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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 11 4224-4230
Copyright © 2000 by The Endocrine Society

Original Studies

Atorvastatin Improves Postprandial Lipoprotein Metabolism in Normolipidemic Subjects1

Klaus G. Parhofer, P. Hugh R. Barrett and Peter Schwandt

Department of Internal Medicine II, Klinikum Grosshadern, Ludwig-Maximilians University (K.G.P., P.S.), 81377 Munich, Germany; and Department of Medicine, University of Western Australia (P.H.R.B.), Perth, Western Australia 6000

Address correspondence and requests for reprints to: Klaus G. Parhofer, M.D., Medical Department II, Klinikum Grosshadern, Marchioninistr. 15, 81377 Munich, Germany. E-mail: parhofer{at}med2.med


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Atorvastatin is a potent HMG-CoA reductase inhibitor that decreases low-density lipoprotein (LDL) cholesterol and fasting triglyceride concentrations. Because of the positive association between elevated postprandial lipoproteins and atherosclerosis, we investigated the effect of atorvastatin on postprandial lipoprotein metabolism. The effect of 4 weeks of atorvastatin therapy (10 mg/day) was evaluated in 10 normolipidemic men (30 ± 2 yr; body mass index, 22 ± 3 kg/m2; cholesterol, 4.84 ± 0.54 mmol/L; triglyceride, 1.47 ± 0.50 mmol/L; high-density lipoprotein cholesterol, 1.17 ± 0.18 mmol/L; LDL-cholesterol, 3.00 ± 0.49 mmol/L). Postprandial lipoprotein metabolism was evaluated with a standardized fat load (1300 kcal, 87% fat, 7% carbohydrates, 6% protein, 80,000 IU vitamin A) given after 12 h fast. Plasma was obtained every 2 h for 14 h. A chylomicron (CM) and a chylomicron-remnant (CR) fraction was isolated by ultracentrifugation, and triglycerides, cholesterol, apolipoprotein B, apoB-48, and retinyl-palmitate were determined in plasma and in each lipoprotein fraction. Atorvastatin therapy significantly (P < 0.001) decreased fasting cholesterol (-28%), triglycerides (-30%), LDL- cholesterol (-41%), and apolipoprotein B (-39%), whereas high-density lipoprotein cholesterol increased (4%, not significant). The area under the curve for plasma triglycerides (-27%) and CR triglycerides (-40%), cholesterol (-49%), and apoB-48 (-43%) decreased significantly (P < 0.05), whereas CR retinyl-palmitate decreased (-34%) with borderline significance (P = 0.08). However, none of the CM parameters changed with atorvastatin therapy. This indicates that, in addition to improving fasting lipoprotein concentrations, atorvastatin improves postprandial lipoprotein metabolism presumably by increasing CR clearance or by decreasing the conversion of CMs to CRs, thus increasing the direct removal of CMs from plasma.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
HYPERLIPOPROTEINEMIA IS AN important risk factor for atherosclerosis. Lipid-lowering drugs, such as HMG-CoA reductase inhibitors, have been shown to be of significant benefit in primary and secondary prevention of atherosclerosis and can reduce morbidity and mortality (1). Atorvastatin is a potent HMG-CoA reductase inhibitor that can decrease total cholesterol and low-density lipoprotein (LDL) cholesterol concentrations by up to 60% (2, 3, 4). In addition to cholesterol and LDL-cholesterol, this drug also decreases triglyceride concentrations (2, 3, 4).

