Rosiglitazone (Avandia®, GlaxoSmithKline) is an oral agent for the treatment of type 2 diabetes mellitus belonging to the thiazolidinediones (also called glitazones class of drugs). It has been registered by HSA since 2000 for use as an adjunct to diet and exercise; as monotherapy or in combination with metformin or a sulfonylurea to reduce insulin resistance and lower elevated blood glucose in patients with type 2 diabetes mellitus. Avandamet® is another registered product containing a combination of two active ingredients, rosiglitazone and metformin.
The risk of cardiac adverse events (i.e. heart failure, fluid retention, oedema) is known to be associated with the thiazolidinediones class of drugs. Recently, concerns have been raised about the possible elevation of ischaemic cardiovascular (CV) risk with rosiglitazone therapy.
Literature reports
A) Meta-analyses of effect of rosiglitazone on the risk of myocardial infarction and death from CV causes
An article published by Nissen and Wolski 1 in the New England Journal of Medicine (NEJM) on 21 May 2007 raised concern about the possibility of a small increased risk of myocardial infarction and CV death in about 15,500 patients treated with rosiglitazone compared with 12,282 who were assigned to comparator groups with regimens that did not include rosiglitazone. The study which was a meta-analysis of 42 clinical studies noted a statistically significant increased risk of myocardial infarction (OR 1.43; 95% CI 1.03–1.98, p=0.03) and a statistically non-significant increase in the risk of CV death (OR 1.64; 95% CI 0.98–2.74, p=0.06) associated with the use of rosiglitazone in comparison to the use of a placebo or other anti-diabetic therapies e.g. metformin, insulin and sulfonylureas. In absolute numbers, the pooled analyses revealed a combined total of 86 myocardial infarctions in the rosiglitazone group and 72 in the control group. There were 39 deaths from CV causes in the rosiglitazone group and 22 in the control group.
The findings of this study have caused considerable debate, largely due to several methodologic limitations. These include pooled data from trials that were not originally intended to explore CV outcomes, short duration of trial periods (24 – 52 weeks), information based on publicly available sources and not on original source data of trials.
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B) Interim findings of the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD) study
In response to recent CV concerns with rosiglitazone, Home et al 2 published an unscheduled interim analysis of an ongoing randomised, multicentre, open-label noninferiority trial involving 4,447 patients in the NEJM on 5 Jun 2007. The RECORD study compares 2,200 patients on rosiglitazone dual therapy (plus metformin or sulfonylurea) with 2,227 patients on a combination of metformin plus sulfonylurea (control group). After a mean follow-up of 3.75 years, 217 patients in the rosiglitazone group and 202 patients in the control group experienced a statistically non-significant difference for the primary end point of hospitalisation or death from CV causes (hazard ratio 1.08; 95% CI 0.89–1.31; p=0.43). A statistically significant difference between the rosiglitazone and control group was seen only in the secondary outcome of congestive heart failure (hazard ratio 2.15; 95% CI 1.30–3.57).
One of the limitations of the study was the lack of statistical power due in part to withdrawal of patients from the trial, higher-than-expected numbers of patients who were lost to follow-up, and unexpectedly low rates of the primary end point in both groups. The trial targets to be completed in late 2008.
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C) Other studies
Two other large studies, namely A Diabetes Outcome and Progression Trial (ADOPT) 3, and the Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) 4 do not show an increased in the risk of cardiac ischaemic events with rosiglitazone. However a recent pooled analysis of 42 clinical trials submitted by GSK to the US Food and Drug Administration (FDA) which included 8,604 patients on rosiglitazone and 5,633 patients randomised to a variety of alternative therapeutic regimens, including placebo suggest that the overall incidence of myocardial ischaemia in rosiglitazone-treated subjects relative to the comparators were 1.99% versus 1.51% with a hazard ratio of 1.3 (95% CI 1.01–1.70). This data is still being analysed by the US FDA due to the complexity of the data sets.
HSA’s advisory
The various studies provide contradictory findings on the ischaemic CV risk of rosiglitazone. HSA will continue to keep rosiglitazone under close surveillance for CV effects (i.e. cardiac failure, myocardial infarction) and monitor the international developments in this area. Healthcare professionals will be updated on new developments in this area when the data becomes clearer.
In the interim, prescribers should continue to carefully make individualised treatment decisions for patients with diabetes mellitus. It is advised that patients on Avandia® should be monitored for signs and symptoms of heart failure, fluid retention, oedema and rapid increases in weight.
Healthcare professionals are reminded to report all serious adverse effects suspected to be associated with thiazolidinediones (i.e. rosiglitazone, pioglitazone) to the Pharmacovigilance Unit.
References
- N Engl J Med 2007 Jun 14; 356(24):2457-71 (Epub May 21).
- N Engl J Med 2007 (Epub Jun 5).
- N Engl J Med 2006 Dec 7; 355(23):2427-43.
- Lancet 2006 Sept 23; 368:1096-105.
