# Should We Use PPAR Agonists to Reduce Cardiovascular Risk?

Authors: Jennifer G. Robinson
Journal: PPAR Research
 (2008)

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## Abstract

Trials of peroxisome proliferator-activated receptor (PPAR) agonists have shown mixed results for cardiovascular prevention.  Fibrates are PPAR-α agonists that act primarily to improve dyslipidemia. Based on low- and high-density
lipoprotein cholesterol (LDL and HDL) effects, gemfibrozil may be of greater cardiovascular benefit than expected, fenofibrate performed about as expected, and bezafibrate performed worse than expected.  Increases in both cardiovascular and noncardiovascular serious adverse events have been observed with some fibrates.  Thiazolidinediones (TZDs) are PPAR-γ agonists used to improve impaired glucose metabolism but also influence lipids.
Pioglitazone reduces atherosclerotic events in diabetic subjects, but has no net cardiovascular benefit due to increased congestive heart failure risk.  Rosiglitazone may increase the risk of atherosclerotic events, and has a net harmful effect on the cardiovascular system when congestive heart failure is included.  The primary benefit of TZDs appears to be the prevention of diabetic microvascular complications. Dual PPAR-α/γ agonists have had unacceptable adverse effects but more selective agents are in development. PPAR-δ and pan-agonists are also in development.  It will be imperative to prove that future PPAR agonists not only prevent atherosclerotic events but also result in a net reduction on total cardiovascular events without significant noncardiovascular adverse effects with long-term use.


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## Body

## 1. Introduction

Drugs affecting peroxisome proliferator-activated receptors (PPARs) are of intense
interest for regulating disorders of glucose and fatty acid metabolism [1]. As an end-stage manifestation of insulin
resistance and glucose intolerance, diabetes confers a 2-to-8-fold higher risk
of coronary heart disease (CHD), stroke, and mortality [2]. Impaired glucose tolerance also contributes
to the development of atherogenic dyslipidemia, which is characterized
by elevated triglycerides, low high-density lipoprotein (HDL) cholesterol,
small dense low-density lipoprotein (LDL) cholesterol, and elevated LDL
particle number. Independent of insulin
resistance and glucose levels, atherogenic dislipidemia imparts a risk for CHD
at least equal to that of the well-characterized risk of isolated,
moderate hypercholesterolemia [3].Agonists
of PPAR-α
and PPAR-γ have been evaluated for the long-term
prevention of cardiovascular events. Fibrates
are low-affinity PPAR-α
agonists
which lower triglycerides by increasing lipolysis and β-oxidation of fatty acids [4]. Fibrates also mildly raise HDL and, in some
cases, lower LDL.  Pharmacologic
activation of PPAR-γ also
lowers triglyceride levels by promoting fatty acid storage [5]. The main benefits of PPAR-γ agonists, however, are improvements in glucose
homeostasis. Thiazolidinediones (TZDs),
or glitazones, are primarily PPAR-γ agonists that
promote fatty acid oxidation and insulin sensitivity in liver and muscle [1]. These beneficial effects appear to be mediated, at least in
part, through inhibition of the release of signaling molecules from adipose
tissue that promote insulin resistance, including inflammatory factors such as
tumor necrosis factor-α
(TNF-α
) and resistin, and stimulating the release of
adiponectin. PPAR-γ agonism may additionally lower plasma glucose
levels via decreased hepatic glucose production.  Dual PPAR-α
and PPAR-γ agonists have also been developed. Drugs affecting the more recently identified
PPAR-δ (also
called β) are in
the early stages of development. PPAR-δ is also a powerful regulator of fatty acid catabolism
and energy homeostasis and has been shown to prevent weight gain, dyslipidemia,
and fatty liver in animals fed high-calorie diets [6, 7]. Given the central role of
PPARs in lipid and glucose metabolism, has the promise of PPAR modulation
translated into a significant cardiovascular risk reduction benefit from these
agents? Several recently completed large
trials addressing this question have had mixed results.


