Thiazolidinediones and risk for atherosclerosis: Pleiotropic effects of PPARγ agonism

Abstract

Despite advances in the development of anti-hyper-glycaemic drugs and a greater focus on cardiovascular risk modification for patients with diabetes, cardiovascular disease remains the most common complication of type 2 diabetes. Since their initial availability in 1997, the thiazolidinediones have become one of the most commonly prescribed classes of medications for type 2 diabetes. In addition to glucose control, the thiazolidinediones have a number of pleiotropic effects on myriad traditional and non-traditional risk factors for cardiovascular disease, and hold promise with regard to modification of cardiovascular risk. In a recently reported large-scale clinical trial, pioglitazone was associated with improved cardiovascular outcomes in patients with type 2 diabetes and prevalent atherosclerotic disease.
In this review, we summarise the experimental, pre-clinical and clinical data regarding the effects of the thiazolidinediones on cardiovascular risk factors and clinical outcomes.

Full text

VOLUME 3 ISSUE 2 .SEPTEMBER 2006 65
Abstract
Despite advances in the development of anti-hyper-
glycaemic drugs and a greater focus on cardiovas-
cular risk modification for patients with diabetes,
cardiovascular disease remains the most common com-
plication of type 2 diabetes. Since their initial availability
in 1997, the thiazolidinediones have become one of the
most commonly prescribed classes of medications for
type 2 diabetes. In addition to glucose control, the thia-
zolidinediones have a number of pleiotropic effects on
myriad traditional and non-traditional risk factors for car-
diovascular disease, and hold promise with regard to
modification of cardiovascular risk. In a recently reported
large-scale clinical trial, pioglitazone was associated with
improved cardiovascular outcomes in patients with type
2 diabetes and prevalent atherosclerotic disease.
In this review, we summarise the experimental, pre-
clinical and clinical data regarding the effects of the thia-
zolidinediones on cardiovascular risk factors and clinical
outcomes.
Diabetes Vasc Dis Res 2006;3:65–71
Key words: thiazolidinedione, pioglitazone, rosiglitazone,
troglitazone, peroxisome proliferator-activated receptor,
inflammation, atherosclerosis.
Introduction
A global epidemic of diabetes mellitus (DM) has emerged,
with the World Health Organization (WHO) estimating a
global prevalence of more than 300 million people with DM
by the year 2025 (more than double the 1995 prevalence).1
This projection may well be an underestimate based on
2004 data from the Centers for Disease Control (CDC)
Behavior Risk Factor Surveillance System – these data pro-
vide a 2004 DM prevalence estimate of 20.7 million adults
in the US with diagnosed DM, a level that was originally pro-
jected to be reached in the year 2010. Moreover, as many
as one-third of patients with type 2 DM, which represents
more than 90% of DM worldwide, remain undiagnosed,2,3
and these estimates do not take into account individuals
who have impaired glucose tolerance (IGT), the metabolic
forerunner to DM.
Cardiovascular disease (CVD) is the most common com-
plication of type 2 DM, accounting for approximately 80%
of deaths.4Therefore, it is imperative to consider cardiovas-
cular risk modification as a key focus for the treatment of
patients with DM, both in clinical decision-making and ther-
apeutic drug development. This review summarises the
effects of the thiazolidinedione (TZD) class of medications
on a number of experimental, pre-clinical and clinical mea-
sures of atherosclerotic cardiovascular risk and disease, and
the potential for TZDs to influence cardiovascular outcomes
among patients with type 2 DM. The latter hypothesis is
being tested in a number of large-scale randomised clinical
outcomes trials.
The thiazolidinediones
The TZD class of drugs, which currently includes rosiglitazone
(Avandia®) and pioglitazone (Actos®), has emerged as an effec-
tive treatment of hyperglycaemia associated with type 2 DM,
alone or in combination with other oral hypoglycaemic med-
ications and with insulin. The first TZD, ciglitazone, was iden-
tified in a compound-screening programme for lipid lowering
and shares structural homology to the fibric acid derivatives,
which are agonists of the PPARαreceptor. While ciglitazone
had only modest effects on lipid parameters in animal mod-
els, it was noted to have unexpected glucose-lowering effects.