In clinical practice, lipoproteins are usually determined following a 10- to 12-h fast. In normolipidemic and many hypercholesterolemic subjects, postprandial lipoproteins [i.e. chylomicrons (CMs) and chylomicron remnants (CRs)] are virtually absent following such a fast. In real life, however, most people are in a postprandial state for much of the day and a significant part of the night. Although LDL, the concentration of which is minimally affected by eating, seems to be the primary link between hyperlipoproteinemia and atherosclerosis, there is evidence that postprandial lipoproteins also have a considerable and independent atherogenic potential (5, 6, 7, 8, 9, 10, 11). The effects of lipid-lowering therapy are usually evaluated by determining fasting lipid concentrations; much less is known about their effect on postprandial lipoprotein metabolism. Fibrates, which decrease fasting tri-glycerides much more than LDL-cholesterol, also positively affect postprandial lipoprotein metabolism. This, at least in part, is mediated by reducing apolipoprotein CIII (apoCIII) levels and, thus, increasing lipoprotein lipase mediated hydrolysis and particle clearance (12). In contrast, pravastatin, simvastatin, and lovastatin, which primarily decrease LDL-cholesterol, have much less effect on postprandial lipoprotein metabolism (13, 14, 15, 16, 17, 18).

Atorvastatin differs from other HMG-CoA reductase inhibitors because it is more effective in decreasing fasting triglyceride concentrations (19, 20, 21). Although it was shown that atorvastatin can improve postprandial lipoprotein metabolism in miniature pigs (22), its effect on human postprandial lipoprotein metabolism is unknown. To address this issue, we evaluated the effect of atorvastatin therapy (10 mg/day for 4 weeks) on postprandial lipoprotein metabolism in 10 healthy normolipidemic subjects.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Ten healthy male subjects were included in the study. All were normolipidemic, and none were taking any medication. Participating subjects (age, 30 ± 2 yr; body mass index, 22 ± 3 kg/m2) were advised not to change their diet 4 weeks before and throughout the study. Postprandial lipoprotein metabolism was evaluated after 4 weeks of stable weight and during stable dietary intake. Thereafter, atorvastatin was started at 10 mg/day, and the postprandial study was repeated after 4 weeks of atorvastatin therapy. Liver function tests (aspartate aminotransferase, alanine aminotransferase, {gamma}-glutamyl-transferase, and alkaline phosphatase) and creatine-kinase were determined before and after 4 weeks of atorvastatin therapy. The Ethics Committee of the Ludwig-Maximilians University Munich approved the study protocol, and all subjects gave informed written consent.

Postprandial study

The postprandial studies were performed as described previously (23, 24). Each postprandial study was performed after subjects had fasted for 12 h. After obtaining fasting blood, subjects received a fatty meal enriched with 80,000 U of vitamin A. The fatty meal consisted of 100 mL milk (3.5% fat), 150 mL cream (30% fat), 70 mL corn oil, 90 g egg, 10 g sugar, and 3.5 g coffee flavor. This fat load yields 1305 kcal, 87% from fat, 7% from carbohydrates, and 6% from protein, and was ingested within 5 min. Following the fat load, blood samples were taken every 2 h for 14 h. During that time, subjects ate no calories but were allowed to drink water without restriction.

Analytical methods

Blood samples were drawn in tubes containing EDTA-sodium covered with aluminum foil to protect the samples from light. Plasma was obtained by centrifugation.

Ultracentrifugation of each plasma sample was performed to obtain two fractions of triglyceride-rich fractions: CM and CR/very low- density lipoprotein (CR/VLDL). To separate CM from CR/VLDL, 3 mL plasma were overlayered with a solution of d 1.006 kg/L and centrifuged for 20 min at 20,000 rpm (Ti 50.4 rotor; Beckman Coulter, Inc., Palo Alto, CA). The supranatant contains CM, whereas the infranatant was used to obtain CR/VLDL by further ultracentrifugation (d 1.006 kg/L, Ti 50.4 rotor, 18 h, 40,000 rpm). In plasma and in both lipoprotein fractions, cholesterol, triglyceride, apoB, apoB-48 (not in plasma), and retinyl-palmitate concentrations were determined.

In plasma the concentrations of high-density lipoprotein (HDL)- and LDL-cholesterol were determined, in addition. HDL-cholesterol was determined after precipitation of apoB containing lipoproteins with sodium phosphotungate and magnesium chloride (Roche Molecular Biochemicals, Mannheim, Germany). In the infranatant of the CR/VLDL-spin LDL-cholesterol was calculated by subtracting HDL-cholesterol from total infranatant cholesterol.