## 2. PPAR-α
Agonists: Fibrates

Randomized,
placebo-controlled trials have shown that gemfibrozil significantly reduces the
risk of CHD in primary and secondary prevention populations of dyslipidemic men,
with evidence of a trend toward a decrease in stroke (Table1) [8, 9]. Less robust results were observed for bezafibrate in
subjects with CHD, and for fenofibrate in subjects with diabetes [10, 11]. The
cardiovascular benefits of gemfibrozil appear to be greater than expected from
changes in LDL and HDL. In the Veterans Affairs HDL Intervention
Trial (VA-HIT), a > 20% reduction in CHD and stroke occurred despite no
effect on LDL and only a 6% increase in HDL. This reduction in risk was also found to be independent of changes in
triglycerides and was largely attributable to the use of gemfibrozil itself [12]. The
only other long-term trial with gemfibrozil, the Helsinki Heart Study, also
reported a greater reduction in cardiovascular risk than have been expected on
the basis of changes in LDL and HDL. Figure 1 is based on the assumption
that each 1% decrease in LDL and each 1% increase in HDL are additive and would therefore result in a
2% reduction in cardiovascular risk.
Data supporting this assumption comes from clinical trials where each 1%
reduction in LDL results in approximately a 1% reduction in the risk of CHD and
stroke, regardless of the method by which LDL is lowered [13]. The VA-HIT study found that a 5 mg/dl increase
in HDL (16%) reduced risk by 11% [12]. This is consistent with epidemiologic data in
which each 1 mg/dl (0.03 mmol, or about a 2-3%, depending on baseline HDL
level) increase in HDL is associated with a 2–4% reduction in the risk of CHD
events, independent of LDL-C cholesterol levels [14]. It is assumed, but not proven, that raising
HDL results in risk reduction additive to that of lowering LDL.Table 1
Selected morbidity and mortality outcomes in large, long-term fibrate trials. CHD = coronary heart disease, CVD =
cardiovascular disease, MI = myocardial infarction, NR = not reported, ns =
reported as “not significant,” RR = Crude relative risk calculated form
reported number of events; hazard ratio was not reported.
Event ratesStudy treatmentNonfatal MICHD mortalityNonfatal MI or CHD deathTotal strokeCancerTotal mortalityHospitalized CHFHelsinki Heart [9]Mean
F/U 5.0 yearsPrimary
preventionDyslipidemiaHigh
LDLPlacebo3.5%0.64%4.1%NR1.3%2.1%N = 2030Gemfibrozil2.2%0.53%2.7%NR1.5%2.2%N = 2051Hazard
ratio (95% CI)RR
0.63RR 0.830.66NRRR 1.15RR 1.05P
< .02p = NRP < .02p = NRp = NRVA-HIT [8]Mean F/U 5.1 yearsCHDHDL < 40 mg/dlLDL < 140 mg/dlPlacebo14.5%9.3%21.7%6.0%10.9%17.4%13.3%N = 1267Gemfibrozil11.6%7.4%17.3%4.6%9.9%15.7%10.6%N = 1264Hazard ratio (95% CI)0.770.780.780.75RR 0.910.890.78(0.62–0.96)(0.59–1.02)(0.65–0.93)(0.53–1.06)(0.73–1.08)(0.62–0.98)P
< .02P = .07P = .006P = .10P = .23P = .04BIP [10]Noncardiac deathMean
F/U 6.2 yearsCHDDyslipidemiaPlacebo11.2%5.7%15.0%5.0%5.9%4.2%N = 1542BezafibrateN = 15489.7%6.1%13.6%4.6%5.5%4.3%Hazard
ratio (95% CI)0.87RR 1.070.91RR 0.92RR 0.93RR 1.02P
= .18P = .61P = .26P=.66 nsP = .87FIELD [11]LasertherapyAlbuminuria not progressing/regressingMean
F/U 5 yearsType
2 diabetesDyslipidemiaLow LDLPlacebo4.2%1.9%6%3.6%8%6.6%5.2%n = 4900Fenofibrate3.2%2.2%5%3.2%8%7.3%3.6%N = 48950.761.190.890.901.110.70RR 1.15P = .002Hazard ratio (95% CI)(0.62–0.94)(0.90–1.57)(0.75–1.05)(0.73–1.12)RR 1.0(0.95–1.29)(0.58–0.85)P = .01P
= .22P
= .16P
= .36P
= .18P
= .0003Figure 1
Approximate expected cardiovascular (CVD) risk reduction from percent changes in LDL and HDL versus
observed percent reduction in coronary heart disease (CHD) or CVD. Above the slope = 1 line, CVD risk reduction
was worse than expected based on lipid changes; below the slope = 1 line, CVD
risk reduction was greater than expected based on the lipid changes.In
contrast to the 2 trials with gemfibrozil, the 11% reduction in cardiovascular
risk observed in the Fenofibrate Intervention and Event Lowering in Diabetes
(FIELD) trial was similar to that expected (about 12%) from average changes in
LDL (−9%) and HDL (+3%) between 4 months and the end of the study (Figure1;
Table 2) [11]. The midpoint of the study was chosen due to
crossover to statin treatment in both treatment arms. By the end of the trial, 17% of the placebo
group and 8% of the fenofibrate group started lipid-lowering therapy, mainly
with statins. As a consequence, the
lipid parameters for the 2 treatment groups became more similar over time.Table 2
Selected laboratory data from fibrate endpoint trials.
Mean baseline level (mg/dL (mmol/L))Percent difference between treatment groupsHelsinki Heart [76]Gemfibrozil versus placebo1 year3 years5 yearsTotal
cholesterol269 (6.98)−11%−10%−9%LDL189 (4.90)−11%−10%−9%HDL47 (1.22)11%10%7%Triglycerides178 (2.01)−39%−37%−33%Non-HDL222 (5.76)−15%−14%−13%VA-HIT [12]Gemfibrozil versus placebo1 yearTotal cholesterol175 (4.53)−4%LDL112 (2.90)0%HDL32 (0.83)6%Triglycerides160 (1.81)−31%BIP [10]Bezafibrate versus placebo1 yearTotal cholesterol212 (5.49)−5%LDL148 (3.83)−7%HDL34.6 (0.90)18%Triglycerides145 (1.64)−21%FIELD [11]Fenofibrate versus placebo4 monthsEnd-of-studyTotal
cholesterol194 (5.04)−11%−7%LDL119 (3.07)−12%−6%HDL42.5 (1.10)5%1%Triglycerides172 (1.94)−29%−22%The Bezafibrate Infarction Prevention (BIP) study showed a nonsignificant reduction
in cardiovascular events of only 9% despite greater changes in LDL and HDL than
those observed in FIELD or VA-HIT (Table2) [8, 10, 11]. Indeed, bezafibrate performed substantially worse
than expected from the LDL and HDL changes (Figure 1), suggesting that bezafibrate may have vascular toxicity
that counteracts its beneficial lipid changes.
This may be due to bezafibrate acting as a pan-PPAR activator, as
discussed below [15].It
has been argued that the lesser cardiovascular benefit observed in FIELD and
BIP was due to inclusion of less dyslipidemic subjects than in the gemfibrozil
trials. A post hoc subgroup analysis of
BIP found a significant (40%) reduction in CHD in those with triglycerides ≥200 mg/dl [10]. VA-HIT found a similar trend toward