This observation led to subsequent development of the TZD
class of compounds for glucose control in the treatment of
type 2 DM. Troglitazone was the first to achieve regulatory
approval, despite poor understanding of the mechanism of
action. Troglitazone was approved for clinical use in the US in
1994, and pioglitazone and rosiglitazone in 1997; troglita-
zone was withdrawn from the market in 1997 due to idio-
syncratic hepatotoxicity, an adverse effect that has not been
observed with the other TZDs.
During the mid-1990s, the TZDs were discovered to be
potent and selective agonists for peroxisome proliferator-
activated receptor γ(PPARγ).5,6 The PPARs, which include
PPARα, PPARγand PPARδ(also referred to as PPARβ), are
members of the nuclear hormone receptor superfamily of
REVIEW
Thiazolidinediones and risk for
atherosclerosis: pleiotropic effects of
PPARγagonism
CHETAN B PATEL, JAMES A DE LEMOS, KATHLEEN L WYNE, DARREN K MCGUIRE
Department of Internal Medicine, Duke University Medical Center,
Durham, NC, US.
Chetan B Patel, Fellow, Division of Cardiovascular Medicine
Department of Internal Medicine, University of Texas Southwestern
Medical Center, Dallas, Texas, US.
James A de Lemos, Associate Professor of Medicine
Kathleen L Wyne, Assistant Professor of Medicine
Darren K McGuire, Assistant Professor of Medicine
Correspondence to: Dr Darren K McGuire
UT-Southwestern Cardiology, 5323 Harry Hines Blvd, Dallas, TX 75390-
9047, US.
Tel: +1 214 645 7500; Fax: +1 214 645 7501
E-mail: darren.mcguire@utsouthwestern.edu

66 DIABETES AND VASCULAR DISEASE RESEARCH
ligand-activated transcription factors, which also includes the
retinoic acid receptor (RXR) and the steroid and thyroid hor-
mone receptors.7Interaction of the PPARs with natural or
synthetic agonist ligands, with or without co-activation with
RXR, induces receptor binding to DNA response elements
(PPAR-response element [PPRE]),8and regulates a number of
physiological actions through transcriptional activation and
repression.9The transcriptional regulation associated with
PPARγprimarily involves adipogenesis, as well as glucose
and lipid metabolism.7
As the target of TZD medications, PPARγis the most
extensively studied of the PPAR subtypes. The receptor is
primarily expressed in adipose tissue, where it regulates adi-
pogenesis, the process of differentiation from pluripotent
stem cells to mature metabolically active adipocytes, and
glucose and lipid homeostasis.10 It has also been identified in
liver, skeletal muscle, cardiac muscle, renal cortex, colonic
epithelium, vascular endothelial cells, renal tubular cells,
renal collecting duct and macrophages.11-14 Although fairly
consistent tissue expression of PPARγhas been observed
across animal species, there are some differences between
the distribution in animals and humans,15 making it impera-
tive that effects observed in animal models be verified in
humans.
