HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Request Reprints Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (11) Citing Articles via Google Scholar Google Scholar Articles by Wagner, J. A. Articles by Gottesdiener, K. M. Search for Related Content PubMed PubMed Citation Articles by Wagner, J. A. Articles by Gottesdiener, K. M. Social Bookmarking                   What's this?

Individual and Combined Effects of Peroxisome Proliferator-Activated Receptor and Agonists, Fenofibrate and Rosiglitazone, on Biomarkers of Lipid and Glucose Metabolism in Healthy Nondiabetic Volunteers

From Merck Research Laboratories, Merck & Co Inc, Rahway, New Jersey (Dr Wagner, P. J. Larson, J. L. Miller, Dr Doebber, M. S. Wu, Dr Moller, Dr Gottesdiener) and Radiant Research, San Diego, California (Dr Weiss).

Address for reprints: J. A. Wagner, MD, PhD, Department of Clinical Pharmacology, Merck Research Laboratories, 126 East Lincoln Avenue, P.O. Box 2000, RY34-A548, Rahway, NJ 07065.

	ABSTRACT

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
This open-label, randomized, placebo-controlled, incomplete-block, 3-period crossover pilot study investigated the effects of peroxisome proliferator-activated receptor - and -agonists on biomarkers of lipid and glucose metabolism in 12 nondiabetic subjects. Plasma samples were collected before and after each 14-day treatment with placebo, fenofibrate (201 mg/d), rosiglitazone (4 mg twice daily), and combined fenofibrate (201 mg/d) plus rosiglitazone (4 mg twice daily). Except for triglycerides (P < .042) and free fatty acids (P < .074), no significant interaction was demonstrated between fenofibrate and rosiglitazone; thus, the effect due to each drug alone was evaluated (presence/absence of drug). Fenofibrate significantly (P < .050) increased lipoprotein lipase activity (35%) and decreased apolipoproteins B (13%) and C-III (20%). Rosiglitazone significantly (P < .050) decreased fasting glucose (7.3%) and increased apolipoprotein C-III (19%) and adiponectin (137%). Fenofibrate and rosiglitazone also produced effects on triglyoerides and free fatty acids, but it was not possible to determine if these effects were synergistic in nature.

Key Words: Peroxisome proliferator-activated receptor (PPAR) / agonists • fenofibrate • rosiglitazone • lipid • glucose

Because of the disparate expression patterns and complementary mechanisms of action of PPAR and on energy metabolism and homeostasis, the potential for a pharmacodynamic interaction between fibrates and TZDs exists with their combined use. Fibrate-induced activation of PPAR results in decreased production of hepatic apolipoprotein C-III (apo C-III) messenger ribonucleic acid (mRNA) and protein, increased production of lipoprotein lipase (LPL) mRNA and protein, and increased LPL activity.^6-9 Fibrates also stimulate cellular free fatty acid (FFA) uptake, conversion to acyl-CoA derivatives, and catabolism by the ß-oxidation path-ways, which, combined with a reduction in FFA and triglyceride (TG) synthesis, results in decreased production of very low-density lipoprotein (VLDL).² In comparison, the effects of TZDs on lipid/lipoprotein metabolism are less clear. Incubation of adipocytes with PPAR-selective agonists, troglitazone and rosiglitazone, produced dramatic reductions in LPL-induced lipolytic activity, despite an increase in LPL mRNA expression.¹⁰ Treatment with troglitazone resulted in a small increase in LPL levels (LPL immunoreactive mass) in patients with type 2 diabetes.¹¹ Because LPL is reduced in patients with type 2 diabetes and increased by non-TZD hypoglycemic medications (eg, insulin and glyburide), it is not clear whether this effect is due to PPAR-activation or improved glycemic control resulting from TZD treatment.^12,13 The effects of TZDs on LPL and lipoprotein metabolism have not been studied in normal volunteers, in whom the confounding effects of insulin sensitization and associated changes in glycemic parameters are minimized.