increasing risk reduction with triglyceride levels ≥180 mg/dl [12]. In FIELD, fenofibrate, there were  similar  with reductions in cardiovascular risk in
subjects with triglycerides less than and greater than 150 mg/dl. On the other hand, the Diabetes
Atherosclerosis Intervention Study (DAIS) found that fenofibrate reduced
angiographic progression of coronary atherosclerosis in a more markedly hypertriglyceridemic
diabetic population [triglycerides 229 mg/dl (2.59 mmol/L); HDL 39 mg/dl (1.01 mmo/L);
LDL 130 mg/dl (3.38 mmol/L)] [16]. However, when looking at the mean lipid levels
across the studies, the case is less clear.
The triglyceride levels in FIELD (172 mg/dl) were similar to those in
the Helsinki Heart Study (178 mg/dl), but somewhat higher than in VA-HIT (160
mg/dl) and BIP (145 mg/dl) (Table 2). HDL levels were markedly lower in BIP (35
mg/dl) and in VA-HIT (32 mg/dl) than in either FIELD (43 mg/dl) or the Helsinki
Heart Study (47 mg/dl). Taken as a
whole, these findings may suggest that gemfibrozil may have a greater impact on
cardiovascular risk than fenofibrate, regardless of the population
studied.Also
of concern, some fibrates used alone may potentially increase the risk of cardiovascular
and noncardiovascular
mortality, and of serious adverse events (Table1). Clofibrate, the earliest fibrate
studied, is rarely used due to a consistent increase in mortality when compared
to placebo, which occurred despite a substantial reduction in CHD events [17, 18]. In BIP, more cases of CHD mortality were
reported for the bezafibrate group compared to placebo, although the difference
was not statistically significant (Table 1) [10]. In FIELD, there were also more adverse events
and deaths among those receiving fenofibrate compared to placebo [11]. The reduction in nonfatal coronary events and
stroke in FIELD was counterbalanced by an 11% increase in cardiovascular deaths
(due to a 19% increase in CHD death) and total mortality that did not reach
statistical significance. The excess in deaths
was due to a variety of causes: sudden cardiac death (70 versus 54,
resp.), heart failure (13 versus 11), noncoronary cardiac (8 versus 4), and pulmonary embolism (4 versus 1, P =
.22). Although a lower rate of
cardiac events in the statin-treated placebo group is one possible explanation
for the unexpected increase in cardiac deaths, a 30% excess of sudden death in
the fenofibrate group is hard to explain if only an excess 9% of the placebo
group received a statin. In contrast,
fewer deaths occurred in the secondary-prevention
population studied in the Veterans Affairs HDL Intervention Trial (VA-HIT) and
in the primary-prevention Helsinki Heart Study [8, 9]. The secondary-prevention component of the
Helsinki Heart Study reported a nonsignificant increase in CHD deaths with
gemfibrozil compared to placebo in a much smaller sample (N = 628, HR 2.2% (95%
CI 0.94–5.05)) [19]. It is important to note that no excess of
harm has emerged in any statin trial. A
meta-analysis of statin therapy in over 90,000 participants in 14 event trials
found a 19% reduction in CHD mortality and a 12% reduction in all-cause
mortality [20].Although
more malignancies were initially reported with clofibrate and gemfibrozil in 5-year
primary-prevention trials, with long-term followup there were no significant
increases in cancer incidence or mortality with gemfibrozil, even with followup
as long as 18 years in the Helsinki Heart Study [8, 21, 22]. Cancer incidence was similar for both the
fenofibrate and placebo groups (8%) in FIELD [11].Also
of concern in FIELD, cardiovascular events, including revascularizations, were
significantly reduced only in those without previous cardiovascular disease and
in those <65 years of age (19% and 20%, resp.;P < .005),
with no benefit (0%) observed in those with previous cardiovascular disease or
who where ≥ age 65 years at baseline.
These finding are in clear contradiction to the findings of the VA-HIT
study where men with both diabetes and CHD experienced a 32% (95% CI 12–47, P =  .004) reduction in cardiovascular
events from gemfibrozil treatment [23]. The analysis has not been published to
determine whether the explanation for the FIELD findings lies in the higher
rate of crossover to other lipid-treatments in those with previous
cardiovascular disease. In those with
previous cardiovascular disease, 23% of the placebo group and 14% of the
fenofibrate group crossed over to lipid-lowering therapy. In comparison, in those without previous
cardiovascular disease, 16% of placebo and 7% of fenofibrate groups crossed
over to statin therapy. On-treatment lipid
values of the various groups were not reported so it is difficult to estimate
whether the lack of benefit in those with previous cardiovascular disease and
those ≥age 65 years was due to crossover to active treatment or to
other factors.In
FIELD, the fenofibrate group also experienced a nonsignificant increase in deep
venous thrombosis [67 (1.4%) versus 48 (1.0%);P = .74)]. No clear explanations for the nonsignificant higher
rates of sudden death, venous thrombosis, and pulmonary embolism in FIELD are
readily aPPARent. It is not known  whether the increased risk of
thrombosis was due to higher homocysteine levels in the fenofibrate group . Gemfibrozil may raise homocysteine levels less than
fenofibrate [24]. It is not known whether the increased
homocysteine levels resulted from the reversible increases in creatinine
observed with fenofibrate, and also bezafibrate, and less commonly gemfibrozil [25]. Fenofibrate is known to raise homocysteine
through a PPAR-α mediated
mechanism [26]. Folic acid appears to lower
fenofibrate-induced homocysteine elevations [27]. However, since clinical trials of folic acid
supplementation to lower homocysteine have not demonstrated a reduction in
cardiovascular events [28], the clinical importance of
fenofibrate-induced homocysteine elevations remains to be established.Nor
is it clear that the increase in creatinine levels with fibrates increases
