Thiazolidinedione use is not associated with worse cardiovascular outcomes: A study in 28,332 high risk patients with diabetes in routine clinical practice: Brief title: Thiazolidinedione use and mortality

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Abstract

Objective

Assess the cardiovascular safety of Thiazolidinediones (TZD) in routine clinical practice.

Background

TZD are insulin-sensitizing antidiabetic drugs commonly used in type 2 diabetes, but their cardiovascular safety has been questioned. We examined the association between TZD use and major cardiovascular outcomes.

Methods

We examined 2-year mortality, non-fatal myocardial infarction (MI), and congestive heart failure (CHF) rates among outpatients with high cardiovascular risk and diabetes according to TZD use in the REACH Registry. Multivariable adjustment and propensity scores were used in the analyses.

Results

A total of 4997 out of 28,332 patients took TZDs at baseline. During follow-up, 1532 patients died. The mortality rates (95% confidence interval [CI]) were 6.5% (5.5–7.6) with TZD and 7.2% (6.33–8.06) without; adjusted hazard ratio (HR) was 1.06 (0.89–1.26, P = 0.54). The lack of association with mortality was consistent across subgroups regardless of history of atherothrombosis or CHF. Rates of non-fatal MI (HR 1.10, 95% CI 0.83–1.45, P = 0.50) and non-fatal CHF (HR 0.90, CI 0.75–1.09, P = 0.27) were similar in users and non-users. TZD use was associated with an increased risk of CHF in patients aged > 80 years (HR 1.59, CI 1.06–2.40, P = 0.03).

Conclusions

Use of TZD was not associated with increased incidence of major cardiovascular events in patients with diabetes from this large registry. Older patients experienced an increased risk of CHF over the study interval. Limitations of this study include its observational design, and thus unmeasured confounders cannot be excluded.

Introduction

Type 2 diabetes is a chronic condition associated with a high cardiovascular burden. Recent clinical trials suggest that an intensive glucose-control strategy may decrease the risk of myocardial infarction (MI), but it does not reduce mortality [1]. Conventional anti-diabetic therapy includes lifestyle modification, metformin, sulfonylurea, and insulin. The thiazolidinediones (TZD) are ligands of Peroxisome Proliferator Activated Receptor-gamma, a transcription factor expressed in the adipose tissue, but also in endothelial cells. The net effect on metabolism is sensitization to insulin and glucose lowering. The cardiovascular safety and efficacy of these drugs were tested in several trials; pioglitazone was tested as secondary prevention via the PROActive study (PROspective pioglitAzone Clinical Trial in macroVascular Events) and rosiglitazone as primary prevention via the RECORD (Rosiglitazone Evaluated for Cardiovascular outcomes in ORal combination therapy for type 2 diabetes study) trial [2], [3]. These two trials did not show a clear connection between TZD and cardiovascular risk, but a meta-analysis has first raised concerns regarding the cardiovascular safety of rosiglitazone, particularly with respect to the risk of MI [4]. However, none of these studies was sufficiently powered for analyzing effects on mortality because the numbers of deaths were small; 363 of 5238 (6.9%) participants in the PROActive study and 293 of 4447 (6.6%) participants in the RECORD trial. Observational studies can complement randomized trials if they are dedicated to specific aims, are of sufficient size, and have a design allowing prospective and extensive collection of relevant characteristics of the participants in order to minimize potential confounding factors.

We compared mortality, non-fatal MI, and congestive heart failure (CHF) rates in patients with diabetes according to the use of TZD in the REACH (REduction of Atherothrombosis for Continued Health) Registry, an international prospective cohort of patients with either established atherosclerotic arterial disease or at risk for atherothrombosis.

Section snippets

Methods

The study design, as well as the baseline description of the REACH Registry has been published previously [5], [6], [7]. Consecutive outpatients aged ≥ 45 years, with established coronary artery disease, cardiovascular disease, or peripheral arterial disease, or patients with ≥ 3 atherothrombotic risk factors were enrolled by 5587 physician practices in 44 countries between December 2003 and December 2004. In each country, the protocol was submitted to the institutional review boards according to

Patient characteristics

Of the 65,441 patients enrolled in the REACH Registry and with data during follow-up, 28,332 patients had type 2 diabetes and available data on TZD use; they represent our study population. The characteristics of this population at baseline, according to TZD use, are presented in Table 1. Patients prescribed TZD differed strongly from TZD non-users regarding baseline characteristics, risk factors, and use of evidence-based therapies for secondary prevention; they were younger, more frequently

Discussion

Diabetes very often coexists with other risk factors for atherosclerosis or even a history of atherosclerotic events, therefore clinicians have to take this background into account when prescribing anti-diabetic drugs. In this large, international, prospective observational study of diabetic outpatients with high cardiovascular risk, the use of TZD was not associated with an increased risk for death, non-fatal MI, or non-fatal CHF, although some increased risk for CHF was noted in the subgroup

Funding

This work was supported by sanofi-aventis, Bristol-Myers Squibb, and the Waksman Foundation (Tokyo, Japan). All analyses from the REACH Registry are prepared by independent authors who are not governed by the funding sponsors and are prioritized and reviewed by an academic publications committee before submission. The statistical analyses were conducted solely by an academic team (BP, PR). The funding sponsors have the opportunity to review manuscript submissions but do not have authority to

Conflict of interest

Dr Roussel has received research grants, honoraria, or consulting fees from sanofi-aventis, MSD Chibret, Servier, Eli Lilly, Novo Nordisk, Medtronic, Janssen-Cilag, and Lifescan. Dr Hadjadj has received research grants, honoraria, or consulting fees from AstraZeneca, sanofi-aventis, MSD Chibret, Servier, Roche, Bristol-Myers Scribb. Prof Wilson has received research grants from sanofi-aventis within the past 3 years. Prof Goto has received honoraria and consulting fees from Eisai,

Author contributions

Dr Roussel had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Roussel, Hadjadj, Krempf, Bhatt, Steg. Acquisition of data: Steg, Goto. Analysis and interpretation of data: Roussel, Hadjadj, Marre, Steg, Bhatt. Drafting of the manuscript: Roussel, Hadjadj, Steg, Bhatt. Critical revision of the manuscript for important intellectual content: Roussel, Hadjadj, Goto, Wilson, Porath,

Acknowledgments

The REACH Registry is endorsed by the World Heart Federation. A complete list of REACH investigators is published in JAMA 2006; 295:180–189. The REACH Registry enforces a no ghost-writing policy. This manuscript was written and edited by the authors, who take full responsibility for its content. The drafts were written by Ronan Roussel. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology.

REACH

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