterol The converse is the individuals are are to absorption, less well on statin treatment in of total cholesterol The that patients are may benefit from with cholesterol absorption In it has been that the absorption the absorption of cholesterol and in the absorption markers are significantly lower T. D. A. M. of intestinal cholesterol absorption by in 2002; PubMed Scopus Google Scholar). a of treatment is a in cholesterol synthesis T. D. A. M. of intestinal cholesterol absorption by in 2002; PubMed Scopus Google L. T. of cholesterol absorption by the of dietary plant sterols and effects on plasma lipid 2005; Full Text Full Text PDF PubMed Scopus Google Scholar), that patients a of statins and have the greatest lipid-lowering in large trials the and in and the of effects Rosuvastatin in with versus Rosuvastatin the of with a significantly a greater of total cholesterol levels with patients with statins F. A.H. E.J. Stein et with or in J. PubMed Scopus Google R. T. A. F. and safety of rosuvastatin or in with in patients at risk of disease from the J. Full Text Full Text PDF PubMed Scopus Google Scholar). the effect of in with statins on markers of cholesterol synthesis and absorption has been and a significant effect of the of and statins on the of these markers G. J. F. H. Plasma are with an increased of coronary in of a of the Full Text Full Text PDF PubMed Scopus Google Scholar). are to the effects these drug have on the synthesis and absorption of The total cholesterol lowering response to statins the of and was the the in the synthesis and absorption with a risk of was to this Although a of have an between increased levels of plasma sterols and disease G. J. F. H. Plasma are with an increased of coronary in of a of the Full Text Full Text PDF PubMed Scopus Google J. T. J. of serum plant sterols and cholesterol in and of and coronary heart disease in and Full Text PDF PubMed Scopus Google T. Serum plant sterols as a risk for coronary heart 2002; Full Text PDF PubMed Scopus Google Gylling H. Miettinen T.A. of serum and sterols with coronary disease in PubMed Scopus Google Scholar), a large prospective this D. R. Plasma levels of plant sterols and the risk of coronary the prospective Full Text Full Text PDF PubMed Scopus Google Scholar). data are with the that cholesterol synthesis and absorption to be linked in a cholesterol balance absorption synthesis and We a for both synthesis and absorption markers and campesterol, with total cholesterol at baseline total cholesterol with the which is the for the cholesterol that in a the effects of synthesis and absorption are and to have an this it be to this in the cholesterol balance is by either or drug and Miettinen et al. T.A. Gylling H. T. serum cholestanol as of coronary in of PubMed Scopus Google that a baseline was with significant risk of in patients with in to patients with a at We have the in the that have on the There is for statins to cholesterol synthesis markers in absolute and and to markers of cholesterol absorption in In an of the data in the between in total cholesterol and absolute reductions in synthesis were significant = P = These data be with the in total C = in We a significant between in plasma in absolute of data is than of individual markers of synthesis and absorption both to in total cholesterol response to statin therapy. as be in there are some subjects lathosterol levels in either absolute or subjects in are of the statin with than lathosterol and as markers for synthesis and absorption, the effects of statin treatment on of lathosterol and cholesterol et al. Miettinen T.A. T. H. and sterols during treatment of with and with or PubMed Scopus Google (80 et al. T.A. Gylling H. sterols and cholesterol lowering by treatment in coronary to serum PubMed Scopus Google et al. T.A. Gylling H. of serum cholesterol by in a of coronary 2002; Full Text Full Text PDF PubMed Scopus Google (40 et al. T.A. Gylling H. Miettinen H. Serum sterols during of cholesterol synthesis by Clin. Full Text Full Text PDF PubMed Scopus Google a treatment a treatment et al. G. F. T.A. of and on sterols in patients with PubMed Scopus Google et (40 (80 statin with than lathosterol and as markers for synthesis and absorption, a treatment in a data are with the of on the effects of statins on markers of cholesterol synthesis and absorption, data have been on and has been to to these alterations and lipid-lowering response. It is that the effect of statins is to reduce cholesterol synthesis, in an of LDL fractional of LDL from and in plasma LDL cholesterol these effects may be offset by an in cholesterol absorption. data that effects on both of these of markers are to for of the statins in the total cholesterol-lowering response. In both statins significantly decreased cholesterol synthesis and increased markers of fractional cholesterol absorption. the that lipid-lowering on the of the In addition, the that in these markers are than baseline We that the lipid-lowering was in patients with the greatest reductions in synthesis and increases in absorption, with the converse the significantly intestinal cholesterol absorption, increases synthesis, and statins have the it that be In addition, statin is measuring sterols may to be a for and with