cardiovascular risk since preliminary studies have shown that fenofibrate increases
creatinine production rather than decreasing the glomerular filtration rate [25, 29]. In FIELD, progression of proteinuria and
renal failure were less frequent in those receiving fenofibrate (Table 2) [11, 25]. No cases of renal
failure were reported with gemfibrozil in the Helsinki Heart Study or in
VA-HIT [8, 9].All
fibrates are known to increase biliary cholesterol saturation with clofibrate
having the greatest effect and gemfibrozil the least effect [25]. In the World Health Organization (WHO)
clofibrate primary prevention study, the excess mortality in the clofibrate
group was due to a 33% increase in noncardiovascular mortality, including
malignancy, postcholecyctomy complications, and pancreatitis [18]. Cholelithiasis and cholecystectomy rates were
also higher in the Coronary Drug Project clofibrate arm and with gemfibrozil in
the Helsinki Heart Study [17, 22]. In FIELD, although the rate of
cholecystectomy was not reported, more cases of pancreatitis occurred in those
receiving fenofibrate than placebo [40 (0.8%) versus 23 (0.5%), resp.; P = .31] [11].Therefore,
for a number of efficacy and safety reasons, fibrates
should not be used indiscriminately for cardiovascular risk
reduction. Furthermore, the role of
fibrates for cardiovascular prevention is not clearly defined in the era of
statin therapy. Statins are first-line
therapy based on an extensive record of safety and efficacy in over 100,000
subjects to date, regardless of LDL or HDL level [30]. Whether adding a fibrate to statin therapy
will reduce cardiovascular risk beyond that of statin monotherapy remains to be
proven in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study
to be completed in 2010 [31]. This trial will also evaluate the safety of
adding fenofibrate to simvastatin therapy.
In a corrected post hoc analysis of FIELD, when adjusting for the use of
other lipid-lowering therapy, fenofibrate reduced major cardiovascular events
by only 4% (95% CI −7 to 14, P = .45) [32]. It should be noted that this degree of risk
reduction could simply be achieved by doubling the statin dose, which would
lower LDL an additional 5–7% [33].Safety
is the other main concern with combination fibrate-statin therapy. There is consistent evidence that fibrates
increase the risk of myopathy when used in combination with currently marketed
statins. Fenofibrate is considered the
fibrate of choice for those requiring statin therapy due to the lesser impact
of fenofibrate on statin pharmacokinetics
compared with gemfibrozil [25]. The risk of myopathy with gemfibrozil-statin
therapy is about 30-fold higher than for fenofibrate-statin therapy [34]. When a gemfibrozil-statin combination is
used in the highest-risk patients who are most likely to benefit (age ≥65
years with CHD and diabetes) the risk of rhabdomyolysis is  almost 50-fold higher (1 in 484) than for statin
monotherapy in unselected hospitalized patients [35].Until
more data become available, the addition of a fibrate to statin therapy should
be reserved for patients at the highest near-term risk of cardiovascular death
with elevated triglycerides and/or low HDL.
In these patients, the reduction in deaths from cardiovascular causes by
far outweighs any excess risk of death from noncardiovascular causes or of
serious adverse events. This would
include patients identified as very high risk by the U.S. National Cholesterol
Education Program Adult Treatment Panel, such as those with cardiovascular
disease with additional high risk characteristics, such as diabetes or
metabolic syndrome, smokers, multiple risk factors, or those with diabetes and
multiple poorly controlled risk factors, including smoking [30]. However, given the modest incremental benefit
beyond that expected from its degree of  LDL-lowering, the FIELD results may dampen
enthusiasm for combination fenofibrate-statin therapy for the treatment
dyslipidemia in the absence of severe hypertriglyceridemia (defined as ≥500 mg/dl
[36]).Even though gemfibrozil may be more effective
for reducing cardiovascular events than fenofibrate, at least when used as
monotherapy, concomitant
use of gemfibrozil with a statin carries a much higher risk of myopathy than the fenofibrate statin combination . There
were no cases of rhabdomyolysis in the 1000 subjects receiving both fenofibrate
and statin therapy in FIELD [11]. Whether gemfibrozil is actually safer than
fenofibrate would depend on the results of a head-to-head trial, although such
a trial is unlikely to be performed. Marine
omega-3 oils might prove to be a superior choice in terms of safety for the
treatment of severe hypertriglyceridemia in patients requiring a statin
therapy, especially in patients with impaired renal function since both
fenofibrate and gemfibrozil have significant renal excretion [25]. Doses of omega-3 fatty acids of 3.4 grams or
greater offer similar triglyceride-lowering efficacy to fibrates in some
patient populations [37]. Although yet to be proven in a clinical trial
in a population without high fish consumption, omega-3 fatty acids may also
provide the added benefit of sudden death prevention and lower risk of total
mortality [38].Fibrates
may also be reasonably considered for cardiovascular prevention in statin
intolerant patients with dyslipidemia (for which gemfibrozil may be preferred). Fenofibrate has been shown to produce
incremental improvements in triglycerides, HDL, and non-high-density lipoprotein
(non-HDL) cholesterol used in combination with ezetimibe [39]. Fibrates are considered first-line drug
therapy for the treatment of severe hypertriglyceridemia to prevent
pancreatitis. Although clinical trials
have not been performed to establish the morbidity and mortality benefits of
treating severe hypertriglyceridemia, fibrates are very effective for treating
triglyceride levels >500 mg/dl [36]. It is not clear whether the small increase in
pancreatitis risk with fenofibrate will increase the overall risk of
pancreatitis in severely hypertriglyceridemic patients.


