Thiazolidinediones and cardiovascular risk - a question of balance

Abstract

Background: Several recent meta-analyses of adverse event data from randomized controlled trials with rosiglitazone reveal a possible association between this thiazolidinedione and an increased risk of ischemic myocardial events. This has led to debate on the overall clinical benefit of glitazone therapy for type 2 diabetes. Pioglitazone, on the other hand, has the most extensive cardiovascular outcomes database of all current glucose-lowering therapies, including a large prospective randomized controlled trial designed specifically to assess cardiovascular outcomes (PROactive). The available data suggest that pioglitazone is associated with a reduction in macrovascular risk.

Aims: In this review, we highlight some of the key factors that need to be considered when assessing the net clinical benefit of thiazolidinediones, focussing on both class effects and those specific to either rosiglitazone or pioglitazone.

Results: For pioglitazone there appears to be no increase in the risk of overall macrovascular events and no adverse clinical consequences of developing signs of heart failure. Furthermore, there is good evidence of significant benefit regarding the composite of death, MI or stroke.

Conclusion: The benefits seen with pioglitazone appear to outweigh the risks.

Fig. (1). Different thiazolidinediones have only partially overlapping gene expression profiles

The total number of genes regulated by a particular TZD is shown next to its name. The number of genes uniquely regulated by a particular TZD is contained in the non-overlapping regions of each circle. The numbers of genes similarly regulated by two or three TZDs are contained in the overlapping regions of the circles [57]. (Reprinted from Biochem Biophys Res Commun, 364(3), Sears DD, Hsiao A, Ofrecio JM, Chapman J, He W, Olefsky JM, Selective modulation of promoter recruitment and transcriptional activity of PPARgamma, 515-521, Copyright © 2007, with permission from Elsevier).

Fig. (2). Pioglitazone decreases the risk of major macrovascular events

Data are for the composite of all-cause mortality, MI and stroke from (A) PROactive and (Reprinted from The Lancet, 366, Dormandy JA, Charbonnel B, Eckland DJ; PROactive investigators, 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, 1279–1289, Copyright © 2005, with permission from Elsevier). (B) a meta-analysis of 19 randomized controlled trials [16,17]. (Reprinted with permission from Lincoff AM et al, JAMA 2007; 298: 1180–1188, Copyright © 2007 American Medical Association. All rights reserved).

Fig. (3). Available safety data for rosiglitazone and pioglitazone in terms of macrovascular risk relative to comparators

Data are from meta-analyses, the interim results of the RECORD trial and the PROactive trial. The primary endpoint in RECORD was the composite of hospitalization or death due to CV causes. The primary endpoint in PROactive was the composite of all-cause mortality, MI (incl. silent MI), stroke, ACS, coronary revascularization, major leg amputation and leg revascularization. The dotted line represents the non-inferiority limit (1.2) for the upper CI in the RECORD study FDA=(US) Food and Drug Administration; GSK=GlaxoSmithKine; IHD=ischemic heart disease; OR=odds ratio; HR=hazard ratio; RR=relative risk. (No permission required).

Fig. (4)

Algorithm for the metabolic management of type 2 diabetes mellitus [1,2]. (Reprinted with permission from Nathan DM, et al, Management of hyperglycaemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. A consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes, Diabetologia 2006; 49: 1711–1721, Copyright © Springer-Verlag 2006).