The pharmacodynamic effects of combined treatment with PPAR and PPAR agonists have yet to be systematically characterized in humans. In 1 retrospective clinical study, treatment with troglitazone appeared to interfere with the lipid-lowering effects of gemfibrozil.¹⁴ However, exploratory data on the effects of dual PPAR/PPAR agonists—muraglitazar, MK-0767, and ragaglitazar—on lipid metabolism in healthy subjects are consistent with decreases in plasma TG and FFA.^15-17 The purpose of the present study was to investigate the effects of potent, selective activators of PPAR (fenofibrate) and PPAR (rosiglitazone) on putative biomarkers of lipid/lipoprotein and glucose metabolism in healthy volunteers. A more thorough understanding of the individual and combined effects of these agents may prove useful in developing novel strategies for the treatment of diabetes and dyslipidemia.

	METHODS

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
The study was conducted at the San Diego Endocrine and Medicine Clinic in San Diego, California. All subjects provided written informed consent. The clinical protocol was conducted in accordance with the Declaration of Helsinki principles and was approved by Schulman Associates Institutional Review Board (Cincinnati, Ohio).

Study Design
This single-center, open-label, randomized, placebocontrolled, balanced, incomplete-block, 4-treatment, 3-period crossover pilot study was conducted in 12 healthy male nondiabetic subjects. Because each subject participated in 3 treatment periods in a balanced fashion, a total of 9 subjects received each treatment. The 4 treatments consisted of placebo once daily, fenofibrate 201 mg once daily, rosiglitazone 4 mg twice daily, and fenofibrate 201 mg once daily plus rosiglitazone 4 mg twice daily. The duration of each treatment was 14 days, with at least a 14-day washout between each treatment period.

Subjects
Healthy, nondiabetic subjects with normal glucose tolerance (fasting plasma glucose <110 mg/dL and <140 mg/dL 2 hours after a 75-g oral glucose load) were enrolled in this study to minimize the confounding effects of improved insulin sensitization on lipid measurements. Only male subjects were enrolled because gender-based variability has been observed with regard to LPL activity.¹⁸ All subjects were nonsmokers and between the ages of 18 and 45 years with normal baseline fasting plasma lipid profiles. Subjects were required to refrain from the use of all other medications from 14 days prior to the study until study completion.

Efficacy Measurements
The primary efficacy measurement in this pilot study was postheparin LPL activity. Clinically, LPL is measured following intravenous heparin treatment, which releases the enzyme into circulation and can be assessed in the serum as immunoreactive mass (measurement of LPL protein concentration) or as lipase activity specific to LPL protein.¹⁹ In the current study, only LPL activity was measured. Secondary efficacy measurements included plasma TG and apolipoprotein (apo) C-III concentrations. Predefined exploratory endpoints included FFA, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), apo A-I, apo B, plasma carnitine, insulin, adiponectin, fasting plasma glucose (FPG), and insulin resistance as measured by the homeostasis model (HOMA-R).²⁰

Laboratory Measurements
Plasma postheparin LPL activity was measured using a modification of the method of Nilsson-Ehle and Ekman.²¹ FFA, plasma lipids, and lipoproteins were measured by standard methods.²¹ Free carnitine was measured as previously described.^22,23 Adiponectin was measured by quantitative Western blotting, as described by Combs et al.²⁴

Statistical Analysis
The log percentage change from baseline (ie, log post-treatment minus log pretreatment baseline) in the various efficacy parameters was analyzed using an analysis of covariance (ANCOVA) model, appropriate for a balanced, incomplete-block, 4-treatment, 3-period crossover study with factors for subject, period, treatment, and baseline parameter values.

To assess the magnitude of the effect between the active treatment group and placebo, 95% confidence intervals (CIs) for the least squares mean difference in the log percentage change from baseline also were computed. All data were back-transformed from the log scale to the original percent change from baseline scale for the purpose of presentation. The threshold for statistical significance was P < .050 and was considered to approach significance at .050 < P < .100.

To take into account the factorial nature of the design (presence/absence of fenofibrate or rosiglitazone), an analysis partitioning the treatment structure in this way yielded an ANCOVA model with terms for subject, period, baseline parameters, fenofibrate (presence/absence), rosiglitazone (presence/absence), and fenofibrate-by-rosiglitazone interaction. In this model, the interaction effect (test for super- and subadditivity) was statistically significant for TG (P = .042) and approached statistical significance for FFA (P = .074). All other efficacy parameters demonstrated a lack of statistically significant interaction, supporting the validity of the analysis partitioning the treatment structure; however, because of the statistically significant interaction for TG and near-significant interaction for FFA, the results for these parameters must be interpreted with caution.