Since their introduction, rosiglitazone and pioglitazone
have quickly become among the most widely prescribed
medications for the treatment of hyperglycaemia associated
with DM, accounting for about 20% of prescriptions for oral
hypoglycaemic medications in the US. Data are rapidly
emerging that suggest diverse effects of the TZDs on a num-
ber of intermediate biomarkers and risk factors associated
with cardiovascular disease (table 1). These include effects
on conventional cardiovascular risk factors such as dyslipi-
daemia and hypertension, and modulation of endothelial
reactivity and the inflammatory cascade implicated in the
earliest stages of atherosclerosis.16
Adipogenesis
PPARγis a critical transcription factor in the regulation of
adipocyte differentiation. Through their effects on PPARγ,
TZDs modulate adipocyte differentiation, increase the num-
ber of insulin-sensitive small adipocytes,17 and lead to a
transfer of fat distribution from visceral to subcutaneous
depots – a pattern that has been associated with lower car-
diovascular risk.18,19 By potentiating the effects of insulin,
TZDs inhibit lipolysis and up-regulate expression of free fatty
acid transporters in adipocytes (fatty acid transport protein
[FATP]-1; CD36),20 thereby reducing circulating free fatty
acids, which have been implicated in induction of insulin
resistance in liver and skeletal muscle.6Therefore, the net
effect of PPARγactivation is an increased mass of small,
insulin-sensitive subcutaneous adipocytes and a larger reser-
voir for free fatty acid deposition. The long-term conse-
quences of this increased fat mass remain unclear, but the
improvement in insulin sensitivity associated with TZDs and
the redistribution of fat from the solid organs and the viscer-
al fat depot to the subcutaneous fat depot support the pos-
sibility of decreased cardiovascular risk despite increasing
adiposity, a hypothesis that requires further investigation.
Lipid metabolism
Dyslipidaemia is common among patients with DM: it is
characterised by high triglycerides, low high-density lipopro-
tein (HDL) cholesterol, and modest elevations of low-densi-
ty lipoprotein (LDL) cholesterol with increased fractions of
small, dense LDL particles, all of which are associated with
increased cardiovascular risk.21 Both rosiglitazone and piogli-
tazone are associated with increases in HDL and LDL cho-
lesterol concentrations, shifting the LDL particle profile
toward larger, more buoyant particles so resulting in little
change in LDL particle concentration despite increased LDL
mass. A recent head-to-head clinical trial showed that piogli-
tazone decreased and rosiglitazone increased triglyceride
concentrations; the net lipid effect was a slightly lower
LDL/HDL ratio with pioglitazone and little change with
rosiglitazone.22 It remains unclear whether the lipoprotein
effects are an indirect result of improved glycaemic control,
a direct effect of the TZDs or a combination, but with iden-
tical glucose control achieved in both groups of the head-to-
head trial,22 it appears that the lipid effects of the TZDs
extend beyond glycaemic modulation.
The clinical relevance of these TZD lipid effects remains
uncertain, especially in the context of recommendations to
treat all patients with type 2 DM who are at increased car-
diovascular risk with either a statin or a fibrate. These treat-
REVIEW
Table 1. Pleiotropic effects of thiazolidinediones (TZDs) on
cardiovascular parameters
Lipids Inflammation
/ Triglycerides IL-6, TNF-α, CRP, MMP-9
HDL-C and LDL-C I-CAM; V-CAM
/ - LDL/HDL ratio
/ - TG/HDL ratio
Buoyancy of LDL particles MCP-1, sCD40L
Coagulation Ventricular performance
PAI-1 / - Systolic function
Fibrinogen / - Cardiac output
Platelet aggregation / - LVH
Proinsulin Diastolic function
Infarct size
Vascular effects Fat distribution
Blood pressure Visceral fat
Intima-media thickness Subcutaneous fat
Brachial artery reactivity Fat content of liver
Coronary flow reserve
Vascular permeability
Other
Intravascular volume
Microalbuminuria
Key: HDL = high-density lipoprotein; LDL = low-density lipoprotein;
TG= triglycerides; PAI-1= plasminogen activator inhibitor;
IL = interleukin; TNF = tumour necrosis factor; CRP = C-reactive
protein; MMP = matrix metalloproteinase; I-ICAM = intercellular
adhesion molecule; V-CAM = vascular cell adhesion molecule;
MCP = monocyte-chemoattractant protein; sCD40L = soluble CD40
ligand; LVH = left ventricular hypertrophy

VOLUME 3 ISSUE 2 .SEPTEMBER 2006 67
ments have been specifically excluded in most studies
assessing the lipid effects of TZDs reported to date.
