Abstract
Diabetes is associated with a range of metabolic abnormalities including insulin resistance, atherogenic dyslipidemia, hypertension, and inflammation. These factors are likely to underlie the adverse cardiovascular outcome typically observed in diabetic cohorts. The family of peroxisome proliferator-activated receptors (PPARs) have been implicated in the regulation of a number of physiologic and metabolic pathways. Pharmacologic agonists directed against various PPARs have been shown to have a beneficial impact on these metabolic risk factors. The potential impact on cardiovascular risk with the use of PPAR agonists will be reviewed. Eur J Cardiovasc Prev Rehabil 17 (Suppl 1):S32-S37 ©2010 The European Society of Cardiology
Get full access to this article
View all access options for this article.
References
1.
King
H
Aubert
RE
Herman
WH
. Global burden of diabetes, 1995-2025:
prevalence, numerical estimates, and projections.
Diabetes Care
1998 ;
21 :1414 –1431 .
2.
Stratton
IM
Adler
AI
Neil
HA
Matthews
DR
Manley
SE
Cull
CA
Association of glycaemia with macrovascular and microvascular
complications of type 2 diabetes (UKPDS 35): prospective observational
study .
BMJ
2000 ;
321 :405 –412 .
3.
American Diabetes Association . Standards of
medical care in diabetes — 2009 .
Diabetes Care
2009 ; 32 (Suppl
1 ):S13 –S61 .
4.
Ray
KK
Seshasai
SR
Wijesuriya
S
Sivakumaran
R
Nethercott
S
Preiss
D
Effect of intensive control of glucose on cardiovascular outcomes
and death in patients with diabetes mellitus: a meta-analysis of randomised
controlled trials .
Lancet
2009 ;
373 :1765 –1772 .
5.
Gerstein
HC
Miller
ME
Byington
RP
Goff
DC
Jr
Bigger
JT
Buse
JB
Effects of intensive glucose lowering in type 2
diabetes .
N Engl J Med
2008 ;
358 :2545 –2559 .
6.
Sone
H
Tanaka
S
Iimuro
S
Oida
K
Yamasaki
Y
Oikawa
S
Components of metabolic syndrome and their combinations as
predictors of cardiovascular disease in Japanese patients with type 2
diabetes. Implications for improved definition. Analysis from Japan Diabetes
Complications Study (JDCS) .
J Atheroscler Thromb
2009 ;
16 :380 –387 .
7.
Greenfield
S
Billimek
J
Pellegrini
F
Franciosi
M
De Berardis
G
Nicolucci
A
Kaplan
SH
. Comorbidity affects the relationship between
glycemic control and cardiovascular outcomes in diabetes.
Ann Int Med
2009 ;
151 :854 –860 .
8.
Vamecq
J
Latruffe
N
. Medical significance of peroxisome
proliferatoractivated receptors.
Lancet
1999 ;
354 :141 –148 .
9.
Campbell
IW
. The clinical significance of PPAR gamma agonism.
Curr Mol Med
2005 ;
5 :349 –363 .
10.
Chang
F
Jaber
LA
Berlie
HD
O'Connell
MB
. Evolution of peroxisome proliferator-activated
receptor agonists.
Ann Pharmacother
2007 ;
41 :973 –983 .
11.
Braissant
O
Foufelle
F
Scotto
C
Dauca
M
Wahli
W
. Differential expression of peroxisome
proliferator-activated receptors (PPARs): tissue distribution of PPAR-alpha,
-beta, and -gamma in the adult rat.
Endocrinology
1996 ;
137 :354 –366 .
12.
Barish
GD
Atkins
AR
Downes
M
Olson
P
Chong
LW
Nelson
M
PPARdelta regulates multiple proinflammatory pathways to suppress
atherosclerosis .
Proc Natl Acad Sci U S A
2008 ;
105 :4271 –4276 .
13.
Wallace
JM
Schwarz
M
Coward
P
Houze
J
Sawyer
JK
Kelley
KL
Effects of peroxisome proliferator-activated receptor alpha/delta
agonists on HDL-cholesterol in vervet monkeys .
J Lipid Res
2005 ;
46 :1009 –1016 .
14.
Brun
RP
Tontonoz
P
Forman
BM
Ellis
R
Chen
J
Evans
RM
Spiegelman
BM
. Differential activation of adipogenesis by
multiple PPAR isoforms.