	RESULTS

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Subjects
All 12 subjects who were randomized to treatment completed the 10-week study and were included in the efficacy and safety analyses. The study population consisted of healthy Caucasian or African American males ranging in age from 18 to 42 years (mean age, 24 years) with a mean weight of 89 kg (range, 61-110 kg) and a mean body mass index of 27 kg/m² (range, 21-34 kg/m²). None of the subjects had any evidence or family history of diabetes mellitus or cardiovascular disease. All subjects had normal baseline fasting plasma glucose and lipid values (including TG and TC).

Lipoprotein Lipase Activity
Baseline LPL activity was generally similar among the 4 treatment groups; however, the mean baseline value appeared numerically lower in the fenofibrate group (Table I). The least squares mean percent changes from baseline in LPL activity for the placebo, fenofibrate, rosiglitazone, and fenofibrate plus rosiglitazone groups were +7.7%, +32.2%, +6.3%, and +53.1%, respectively (Table II). The least squares mean percent differences from placebo in LPL activity were +24.5% for fenofibrate (P = .235), -1.4% for rosiglitazone (P = .940), and +45.5% for fenofibrate plus rosiglitazone (P = .044) (Table II). Postheparin LPL activity increased by at least 9.9% in all subjects who received fenofibrate alone (Figure 1). Because no interaction between fenofibrate and rosiglitazone on postheparin LPL activity was observed, the increase in LPL activity due to the presence of fenofibrate was 35.3% (P = .023) (Table III). No main effect (presence of drug minus absence of drug) on postheparin LPL due to the presence of rosiglitazone was observed in this analysis.

View larger version (21K): [in this window] [in a new window]   Figure 1. Mean change in postheparin lipoprotein lipase activity (nmol/min/mL) from day 1 (baseline; filled circles) to day 14 (open circles) in individual subjects.

Lipids and Apolipoproteins
Baseline lipid and apolipoprotein values were generally similar among the 4 treatment groups; however, mean TG and apo C-III were numerically higher in the fenofibrate group (Table I). The least squares mean percent changes from baseline in TG for placebo, fenofibrate, rosiglitazone, and fenofibrate plus rosiglitazone were -23.8%, -29.7%, +38.3%, and -26.1%, respectively. The least squares mean percent differences from placebo in TG for fenofibrate, rosiglitazone, and fenofibrate plus rosiglitazone were -5.9% (P = .686), +62.1% (P = .003), and -2.3% (P = .865), respectively. Except for TG, no significant interaction was observed between fenofibrate and rosiglitazone on lipids and apolipoproteins. Thus, the main effect parameters of fenofibrate alone and rosiglitazone alone on lipids and apolipoproteins were evaluated as the mean percent difference in the presence of drug minus that in the absence of drug (Table III). The presence of fenofibrate significantly decreased TG and apo C-III by 30.5% (P = .016) and 20.3% (P = .007), respectively. In contrast, the presence of rosiglitazone led to significant increases in TG (27.9%; P = .025) and apo C-III (19.3%; P = .008). Scatter plots showing individual TG and apo C-III values before and after treatment are provided in Figures 2 and 3, respectively. The presence of fenofibrate produced significant reductions in apo B (-13.4%; P = .006), whereas no main effect of rosiglitazone on apo B was observed in this analysis. The decrease in TC observed in the presence of fenofibrate (9.8%; .05 < P < .10) approached but did not attain significance. No main effects (presence of drug minus absence of drug) for fenofibrate alone or rosiglitazone alone were identified for LDL-cholesterol, HDL-cholesterol, or apo A-I (Table III).

View larger version (20K): [in this window] [in a new window]   Figure 2. Mean change in apolipoprotein C-III (g/L) from day 1 (baseline; filled circles) to day 14 (open circles) in individual subjects.

View larger version (16K): [in this window] [in a new window]   Figure 3. Mean change in triglycerides (mmol/L) from day 1 (baseline; filled circles) to day 14 (open circles) in individual subjects.