## 3. PPAR-γ Agonists: Thiazolidinediones

Four large trials of TZDs with cardiovascular endpoints have now been reported. The first cardiovascular endpoint trial, the
PROspective pioglitAzone Clinical Trial In macroVascular Events (PROACTIVE) study,
enrolled over 5200 subjects with both diabetes and clinical CHD or
peripheral arterial disease [40]. When acute coronary syndromes,
revascularization, and amputation were included along with the accepted “hard”
endpoints of nonfatal myocardial infarction, stroke, and total mortality in the
primary endpoint, pioglitazone was not of significant benefit [HR 0.90% (95%
CI 0.80 to 1.02), P =  .095] (Table 3).
However, for the secondary endpoint of nonfatal myocardial infarction, stroke, and total mortality, those receiving
pioglitazone experienced a significant 16% reduction over the 3 years of the
trial. The 16% reduction in ischemic
events and death appears to be better than expected for the degree of lipid
changes (Figure 1). The approximate 9% decrease in risk from the increase
in HDL with pioglitazone might have been counterbalanced by the 2% increase in
risk due to the 2% increase in LDL (Table 4) for a net expected cardiovascular risk reduction of 7%. Based on a meta-analysis, the 0.5% absolute
decrease in hemoglobin A1c (HbA1c) would be expected to result in a 6-7% decrease in
cardiovascular risk [41]. Thus, it appears that the reduction in
cardiovascular risk observed with pioglitazone is similar to the expected 14%
reduction from the combined changes in HDL, LDL, and HbA1C.Table 3
Selected morbidity and mortality outcomes in large, long-term trials of PPAR-γ agonists. CHD = coronary heart disease, CVD =
cardiovascular disease, MI = myocardial infarction, NR = not reported.
Event ratesPROACTIVE [40]Nonfatal MIStrokeNonfatalTotal mortalityHospitalizedCHFCancerMean
F/U 2.9 yearsMI/stroke/Type
2 diabetesany deathPlacebo5.5%4.1%13.6%7.1%4%4%N = 2633Pioglitazone4.6%3.3%11.6%6.8%6%4%N = 2605Hazard ratio (95% CI)0.83 (0.65–1.06)0.81
(0.61–1.07)0.840.96 (0.78–1.18)RR* 1.5 P = .007RR* 1.0(0.72–0.98)P = .03DREAM [50]All MICVD deathStrokeNonfatal MI/stroke/CVD deathTotal mortalityCHFDiabetesMedian
F/U 3.0 yearsGlucose
intolerancePlacebo0.3%0.4%0.2%0.9%1.3%0.1%25%N = 2634Rosiglitazone0.6%0.5%0.3%1.2%1.1%0.5%10.6%N = 2365Hazard
ratio (95% CI)1.661.201.391.390.917.030.38(0.73–3.80)(0.52–2.77)(0.44–4.40)(0.55–1.49)(1.60–30.9)(0.33–0.44)P = .2P = .7P = .6P = .2P = .7P = .01P < .0001ADOPT [49]All MIStrokeMI/strokeCHFMedian
F/U 4.0 yearsType
2 diabetesMetformin
(M)1.5%1.3%2.8%1.3%N = 145438%
drop-out rateGlyburide
(G)1.2%1.2%2.4%0.6%N = 144137%
drop-out rateRosiglitazone
(R)1.8%1.1%2.9%1.5%N = 145644%
drop-out rateHazard ratio (95% CI)R versus MR versus MR versus MR versus M 1.22 (0.66–2.26,P = .52)     R versus G 2.20 (1.01–4.79, P = .05)RR* 1.2RR* 0.85RR* 1.03R versus GR versus GR versus GRR* 1.5RR* 0.92RR* 1.21RECORD [51] interimAll MICVD deathNonfatalMI/stroke/CVD deathTotal mortalityCHFanalysisMean F/U 3.75 yearsType 2 diabetesMetformin/sulfonylurea1.8%2.1%5.1%3.6%1.0%N = 222710%
drop-out rateRosiglitazone2.2%1.7%4.9%3.3%2.1%added
on tometformin/sulfonylureaN = 222010%
drop-out rateHazard ratio (95% CI)1.230.800.960.932.15(0.81–1.86)(0.52–1.24)(0.74–1.24)(0.67–1.27)(1.30–3.57)P = .34P = .32P = .74P = .63P = .003*RR = Crude relative risk; hazard ratio not reported.Table 4
Selected laboratory data from endpoint trials
of PPAR-γ agonists.
Mean baseline level [mg/dL (mmol/L)]Difference  between treatment groupsEnd-of-studyPROACTIVE [40]HbA1c7.9%−6%LDL112 (2.9)2%HDL42 (1.1)9%Triglycerides159 (1.8)−13%DREAM [50]HbA1c and lipids not
reportedADOPT [49]Median baseline
level [mg/dL (mmol/L)]Rosiglitazone versus
MetforminRosiglitazone versus
GlyburideGlycated
Hgb7.4%−2%−6%Total
cholesterol204 (5.28)NRNRLDL120 (3.11)8%5%HDL47 (1.22)3%6%Triglycerides161 (1.82)−2%−5%RECORD [51, 77]Mean baseline level [mg/dL (mmol/L)]Glycated
Hgb7.9%NRLDL127 (3.29)NRHDL46 (1.20)NRTriglycerides202 (2.28)NRThe US Food and Drug Administration recently required that a “black box” warning
for congestive heart failure be placed on the labels of both currently
available TZDs, pioglitazone and rosiglitazone [42]. TZDs, as a class, are
well known to increase fluid retention through unknown mechanisms, which appear
to be the primary contributor to the increased risk of congestive heart failure
with TZDs [43, 44]. Fluid retention or edema occurs in 3–5% of
patients with diabetes started on TZDs and upto 15% of patients treated with
