This Article  • Full text  • PDF  • Send to a friend  • Save in My Folder  • Save to citation manager  • Permissions  Citing Articles  • Citation map  • Citing articles on HighWire  • Citing articles on Web of Science (190)  • Contact me when this article is cited  Related Content  • Related articles  • Similar articles in JAMA  Topic Collections  • Cardiovascular System  • Quality of Care  • Evidence-Based Medicine  • Randomized Controlled Trial  • Prognosis/ Outcomes  • Cardiovascular Disease/ Myocardial Infarction  • Drug Therapy, Other  • Alert me on articles by topic  Social Bookmarking   What's this?

A Meta-analysis of Randomized Trials

A. Michael Lincoff, MD; Kathy Wolski, MPH; Stephen J. Nicholls, MBBS, PhD; Steven E. Nissen, MD

JAMA. 2007;298:1180-1188.

Context  Pioglitazone is widely used for glycemic control in patients with type 2 diabetes mellitus, but evidence is mixed regarding the influence of medications of this class on cardiovascular outcomes.

Objective  To systematically evaluate the effect of pioglitazone on ischemic cardiovascular events.

Data Sources and Study Selection  A database containing individual patient-level time-to-event data collected during pioglitazone clinical trials was transferred from the drug's manufacturer for independent analysis. Trials were included if they were randomized, double-blinded, and controlled with placebo or active comparator.

Data Extraction  The primary outcome was a composite of death, myocardial infarction, or stroke. Secondary outcome measures included the incidence of serious heart failure. A fixed-effects approach was used to combine the estimates across the duration strata and statistical heterogeneity across all the trials was tested with the I² statistic.

Data Synthesis  A total of 19 trials enrolling 16 390 patients were analyzed. Study drug treatment duration ranged from 4 months to 3.5 years. Death, myocardial infarction, or stroke occurred in 375 of 8554 patients (4.4%) receiving pioglitazone and 450 of 7836 patients (5.7%) receiving control therapy (hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.72-0.94; P = .005). Progressive separation of time-to-event curves became apparent after approximately 1 year of therapy. Individual components of the primary end point were all reduced by a similar magnitude with pioglitazone treatment, with HRs ranging from 0.80 to 0.92. Serious heart failure was reported in 200 (2.3%) of the pioglitazone-treated patients and 139 (1.8%) of the control patients (HR, 1.41; 95% CI, 1.14-1.76; P = .002). The magnitude and direction of the favorable effect of pioglitazone on ischemic events and unfavorable effect on heart failure was homogeneous across trials of different durations, for different comparators, and for patients with or without established vascular disease. There was no evidence of heterogeneity across the trials for either end point (I² = 0%; P = .87 for the composite end point and I² = 0%; P = .97 for heart failure).

Conclusions  Pioglitazone is associated with a significantly lower risk of death, myocardial infarction, or stroke among a diverse population of patients with diabetes. Serious heart failure is increased by pioglitazone, although without an associated increase in mortality.

Author Affiliations: Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio.

CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter     What's this?

RELATED ARTICLES

Long-term Risk of Cardiovascular Events With Rosiglitazone: A Meta-analysis
Sonal Singh, Yoon K. Loke, and Curt D. Furberg
JAMA. 2007;298(10):1189-1195.
ABSTRACT | FULL TEXT  

Cardiovascular Risk and the Thiazolidinediones: Déjà Vu All Over Again?
Daniel H. Solomon and Wolfgang C. Winkelmayer
JAMA. 2007;298(10):1216-1218.
EXTRACT | FULL TEXT  

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES

Treatment of type 2 diabetes
Gadsby
InnovAiT 2009;2:702-707.
ABSTRACT | FULL TEXT  

Is There Evidence That Oral Hypoglycemic Agents Reduce Cardiovascular Morbidity/Mortality? Yes
Bianchi et al.
Diabetes Care 2009;32:S342-S348.
FULL TEXT  

Disruption of endothelial peroxisome proliferator-activated receptor-{gamma} reduces vascular nitric oxide production
Kleinhenz et al.
Am. J. Physiol. Heart Circ. Physiol. 2009;297:H1647-H1654.
ABSTRACT | FULL TEXT  

Peroxisome-proliferator activator receptor-gamma activation decreases attachment of endometrial cells to peritoneal mesothelial cells in an in vitro model of the early endometriotic lesion
Kavoussi et al.
Mol Hum Reprod 2009;15:687-692.
ABSTRACT | FULL TEXT  

Adverse cardiovascular events during treatment with pioglitazone and rosiglitazone: population based cohort study
Juurlink et al.
BMJ 2009;339:b2942-b2942.
ABSTRACT | FULL TEXT  

