Reassessing the cardiovascular risks and benefits of thiazolidinediones.
This article is designed for the general cardiologist, endocrinologist, and internist caring for patients with diabetes and coronary artery disease. Despite the burden of coronary disease in diabetics, little is known about the impact of commonly used oral hypoglycemic agents on cardiovascular outcomes. As the untoward effects of insulin resistance (IR) are increasingly recognized, there is interest in targeting this defect. Insulin resistance contributes to dyslipidemia, hypertension, inflammation, hypercoagulability, and endothelial dysfunction. The aggregate impact of this process is progression of systemic atherosclerosis and an increased risk of adverse cardiovascular outcomes. As such, much attention has been paid to the peroxisome-proliferator-activated receptor gamma (PPARg) agonists rosiglitazone and pioglitazone (thiazolidinediones [TZDs]). Many studies have demonstrated a beneficial effect on the atherosclerotic process; specifically, these agents have been shown to reduce markers of inflammation, retard progression of carotid intimal thickness, prevent restenosis after coronary stenting, and prevent cardiovascular death and myocardial infarction in 1 large trial. Such benefits come at the risk of fluid retention and heart failure (HF) exacerbation, and the net effect on plasma lipids is still poorly understood. Thus, the aggregate risk-benefit ratio is poorly defined. A recent meta-analysis has raised significant concerns regarding the overall cardiovascular safety of 1 particular PPARg agonist (rosiglitazone), prompting international debate and regulatory changes. This review scrutinizes the clinical evidence regarding the cardiovascular risks and benefits of PPARg agonists. Future studies of PPARg agonists, and other emerging drugs that treat IR and diabetes, must be designed to look at cardiovascular outcomes.
Zinn
Andrew
A
The Leon H. Charney Division of Cardiology, Department of Medicine, New York University School of Medicine, New York, NY 10016, USA. zinnao1@med.nyu.edu
Felson
Sabrina
S
Fisher
Edward
E
Schwartzbard
Arthur
A
D002318:Cardiovascular Diseases / Q000139:chemically induced*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D007333:Insulin Resistance; D024821:Metabolic Syndrome / Q000188:drug therapy / Q000503:physiopathology; D047495:PPAR gamma / Q000819:agonists / Q000494:pharmacology; D000077205:Pioglitazone; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000009:adverse effects* / Q000627:therapeutic use*
D007004:Hypoglycemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D000077205:Pioglitazone
N Engl J Med. 1993 Sep 30;329(14):977-86
8366922
N Engl J Med. 2005 Dec 22;353(25):2643-53
16371630
N Engl J Med. 2007 Jun 14;356(24):2457-71
17517853
Am Heart J. 2005 Jan;149(1):20-32
15660031
Am J Cardiol. 2002 Feb 1;89(3):318-22
11809434
Clin Ther. 2004 Mar;26(3):379-89
15110130
J Clin Endocrinol Metab. 2001 Jul;86(7):3452-6
11443224
Am J Cardiol. 2002 Nov 1;90(9):947-52
12398960
Diabetes Care. 2004 Nov;27(11):2654-60
15505001
Diabetologia. 2005 Sep;48(9):1726-35
16025252
Am Heart J. 2003 Aug;146(2):E5
12891212
N Engl J Med. 2006 Oct 12;355(15):1551-62
16980380
Diabetes Care. 2005 Jul;28(7):1547-54
15983299
Circulation. 2005 Nov 1;112(18):2792-8
16246947
Arterioscler Thromb Vasc Biol. 2004 May;24(5):930-4
15001452
Circulation. 2005 May 17;111(19):2525-31
15883215
N Engl J Med. 2007 Aug 30;357(9):844-6
17687124
JAMA. 2002 Jan 16;287(3):356-9
11790215
Lancet. 1998 Sep 12;352(9131):837-53
9742976
Lancet. 2005 Oct 8;366(9493):1279-89
16214598
JAMA. 2006 Dec 6;296(21):2572-81
17101640
Am J Cardiol. 2006 Jun 19;97(12A):20G-30G
16813735
Lancet. 2006 Sep 23;368(9541):1096-105
16997664
Circulation. 2005 Feb 8;111(5):583-90
15699279
Physiol Rev. 1995 Jul;75(3):473-86
7624391
Diabetologia. 2004 Sep;47(9):1519-27
15322749
N Engl J Med. 2004 Sep 9;351(11):1106-18
15356308
Am Heart J. 2006 Jul;152(1):27-38
16824829
J Am Coll Cardiol. 2000 Nov 1;36(5):1529-35
11079654
Lancet. 1998 Sep 12;352(9131):854-65
9742977
J Clin Endocrinol Metab. 1998 May;83(5):1818-20
9589700
Am Heart J. 2005 Jan;149(1):33-45
15660032
Arterioscler Thromb Vasc Biol. 2006 Mar;26(3):624-30
16357312
Diabetes Care. 2005 Jul;28(7):1680-9
15983320
Endocr Pract. 2006 Jan-Feb;12 Suppl 1:142-7
16627399
Arterioscler Thromb Vasc Biol. 2006 Jan;26(1):28-40
16239592