Triglyceride and cholesterol concentrations were measured by using a commercial kit (Roche Molecular Biochemicals). ApoB concentrations were determined by immunonephelometry. Proteins of the CM and VLDL/CR samples were separated by PAGE (5%) and stained with Comassie Blue (25). The protein bands corresponding to apoB-100 and apoB-48 were scanned by laser densitometry. Based on the assumption that both forms of apoB have the same chromogenicity (26), the concentrations of CM-apoB-48 and CR-apoB-48 were estimated by dividing total apoB in CM and CR into apoB-100 and apoB-48 according to the scanned area.

Retinyl-palmitate concentrations in plasma CM and VLDL/CR were determined as described previously (24). Briefly, an internal standard (retinyl-acetate) was added to an aliquot of plasma, CM, or VLDL/CR, and fractions were extracted by ethanol-hexane-water (3:4:3 by vol). The upper hexane phase was evaporated under nitrogen, redissolved with methanol, and injected into a reversed phase high-performance liquid chromatography column (250 1 4.6 mm) filled with Ultrasphere ODS, C18, 5 µm, pore size 80 A (Beckman Coulter, Inc.). Methanol heptane 95:5 mixture was used as a mobile phase at a flow rate of 1 mL/min in a high-performance liquid chromatography system (Kontron Instruments Ltd., Zurich, Switzerland). The effluent was monitored at 340 nm. The peak of retinyl palmitate was identified by comparing it with a purified standard (Sigma, St. Louis, MO) and quantified by the area ratio method using retinyl-acetate as internal standard (27).

Postprandial metabolism was quantified by calculating the area under the curve (AUC) and the incremental AUC for plasma triglycerides, cholesterol, apoB, and retinyl-palmitate; for CM-triglycerides, -cholesterol, -apoB-48, and -retinyl-palmitate; and for CR-triglycerides, -cholesterol, -apoB-48, and -retinyl-palmitate. Concentrations obtained over the 14-h period following the ingestion of the fat meal were used for this calculation. The AUC related to the fat load was calculated to separate VLDL from CR. The incremental AUC was determined as the area between the plasma concentration and a baseline or fasting concentration observed at 0 h and 14 h. The incremental AUC represents the increase in area following the response of the fat load above fasting concentrations. The SAAM-II program (SAAM Institute Inc, Seattle, WA) was used to perform the calculations.

Statistical analysis

Differences between parameters obtained before and during atorvastatin therapy were evaluated by paired t test analysis. Associations between variables were identified with the Pearson’s product moment correlation coefficient. All statistical tests were performed using the SPSS, Inc. software (SPSS, Inc., Chicago, IL). The critical P value for significance was set at 0.05.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
All subjects tolerated atorvastatin well; there were no side effects reported, and there was no change in liver function tests or creatine kinase. Fasting cholesterol (-28%), triglyceride (-30%), apoB (-37%), LDL-cholesterol (-40%), VLDL-cholesterol (-40%), and VLDL-triglyceride (-37%) concentrations decreased significantly, and HDL-cholesterol (+4%) increased nonsignificantly during atorvastatin therapy (Table 1Go).


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  		Table 1. Fasting lipid parameters (mean ± SD) before and after 4 weeks of atorvastatin therapy (10 mg/day)

