<title>1. INTRODUCTION</title> <p>Peroxisome proliferator-activated receptors (PPARs) play an important role in regulating
both glucose and lipid metabolism. Agonists for both PPAR<italic>α</italic> and PPAR<italic>γ</italic> have been used to treat dyslipidemia
and hyperglycemia, respectively. In
addition to affecting glucose metabolism, PPAR<italic>γ</italic> agonists also regulate lipid
metabolism.</p> <p>The dyslipidemia of type 2 diabetes mellitus is characterized by elevations in
serum triglycerides and increased very low-density lipoprotein (VLDL) particle
size, reduced high-density lipoprotein (HDL) cholesterol and HDL particle size,
and the predominance of small, dense low-density lipoprotein (LDL) particles
with generally normal LDL cholesterol. Many studies have examined the effect of improvements in glycemic control
on serum lipids and lipoproteins utilizing a variety of glucose-lowering
medications [##UREF##0##1##]. These include insulin, sulfonylureas,
biguanides, thiazolidinediones, glucagon-like peptides, <italic>α</italic>-glucosidase inhibitors, and dipeptidyl
peptidase-IV inhibitors. In general,
improving glycemic control reduces serum triglycerides and increases HDL cholesterol. Numerous studies have compared the effect of
thiazolidinediones with other oral glucose-lowering medications. In general, thiazolidinediones have better
overall effects on lipids compared to sulfonylureas or insulin [##UREF##1##2##, ##REF##15356308##3##]. In this review, we will focus on the
randomized clinical trials that directly compared the lipid effects of the
thiazolidinedione class of PPAR<italic>γ</italic> agonists, pioglitazone and
rosiglitazone, head to head either as monotherapy or in combination with other
lipid-altering or glucose-lowering agents. The effects of troglitazone (Rezulin), which has been removed from the
market, will not be discussed.</p>
<p>Recommended by Francine Gregoire</p> <p>Peroxisome proliferator-activated receptors (PPARs) play an important role in regulating both glucose and lipid metabolism. Agonists for both PPAR<italic>γ</italic> and PPAR<italic>γ</italic> have been used to treat dyslipidemia and hyperglycemia, respectively. In addition to affecting glucose metabolism, PPAR<italic>γ</italic> agonists also regulate lipid metabolism. In this review, we will focus on the randomized clinical trials that directly compared the lipid effects of the thiazolidinedione class of PPAR<italic>γ</italic> agonists, pioglitazone and rosiglitazone, head-to-head either as monotherapy or in combination with other lipid-altering or glucose-lowering agents</p>
<title>2. ROLE OF PPAR<italic>γ</italic> IN REGULATING FATTY ACID/TRIGLYCERIDE METABOLISM</title> <p>The whole-body
response to activating PPAR<italic>γ</italic> is storage of energy, as triglycerides,
in adipocytes. This is accomplished by
the coordinated regulation of tissue-specific gene expression in adipocytes,
liver, and cells that utilize fatty acids for energy as well as various
circulating factors that coordinate and regulate fatty acid synthesis and
utilization. Although often only serum
triglycerides are measured and monitored in patients, serum triglycerides
represent just one compartment within which PPAR<italic>γ</italic> medications affect whole-body
triglyceride/fatty acid metabolism. Serum triglycerides within VLDL and chylomicrons may be considered the
mechanism by which energy (as triglycerides) is transported from one tissue to
another (##FIG##0##Figure 1##).</p> <p>In the adipocyte, both pioglitazone and rosiglitazone increase the expression of genes associated
with hydrolysis of triglyceride-rich lipoproteins and fatty acid uptake and
storage [##REF##16894240##4##, ##REF##16896939##5##] (##FIG##0##Figure 1##). Thiazolidinediones also reduce fatty acid
release from adipocytes. This in turn
leads to less fatty acid delivery to the liver and a decrease in hepatic
triglyceride synthesis. In addition, PPAR<italic>γ</italic> medications influence secretion of
adipokines that affect lipid and glucose metabolism. Pioglitazone and rosiglitazone therapies increase adiponectin [##REF##11815513##6##, ##REF##14715850##7##] and decrease retinol binding