Free Fatty Acids
The mean baseline FFA values were generally similar among the 4 treatment groups; however, FFA was numerically higher in the rosiglitazone group (Table I). The least squares mean percent changes from baseline in FFA for the placebo, fenofibrate, rosiglitazone, and fenofibrate plus rosiglitazone groups were -7.6%, -13.6%, +13.7%, and -47.5%, respectively. The least squares mean percent differences from placebo in FFA for the fenofibrate, rosiglitazone, and fenofibrate plus rosiglitazone groups were -6.0% (P = .802), +21.3% (P = .441), and -39.9% (P = .046), respectively. A significant decrease in FFA was observed in the fenofibrate plus rosiglitazone group, and the fenofibrate-by-rosiglitazone interaction test for this parameter approached statistical significance. Nonetheless, the main effect parameters for fenofibrate and rosiglitazone were evaluated separately as the mean percent difference in the presence of drug minus that in the absence of drug (Table III). The presence of fenofibrate decreased FFA by 35.2% (P = .037). No main effect of rosiglitazone on FFA was observed in this analysis.

Insulin and Glucose
The mean baseline values for fasting plasma glucose and insulin were similar among the 4 groups; however, the mean fasting insulin value in the fenofibrate plus rosiglitazone group was numerically lower than that in the other groups (Table I). The least squares mean percent differences from placebo in fasting plasma glucose for the fenofibrate, rosiglitazone, and fenofibrate plus rosiglitazone groups were +5.7%, -3.9%, and -5.1%, respectively (Table II). The least squares mean percent differences from placebo in fasting plasma insulin for the fenofibrate, rosiglitazone, and fenofibrate plus rosiglitazone groups were +1.5%, -9.6%, and -13.5%, respectively. For HOMA-R, the least squares mean percent differences from placebo were +4.1% for fenofibrate, -15.4% for rosiglitazone, and -21.3% for fenofibrate plus rosiglitazone. None of these changes approached significance (P > .10). No significant interaction between fenofibrate and rosiglitazone was observed for fasting glucose or insulin; thus, the main effect parameters for fenofibrate and rosiglitazone were evaluated as the mean percent difference in the presence of drug minus that in the absence of drug (Table III). Fasting plasma glucose was decreased by 7.3% in the presence of rosiglitazone (P = .034). No main effect of fenofibrate on fasting plasma glucose was observed. No main effect of either fenofibrate or rosiglitazone on fasting plasma insulin or HOMA-R was observed in this analysis.

Plasma Carnitine
Mean baseline values of plasma carnitine were similar across the placebo, fenofibrate, rosiglitazone, and rosiglitazone plus fenofibrate groups (Table I). The least squares mean percent difference from placebo did not reach significance (P > .05) for fenofibrate alone (+15.9%), fenofibrate plus rosiglitazone (+17.4%), and rosiglitazone alone (+7.3%) (Table II). Because there was no significant interaction between fenofibrate and rosiglitazone on plasma carnitine, the main effect parameters for fenofibrate and rosiglitazone were evaluated as the mean difference in the presence of drug minus that in the absence of drug (Table III). The increase in plasma carnitine observed in the presence of fenofibrate (13.1%; .05 < P < .10) approached but did not attain significance. No main effect of rosiglitazone on plasma carnitine was observed in this analysis.

Adiponectin
Mean baseline values of plasma adiponectin were similar across the placebo, fenofibrate, rosiglitazone, and rosiglitazone plus fenofibrate groups (Table I). The least squares mean percent changes from baseline in plasma adiponectin were +16.8%, -12.3%, +131.6%, and +144.3% for placebo, fenofibrate, fenofibrate plus rosiglitazone, and rosiglitazone, respectively. The least squares mean percent differences from placebo for fenofibrate alone, fenofibrate plus rosiglitazone, and rosiglitazone alone were -29.1% (P = .210), +114.8% (P = .007), and +127.5% (P = .005), respectively. The main effect parameters for fenofibrate and rosiglitazone were evaluated separately because no significant interaction for fenofibrate and rosiglitazone on plasma adiponectin was observed (Table III). The presence of rosiglitazone produced significant increases in plasma adiponectin levels (136.7%; P < .001). No main effect of fenofibrate on plasma adiponectin was observed in this analysis.