Genes Dev
1996 ;
10 :974 –984 .
15.
Billin
AN
. PPAR-beta/delta agonists for type 2 diabetes and
dyslipidemia: an adopted orphan still looking for a home.
Expert Opin Invest Drugs
2008 ;
17 :1465 –1471 .
16.
Pelton
P
. GW-501516 GlaxoSmithKline/Ligand.
Curr Opin Invest Drugs
2006 ;
7 :360 –370 .
17.
Reginato
MJ
Krakow
SL
Bailey
ST
Lazar
MA
. Prostaglandins promote and block adipogenesis
through opposing effects on peroxisome proliferatoractivated receptor gamma.
J Biol Chem
1998 ;
273 :1855 –1858 .
18.
Tontonoz
P
Nagy
L
Alvarez
JG
Thomazy
VA
Evans
RM
. PPARgamma promotes monocyte/macrophage
differentiation and uptake of oxidized LDL.
Cell
1998 ;
93 :241 –252 .
19.
Goodman
LS
Gilman
A
Brunton
LL
Lazo
JS
Parker
KL
.
Goodman & Gilman's the pharmacological basis
of therapeutics
. 11th ed.
New York : McGraw-Hill Medical
Pub. Division ; 2006 .
20.
DeFronzo
RA
. Pharmacologic therapy for type 2 diabetes
mellitus.
Ann Int Med
1999 ;
131 :281 –303 .
21.
Keech
A
Simes
RJ
Barter
P
Best
J
Scott
R
Taskinen
MR
Effects of long-term fenofibrate therapy on cardiovascular events
in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised
controlled trial .
Lancet
2005 ;
366 :1849 –1861 .
22.
Rubins
HB
Robins
SJ
Collins
D
Fye
CL
Anderson
JW
Elam
MB
Gemfibrozil for the secondary prevention of coronary heart
disease in men with low levels of high-density lipoprotein cholesterol.
Veterans Affairs High-density Lipoprotein Cholesterol Intervention Trial
Study Group .
N Engl J Med
1999 ;
341 :410 –418 .
23.
Nissen
SE
Wolski
K
. Effect of rosiglitazone on the risk of
myocardial infarction and death from cardiovascular causes.
N Engl J Med
2007 ;
356 :2457 –2471 .
24.
Dormandy
JA
Charbonnel
B
Eckland
DJ
Erdmann
E
Massi-Benedetti
M
Moules
IK
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 .
Lancet
2005 ;
366 :1279 –1289 .
25.
Buse
JB
Rubin
CJ
Frederich
R
Viraswami-Appanna
K
Lin
KC
Montoro
R
Muraglitazar, a dual (alpha/gamma) PPAR activator: a randomized,
double-blind, placebo-controlled, 24-week monotherapy trial in adult
patients with type 2 diabetes .
Clin Ther
2005 ;
27 :1181 –1195 .
26.
Henry
RR
Lincoff
AM
Mudaliar
S
Rabbia
M
Chognot
C
Herz
M
. Effect of the dual peroxisome
proliferator-activated receptor-alpha/gamma agonist aleglitazar on risk of
cardiovascular disease in patients with type 2 diabetes (SYNCHRONY): a phase
II, randomised, dose-ranging study.
Lancet
2009 ;
374 :126 –135 .
27.
Derosa
G
Tinelli
C
Maffioli
P
. Effects of pioglitazone and rosiglitazone
combined with metformin on body weight in people with diabetes.
Diabetes Obes Metab
2009 ;
11 :1091 –1099 .
28.
Krey
G
Braissant
O
L'Horset
F
Kalkhoven
E
Perroud
M
Parker
MG
Wahli
W
. Fatty acids, eicosanoids, and hypolipidemic
agents identified as ligands of peroxisome proliferator-activated receptors
by coactivator-dependent receptor ligand assay.
Mol Endocrinol
1997 ;
11 :779 –791 .
29.
Vu-Dac
N
Schoonjans
K
Kosykh
V
Dallongeville
J
Fruchart
JC
Staels
B
Auwerx
J
. Fibrates increase human apolipoprotein A-II
expression through activation of the peroxisome proliferator-activated
receptor.
J Clin Invest
1995 ;
96 :741 –750 .
30.
(FDA) FaDA .
Center for Drug Evaluation and Research Application Number
: 021071. 1999.
31.