protein 4 [##REF##17595259##8##] and resistin [##REF##15024400##9##]. These adipokines influence lipid metabolism
and insulin sensitivity.</p> <p>In the liver, PPAR<italic>γ</italic> therapy is associated with changes in
expression of various genes involved in lipid metabolism including
apolipoproteins CII and CIII. Apolipoproteins CII and CIII stimulate and inhibit lipoprotein lipase,
respectively. Lipoprotein lipase is the
major enzyme involved in hydrolyzing and removing triglyceride-rich
lipoproteins from the serum.</p> <title>3. COMPARISON OF LIPID EFFECTS OF PIOGLITAZONE AND ROSIGLITAZONE IN
HEAD-TO-HEAD RANDOMIZED CLINICAL TRIALS</title> <title>3.1. Thiazolidinediones as monotherapy: effects on fasting lipids</title> <p>Goldberg et al. [##REF##15983299##10##] and Deeg et al. [##REF##17595355##11##] compared the effects of pioglitazone and rosiglitazone
in patients with type 2 diabetes mellitus and dyslipidemia on non-lipid-altering
medications (see ##TAB##0##Table 1##). After discontinuing
their glucose-lowering and lipid-altering medications, if they were on them,
patients were randomized to pioglitazone or rosiglitazone. Patients were treated with 30 mg once a day
(QD) of pioglitazone or 4 mg of rosiglitazone QD for 12 weeks with a forced
titration to 45 mg QD and 4 mg twice a day (bid) for additional 12 weeks,
respectively. Both medications reduced
hemoglobin A1c (A1c), insulin resistance (as determined by HOMA-IR), and
fasting free fatty acids to a similar extent. However, the effects on fasting triglycerides were divergent. Pioglitazone therapy was associated with a
reduction in fasting triglycerides throughout the study, whereas rosiglitazone
increased triglycerides within 4 weeks, which then declined with time. At the end of the study, triglycerides were
decreased by 12% with pioglitazone, and elevated by 15% in patients on
rosiglitazone.</p> <p>The decrease in triglycerides
with pioglitazone was associated with a decrease in large VLDL and intermediate
density lipoproteins (IDLs), whereas the increase in triglycerides with
rosiglitazone was associated with an increase in both large- and medium-sized
VLDL and IDL concentrations. Pioglitazone decreased whereas rosiglitazone
increased apolipoprotein CIII.</p> <p>Both medications raised LDL cholesterol; however, the increase was significantly greater with rosiglitazone
compared to pioglitazone (12.3% and 21.3%, resp.). Both therapies increased the average size of
LDL particles, but the effect of pioglitazone was greater than that of
rosiglitazone. Consistent with the
changes in LDL cholesterol, pioglitazone did not significantly change
apolipoprotein B levels but did reduce LDL particle concentration. Conversely, rosiglitazone increased both
apolipoprotein B and LDL particle concentration. The clinical significance of the difference
in particle concentration is unclear although decreased LDL particle
concentration has been associated with a reduced risk for coronary heart
disease [##UREF##2##12##, ##REF##16534013##13##]. Both medications raised serum levels of
lipoprotein (a).</p> <p>As expected, both medications increased HDL cholesterol and the average size of
HDL particles; however the increase in HDL cholesterol was significantly
greater with pioglitazone therapy compared with rosiglitazone therapy (14.9%
and 7.8%, resp.). Again, there was a
difference in HDL particle subclasses between the medications. Pioglitazone increased total, large, and
medium HDLs while decreasing small HDL concentration. Rosiglitazone, in contrast, decreased total,
large, and small HDLs while increasing medium HDL particle concentration. These suggest that there are differences in
HDL metabolism with these two agents. Pioglitazone had no effect on serum apolipoprotein AI levels, but rosiglitazone
therapy was associated with a decrease in apolipoprotein AI levels.</p> <title>3.2. Thiazolidinediones as monotherapy: effects on postprandial lipemia</title> <p>Postprandial dyslipidemia is a feature of type 2 diabetes. Two small studies compared the effects of pioglitazone and rosiglitazone on