Safety
Treatment with fenofibrate and rosiglitazone individually and in combination was generally well tolerated in healthy subjects during this short-term pilot study. Adverse experiences were reported in 7 of 12 subjects; all were rated mild in intensity and considered definitely not related to study drug by the investigator. Five subjects reported symptoms of upper respiratory infection. Reported adverse experiences did not include anemia, weight gain, edema, musculoskeletal symptoms, or increases in hepatic transaminases.

	DISCUSSION

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Drugs with combined PPAR and PPAR activities hold promise for providing the benefits of fibrates on lipid/lipoprotein metabolism and the benefits of TZDs on glucose metabolism.^15-17 This combination may have additive or synergistic therapeutic effects and may also mitigate some of the adverse effects, such as weight gain, that have been observed with TZDs. In animal studies, for example, the administration of fenofibrate 400 mg/kg/d and rosiglitazone 10 mg/kg/d to healthy rats for 7 days resulted in a more pronounced decrease in plasma TG levels relative to that seen with each drug alone, primarily resulting from decreased hepatic synthesis of apo C-III and increased expression of LPL mRNA in adipose tissue.²⁵ The present study examined the influence of PPAR and PPAR agonists, individually and together, on lipid/lipoprotein and glucose metabolism in 12 healthy nondiabetic male subjects.

In this short-term pilot study, little evidence for significant interactions between fenofibrate and rosiglitazone, either superadditivity or subadditivity, was found for variables reflecting lipid or glucose metabolism, although this pilot study was not necessarily powered at the design stage to fully assess these effects. The effects of combination treatment were analyzed for each of the efficacy variables (Table II), despite the lack of significant interaction for most of the variables tested. Compared to placebo, 14 days of combined treatment with rosiglitazone and fenofibrate produced significant mean percent changes from baseline in postheparin LPL (+46%), adiponectin (+115%), and FFA (-40%). Overall, these results are consistent with a generally favorable efficacy profile in healthy subjects. Of note, a statistically significant fenofibrate-by-rosiglitazone interaction test was observed for TG, and this test approached significance for FFA.

Because fenofibrate and rosiglitazone did not demonstrate a significant interaction for most of the parameters tested (LPL activity, LDL-C, HDL-C, TC, apo C-III, apo B, apo A-I, free carnitine, fasting glucose, insulin, HOMA-R, and adiponectin), this permitted analysis of the pharmacodynamic effects of each drug individually (ie, presence/absence analysis; Table III). In this analysis, fenofibrate produced the expected lipid and lipoprotein effects of PPAR agonist treatment, including increased postheparin LPL activity (+35%) and decreased plasma levels of TG (-31%), FFA (-35%), apo C-III (-20%), and apo B (-13%) (Table III). As discussed, fenofibrate effects on TG and FFA were harder to assess due to the significant and near-significant interaction tests observed for these parameters. Nonetheless, the effects of fenofibrate were consistent with those reported in other studies of nondiabetic volunteers treated with fibrates.^21,26,27 Fibrates have been shown to modify transcription of the apo C-III and LPL genes through the PPAR nuclear receptor.^6-9 Desager and coworkers²¹ demonstrated a decrease in apo B (17%; P < .01) in healthy subjects receiving fenofibrate 200 mg daily for 23 days, as well as significant changes in HDL-C (+6%; P < .05) and LDL-C (-18%; P < .01). In the present study, the observed increase in HDL-C was numerically similar but did not attain statistical significance, most likely due to variability in this measurement and the small sample size. Similarly, the changes in plasma carnitine (+13%) and TC (-10%) observed in the present study with fenofibrate approached but did not reach significance (.05 < P < .10). Overall, postheparin LPL activity, apo C-III, and apo B appeared to be robust biomarkers of PPAR agonists in healthy volunteers.

