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Diabetes Care. 2009 November; 32(11): 2111–2113.
Published online 2009 August 3. doi:  10.2337/dc09-0519
PMCID: PMC2768190

Regulatory Effects of Fenofibrate and Atorvastatin on Lipoprotein A-I and Lipoprotein A-I:A-II Kinetics in the Metabolic Syndrome

Abstract

OBJECTIVE

Subjects with the metabolic syndrome have reduced HDL cholesterol concentration and altered metabolism of high-density lipoprotein (Lp)A-I and LpA-I:A-II particles. In the metabolic syndrome, fenofibrate and atorvastatin may have differential effects on HDL particle kinetics.

RESEARCH DESIGN AND METHODS

Eleven men with metabolic syndrome were studied in a randomized, double-blind, crossover trial of 5-week intervention periods with placebo, fenofibrate (200 mg/day), and atorvastatin (40 mg/day). LpA-I and LpA-I:A-II kinetics were examined using stable isotopic techniques and compartmental modeling.

RESULTS

Compared with placebo, fenofibrate significantly increased the production of both LpA-I:A-II (30% increase; P < 0.001) and apoA-II (43% increase; P < 0.001), accounting for significant increases of their corresponding plasma concentrations (10 and 23% increases, respectively), but it did not alter LpA-I kinetics or concentration. Atorvastatin did not significantly alter HDL concentration or the kinetics of HDL particles.

CONCLUSIONS

In the metabolic syndrome, fenofibrate, but not atorvastatin, influences HDL metabolism by increasing the transport of LpA-I:A-II particles.

Atherogenic dyslipidemia, reflected by elevated plasma triglyceride and reduced HDL cholesterol concentrations, is a cardinal feature of the metabolic syndrome (1). Recent findings from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study demonstrated that metabolic syndrome subjects with atherogenic dyslipidemia had the highest risk of cardiovascular disease (CVD) (2). Disturbed metabolism of high-density lipoprotein (Lp)A-I and LpA-I:A-II particles may partly account for the increased risk of CVD (3).

In a previous study of 11 metabolic syndrome subjects, we reported that fenofibrate, but not atorvastatin, had significant effects on HDL apolipoprotein (apo)A-I kinetics (4). Given the differential role of LpA-I and LpA-I:A-II in reverse cholesterol transport (5), it is important to elucidate the precise effects of these agents on HDL particle kinetics. Using stored samples (4), we extended this study by investigating the effects of these agents on LpA-I and LpA-I:A-II particle kinetics.

RESEARCH DESIGN AND METHODS

Eleven nondiabetic men with metabolic syndrome entered a randomized, double-blind, placebo-controlled, crossover trial, in which they were randomized to a 5-week treatment period of either fenofibrate (200 mg/day), atorvastatin (40 mg/day), or placebo. A 2-week washout phase was included at the end of each treatment period. All subjects provided written consent as approved by the ethics committee of the South Eastern Sydney Area Health Service. This clinical protocol, including administration of [d3]-leucine and blood sampling, has previously been described (4).

Measurement of isotopic enrichments and calculation of kinetic parameters

HDL–apoA-I and –apoA-II were isolated by ultracentrifugation and electrophoresis, delipidated, hydrolyzed, and derivatized as previously described (6). Isotopic enrichment was assessed using gas-chromatography mass spectrometry with selected ion monitoring of derivatized samples. The SAAM II program (SAAM Institute, Seattle, WA) was used to fit the model to the observed tracer-to-tracee ratio data. The fractional catabolic rates (FCRs) of apoA-I in LpA-I, LpA-I:A-II, apoA-I, and apoA-II were derived from the model parameters giving the best fit. The corresponding production rates were calculated as the product of FCR and pool size.

Plasma biochemistry

ApoA-I and apoA-II concentrations were determined by immunonephelometry (Dade Behring). ApoA-I concentration in LpA-I particles was measured by differential electroimmuoassay (Sebia, Moulineaux, France). ApoA-I concentration in LpA-I:A-II particles was calculated as total apoA-I − apoA-I in LpA-I. As previously described (4), plasma lipid and glucose concentrations were determined by enzymatic methods. Plasma insulin was measured by radioimmunoassay. Insulin resistance was estimated using the homeostasis model assessment score.

Statistical analyses

Data at the end of the three treatment periods were compared using a mixed-effects model (SAS Proc Mixed, SAS Institute). To adjust for multiple comparisons across the three treatment periods, we defined statistical significance at the 1.7% level.