postprandial lipemia using a prospective, randomized crossover design [##REF##18220486##14##, ##REF##17211855##15##]. After washing out both glucose-lowering (8
weeks) and lipid-altering medications (4 weeks), patients were randomized to
either pioglitazone (30 mg QD for 4 weeks, then 45 mg QD for 8 weeks) or
rosiglitazone (4 mg QD for 4 weeks followed by 4 mg bid for 8 weeks) with an 8-week
washout during the crossover. Before and
after each treatment, a standardized breakfast was served and postprandial
glucose, lipids, and hormones were measured.</p> <p>Both agents had similar effects on A1c and HOMA-IR. Pioglitazone reduced fasting and postprandial triglycerides that were
associated with decreases in the smaller VLDL subfractions: VLDL-2 and
VLDL-3. Rosiglitazone increased the
postprandial triglycerides with increases in VLDL-2 and VLDL-3. There was no effect with either medication on
fasting apolipoprotein B, AI, or CII/CIII ratio, and lipoprotein lipase or
hepatic lipase activity did not differ between therapies. Cholesterol ester transfer protein activity
decreased with rosiglitazone and increased after pioglitazone therapy. The second study demonstrated that
pioglitazone was more effective than rosiglitazone in increasing larger LDL
concentrations (fasting and postprandial) as well as in reducing levels of
small, dense LDL particles [##REF##18220486##14##].</p> <title>3.3. Thiazolidinediones in combination with other oral antihyperglycemic medications</title> <p>Derosa et al. [##REF##15220018##16##] compared the effect of adding
pioglitazone (15 mg QD) or rosiglitazone (4 mg QD) on patients with type 2
diabetes treated with glimepiride (4 mg QD). After 12 months, both groups had significant reductions in A1c
(1.3%). The group treated with the
pioglitazone combination had a reduction in total cholesterol, LDL cholesterol,
lipoprotein (a), and apolipoprotein B with an increase in HDL cholesterol. The rosiglitazone group had increases in
total cholesterol, LDL cholesterol, triglycerides, and apolipoprotein B but no
effect on HDL cholesterol or lipoprotein
(a) [##REF##16861090##17##]. Both groups showed a reduction in
homocysteine.</p> <p>In a similarly designed trial, patients with type 2 diabetes were treated with
metformin and randomized to pioglitazone or rosiglitazone [##REF##17229249##18##]. After 12 months, both groups had similar
reductions in A1c and insulin resistance (as determined by HOMA-IR). Total cholesterol, LDL cholesterol,
triglycerides, and apolipoprotein B decreased in the pioglitazone group with
increases in HDL cholesterol and apolipoprotein AI. There were no changes observed in the
rosiglitazone group.</p> <title>3.4. Thiazolidinediones in combination with statins</title> <p>Berhanu et al. [##REF##16784180##19##] examined the changes in
lipids when patients were switched from rosiglitazone and a statin to
pioglitazone (30 mg) while maintaining a stable statin dose. At the end of the trial (17 weeks), although
the A1c did not change, patients had a significant reduction in triglycerides,
total cholesterol, and LDL particle concentration (189 nmol/L) and increases in
LDL cholesterol, HDL cholesterol, and LDL particle diameter (0.23 nm). Apolipoprotein B did not change but
apolipoprotein AI increased.</p> <p>In summary, although the head-to-head and rosiglitazone-only
[##REF##17848652##20##] clinical trials demonstrate a benefit of
rosiglitazone on HDL cholesterol, there isa relatively consistent and overall favorable impact of
pioglitazone compared to rosiglitazone on serum lipids, lipoproteins, and
apolipoproteins. It is also clear that
the lipids' effects are unrelated to the changes in insulin sensitivity since [##UREF##0##1##]
both agents have similar effects to improve insulin sensitivity and [##UREF##1##2##] the
effect on insulin sensitivity can be clearly differentiated from lipid changes [##REF##18285418##21##]. Thus, there must be other differences in the
action of the thiazolidinediones that account for the divergent lipid effects.</p> <title>3.5. Comparison of mechanisms of action on lipid metabolism</title> <p>Whole-body fatty acid/triglyceride metabolism involves the interaction of numerous organs as