Although the effects of fibrates on lipid and lipoprotein metabolism are well characterized, less has been reported regarding TZD-induced effects. Rosiglitazone has been shown to decrease plasma TG in diabetic rats^28,29 but has variable effects in patients with type 2 diabetes.³⁰ Our analysis of the individual effects of rosiglitazone (ie, presence/absence) demonstrated significant increases in TG (28%), apo C-III (19%), and adiponectin (137%); however, rosiglitazone did not produce significant changes (P > .05) in postheparin LPL activity, FFA, apo A-I, apo B, or carnitine in healthy volunteers (Tables III and IV). The statistically significant fenofibrate-by-rosiglitazone interaction test for TG and near-significance test for FFA made it difficult to interpret the effect of rosiglitazone alone on these parameters. In this study, PPAR agonist treatment also produced significant reductions in fasting plasma glucose (7%), a finding not previously reported in healthy volunteers.

View this table: [in this window] [in a new window]   Table IV Summary of Treatment Effects of Fenofibrate and Rosiglitazone on PPAR and PPAR Biomarkers in Healthy Volunteers as Determined by the Absence Versus Presence Analysis

Finally, plasma levels of adiponectin more than doubled in healthy subjects receiving rosiglitazone alone and fenofibrate plus rosiglitazone coadministration. Adiponectin has been shown to be a PPAR biomarker in healthy volunteers as well as in type 2 diabetic patients.^24,31 Administration of the globular head domain of adiponectin significantly decreased plasma FFA in mice receiving either a high-fat test meal or intravenous lipid.³² In that study, administration of adiponectin to mice consuming a high-fat/sucrose diet resulted in weight loss without altering food consumption. Furthermore, in a mouse model of diabetes, a single administration of adiponectin normalized hyperglycemia without an associated increase in insulin levels.³³ Thus, treatments that increase the expression of this important factor may hold promise for the treatment of diabetes and dyslipidemias.

In summary, the results of the present study suggest that postheparin LPL activity, apo C-III, and apo B are biomarkers of PPAR activity, whereas apo C-III, fasting glucose, and adiponectin are biomarkers of PPAR activity in healthy human subjects. Fenofibrate and rosiglitazone also produced effects on TG and FFA, but it was not possible to determine if these effects were synergistic in nature. Importantly, the lipid-modifying and insulin-sensitizing effects of fenofibrate and rosiglitazone were preserved when both drugs were administered together. The beneficial TG-lowering effects of fenofibrate predominated, despite a trend toward increased TG levels with rosiglitazone monotherapy. Similarly, rosiglitazone's effect on adiponectin was maintained when fenofibrate was administered concurrently. Taken together, these findings lend support for the hypothesis that dual PPAR/PPAR agonists may represent a more comprehensive and efficacious therapy for the treatment of type 2 diabetes, dyslipidemias, and metabolic syndrome than PPAR- and PPAR-selective agents. The identification of biomarkers may support early stages of development for drugs of the PPAR agonist class.

	ACKNOWLEDGEMENTS

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
The authors thank Dr Amy O. Johnson-Levonas, PhD, for her assistance with preparing this manuscript for publication.

DOI: 10.1177/0091270004273136

	REFERENCES

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 

1. Kliewer SA, Forman BM, Blumberg B, et al. Differential expression and activation of a family of murine peroxisome proliferator-activated receptors. Proc Natl Acad Sci USA. 1994;91: 7355-7359.[Abstract/Free Full Text]

2. Staels B, Auwerx J. Role of PPAR in the pharmacological regulation of lipoprotein metabolism by fibrates and thiazolidinediones. Curr Pharm Design. 1997;3: 1-14.

3. Braissant O, Foufelle F, Scotto C, Dauca M, Wahli W. Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-alpha, -beta, and -gamma in the adult rat. Endocrinology. 1996;137: 354-366.[Abstract]

4. Forman BM, Tontonoz P, Chen J, Brun RP, Spiegelman BM, Evans RM. 15-Deoxy-delta 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma. Cell. 1995;83: 803-812.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

5. Lehmann JM, Moore LB, Smith-Oliver TA, Wilkison WO, Willson TM, Kliewer SA. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J Biol Chem. 1995;270: 12953-12956.[Abstract/Free Full Text]

6. Schoonjans K, Peinado-Onsurbe J, Lefebvre AM, et al. PPARalpha and PPARgamma activators direct a distinct tissue-specific transcriptional response via a PPRE in the lipoprotein lipase gene. EMBO J. 1996;15: 5336-5348.[Web of Science][Medline] [Order article via Infotrieve]

7. Staels B, Vu-Dac N, Kosykh VA, et al. Fibrates downregulate apolipoprotein C-III expression independent of induction of peroxisomal acyl coenzyme A oxidase: a potential mechanism for the hypolipidemic action of fibrates. J Clin Invest. 1995;95: 705-712.