Hypertension
In animal models, TZDs attenuate the pressor response to
norepinephrine and angiotensin II and prevent the develop-
ment of hypertension.23-26 The mechanism of these observa-
tions remains unclear, but appears to be independent of the
metabolic effects of PPARγagonism. One possible mecha-
nism is blockade of voltage-gated (L-type) calcium channels,
the target of action of dihydropyridine calcium channel
blockers and a property of all TZDs.26 The TZDs also
increase expression of vascular endothelial growth factor
(VEGF) and inhibit expression of endothelin (ET)-1,27 both of
which may contribute to their favourable influence on blood
pressure. In patients with DM with and without hyperten-
sion, TZDs have been shown to reduce blood pressure,
although the changes tend to be modest (1–3 mmHg).28,29
Vascular effects
Endothelial function
Endothelial dysfunction, a precursor to atherosclerotic dis-
ease, is favourably affected by TZDs.30-31 One proposed
mechanism for this observation involves augmentation of
insulin-dependent endothelial nitric oxide (eNO) release,
resulting in enhanced endothelium-dependent vasodila-
tion.32,33 Support for this theory comes from experimental
data showing an increase in eNO production with troglita-
zone treatment in a bovine aortic endothelial cell prepara-
tion,30 and reversal of angiotensin II effects on endothelial
dysfunction in mice treated with pioglitazone or rosiglita-
zone.34 In controlled human studies, both troglitazone and
pioglitazone have been shown to increase forearm blood
flow in response to acetylcholine in patients with type 2
DM,35,36 while rosiglitazone improved coronary flow reserve
in response to cold-pressor stimulus.37
Inflammation
Data continue to accumulate supporting a potential causal
relationship between inflammation and the development
and progression of atherosclerosis.38 TZDs have been shown
to inhibit the initial inflammatory cascade in ex vivo prepa-
rations of human endothelial cells,39,40 and to inhibit the
expression of adhesion molecules on endothelial cells.41 The
TZDs also exhibit direct effects on monocytes/macrophages,
with reduced expression of inflammatory cytokines.42 In
human studies, TZDs decrease circulating markers of inflam-
mation, including TNFα, C-reactive protein, monocyte-
chemoattractant protein (MCP)-1, matrix metalloproteinase
(MMP)-9, soluble CD40 ligand (sCD40L) and white blood
cell count.43-45
The TZDs also have a potentially pro-atherogenic effect
via the up-regulation of expression of the macrophage free
fatty acid scavenger receptor CD36, which increases uptake
of oxidised LDL and may increase development of foam
cells that are directly implicated in plaque formation and
progression. However, this potentially deleterious effect may
be countered by up-regulation of ABCA-1, a transporter that
facilitates cholesterol efflux from macrophages.46,47
In summary, the TZDs have divergent effects on parame-
ters of inflammation, but most data support a fairly robust
anti-inflammatory effect associated with these drugs.16 The
net influence of inflammatory modulation of the TZDs on
atherosclerosis disease development and clinical manifesta-
tions remains to be defined.
Atherosclerosis development and progression
In ex-vivo preparations of animal and human vascular smooth
muscle and endothelial cells, TZDs are potent inhibitors of
cellular migration and proliferation, important contributors to
atherosclerosis.48,49 In the LDL-receptor null mouse model of
atherosclerosis, troglitazone and rosiglitazone attenuated aor-
tic atherosclerotic disease progression in mice fed both high-
fat and high-fructose diets.50,51 In the clinical setting, TZDs
attenuate the progression of carotid intima media thickness
(IMT) and decrease restenosis following percutaneous coro-
nary intervention in patients with and without diabetes;52-57
these differences were independent of glycaemic control or
changes in lipid concentrations.53,57 The accumulated data
from animal and human investigations support the potential
efficacy of the TZDs on atherosclerotic disease development
and progression and on cardiovascular risk modification
among patients with type 2 DM.