 
Figure 1Go shows the mean of plasma triglycerides and cholesterol before and during atorvastatin therapy. Figures 2Go and 3Go show triglycerides (A), apoB-48 (B), and retinyl-palmitate (C) in the CM (Fig. 2Go) and CR (Fig. 3Go) fractions, respectively, before and during atorvastatin therapy. The fasting lipid concentration in the CR/VLDL fraction, presumably representing mostly VLDL in these normolipidemic subjects, decreased during atorvastatin therapy. Following the oral fat load, the incremental AUC did not change significantly for any of the CM parameters, whereas the incremental AUC of CR triglycerides, cholesterol, and apoB-48 decreased significantly (P < 0.05). A trend toward reduction was observed for retinyl-palmitate (P = 0.08). Furthermore, incremental AUC for plasma triglycerides decreased significantly (P < 0.05) (Table 2Go). Although atorvastatin affected the maximal peak height and incremental AUC in CR, it did not affect the time to peak. Furthermore, it should be noted that CM tri-glycerides and apoB-48 (and cholesterol; data not shown) peak ~5 h after the fat load, whereas CM retinyl-palmitate peaks considerably later (~8 h after the fat load) (Fig. 2Go). Similarly, in the CR fraction the peak of retinyl-palmitate is later than that of triglycerides and apoB-48 (Fig. 3Go).



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  		Figure 1. Means (±SEM) of plasma cholesterol and triglycerides following the oral fat load. Open and closed symbols represent data obtained before and during atorvastatin therapy, respectively. Plasma triglycerides (circles) increased following the fat meal, whereas plasma cholesterol (triangles) did not change.

 


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  		Figure 2. Means (±SEM) of CM-triglycerides (A), CM-apoB-48 (B), and CM-retinyl-palmitate (C) following the oral fat load. Open and closed symbols represent data obtained before and during atorvastatin therapy, respectively. No significant differences were observed.

 


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  		Figure 3. Means (±SEM) of CR-triglycerides (A), CR-apoB-48 (B), and CR-retinyl-palmitate (C) following the oral fat load. Open and closed symbols represent data obtained before and during atorvastatin therapy, respectively. Differences in AUC are significant (P < 0.05) for triglycerides and apoB-48 and borderline significant for retinyl-palmitate (P < 0.08).

 

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  		Table 2. Incremental AUC (mean ± SD) following an oral fat load before and after 4 weeks of atorvastatin therapy (10 mg/day)

 
Two subjects did not respond with a decrease in incremental AUC for plasma or CR triglycerides while on atorvastatin therapy, although fasting lipid concentrations decreased similar to the other subjects.

There was a significant positive correlation between fasting triglyceride concentrations and incremental AUC of plasma triglycerides (r = 0.6, P = 0.033; Fig. 4Go), as well as CM-triglycerides (r = 0.62, P = 0.027) and CR-triglycerides (r = 0.66, P = 0.019). As expected, these associations were also significant when total AUC (incremental + area below fasting concentrations) was used in the analysis (data not shown). Furthermore, there was no significant correlation between changes in fasting lipid concentrations induced by atorvastatin (LDL-cholesterol or triglyceride reduction) and any of the AUC at baseline or changes of AUC with atorvastatin.



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  		Figure 4. Individual incremental AUC of plasma triglycerides following the oral fat load before and during atorvastatin therapy. Large point and dotted line represent the mean. All, except two, subjects had a decrease in AUC with atorvastatin therapy.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This study was performed to assess the effects of atorvastatin on postprandial lipoprotein metabolism in normolipidemic subjects. In addition to significantly decreasing fasting cholesterol, triglycerides, and LDL-cholesterol, atorvastatin therapy decreased the AUC of CR-triglycerides, -cholesterol, -retinyl-palmitate, and -apoB-48 following an oral fat load. In contrast, atorvastatin treatment did not change any AUC in the CM fraction. This finding suggests that atorvastatin therapy did not impact on CM production or the rate of clearance. However, the reduced AUC in the CR fraction is consistent with an increased removal of CR and/or a reduced conversion of CMs to CRs. The latter also implies an increased direct removal of CMs during atorvastatin therapy to maintain a constant rate of CM clearance.