Stearic acid-induced cardiac lipotoxicity is independent of cellular lipid and is mitigated by the fatty acids oleic and capric acid but not by the PPAR agonist troglitazone
Rabkin and Lodha
Exp Physiol 2009;94:877-887.
ABSTRACT | FULL TEXT  

Treatment of Type 2 Diabetes: One Extreme to Another
Zaidi
Arch Intern Med 2009;169:1246-1247.
FULL TEXT  

Results of the LEAD-2 study in relation to NICE and ADA/EASD guidelines for the treatment of type 2 diabetes in the UK
Wilding
British Journal of Diabetes & Vascular Disease 2009;9:177-185.
ABSTRACT  

Paradoxical fall in HDL cholesterol observed in a patient treated with rosiglitazone and pioglitazone
Saraf et al.
British Journal of Diabetes & Vascular Disease 2009;9:186-189.
 

Review article: Thiazolidinediones and heart failure
Chaggar et al.
Diabetes and Vascular Disease Research 2009;6:146-152.
ABSTRACT  

Oral hypoglycaemic agents, insulin resistance and cardiovascular disease in patients with type 2 diabetes
Hemmingsen et al.
Eur J Endocrinol 2009;161:1-9.
ABSTRACT | FULL TEXT  

Efficacy and safety of pioglitazone in patients with ST elevation myocardial infarction treated with primary stent implantation
Kaneda et al.
Heart 2009;95:1079-1084.
ABSTRACT | FULL TEXT  

Dapagliflozin for the Treatment of Type 2 Diabetes
Brooks and Thacker
The Annals of Pharmacotherapy 2009;43:1286-1293.
ABSTRACT | FULL TEXT  

A Prospective, Multicenter, Randomized Trial to Assess Efficacy of Pioglitazone on In-Stent Neointimal Suppression in Type 2 Diabetes: POPPS (Prevention of In-Stent Neointimal Proliferation by Pioglitazone Study)
Takagi et al.
J Am Coll Cardiol Intv 2009;2:524-531.
ABSTRACT | FULL TEXT  

Pioglitazone to Reduce Restenosis After Bare-Metal Stent Placement?
Nissen
J Am Coll Cardiol Intv 2009;2:532-533.
FULL TEXT  

Rosiglitazone Is Associated with Mortality in Chronic Hemodialysis Patients
Ramirez et al.
J. Am. Soc. Nephrol. 2009;20:1094-1101.
ABSTRACT | FULL TEXT  

A taxi driver with type 2 diabetes
Brice
BMJ 2009;338:b1369-b1369.
FULL TEXT  

Pioglitazone Improves Cardiac Function and Alters Myocardial Substrate Metabolism Without Affecting Cardiac Triglyceride Accumulation and High-Energy Phosphate Metabolism in Patients With Well-Controlled Type 2 Diabetes Mellitus
van der Meer et al.
Circulation 2009;119:2069-2077.
ABSTRACT | FULL TEXT  

Peroxisome Proliferator-Activated Receptor {gamma} Activation Restores Islet Function in Diabetic Mice through Reduction of Endoplasmic Reticulum Stress and Maintenance of Euchromatin Structure
Evans-Molina et al.
Mol. Cell. Biol. 2009;29:2053-2067.
ABSTRACT | FULL TEXT  

The Benefit and Risk of Antidiabetic Agents Used in Patients With Heart Disease
Cheng et al.
Journal of Pharmacy Practice 2009;22:179-193.
ABSTRACT  

Visceral Obesity: The Link Among Inflammation, Hypertension, and Cardiovascular Disease
Mathieu et al.
Hypertension 2009;53:577-584.
FULL TEXT  

Review: Durable glycaemia -- the promised land
Campbell
British Journal of Diabetes & Vascular Disease 2009;9:53-63.
ABSTRACT  

Heart Failure as a Multiple Hormonal Deficiency Syndrome
Sacca
Circ Heart Fail 2009;2:151-156.
FULL TEXT  

Does reversal of oxidative stress and inflammation provide vascular protection?
Koh et al.
Cardiovasc Res 2009;81:649-659.
ABSTRACT | FULL TEXT  

Potential Molecular Targets for Translational Stroke Research
Vosler and Chen
Stroke 2009;40:S119-S120.
FULL TEXT  

Coronary circulatory function abnormalities in insulin resistance insights from positron emission tomography.
Schelbert
J Am Coll Cardiol 2009;53:S3-S8.
ABSTRACT | FULL TEXT  

Defining the role of basal and prandial insulin for optimal glycemic control.
Horton
J Am Coll Cardiol 2009;53:S21-S27.
ABSTRACT | FULL TEXT  

Comment: Thiazolidinediones in Type 2 Diabetes: A Cardiology Perspective
Musini et al.
The Annals of Pharmacotherapy 2009;43:391-392.
FULL TEXT  