Acute coronary syndromes
Diabetes is associated with a 2–4-fold increased risk for
developing acute coronary complications,58 including unsta-
ble angina and myocardial infarction, and with increased risk
for subsequent cardiovascular morbidity and mortality com-
pared with patients without diabetes.59 Increased plaque vul-
nerability among patients with DM and coronary disease
may account for this increased risk, with a pro-inflammato-
ry state and perturbations of the coagulation system as
potential contributors. Evidence of a pro-thrombotic state
associated with DM is increased circulating plasminogen
activator inhibitor 1 (PAI-1) and sCD40L, both of them asso-
ciated with pro-coagulant effects and inflammation.60-63
Exposure to TZDs decreases PAI-1 expression in ex vivo
human endothelial cell and adipocyte preparations,64 and is
associated with decreased plasma levels of PAI-1 in obese
patients who do not have diabetes.65 Compared with place-
bo, rosiglitazone treatment is associated with decreased cir-
culating sCD40L in patients with DM,45 whereas pioglitazone
had no effect on sCD40L levels compared with glimepiri-
de.66 Likewise, measures of platelet activity dropped in a
controlled study of patients with stable coronary artery dis-
ease but without diabetes who were treated with rosiglita-
zone.67
Once a plaque becomes unstable and an acute coronary
ischaemic event occurs, TZDs may further influence the
ischaemic complications favourably. In several animal mod-
els of myocardial ischaemia/reperfusion, PPARγagonism
with either natural ligand (15d PGJ2) or with TZDs resulted
in dose-dependent decreases in myocardial infarct size and
improved parameters of cardiac performance.68-70 In the
studies by Khandoudi and Liu, rosiglitazone treatment inhib-
ited activation of the mitogen-activated protein (MAP) kinase
and the Jun NH2-terminal kinase (JNK) pathways, which play
REVIEW

68 DIABETES AND VASCULAR DISEASE RESEARCH
a key role in cardiac myocyte apoptosis. This observation
suggests that the decrease in infarct size may at least in part
be due to decreased apoptosis in response to ischaemic
injury. Whether similar mechanisms are present in humans
has yet to be investigated.
Cardiovascular clinical outcomes trials
Based on the accumulated data suggesting potential direct
cardiovascular benefits of the TZDs, a number of large-scale
randomised controlled trials have been initiated to assess the
effect of rosiglitazone and pioglitazone on major adverse
cardiovascular clinical outcomes (table 2). While most of
these studies are 2–4 years from completion, the
PROspective pioglitAzone Clinical Trial in macroVascular
Events (PROactive) study results were recently reported. This
was the first large-scale randomised clinical outcomes study
to evaluate the effect of a TZD on secondary prevention of
major adverse cardiovascular outcomes.29
The PROactive study was a double-blind, placebo-con-
trolled study that enrolled patients with type 2 DM and
prevalent atherosclerotic vascular disease. Participants were
randomised to treatment with pioglitazone versus placebo,
added to existing therapy, with mean follow-up of three
years.29,71 Pioglitazone was initiated at 15 mg daily, with
monthly increases to the target dose of 45 mg daily that was
continued throughout the study. The primary end point was
the time to the first occurrence of a composite of seven
major adverse cardiovascular events, including spontaneous
clinical events (all-cause mortality, myocardial infarction
[MI], cerebrovascular accident [CVA] or acute coronary syn-
drome [ACS]) and clinically-driven vascular events (coronary
or leg revascularisation or leg amputation). A prospectively
determined hierarchical series of secondary end points
included, in order: the time to the first occurrence of a com-
posite of death, MI and CVA (the 'principal' secondary end
point); cumulative cardiovascular death; and time to first
occurrence of each of the primary composite component
end points.
The study included 5,238 participants who were
enrolled between May 2001 and April 2002 from 321 cen-
tres in 19 European countries. Mean treatment duration was
2.9 years. Despite accumulating more than 1,000 primary
end point events (514 in the pioglitazone arm versus 572 in
the placebo arm), the study failed to demonstrate a statisti-
cally significant difference in the primary end point between
the treatment groups, but there was a trend toward a 10%
reduction (23.5% vs. 21%; p=0.095) favouring pioglitazone.