8. Staels B, Schoonjans K, Fruchart JC, Auwerx J. The effects of fibrates and thiazolidinediones on plasma triglyceride metabolism are mediated by distinct peroxisome proliferator activated receptors (PPARs). Biochimie. 1997;79: 95-99.[Medline] [Order article via Infotrieve]

9. 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.[Abstract/Free Full Text]

10. Ranganathan S, Kern PA. Thiazolidinediones inhibit lipoprotein lipase activity in adipocytes. J Biol Chem. 1998;273: 26117-26122.[Abstract/Free Full Text]

11. Kobayashi J, Nagashima I, Hikita M, et al. Effect of troglitazone on plasma lipid metabolism and lipoprotein lipase. Br J Clin Pharmacol. 1999;47: 433-439.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

12. Pfeifer MA, Brunzell JD, Best JD, Judzewitsch RG, Halter JB, Porte D Jr. The response of plasma triglyceride, cholesterol, and lipoprotein lipase to treatment in non-insulin-dependent diabetic subjects without familial hypertriglyceridemia. Diabetes. 1983;32: 525-531.[Abstract]

13. Simsolo RB, Ong JM, Saffari B, Kern PA. Effect of improved diabetes control on the expression of lipoprotein lipase in human adipose tissue. J Lipid Res. 1992;33: 89-95.[Abstract]

14. Bell DS, Ovalle F. Troglitazone interferes with gemfibrozil's lipid-lowering action. Diabetes Care. 1998;21: 2028-2029.

15. Frost CE, Swaminathan A, Raymond R, et al. Lipid lowering effects of multiple dose administration of muraglitazar (BMS-298585), a novel PPAR alpha/gamma dual agonist, in type 2 diabetic patients. Program and abstracts of the 64th Scientific Sessions of the American Diabetes Association; June 4-8, 2004; Orlando, Fla. Abstract 139 OR.

16. Wagner J, Chen X, Rippley R, et al. Single and multiple doses of MK-0767 reduce free fatty acids and lipids in healthy subjects. Diabetes. 2003;52(suppl 1): A137.

17. Skrumsager BK, Nielsen KK, Muller M, Pabst G, Drake PG, Edsberg B. Ragaglitazar: the pharmacokinetics, pharmacodynamics, and tolerability of a novel dual PPAR alpha and gamma agonist in healthy subjects and patients with type 2 diabetes. J Clin Pharmacol. 2003;43: 1244-1256.[Abstract/Free Full Text]

18. Despres JP, Gagnon J, Bergeron J, et al. Plasma post-heparin lipase activities in the HERITAGE Family Study: the reproducibility, gender differences, and associations with lipoprotein levels. HEalth, RIsk factors, exercise Training and GEnetics. Clin Biochem. 1999;32: 157-165.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

19. Brunzell JD, Porte D Jr, Bierman EL. Reversible abnormalities in postheparin lipolytic activity during the late phase of release in diabetes mellitus (postheparin lipolytic activity in diabetes). Metabolism. 1975;24: 1123-1137.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

20. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28: 412-419.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

21. Desager JP, Horsmans Y, Vandenplas C, Harvengt C. Pharmacodynamic activity of lipoprotein lipase and hepatic lipase, and pharmacokinetic parameters measured in normolipidaemic subjects receiving ciprofibrate (100 or 200 mg/day) or micronised fenofibrate (200 mg/day) therapy for 23 days. Atherosclerosis. 1996;124(suppl): S65-S73.