RESULTS

The 11 subjects recruited were middle-aged, centrally obese, normotensive, dyslipidemic, and insulin resistant. Compared with normolipidemic lean subjects, metabolic syndrome subjects exhibited hypercatabolism of both LpA-I and LpA-I:A-II with overproduction of LpA-I (data not shown).

As previously reported (4), fenofibrate significantly decreased plasma concentrations of triglyceride and apoB; it also significantly increased plasma HDL, HDL2, and HDL3 cholesterol concentrations. Compared with placebo, atorvastatin significantly decreased total cholesterol, triglyceride, LDL cholesterol, and apoB concentrations. Homeostasis model assessment score did not change significantly on either treatment.

Table 1 gives the kinetic parameters for LpA-I, LpA-I:A-II, apoA-II, and apoA-I after intervention. Compared with placebo, fenofibrate significantly increased the production rates of LpA-I:A-II (by 30%; P < 0.001) and apoA-II (by 43%; P < 0.001). Furthermore, fenofibrate increased the FCR of LpA-I:A-II (and apoA-II) by 16% (P = 0.015) compared with placebo, accounting for the overall 10% (P = 0.005) increase in plasma HDL apoA-I FCR. Collectively, these kinetic effects accounted for the significant increase in concentration of LpA-I:A-II (10%), apoA-II (23%), and apoA-I (6%) on fenofibrate treatment. Compared with placebo, atorvastatin did not significantly alter the kinetics or concentrations of LpA-I, LpA-I:A-II, or apoA-II.

Table 1
Kinetic parameters of LpA-I, LpA-I:A-II, apoA-II, and plasma apoA-I after treatment with fenofibrate, atorvastatin, or placebo

CONCLUSIONS

Our new findings show that in subjects with the metabolic syndrome, fenofibrate significantly increased the production of both LpA-I:A-II and apoA-II, accounting for the significant increase in their plasma concentrations. These effects were achieved with no significant alteration in insulin resistance or body weight. By contrast, atorvastatin had no significant effect on any parameters of HDL metabolism.

The fenofibrate data concur with previous reports showing that this agent increased the production of apoA-I in mixed hyperlipidemia and metabolic syndrome (7). We extend our previous study (4) by showing that the increased apoA-I production is restricted to apoA-I in LpA-I:A-II particles and is closely coupled with the increased production of apoA-II. This is consistent with the notion that the gene expression of both apoA-I and apoA-II is increased with this peroxisome proliferator–activated receptor-α agonist (8).

The lack of significant effect of atorvastatin on HDL apoA-I kinetics concurs with the findings of a previous study (9). We extend these findings to metabolic syndrome subjects and a wider range of HDL kinetic measurements including new data on apoA-II, LpA-I, and LpA-I:A-II. We do not confirm data showing that atorvastatin increases LpA-I and decreases LpA-I:A-II concentrations in patients with coronary heart disease (10). This may be due to metabolic differences in study populations and that the coronary heart disease patients studied were not obese or insulin resistant. It is noteworthy that rosuvastatin, a more potent HDL cholesterol–raising agent than atorvastatin, decreases LpA-I and LpA-I:A-II catabolism in subjects with the metabolic syndrome (11). A recent study by Verges et al. (12) also showed that rosuvastatin reduces HDL apoA-I catabolism in type 2 diabetes. The precise reason for the difference between atorvastatin and rosuvastatin remains unclear.

Our kinetic findings could be clinically important. Decreased plasma LpA-I:A-II concentration is a predictor of coronary events in population studies (3) and, in type 2 diabetes, is independently associated with angiographic coronary disease (13). In the FIELD trial, fenofibrate altered HDL composition and increased the plasma concentration of A-II and LpA-I:A-II (14). Our study suggests that this may be due to increased production of apoA-II and LpA-I:A-II particles. The complementary effects of fenofibrate and atorvastatin on lipoprotein metabolism, including disparate changes in apoB-100 kinetics (4) and, as we show here, in the kinetics of LpA-I and LpA-I:A-II particles, support the use of combination therapy to optimally regulate dyslipidemia in metabolic syndrome.

Acknowledgments

P.H.R.B. is a National Health and Medical Research Council (NHMRC) Senior Research Fellow. D.C.C. is a Career Development Fellow of the NHMRC. E.M.M.O. is a postdoctoral fellow of the National Heart Foundation of Australia.