Treatment with pioglitazone did significantly reduce the
prospectively identified principal secondary end point, the
time to occurrence of the first event of a composite of all-
cause mortality/MI/stroke (14.4% vs. 12.3%; HR 0.84;
p=0.027). Therefore, the authors concluded that pioglita-
zone reduced the composite of all-cause mortality, non-fatal
MI and stroke in patients with type 2 DM who have a high
risk of macrovascular events.29
This conclusion is further supported when considering all
accumulated cardiovascular events in the study, which num-
bered more than 1,700. In this comparison, 803 events
occurred in the group allocated to pioglitazone treatment
compared with 900 events in the placebo group, represent-
ing a 10.8% relative reduction (statistical testing of this com-
parison was not reported). These data are the first to suggest
that addition of a TZD to the medical regimen of patients
with type 2 DM and macrovascular disease may prevent fur-
ther cardiovascular morbidity and mortality.
Congestive heart failure
While most of the CV effects of TZDs appear favourable,
there remains a concern with regard to the propensity for
these drugs to cause peripheral oedema and to precipitate
REVIEW
Table 2. Randomised clinical trials underway to evaluate the effect of TZDs on cardiovascular clinical outcomes
Study Objective Treatments Size Length 10end points 20end points
IRIS Prevent CV Pio vs. Plac 3,136 3 years CVA or MI CVA, ACS, new DM,
events mortality
RECORD Prevent CV Met+Rsg; 4,000 6 years Time to CV Individual CV events
events Rsg+SU; event composite and glycaemic
Met+SU parameters
BARI-2D Prevent death IP (ins+/-SU) 3,000 5 years All-cause mortality CV events
and CV vs. IS (TZD Quality of life
events +/- Met)
DREAM Prevent Rsg vs. plac; 4,000 3 years New DM or death MACE;
IGT DM Ram vs. plac Microvascular
and death end points
Key: CV = cardiovascular; Pio = pioglitazone; Plac = placebo; MI = myocardial infarction; CVA = cerebrovascular accident; ACS = acute coronary
syndromes; DM = diabetes mellitus; IGT = impaired glucose tolerance; Met = metformin; Rsg = rosiglitazone; SU = sulfonylurea; IP = insulin-
providing therapy; Ins = insulin; IS = insulin-sensitising therapy; Ram = ramipril; MACE = major adverse cardiovascular events; IRIS = Insulin Resistance
Intervention after Stroke: effect of pioglitazone versus placebo on subsequent stroke and myocardial infarction in population with prior stroke and insulin
resistance but without DM; RECORD = Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of glycaemia in DM; BARI-2D = Bypass
Angioplasty Revascularisation Intervention in type 2 DM; DREAM = Diabetes Reduction Assessment with rosiglitazone and ramipril Medication

VOLUME 3 ISSUE 2 .SEPTEMBER 2006 69
or exacerbate congestive heart failure (CHF).72 The clinical
relevance of these observations remains unclear but has
prompted inclusion in the product labelling for both rosigli-
tazone and pioglitazone of a caution against the use of TZDs
for patients with, or at high risk of developing, CHF.73,74 These
warnings are further supported by a position statement from
a joint panel of the American Diabetes Association (ADA)
and the American Heart Association (AHA).75
Several lines of evidence suggest that although plasma
volume expansion occurs with the TZDs,74,76,77 and some
patients develop signs and symptoms of CHF, direct cardiac
toxicity does not result from administration of these drugs. In
animal models, PPARγagonists improve contractility and sys-
tolic performance,78-81 enhance diastolic performance,79-82
and decrease cardiac hypertrophy independent of loading
conditions.83-85 Similarly, randomised controlled trials of
patients with DM have demonstrated no untoward effects
on cardiac performance, assessed using echocardiography,
and some trends toward improved function associated with
longer-term TZD therapy.78,86
The mechanism contributing to peripheral oedema and
incremental risk for CHF is most likely to be alteration of
sodium handling resulting in net volume retention.14 In mice,
PPARγexpression was identified in endothelial cells lining
the renal collecting duct (CD), and a mouse model with CD-
specific knockout of PPARγwas resistant to rosiglitazone-
induced increases in body weight and plasma volume
expansion (dietary sodium intake was unchanged). These
provocative findings demonstrate a mechanism of PPARγ-
dependent sodium retention and require confirmation in
humans.