described above. Since both pioglitazone
and rosiglitazone have similar effects in the adipocyte on adipokines'
expression and genes involved in fatty acid/triglyceride metabolism, the difference
between these medications on serum triglycerides likely occurs within the liver
and/or plasma compartment.</p> <p>The most profound difference between the lipid effects of pioglitazone versus rosiglitazone is in
fasting and postprandial triglycerides. As both medications have similar effects on glycemic control and insulin
resistance, an additional mechanism must account for these differences. The differences in serum triglycerides occur
in smaller VLDL particles which are produced in an insulin-independent fashion
consistent with the observations that it is not the change in insulin
resistance that accounts for the differences. One potential difference, which may account for the difference, is the
effect on apolipoprotein CIII. Two
studies have demonstrated that pioglitazone decreases and rosiglitazone
increases apolipoprotein CIII [##REF##15983299##10##, ##REF##15841215##22##]. A decrease in apolipoprotein CIII would lead
to an increase in lipoprotein lipase activity, and hence an increase in the
hydrolysis of triglycerides and catabolic rate of triglyceride-rich
lipoproteins including chylomicrons and VLDL [##REF##3095375##23##]. This hypothesis is supported by the
observation that pioglitazone increases the lipolysis of VLDL triglycerides
without affecting the removal of VLDL particles [##REF##15841215##22##]. Conversely, rosiglitazone increases the
production and reduces the catabolism of triglyceride-rich lipoproteins
including both VLDL and chylomicrons [##REF##18285418##21##].</p> <p>Another possibility is that genetic differences may contribute to the different lipid
effects. Polymorphism of the PPAR<italic>γ</italic>2 gene influences the glycemic response
to rosiglitazone [##REF##16084854##24##] but not to pioglitazone [##REF##12610044##25##]. A lipoprotein lipase variant influences the
glycemic effect of pioglitazone [##REF##17394430##26##], while a polymorphism of the
adiponectin [##REF##15855579##27##] and perilipin [##REF##16732015##28##] genes influences the glycemic
and weight gain responses, respectively, to rosiglitazone. Since
none of these studies directly compared both rosiglitazone and pioglitazone, it
is unclear if polymorphism contributes to the differences. Most of these studies also did not show a
linkage between lipid effects and polymorphisms, but a link between the
adiponectin genotype at position 45 and the triglyceride effect of
rosiglitazone did statistically approach significance [##REF##15855579##27##]. Whether this occurs with pioglitazone has not
been published to date.</p> <p>It is possible that pharmacokinetic
differences between pioglitazone and rosiglitazone may account for the
differences in lipid effects; however, this is an unlikely contributor since
the gene expression and pharmacodynamic effects of both agents exceed the
presence of active drug in the serum.</p> <p>Do the differences in lipid effects have clinical significance? Increased fasting and postprandial triglycerides [##REF##17635891##29##, ##REF##17635890##30##] as well as LDL particle
concentration [##UREF##2##12##, ##REF##16534013##13##] are risk factors for cardiovascular
disease. Conversely, increases in large
HDL and adiponectin are associated with reduction in risk. It is also likely that other effects
influence the risk of coronary artery disease (CAD) events. It is likely that the integrated sum of these lipid effects, together with yet-defined factors, will determine the influence on atherosclerosis.</p> <p>Clinical outcome trials with both
pioglitazone and rosiglitazone have been published. Both pioglitazone and rosiglitazone improve
endothelial function and reduce the progression of carotid intramedial
thickness in patients [##REF##15883215##31##–##UREF##3##34##]. These observations suggest a clinical benefit with both agents. In the PROACTIVE study, adding pioglitazone