Atorvastatin is a potent HMG-CoA reductase inhibitor that can decrease LDL-cholesterol and fasting triglycerides. In our study, the decrease in fasting plasma triglyceride concentration was profound but within the limits previously described for this medication (3, 4). Studies in the HepG2 cell have demonstrated that atorvastatin does not impact on triglyceride synthesis (28). Therefore, atorvastatin’s triglyceride lowering effect is primarily related to its strong inhibition of cholesterol biosynthesis, which also affects the secretion of apoB-containing lipoproteins (29, 30). Furthermore, it is known that VLDL and LDL compete for the same removal mechanisms (31), thus, the profound reduction in the number of circulating LDL particles may also increase the removal of VLDL particles.

Our study shows that atorvastatin not only decreases fasting triglycerides, but that it also improves postprandial lipoprotein metabolism. That atorvastatin does not affect the AUC of CM or the time to peak of CM and CR following a fat load indicates that the formation and secretion of CM is not altered. In contrast, the AUC of all CR parameters (CR-triglycerides, -cholesterol, -apoB-48, and -retinyl-palmitate) decreased with atorvastatin therapy. This can best be explained by hypothesizing that atorvastatin increases the removal rate of CR or decreases the conversion of CM to CR. The latter hypothesis would indicate that direct catabolism of CM is increased at the same time to account for the unchanged AUC of CM during atorvastatin therapy. Although in vitro studies indicate that CM may be removed directly from plasma (32), in vivo data are not available. Furthermore, one has to be aware that the lipoprotein fraction isolated as CM does not correspond to native CM but has already undergone some changes.

The differences were more pronounced for CR triglycerides and CR cholesterol than for CR-apoB-48, and CR-retinyl-palmitate, which may indicate that atorvastatin induces differences in the postprandial metabolism of lipoproteins derived from both intestine and liver, because only apoB-48 and retinyl-palmitate are intestine specific (33).

Our findings are in good agreement with results from an animal study (22). That study, which was performed in miniature pigs, involved multicompartmental modeling to interpret retinyl palmitate that was used as a tracer. The primary findings were that atorvastatin increased the fractional catabolic rate of triglyceride-rich lipoproteins and decreased the conversion from a more rapid-turnover compartment to a slow-turnover compartment, whereas synthesis and secretion of triglyceride rich lipoproteins were not affected. Although CM and CR were not separated in that study, it is likely that the rapid turnover and the slow-turnover compartments correspond to CM and CR, respectively. The similarity of the findings supports the role of the miniature pig as an appropriate model to study human postprandial lipoprotein metabolism.

Although it is known that atorvastatin, like other HMG-CoA reductase inhibitors, may up-regulate LDL receptor activity (28, 34), its effect on receptors of triglyceride-rich lipoproteins is unknown. However, even if atorvastatin does not affect the number or activity of such receptors, the decrease in fasting triglycerides and, hence, number of VLDL particles, could decrease the competition for removal mechanisms, and CR may be cleared preferentially. In addition, statins reduce apoCIII (35, 36), which plays an inhibitory role in the uptake of CR particles (37). The effect of apoCIII has been nicely demonstrated in transgenics for overexpression of apoCIII (38). Thus, decreased apoCIII may, in part, result in the increased clearance of remnant particles.

Previous studies involving other generally less potent HMG-CoA reductase inhibitors such as lovastatin, pravastatin, and simvastatin generated mixed results (13, 14, 15, 16, 17, 18). No effect was seen in patients with hypercholesterolemia. In 7 of 10 patients with low HDL and hypertriglyceridemia lovastatin induced an improvement of postprandial lipoprotein metabolism (17); similarly, in diabetic patients postprandial lipoprotein metabolism improved with pravastatin therapy, although this was estimated from a single sample drawn 5 h after a standardized meal (18). The effects demonstrated in these studies, and even in hyperlipoproteinemic patients, are, however, less pronounced than those reported here. This observation may be related to the increased efficacy of atorvastatin on fasting triglyceride concentrations. Similarly, the effect of fibrates on postprandial lipoprotein metabolism was predominantly evaluated in patients with dyslipoproteinemia, and it was shown that fibrates not only improve fasting triglycerides but also postprandial lipoprotein metabolism (39). In general, it seems that whenever a lipid-lowering medication reduces fasting triglycerides, postprandial lipoprotein metabolism is also improved. However, the improvement in postprandial lipoprotein metabolism could also contribute significantly to the lower fasting triglycerides. This is supported by the observation that the postprandial response following a fat challenge is proportional to the fasting concentration in this and in previous studies (40).