In the placebo-controlled PROactive study,29 pioglitazone
was associated with a 2% absolute increase in hospitalisation
for incident CHF compared with placebo. Although there
were too few CHF mortality events to assess the effect rigor-
ously, there was no evident increase in risk with pioglitazone
therapy: the risk was 1% in both groups. Similarly, among
16,417 Medicare beneficiaries with DM discharged with a
primary diagnosis of CHF, the use of TZDs was associated
with a significant 13% reduced adjusted odds for mortality,
despite a statistically significant 6% increased rate of rehos-
pitalisation for CHF.87 In another observational study evalu-
ating TZD use in 111 patients with CHF, TZDs were associ-
ated with an increased rate of peripheral oedema, but there
was no change in New York Heart Association (NYHA) class
or echocardiographic severity of cardiac dysfunction,88 and
the fluid retention was reversible with drug withdrawal or
dose reduction.
The mechanisms and clinical relevance of peripheral
oedema and incident CHF resulting from TZD use remain to
be defined. Until further data are available, the cautionary
guidelines from the product manufacturers, AHA and ADA
should guide clinical decision-making with regard to the
judicious use of TZDs in patients with impaired left ventric-
ular function and CHF. For Class I and II CHF, TZDs may be
used with close observation for signs and symptoms of CHF,
with dose reduction or drug discontinuation if such findings
are observed; TZDs are presently not recommended for use
in patients with Class III or IV CHF.
Conclusions
The TZDs are safe and effective in the treatment of
hyperglycaemia associated with type 2 DM as an adjunct to
therapeutic lifestyle modification, as monotherapy or in
combination with existing therapies. The apparent
pleiotropic cardiovascular effects of these medications have
fostered optimism regarding their use to improve cardiovas-
cular outcomes among this high-risk population of patients,
and the PROactive study results demonstrate the efficacy of
pioglitazone in a population at high risk for cardiovascular
events. These accumulated data provide support for use of a
thiazolidinedione as an 'evidence-based' strategy for the
treatment of DM patients with increased cardiovascular risk.
Despite their efficacy in glucose control and cardiovas-
cular risk modification, a caution remains with regard to the
propensity for TZDs to precipitate or exacerbate CHF, and
improved understanding of the mechanism(s) and relevance
of the CHF signal remain important research objectives.
Conflicts of interest
DKM has received honoraria (Speakers Bureau) from Takeda
Pharmaceuticals and has research grant support from
GlaxoSmithKline. KLW has received honoraria (Speakers
Bureau) and research grant support from GlaxoSmithKline.
CBP and JADL have no conflicts of interest to declare.
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Erratum: Effects of pioglitazone on lipid and lipoprotein
profiles in patients with type 2 diabetes and dyslipidaemia
after treatment conversion from rosiglitazone while continuing
stable statin therapy
PAULOS BERHANU, MARK S KIPNES, MEHMOOD A KHAN, ALFONSO T PEREZ, STUART F KUPFER,
ROBERT G SPANHEIMER, SELESHI DEMISSIE, PENNY R FLECK Diabetes Vasc Dis Res 2006;3:39–44
In the above article which was published in the May 2006 issue of the journal, the incorrect conversion factor
was inadvertently used for the conversion of triglyceride levels from mg/dL to mmol/L. Also the SI unit for
HsCRP is mg/L instead of mmol/L, as provided in table 1.
This has now been corrected and appears in the correct form on the website, www.dvdres.com