Long-term use of thiazolidinediones and fractures in type 2 diabetes: a meta-analysis
Loke et al.
CMAJ 2009;180:32-39.
ABSTRACT | FULL TEXT  

Thiazolidinediones: Do harms outweigh benefits?
Lipscombe
CMAJ 2009;180:16-17.
FULL TEXT  

Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy: A consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes
Nathan et al.
Clin. Diabetes 2009;27:4-16.
FULL TEXT  

Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy: A consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes
Nathan et al.
Diabetes Spectr. 2009;22:6-17.
FULL TEXT  

Thiazolidinediones and cardiovascular outcomes in type 2 diabetes
Singh and Furberg
Heart 2009;95:1-3.
FULL TEXT  

Formation of STAT5/PPAR{gamma} Transcriptional Complex Modulates Angiogenic Cell Bioavailability in Diabetes
Dentelli et al.
Arterioscler. Thromb. Vasc. Bio. 2009;29:114-120.
ABSTRACT | FULL TEXT  

Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy: A consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes
Nathan et al.
Diabetes Care 2009;32:193-203.
ABSTRACT | FULL TEXT  

CHAPTER 14 Diabetes Mellitus and Metabolic Syndrome
Cosentino et al.
ESC Textbook of Cardiovascular Medicine 2009;2:med-9780199566990-chapter-med-9780199566990-chapter.
ABSTRACT | FULL TEXT  

Adipose tissue dysfunction in obesity, diabetes, and vascular diseases
Hajer et al.
Eur Heart J 2008;29:2959-2971.
ABSTRACT | FULL TEXT  

Pioglitazone protects the myocardium against ischemia-reperfusion injury in eNOS and iNOS knockout mice
Ye et al.
Am. J. Physiol. Heart Circ. Physiol. 2008;295:H2436-H2446.
ABSTRACT | FULL TEXT  

Comparison of Cardiovascular Outcomes in Elderly Patients With Diabetes Who Initiated Rosiglitazone vs Pioglitazone Therapy
Winkelmayer et al.
Arch Intern Med 2008;168:2368-2375.
ABSTRACT | FULL TEXT  

Glycemic Management of Type 2 Diabetes: How Tight Is Right and How to Get There
Nathan
Arch Intern Med 2008;168:2064-2066.
FULL TEXT  

Cardiovascular Outcomes in Trials of Oral Diabetes Medications: A Systematic Review
Selvin et al.
Arch Intern Med 2008;168:2070-2080.
ABSTRACT | FULL TEXT  

Rosiglitazone and pioglitazone in the treatment of diabetes mellitus
Odom et al.
Am J Health Syst Pharm 2008;65:1846-1850.
FULL TEXT  

Treatment of Diabetes in Long-Term Care Facilities: A Primary Care Approach
Johnson et al.
Clin. Diabetes 2008;26:152-156.
ABSTRACT | FULL TEXT  

Thiazolidinediones in Type 2 Diabetes: A Cardiology Perspective
Khanderia et al.
The Annals of Pharmacotherapy 2008;42:1466-1474.
ABSTRACT | FULL TEXT  

The Peroxisome Proliferator-Activated Receptor-{gamma} Agonist Pioglitazone Represses Inflammation in a Peroxisome Proliferator-Activated Receptor-{alpha}-Dependent Manner In Vitro and In Vivo in Mice
Orasanu et al.
J Am Coll Cardiol 2008;52:869-881.
ABSTRACT | FULL TEXT  

Pharmacological Differences of Glitazones: Does Peroxisome Proliferator-Activated Receptor-{alpha} Activation Make the Difference?
Kintscher
J Am Coll Cardiol 2008;52:882-884.
FULL TEXT  

Review: Stroke in type 2 diabetes
Sander et al.
British Journal of Diabetes & Vascular Disease 2008;8:222-229.
ABSTRACT  

Approach to the Human Immunodeficiency Virus-Infected Patient with Lipodystrophy
Brown
J. Clin. Endocrinol. Metab. 2008;93:2937-2945.
ABSTRACT | FULL TEXT  

A Lesson in Moderation: Applying Pharmacodynamics to Clarify the Relationship Between Thiazolidinediones and Adverse Vascular Outcomes in Type 2 Diabetes
Lehmann and Lohray
J Clin Pharmacol 2008;48:999-1002.
FULL TEXT  

A Practical 'ABCDE' Approach to the Metabolic Syndrome
Blaha et al.
Mayo Clin Proc. 2008;83:932-943.
ABSTRACT | FULL TEXT  

Best Practices for Lowering the Risk of Cardiovascular Disease in Diabetes
Triplitt and Alvarez
Diabetes Spectr. 2008;21:177-189.
ABSTRACT | FULL TEXT  