22. Christiansen RZ, Bremer J. Acetylation of tris(hydroxymethyl)aminomethane (Tris) and Tris derivatives by carnitine acetyltransferase. FEBS Lett. 1978;86: 99-102.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

23. Ramsay RR, Tubbs PK. The mechanism of fatty acid uptake by heart mitochondria: an acylcarnitine-carnitine exchange. FEBS Lett. 1975;54: 21-25.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

24. Combs TP, Wagner JA, Berger J, et al. Induction of adipocyte complement-related protein of 30 kilodaltons by PPARgamma agonists: a potential mechanism of insulin sensitization. Endocrinology. 2002;143: 998-1007.[Abstract/Free Full Text]

25. Lefebvre AM, Peinado-Onsurbe J, Leitersdorf I, et al. Regulation of lipoprotein metabolism by thiazolidinediones occurs through a distinct but complementary mechanism relative to fibrates. Arterioscler Thromb Vasc Biol. 1997;17: 1756-1764.[Abstract/Free Full Text]

26. Greten H, Laible V, Zipperle G, Augustin J. Comparison of assay methods for selective measurement of plasma lipase: the effect of clofibrate on hepatic and lipoprotein lipase in normals and patients with hypertriglyceridemia. Atherosclerosis. 1977;26: 563-572.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

27. Heller F, Harvengt C. Effects of clofibrate, bezafibrate, fenofibrate and probucol on plasma lipolytic enzymes in normolipaemic subjects. Eur J Clin Pharmacol. 1983;25: 57-63.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

28. Brand CL, Sturis J, Gotfredsen CF, et al. Dual PPARalpha/gamma activation provides enhanced improvement of insulin sensitivity and glycemic control in ZDF rats. Am J Physiol Endocrinol Metab. 2003;284: E841-E854.[Abstract/Free Full Text]

29. Chaput E, Saladin R, Silvestre M, Edgar AD. Fenofibrate and rosiglitazone lower serum triglycerides with opposing effects on body weight. Biochem Biophys Res Commun. 2000;271: 445-450.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

30. Avandia (rosiglitazone maleate) tablets [prescriber information]. Research Triangle Park, NC: GlaxoSmithKline; 2001.

31. Yang WS, Jeng CY, Wu TJ, et al. Synthetic peroxisome proliferator-activated receptor-gamma agonist, rosiglitazone, increases plasma levels of adiponectin in type 2 diabetic patients. Diabetes Care. 2002;25: 376-380.[Abstract/Free Full Text]

32. Fruebis J, Tsao TS, Javorschi S, et al. Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice. Proc Natl Acad Sci USA. 2001;98: 2005-2010.[Abstract/Free Full Text]

33. Berg AH, Combs TP, Du X, Brownlee M, Scherer PE. The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat Med. 2001;7: 947-953.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				J.-C. Fruchart, F. M Sacks, M. P Hermans, G. Assmann, W V. Brown, R. Ceska, M J. Chapman, P. M Dodson, P. Fioretto, H. N Ginsberg, et al. The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in dyslipidaemic patients Diabetes and Vascular Disease Research, November 1, 2008; 5(4): 319 - 335. [Abstract] [PDF]

				A. Hiuge, A. Tenenbaum, N. Maeda, M. Benderly, M. Kumada, E. Z. Fisman, D. Tanne, Z. Matas, T. Hibuse, K. Fujita, et al. Effects of Peroxisome Proliferator-Activated Receptor Ligands, Bezafibrate and Fenofibrate, on Adiponectin Level Arterioscler. Thromb. Vasc. Biol., March 1, 2007; 27(3): 635 - 641. [Abstract] [Full Text] [PDF]

				G. Boden, C. Homko, M. Mozzoli, M. Zhang, K. Kresge, and P. Cheung Combined Use of Rosiglitazone and Fenofibrate in Patients With Type 2 Diabetes: Prevention of Fluid Retention Diabetes, January 1, 2007; 56(1): 248 - 255. [Abstract] [Full Text] [PDF]

				L M. Gutschi, J. C Malcolm, C. M Favreau, and T. C. Ooi Paradoxically Decreased HDL-Cholesterol Levels Associated with Rosiglitazone Therapy Ann. Pharmacother., September 1, 2006; 40(9): 1672 - 1676. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Request Reprints Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (11) Citing Articles via Google Scholar Google Scholar Articles by Wagner, J. A. Articles by Gottesdiener, K. M. Search for Related Content PubMed PubMed Citation Articles by Wagner, J. A. Articles by Gottesdiener, K. M. Social Bookmarking                   What's this?