both TZDs and insulin [45, 46]. In PROactive, more cases of congestive heart
failure occurred with pioglitazone (11%) compared to placebo (8%; P <
.0001). The additional 56 cases of heart
failure in the pioglitazone group directly counterbalanced the 55 fewer primary
event endpoints (excluding silent myocardial infarctions). Despite 25 of the 47 cases of fatal heart
failure occurring in the pioglitazone group, those receiving  pioglitazone still had fewer deaths, 177 versus
186, although this was not statistically significant. In the Figure 1, when the increased
risk of congestive heart failure is combined with the reduction in nonfatal MI,
stroke, and death, pioglitazone performs worse than expected based on the lipid
changes and appears to obviate the reduction in risk from improved glucose
control. Taken together, these findings
suggest that overall cardiovascular prevention is not a significant benefit of
pioglitazone. There is a suggestion,
however, that pioglitazone may have a net cardiovascular benefit over a period as
short at 3 years if a method to prevent the fluid retention of TZDs is found.On
the other hand, rosiglitazone may not provide any clear cardiovascular
benefits, and indeed there is concern that rosiglitazone may increase CHD risk. In a recent meta-analysis of 42 trials of at
least 24 weeks duration, Nissen and Wolski found that those receiving rosiglitazone
had a 43% higher risk of myocardial infarction and a 64% higher risk of
cardiovascular death [47]. However, substantial methodologic limitations
prevent definitive conclusions from being drawn regarding the safety of
rosiglitazone from this analysis [48]. In the 3 large, long-term trials of rosiglitazone
reported to date, findings have been mixed regarding its benefits [49–51]. Two trials were performed in subjects with
type 2 diabetes, and 1 trial was for diabetes prevention. In all 3 trials, nonsignificant increases in nonfatal
and fatal myocardial infarctions occurred in the rosiglitazone compared to
control groups (Table 3). However, in all 3 trials, total mortality was
lower in the rosiglitazone-treated groups, albeit again not achieving
statistical significance. Since
myocardial infarction, stroke, and death rates were low over the 3-4 years of
observation in these trials, they were not powered to detect a difference in
macrovascular events or mortality. As
expected, all trials observed an increase in congestive heart failure, which
further exacerbated the lack of cardiovascular benefit for rosiglitazone
compared to control.Both
currently approved TZDs lower HbA1c by 1% when
used alone or in combination in patients with poorly controlled diabetes [45, 46]. Both TZDs modify lipids to a lesser degree
than fibrates. Rosiglitazone, however,
appears to increase HDL half as much and LDL twice as much as pioglitazone [52]. The only TZD endpoint trial reporting both baseline
and end-of-study laboratory values was the A Diabetes Outcome Progression Trial
(ADOPT), comparing rosiglitazone to metformin or glyburide [Table 4] [49]. About 35% of subjects dropped out of the rosiglitazone
and metformin groups during the trial, and over 45% dropped out of the
glyburide group, limiting conclusions that can be drawn regarding the relative
cardiovascular effects of these agents. Acknowledging
this limitation, in Figure 1, rosiglitazone
performed about as well in terms of a reduction in cardiovascular events, even
if congestive heart failure events were included, as would be expected from the
lipid changes when compared to metformin.
It is perhaps surprising that rosiglitazone performed much worse than expected
when compared to
glyburide. An analysis of a large insurance database suggested that the risk of
cardiovascular events with rosiglitazone was higher than with metformin, but
lower than with sulfonylureas [53]. Another analysis of a large Veterans Health
Administration database, however, suggested no differences in overall
mortality for those receiving metformin,
sulfonylureas, or TZDs [54].Only
baseline lipids were reported for the Rosiglitazone Evaluated for Cardiac
Outcomes and Regulation of Glycaemia in Diabetes (RECORD) trial [51]. Extrapolating the relative degree of lipid
changes observed in a head-to-head comparison of rosiglitazone to pioglitazone [52], it can be seen in Figure 1 that the cardiovascular event rates in RECORD was
about what was expected from the extrapolated lipid changes (4.5% increase in
HDL and 4% increase in LDL, or a 1% expected decrease in cardiovascular risk). Rosiglitazone has a net cardiovascular harm