to the current treatment in patients with type 2 diabetes was associated with
reductions in major atherosclerotic events as defined in the main secondary
end-point [##UREF##4##35##], recurrent myocardial
infarction [##REF##17466227##36##], and recurrent stroke [##REF##17290029##37##]. Meta-analysis of pioglitazone clinical trials
showed a significantly lower risk of death, myocardial infarction, or stroke in
patients with diabetes [##REF##17848652##20##].</p> <p>The effect of rosiglitazone on CAD events is more controversial. Some post hoc meta-analysis studies have
suggested that rosiglitazone is associated with an increased risk of CAD events
[##REF##17517853##38##, ##REF##17848653##39##]. However, in the RECORD trial, a prospective
trial in patients with type 2 diabetes, no evidence for an increased event rate was found in an interim analysis
[##REF##17551159##40##]. Completion of this along with other studies is
needed to fully answer the effect of rosiglitazone on CAD events.</p> <title>4. SUMMARY</title> <p>Both pioglitazone
and rosiglitazone reduce insulin resistance and improve glycemic control in
patients with type 2 diabetes. However,
the head-to-head clinical trials demonstrate a relatively consistent and
favorable impact of pioglitazone compared to rosiglitazone on serum lipids,
lipoproteins, and apolipoproteins. Whether these differences result in
different outcomes that are clinically significant remains to be determined.</p>
<fig id="fig1" position="float"><label>Figure 1</label></fig>
<table-wrap id="tab1" position="float"><label>Table 1</label><caption><p>Summary of clinical trials comparing lipid effects of pioglitazone and rosiglitazone.</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="left" rowspan="1" colspan="1"/><th align="left" rowspan="1" colspan="1">Concomitant glucose/lipid therapy</th><th align="center" rowspan="1" colspan="1">
<italic>N</italic>
</th><th align="center" rowspan="1" colspan="1">Duration</th><th align="left" rowspan="1" colspan="1">Pioglitazone effects</th><th align="left" rowspan="1" colspan="1">Rosiglitazone effects</th></tr></thead><tbody><tr><td rowspan="3" align="left" colspan="1">Derosa et al. [##REF##15220018##16##, ##REF##16861090##17##]</td><td rowspan="3" align="left" colspan="1">Glimepiride</td><td rowspan="3" align="center" colspan="1">91</td><td rowspan="3" align="center" colspan="1">52 wk</td><td align="left" rowspan="1" colspan="1">↑HDL-C, apo AI</td><td align="left" rowspan="1" colspan="1">
↑TC*, LDL-C*, HDL-C, </td></tr><tr><td align="left" rowspan="1" colspan="1">↓TC*, LDL-C*,</td><td align="left" rowspan="1" colspan="1">↑TG*, apo AI, apo B*, lipoprotein (a)</td></tr><tr><td align="left" rowspan="1" colspan="1"> ↓TG*, apo B*, Lp(a)*</td><td rowspan="1" colspan="1"/></tr><tr><td align="center" colspan="6" rowspan="1">
<hr/>
</td></tr><tr><td rowspan="4" align="left" colspan="1">Goldberg et al. [##REF##15983299##10##], Deeg et al. [##REF##17595355##11##]</td><td rowspan="4" align="left" colspan="1">None</td><td rowspan="4" align="center" colspan="1">802</td><td rowspan="4" align="center" colspan="1">24 wk</td><td align="left" rowspan="1" colspan="1">
↑HDL-C*, LDL-C*, TC*</td><td align="left" rowspan="1" colspan="1">
↑TG*, HDL-C*, LDL-C*,</td></tr><tr><td align="left" rowspan="1" colspan="1">↓TG*</td><td align="left" rowspan="1" colspan="1">↑TC*, apo B*</td></tr><tr><td align="left" rowspan="1" colspan="1">↑VLDL-P, HDL-P*, apo AI</td><td align="left" rowspan="1" colspan="1">↑VLDL-P, HDL-P*, LDL-P*, apo CIII*</td></tr><tr><td align="left" rowspan="1" colspan="1">↓LDL-P*, apo CIII*</td><td align="left" rowspan="1" colspan="1">↓apo AI*</td></tr><tr><td align="center" colspan="6" rowspan="1">
<hr/>
</td></tr><tr><td rowspan="3" align="left" colspan="1">Berhanu et al. [##REF##16784180##19##]</td><td rowspan="3" align="left" colspan="1">Statins</td><td rowspan="3" align="center" colspan="1">305</td><td rowspan="3" align="center" colspan="1">17 wk</td><td align="left" rowspan="1" colspan="1">