In considering the use of atorvastatin in patients with hypertriglyceridemia, it is interesting to investigate whether subjects with higher fasting triglycerides have more pronounced improvements of postprandial lipoprotein metabolism than those with lower fasting triglyceride concentrations. Although there was a significant correlation between fasting triglycerides and the incremental AUC of CM and CR, there was no correlation between fasting triglyceride concentrations and response to atorvastatin therapy in these normolipidemic subjects. Furthermore, we observed that the two patients who did not respond with a decreased incremental AUC following atorvastatin therapy (Fig. 5Go) had a good response with respect to fasting triglycerides and LDL-cholesterol. There was also no correlation between changes in postprandial lipoprotein metabolism and change in LDL-cholesterol. However, one has to be aware that the power to detect such associations is a function of the number of subjects and the fasting triglyceride concentrations that were already within the normal range at baseline. Therefore, we cannot exclude the possibility that improvement in postprandial lipoprotein metabolism is related to changes in fasting triglycerides and/or LDL-cholesterol if larger groups of subjects or patients with different forms of hyperlipoproteinemia were studied. Furthermore, our conclusions are based on a study that was open-label and did not include a crossover period. Despite this, the changes we observed in fasting lipids on atorvastatin are comparable with those of blinded studies, and we feel confident that our results reflect the effect of treatment and are not simply an effect of regression to the mean.



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  		Figure 5. Relationship between postprandial triglyceride response (incremental AUC) and fasting plasma triglyceride concentration at baseline (r = 0.6, P = 0.033).

 
An interesting finding of our study is that the time to peak concentration of triglyceride, cholesterol, and apoB-48 differs from that of retinyl-palmitate in CM or in CR. This phenomenon has been observed in previous studies (41, 42, 43) and was the focus of a recent study (44). This study indicated that retinyl-palmitate and apoB-48 are not equivalent markers of postprandial lipoproteins and that heterogeneity in catabolism may account for the observed differences. The issue of heterogeneity within the CM fraction is complex, and careful analysis of postprandial data are required (45) to take into account the metabolic processes associated with the synthesis, packaging, and secretion of apoB-48, triglyceride, and retinol-palmitate into CM particles. Additional studies are necessary to clarify which processes account for the disparity between these moieties. However, despite this disparity, our studies indicate that the changes in retinyl-palmitate and triglycerides (and cholesterol and apoB-48) to atorvastatin therapy are similar.

Although we evaluated the effect of atorvastatin in normolipidemic subjects, there is little reason to believe that patients with hypertriglyceridemia will show a different response, particularly since atorvastatin’s ability to decrease triglycerides seems to be particularly good in hypertriglyceridemia (3, 4).

In summary, postprandial lipoprotein metabolism is improved in normolipidemic subjects receiving 10 mg atorvastatin per day. Atorvastatin increases CR catabolism and/or decreases the conversion of CM to CR, whereas CM formation, secretion, and catabolism seems to be affected little, if at all.


   Acknowledgments
 
We are indebted to Ms. E. Fleischer-Brielmaier for excellent technical assistance in preparing the samples and to Ms. E. Hund-Wissner and Ms. D. Nissle for preparing the test meals.


   Footnotes
 
1 Supported by grants from Parke-Davis (to K.G.P. and P.S.), the NIH National Center for Research Resources (Grant 12609), and the Raine Medical Research Foundation (to P.H.R.B.). Back

Received March 21, 2000.

Revised May 22, 2000.

Revised July 7, 2000.

Accepted July 12, 2000.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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