when congestive heart failure is added to myocardial infarctions and strokes
(131 events versus 113 events, crude relative risk 1.16). Unfortunately, neither lipids nor HbA1c were
reported for the Diabetes REduction Assessment with ramipril and rosiglitazone Medication
(DREAM) trial, which evaluated the effect of rosiglitazone for the prevention
of type 2 diabetes in 5269 adults at high risk on the basis of impaired fasting
glucose and/or impaired glucose tolerance [50].Taken
as a whole, these findings may suggest that rosiglitazone has adverse effects on
both heart failure and non-heart failure cardiovascular events that outweigh
any beneficial changes in HbA1c. It is
possible that a period of treatment longer than 3-4 years is needed to
demonstrate a reduction in cardiovascular events, and ongoing trials of
rosiglitazone will help to address this question, the Bypass Angioplasty
Revascularization Investigation 2 Diabetes (BARI 2D) Trial,  Veterans Affairs Diabetes Trial (VADT), and ACCORD [31, 55, 56]. However, it should be noted that pioglitazone
already appears to perform better than expected  from its lipid-modifying effects over a period of 3 years. Pioglitazone has been shown to reduce
inflammation additive to that of simvastatin therapy, an effect that appears to
be related to improvements in insulin resistance [57]. As for fibrates, it remains to be
established whether adding pioglitazone to statin therapy will provide
additional cardiovascular risk reduction.
Some data regarding this question may emerge from ACCORD if pioglitazone replaces
rosiglitazone as part of the diabetes management regimen [58].Safety
concerns in addition to congestive heart failure have emerged for TZDs. Both pioglitazone and rosiglitazone have an
increased fracture risk [46, 59]. This may influence net benefits in women, and
in older men, with long-term use. Cancer
rates were reported only for PROactive among the longer-term TZD trials. Rates were similar in both treatment groups,
with the exception of bladder cancer which was more frequent in the pioglitazone
group [40]. Once bladder cancers occurring within the
first year of the study were excluded from the analysis, 6 of the 9 cases were
in the pioglitazone group and the imbalance was not felt to be related to
pioglitazone treatment by the investigators.
There have not yet been sufficient long-term follow-up studies to
confirm if this finding is other than chance.
Given the short duration of the study, this finding could eventually be
of importance since rodents have shown an excess of bladder cancers with
pioglitazone despite in vitro antineoplastic effects [45, 60].In sum, PROACTIVE demonstrated that pioglitazone can be
used without a net excess of serious adverse cardiovascular effects to manage
hyperglycemia in a population of patients with diabetes and advanced
cardiovascular disease.   Piogltiazone
may have benefits other than cardiovascular prevention, including its use in
combination with other agents to control glucose and prevent microvascular
events in properly selected patients.
Piogltiazone should be used with caution in patients with New York Heart
Association (NYHA) functional class 1 and 2 heart failure and are
contraindicated in patients with class 3 or 4 heart failure. [43]. There were consistently fewer
atherosclerotic CHD and stroke events in those who received pioglitazone who
had history of either CHD or stroke at baseline and the risk of congestive
heart failure with pioglitazone was similar in those with and without CHD and
with and without stroke [61, 62].However, in PROactive, in addition
to hospitalized and unhospitalized heart failure, 1 out of 10 patients
experienced discomfort and concern from fluid retention not requiring hospitalization
[221 excess cases of edema without heart failure, number needed to treat (NNT) =
12]. These findings confirm that pioglitazone
should remain second- or third-line therapy for the treatment of diabetes in patients [63]. Given the
suggestion that rosiglitazone may carry an excess of cardiovascular events
beyond the expected increase in congestive heart failure, until more data from
long-term studies are available, rosiglitazone should be avoided and pioglitazone
used preferentially for glucose management if indicated. Long-term event trials will be needed  necessary to establish both efficacy
and safety of any future PPAR-γ agonists, especially in light of the earlier
withdrawal of troglitazone due to excess hepatic toxicity the emerged in postmarketing
experience.