Treating Elderly People with Diabetes and Stages 3 and 4 Chronic Kidney Disease
Abaterusso et al.
CJASN 2008;3:1185-1194.
ABSTRACT | FULL TEXT  

Cardiovascular Disease in Diabetes
Bloomgarden
Diabetes Care 2008;31:1260-1266.
FULL TEXT  

Regulation of Macrophage Functions by PPAR-{alpha}, PPAR-{gamma}, and LXRs in Mice and Men
Rigamonti et al.
Arterioscler. Thromb. Vasc. Bio. 2008;28:1050-1059.
ABSTRACT | FULL TEXT  

Diabetic retinopathy and risk of heart failure.
Cheung et al.
J Am Coll Cardiol 2008;51:1573-1578.
ABSTRACT | FULL TEXT  

Increased High-Density Lipoprotein Cholesterol Predicts the Pioglitazone-Mediated Reduction of Carotid Intima-Media Thickness Progression in Patients With Type 2 Diabetes Mellitus
Davidson et al.
Circulation 2008;117:2123-2130.
ABSTRACT | FULL TEXT  

PROactive: time for a critical appraisal
Betteridge et al.
Eur Heart J 2008;29:969-983.
ABSTRACT | FULL TEXT  

Comparison of Pioglitazone vs Glimepiride on Progression of Coronary Atherosclerosis in Patients With Type 2 Diabetes: The PERISCOPE Randomized Controlled Trial
Nissen et al.
JAMA 2008;299:1561-1573.
ABSTRACT | FULL TEXT  

Does PERISCOPE Provide a New Perspective on Diabetic Treatment?
Steg and Marre
JAMA 2008;299:1603-1604.
FULL TEXT  

Glitazones in type 2 diabetes: an update
DTB 2008;46:25-29.
ABSTRACT | FULL TEXT  

The year in atherothrombosis.
Sanz et al.
J Am Coll Cardiol 2008;51:944-955.
FULL TEXT  

The importance of treating cardiometabolic risk factors in patients with type 2 diabetes
Barnett
Diabetes and Vascular Disease Research 2008;5:9-14.
ABSTRACT  

Management of Cardiovascular Disease in Renal Transplant Recipients
Shirali and Bia
CJASN 2008;3:491-504.
ABSTRACT | FULL TEXT  

Antitumorigenic Effects of Peroxisome Proliferator-Activated Receptor-{gamma} in Non-Small-Cell Lung Cancer Cells Are Mediated by Suppression of Cyclooxygenase-2 via Inhibition of Nuclear Factor-{kappa}B
Bren-Mattison et al.
Mol. Pharmacol. 2008;73:709-717.
ABSTRACT | FULL TEXT  

Effects of Antidiabetic and Antihyperlipidemic Agents on C-Reactive Protein
Dandona
Mayo Clin Proc. 2008;83:333-342.
ABSTRACT | FULL TEXT  

Peroxisome Proliferator-Activated Receptor-{gamma}-Mediated Effects in the Vasculature
Duan et al.
Circ. Res. 2008;102:283-294.
ABSTRACT | FULL TEXT  

New Drugs for the Treatment of Diabetes Mellitus: Part I: Thiazolidinediones and Their Evolving Cardiovascular Implications
McGuire and Inzucchi
Circulation 2008;117:440-449.
FULL TEXT  

Management of Type 2 Diabetes
NEJM 2008;358:293-297.
FULL TEXT  

Thiazolidinediones and cardiovascular outcomes
Barnett
British Journal of Diabetes & Vascular Disease 2008;8:45-49.
ABSTRACT  

Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy: Update regarding thiazolidinediones: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes
Nathan et al.
Diabetes Care 2008;31:173-175.
FULL TEXT  

Thiazolidinediones and Cardiovascular Outcomes in Older Patients With Diabetes
Lipscombe et al.
JAMA 2007;298:2634-2643.
ABSTRACT | FULL TEXT  

Vascular disease in paediatric type 2 diabetes: the state of the art
Vaughan et al.
Diabetes and Vascular Disease Research 2007;4:297-304.
ABSTRACT  

Pioglitazone Increases Macrophage Apoptosis and Plaque Necrosis in Advanced Atherosclerotic Lesions of Nondiabetic Low-Density Lipoprotein Receptor Null Mice
Thorp et al.
Circulation 2007;116:2182-2190.
ABSTRACT | FULL TEXT  

Thiazolidinediones and Increased MI Risk: A Class Effect?
Journal Watch Cardiology 2007;2007:3-3.
FULL TEXT  

Cardiovascular Risk and the Thiazolidinediones: Deja Vu All Over Again?
Solomon and Winkelmayer
JAMA 2007;298:1216-1218.
FULL TEXT  

Thiazolidinediones and Heart Disease Risk
JWatch General 2007;2007:2-2.
FULL TEXT