Lincoff
AM
Wolski
K
Nicholls
SJ
Nissen
SE
. Pioglitazone and risk of cardiovascular events
in patients with type 2 diabetes mellitus: a metaanalysis of randomized
trials.
JAMA
2007 ;
298 :1180 –1188 .
32.
Juurlink
DN
Gomes
T
Lipscombe
LL
Austin
PC
Hux
JE
Mamdani
MM
. Adverse cardiovascular events during treatment
with pioglitazone and rosiglitazone: population based cohort
study .
BMJ
2009 ; 339 :b2942 .
33.
Home
PD
Pocock
SJ
Beck-Nielsen
H
Curtis
PS
Gomis
R
Hanefeld
M
Rosiglitazone evaluated for cardiovascular outcomes in oral agent
combination therapy for type 2 diabetes (RECORD): a multicentre, randomised,
open-label trial .
Lancet
2009 ;
373 :2125 –2135 .
34.
(FDA) FaDA .
Center for Drug Evaluation and Research Application Number
: 021073. http://www.accessdata.fda.gov/drugsatfda_docs/nda/99/021073A_Actos.cfm
(13 November 2009).
35.
Yki-Jarvinen
H
. Thiazolidinediones.
N Engl J Med
2004 ;
351 :1106 –1118 .
36.
Mazzone
T
Meyer
PM
Feinstein
SB
Davidson
MH
Kondos
GT
D'Agostino
RB
Sr
Effect of pioglitazone compared with glimepiride on carotid
intima-media thickness in type 2 diabetes: a randomized
trial .
JAMA
2006 ;
296 :2572 –2581 .
37.
Nissen
SE
Nicholls
SJ
Wolski
K
Nesto
R
Kupfer
S
Perez
A
Comparison of pioglitazone vs glimepiride on progression of
coronary atherosclerosis in patients with type 2 diabetes: the PERISCOPE
randomized controlled trial .
JAMA
2008 ;
299 :1561 –1573 .
38.
Davidson
M
Meyer
PM
Haffner
S
Feinstein
S
D'Agostino
R
Sr
Kondos
GT
Increased high-density lipoprotein cholesterol predicts the
pioglitazone-mediated reduction of carotid intima-media thickness
progression in patients with type 2 diabetes mellitus .
Circulation
2008 ;
117 :2123 –2130 .
39.
Lonn
EM
Gerstein
HC
Sheridan
P
Smith
S
Diaz
R
Mohan
V
Effect of ramipril and of rosiglitazone on carotid intima-media
thickness in people with impaired glucose tolerance or impaired fasting
glucose: STARR (STudy of Atherosclerosis with Ramipril and
Rosiglitazone) .
J Am Coll Cardiol
2009 ;
53 :2028 –2035 .
40.
Frick
MH
Elo
O
Haapa
K
Heinonen
OP
Heinsalmi
P
Helo
P
Helsinki Heart Study: primary-prevention trial with gemfibrozil
in middle-aged men with dyslipidemia. Safety of treatment, changes in risk
factors, and incidence of coronary heart disease .
N Engl J Med
1987 ;
317 :1237 –1245 .
41.
Manninen
V
Elo
MO
Frick
MH
Haapa
K
Heinonen
OP
Heinsalmi
P
Lipid alterations and decline in the incidence of coronary heart
disease in the Helsinki Heart Study .
JAMA
1988 ;
260 :641 –651 .
42.
Asztalos
BF
Collins
D
Cupples
LA
Demissie
S
Horvath
KV
Bloomfield
HE
Value of high-density lipoprotein (HDL) subpopulations in
predicting recurrent cardiovascular events in the Veterans Affairs HDL
Intervention Trial .
Arterioscler Thromb Vasc Biol
2005 ;
25 :2185 –2191 .
43.
Bays
H
McElhattan
J
Bryzinski
BS
. A double-blind, randomised trial of tesaglitazar
versus pioglitazone in patients with type 2 diabetes mellitus.
Diab Vasc Dis Res
2007 ;
4 :181 –193 .
44.
Saad
MF
Greco
S
Osei
K
Lewin
AJ
Edwards
C
Nunez
M
Reinhardt
RR
. Ragaglitazar improves glycemic control and lipid
profile in type 2 diabetic subjects: a 12-week, double-blind,
placebo-controlled dose-ranging study with an open pioglitazone arm.
Diabetes Care
2004 ;
27 :1324 –1329 .