↓TG*, TC*, LDL-P,</td></tr><tr><td align="left" rowspan="1" colspan="1">↑LDL-C*, HDL-C</td></tr><tr><td align="left" rowspan="1" colspan="1">(changes following switch from rosiglitazone to pioglitazone)</td></tr><tr><td align="center" colspan="6" rowspan="1">
<hr/>
</td></tr><tr><td rowspan="2" align="left" colspan="1">Chappuis et al. [##REF##17211855##15##]</td><td rowspan="2" align="left" colspan="1">None</td><td rowspan="2" align="center" colspan="1">17</td><td rowspan="2" align="center" colspan="1">12 wk</td><td align="left" rowspan="1" colspan="1">
↓AUC-TG*</td><td align="left" rowspan="1" colspan="1">
↑AUC-TG*</td></tr><tr><td align="left" rowspan="1" colspan="1">↑CETP*</td><td align="left" rowspan="1" colspan="1">↓CETP*</td></tr><tr><td align="center" colspan="6" rowspan="1">
<hr/>
</td></tr><tr><td rowspan="2" align="left" colspan="1">Derosa et al. [##REF##17229249##18##]</td><td rowspan="2" align="left" colspan="1">Metformin</td><td rowspan="2" align="center" colspan="1">96</td><td rowspan="2" align="center" colspan="1">52 wk</td><td align="left" rowspan="1" colspan="1">↓TC*, LDL-C*, TG*, apo B*</td><td rowspan="2" align="left" colspan="1">No significant changes in any lipid parameter</td></tr><tr><td align="left" rowspan="1" colspan="1">↑HDL-C*, apo AI*</td></tr><tr><td align="center" colspan="6" rowspan="1">
<hr/>
</td></tr><tr><td rowspan="2" align="left" colspan="1">Berneis et al. [##REF##18220486##14##]</td><td rowspan="2" align="left" colspan="1">None</td><td rowspan="2" align="center" colspan="1">9</td><td rowspan="2" align="center" colspan="1">12 wk</td><td align="left" rowspan="1" colspan="1">
↑TC, HDL, LDL, LDL IIA*</td><td rowspan="2" align="left" colspan="1">
↑TC, TG*, HDL, LDL, LDL-IIA</td></tr><tr><td align="left" rowspan="1" colspan="1">↓TG*</td></tr></tbody></table></table-wrap>
<table-wrap-foot><fn><p>
<italic>N</italic> = number of patients enrolled. Pioglitazone and rosiglitazone
effects are summarized as % change from baseline and listed in
parentheses. (*) indicates a
statistically significant change from baseline. TC = total cholesterol, TG = triglycerides, LDL-C = LDL cholesterol,
HDL-C = HDL cholesterol, LDL-P = LDL particle number, HDL-P = HDL particle
number, apo = apolipoprotein, AUC-TG = area under the curve for TG.</p></fn></table-wrap-foot>
<graphic xlink:href="PPAR2008-520465.001"/>
[{"label": ["1"], "surname": ["Buse", "Tan", "Prince", "Erickson"], "given-names": ["JB", "MH", "MJ", "PP"], "article-title": ["The effects of oral anti-hyperglycaemic medications on serum lipid profiles in patients with type 2 diabetes"], "italic": ["Diabetes, Obesity and Metabolism"], "year": ["2004"], "volume": ["6"], "issue": ["2"], "fpage": ["133"], "lpage": ["156"]}, {"label": ["2"], "surname": ["Bell"], "given-names": ["DS"], "article-title": ["Beneficial effects resulting from thiazolidinediones for treatment of type 2 diabetes mellitus"], "italic": ["Postgraduate Medicine"], "year": ["2003"], "fpage": ["35"], "lpage": ["44"]}, {"label": ["12"], "surname": ["Kuller", "Arnold", "Tracy"], "given-names": ["L", "A", "R"], "article-title": ["Nuclear magnetic resonance spectroscopy of lipoproteins and risk of coronary heart disease in the cardiovascular health study"], "italic": ["Arteriosclerosis, Thrombosis, and Vascular Biology"], "year": ["2002"], "volume": ["22"], "issue": ["7"], "fpage": ["1175"], "lpage": ["1180"]}, {"label": ["34"], "surname": ["Sidhu", "Kaposzta", "Markus", "Kaski"], "given-names": ["JS", "Z", "HS", "JC"], "article-title": ["Effect of rosiglitazone on common carotid intima-media thickness progression in coronary artery disease patients without diabetes mellitus"], "italic": ["Arteriosclerosis, Thrombosis, and Vascular Biology"], "year": ["2004"], "volume": ["24"], "issue": ["5"], "fpage": ["930"], "lpage": ["934"]}, {"label": ["35"], "surname": ["Dormandy", "Charbonnel", "Eckland"], "given-names": ["JA", "B", "DJ"], "article-title": ["Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial in macroVascular Events): a randomised controlled trial"], "italic": ["The Lancet"], "year": ["2005"], "volume": ["366"], "issue": ["9493"], "fpage": ["1279"], "lpage": ["1289"]}]
PPAR Res. 2008 Aug 21; 2008:520465