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Thiazolidinediones and clinical outcomes in type 2 diabetes Comment
  The Lancet, Early Online Publication, 5 June 2009
doi:10.1016/S0140-6736(09)61029-1Cite or Link Using DOI

Ravi Retnakaran a b, Bernard Zinman a b c
a Leadership Sinai Centre for Diabetes, Mount Sinai Hospital, 60 Murray Street, Toronto, ON M5T 3L9, Canada
b Division of Endocrinology, University of Toronto, Toronto, ON, Canada
c Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada

Type 2 diabetes is characterised by two main metabolic defects: target-cell resistance to the action of insulin (insulin resistance) and insufficient secretion of insulin by pancreatic ß cells (ß-cell dysfunction).1 Thiazolidinedione medications (rosiglitazone and pioglitazone), through modulation of the transcription factor peroxisome proliferator-activated receptor γ, have remarkable beneficial effects on both insulin action and ß-cell function.1-3 The clinical significance of these effects is underscored by the fact that treatment with thiazolidinediones results in more durable glycaemic control compared with other antidiabetic agents (especially sulfonylureas).4 Furthermore, the thiazolidinediones have several other beneficial cardiometabolic effects, including reduction of visceral fat mass, decreased systemic inflammation, and improvement in biomarkers and surrogate outcomes associated with atherosclerosis.1, 2, 5, 6

In clinical practice, the beneficial effects of a therapy should be considered in relation to its potential risks. Adverse effects that have been associated with both rosiglitazone and pioglitazone include weight gain, increased incidence of fractures, fluid retention, and a two-fold increased risk of heart failure.7, 8 Most importantly, meta-analyses9-11 have reported a 30-40% increase in the risk of myocardial infarction in patients treated with rosiglitazone. These findings have raised considerable uncertainty about the effects of thiazolidinediones on cardiovascular disease.

In The Lancet today, the rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD) study was specifically designed to assess the effect of rosiglitazone on cardiovascular outcomes.12 In this open-label non-inferiority study, 4447 patients with type 2 diabetes on metformin or sulfonylurea monotherapy were randomly assigned to either add-on rosiglitazone or metformin and sulfonylurea combination therapy. Over 5·5 years mean follow-up, non-inferiority was indeed shown for the primary endpoint of cardiovascular hospitalisation or cardiovascular death (HR 0·99, 95% CI 0·85-1·16).

Nevertheless, definitive conclusions about the relation between rosiglitazone and cardiovascular disease remain elusive, owing to study limitations. Specifically, the study was open label in design and cardiovascular disease event rates were much lower than anticipated. Furthermore, the findings are inconclusive for myocardial infarction, for which a non-statistically significant increased risk was noted in the rosiglitazone group (HR 1·14, 0·80-1·63). Low event rates might have precluded the statistical confirmation of significant risk, if present. Rosiglitazone was associated with higher LDL cholesterol levels, leading to an increased use of statins in the rosiglitazone group, which might have reduced the incidence of cardiovascular events. Thus, although the RECORD study has confirmed known risks associated with rosiglitazone (including increased rates of heart failure, fractures, and hyperlipidaemia), uncertainty remains regarding the effect of rosiglitazone on cardiovascular disease.

Although rosiglitazone and pioglitazone share many similarities in their adverse-event profiles, one difference is that pioglitazone seems to be associated with improvements in lipid phenotype,13 suggesting that the drugs have different effects on cardiovascular risk. In the secondary prevention PROactive study,14 pioglitazone did not have any significant effect on the primary cardiovascular disease composite outcome, although a 16% reduction was observed in a secondary endpoint composed of death, myocardial infarction, and stroke. In a meta-analysis,15 pioglitazone was associated with a lower risk of cardiovascular events compared with other antidiabetic therapies. Nevertheless, no definitive data show either a beneficial effect of pioglitazone or a harmful effect of rosiglitazone on cardiovascular risk. However, as evidence currently favours pioglitazone, the joint consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes on the medical management of hyperglycaemia in type 2 diabetes recommends the use of pioglitazone, instead of rosiglitazone, when prescribing thiazolidinedione therapy.7 The effects of pioglitazone and rosiglitazone on cardiovascular outcomes will be assessed in a direct comparison in the thiazolidinedione intervention with vitamin D evaluation (TIDE) study (ClinicalTrials.govNCT00879970).

We believe that the evidence regarding the risk-benefit ratio for thiazolidinediones needs a prudent approach to the use of these medications in the management of type 2 diabetes. It is generally accepted that the use of half-maximal doses could provide more than half-maximal therapeutic effects while limiting the magnitude of unwanted side-effects. Although no studies have tested this strategy, we suggest that low-dose thiazolidinediones in combination with metformin might provide glycaemic durability with lower risk. Indeed, this combination therapy is currently being assessed for the prevention of diabetes in individuals with impaired glucose tolerance.16 If the efficacy of this strategy is confirmed, we might be able to find the optimal way to use this class of medications in the treatment of type 2 diabetes.

BZ has received research support and scientific advisory board honoraria from GlaxoSmithKline, and scientific advisory board and speaking honoraria from Eli Lilly. RR declares that he has no conflicts of interest.

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