## 4. Dual Agonists

The dual PPAR-α/γ agonists, or glitazars, developed to date
display significantly higher PPAR-γ affinity than PPAR-α
affinity, although
their affinity for PPAR-α
is higher than that of clinically used fibrates [64]. The dual PPAR-α
/γ agonists have
also been a disappointment in terms of cardiovascular prevention.  Muraglitazar came the furthest along in
development, and appears to have compounded the worst properties of the PPAR-α
and PPAR-γ agonists used separately. In another review by Nissen et al. of Phase 2
and 3 trials ranging from 24 weeks to 2 years in duration, muraglitazar had a
more than 2-fold incidence of CHD and stroke over placebo [65]. The adverse impact on cardiovascular risk
occurred despite superior glucose-lowering and HDL-raising over pioglitazone [66]. Despite some suggestion that fenofibrate may
attenuate fluid retention from rosiglitazone [67], fluid retention with
muraglitazar occurred at a rate significantly higher than placebo. Development
of tesaglitazar, another dual PPAR-α
/γ agonist, was also terminated in Phase 3
development due to impairments of renal function [25, 68]. Bezafibrate is a pan-PPAR activator [15] and was associated with increased cardiovascular mortality in
the Bezafibrate Infarction Prevention study, despite a large increase in HDL
and improvements in LDL and triglyceride levels [10]. A number of other glitazars, including
ragaglitazar, farglitazar, and imiglitazar, some with even more impressive
effects on HDL and LDL than muraglitazar, have been terminated in late stage
clinical trials due to safety concerns including carcinogenic effects, liver
function test abnormalities, anemia, and decreased blood counts in part due to
fatty infiltration of the bone marrow, in addition to fluid retention [64, 69].


## 5. PPAR Agonists and Cardiovascular  Prevention—What Next?

In regard to pioglitazone,
and perhaps other drugs activating PPAR-γ, if the mechanism underlying excess fluid
retention can be addressed, the benefits should begin to outweigh adverse
effects when used in high-risk populations.
In the absence of such atherapeutic advance, a gene strongly predicting
fluid overload with PPAR-γ and dual PPAR α
/γ has been identified. If replicated in larger populations, this
genetic polymorphism may identify which patients are least likely to experience
fluid overload, which should result in a net cardiovascular benefit, at
least for pioglitazone [70].Research
into other dual PPARα
/γ agonists with an improved safety margin is ongoing [64]. Selective
modulation has been described for both PPAR-α
[71] and PPAR-γ [72] and could explain the
variation in biologic activity of various PPAR ligands  within the same pharmacologic class. Since PPARs control numerous genes, beyond those
influencing lipid and glucose metabolism, it is not surprising that the diverse
origins adverse effects with PPAR agonists appear to be compound-specific, rather
than a result of activation of more than one PPAR. The selective PPAR modulator (SPPARM)
approach has been proposed as a method for developing ligands that differentially
regulate genes specific for desirable biological effects but devoid of adverse
effects. Several selective dual PPAR
agonists in development do not appear to have adverse effects on fat
accumulation and edema [64]. Metaglidasen is one such compound [73]. To further enhance safety, partial selective
agonists appear to be more desirable than potent agonists. For example, potent PPAR-α
activators may increase insulin resistance,
induce cardiac hypertrophy, and reduce cardiac function [74]. Since gemfirbrozil appears to be of greater
benefit for cardiovascular prevention while fenofibrate appears to be safer, a
potentially fruitful avenue of investigation may be using the SPPARM approach
to characterize the differential patterns of gene activation in various tissues
for these 2 drugs.The
more recently discovered PPAR-δ has also
been found to be a powerful regulator of fatty acid catabolism and energy
homeostasis [6]. PPAR-δ agonism
has been shown to prevent weight gain, dyslipidemia, and fatty liver in animals
fed high-calorie diets [7]. A synthetic PPAR-δ agonist, GW501516, has been shown to modestly increase HDL-C levels
and enhance serum fat clearance in an early human study [75]. Pan PPAR-α
, δ, γ agonists have the potential to address
multiple aspects of the metabolic syndrome with a single medication. One such pan-agonist, netoglitazone, has
improved cell and tissue selectivity and is undergoing Phase II and III trials [73].As
our understanding of the effects modulating genetic expression in a variety of
tissues continues to develop, safe and effective drugs to prevent the
complications of obesity and diabetes should emerge. Clearly, all such drugs will need to undergo
rigorous evaluation in long-term morbidity/mortality trials early in their
development. Appropriate composite
endpoints in these trials will be needed to evaluate the net benefits of PPAR activating
drugs.



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*Source: 891425-2008-01-28.xml*