This study was funded by research grants from GlaxoSmithKline. No other potential conflicts of interest relevant to this article were reported.

Footnotes

Clinical trial reg. no. NCT00632840, clinicaltrials.gov.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

References

1. Ford ES.: Prevalence of the metabolic syndrome in US populations. Endocrinol Metab Clin North Am 2004;33:333–350 [PubMed]
2. Scott R, O'Brien R, Fulcher G, Pardy C, d'Emden M, Tse D, Taskinen MR, Ehnholm C, Keech A.: Effects of fenofibrate treatment on cardiovascular disease risk in 9,795 individuals with type 2 diabetes and various components of the metabolic syndrome: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. Diabetes Care 2009;32:493–498 [PMC free article] [PubMed]
3. Asztalos BF, Roheim PS, Milani RL, Lefevre M, McNamara JR, Horvath KV, Schaefer EJ.: Distribution of apoA-I–containing HDL subpopulations in patients with coronary heart disease. Arterioscler Thromb Vasc Biol 2000;20:2670–2676 [PubMed]
4. Watts GF, Barrett PH, Ji J, Serone AP, Chan DC, Croft KD, Loehrer F, Johnson AG.: Differential regulation of lipoprotein kinetics by atorvastatin and fenofibrate in subjects with the metabolic syndrome. Diabetes 2003;52:803–811 [PubMed]
5. Huang Y, von Eckardstein A, Wu S, Assmann G.: Cholesterol efflux, cholesterol esterification, and cholesteryl ester transfer by LpA-I and LpA-I/A-II in native plasma. Arterioscler Thromb Vasc Biol 1995;15:1412–1418 [PubMed]
6. Ji J, Watts GF, Johnson AG, Chan DC, Ooi EMM, Rye KA, Serone AP, Barrett PHR.: High-density lipoprotein transport in the metabolic syndrome: application of a new model for HDL particle kinetics. J Clin Endocrinol Metab 2006;91:973–979 [PubMed]
7. Bilz S, Wagner S, Schmitz M, Bedynek A, Keller U, Demant T.: Effects of atorvastatin versus fenofibrate on apolipoprotein B-100 and apolipoprotein A-I kinetics in mixed hyperlipidaemia. J Lipid Res 2004;45:174–185 [PubMed]
8. Staels B, Dallongeville J, Auwerx J, Schoonjans K, Leitersdorf E, Fruchart JC.: Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation 1998;98:2088–2093 [PubMed]
9. Bach-Ngohou K, Ouguerram K, Frenais R, Maugere P, Ripolles-Piquer B, Zair Y, Krempf M, Bard JM.: Influence of atorvastatin on apolipoprotein E and AI kinetics in patients with type 2 diabetes. J Pharmacol Exp Ther 2005;315:363–369 [PubMed]
10. Asztalos BF, Horvath KV, McNamara JR, Roheim PS, Rubinstein JJ, Schaefer EJ.: Effects of atorvastatin on the HDL subpopulation profile of coronary heart disease patients. J Lipid Res 2002;43:1701–1707 [PubMed]
11. Ooi EMM, Watts GF, Nestel PJ, Sviridov D, Hoang A, Barrett PHR.: Dose-dependent regulation of high-density lipoprotein metabolism with rosuvastatin in the metabolic syndrome. J Clin Endocrinol Metab 2008;93:430–437 [PubMed]
12. Verges B, Florentin E, Baillot-Rudoni S, Petit JM, Brindisi MC, de Barros JP, Lagrost L, Gambert P, Duvillard L.: Rosuvastatin 20 mg restores normal HDL-apoA-I kinetics in type 2 diabetes. J Lipid Res 2009;50:1209–1215 [PMC free article] [PubMed]
13. Syvänne M, Kahri J, Virtanen KS, Taskinen MR.: HDLs containing apolipoproteins A-I and A-II (LpA-I:A-II) as markers of coronary artery disease in men with non-insulin-dependent diabetes mellitus. Circulation 1995;92:364–370 [PubMed]
14. Hiukka A, Jauhiainen LM, Sundvall J, Ehnholm C, Keech AC, Taskinen MR.: Long-term effects of fenofibrate on VLDL and HDL subspecies in participants with type 2 diabetes mellitus. Diabetologia 2007;50:2067–2075 [PubMed]

Articles from Diabetes Care are provided here courtesy of American Diabetes Association