Fast track — ArticlesRosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial
Introduction
Individual oral glucose-lowering medications have limited efficacy,1, 2, 3 and hence are commonly used in combination.4 In 2000, the thiazolidinediones rosiglitazone and pioglitazone received marketing authorisation for use in combination with metformin and sulfonylureas in Europe. These thiazolidinediones were known to cause fluid retention and possibly heart failure, and both manufacturers were requested to undertake a post-marketing cardiovascular outcome study.5, 6
From data reported in the UK Prospective Diabetes Study (UKPDS) in 1998, metformin seemed to protect against cardiovascular risk, but uncertainty remained for sulfonylureas.1, 7 After 1999, evidence showed that thiazolidinediones improved some cardiovascular risk markers associated with diabetes—including insulin sensitivity, blood pressure, and coagulation factors.2, 8, 9 However, higher LDL cholesterol concentrations, albeit in the context of improvement in LDL phenotype and unchanged LDL to HDL cholesterol ratio,10 raised concern about the overall cardiovascular effect of rosiglitazone.
Concerns increased because several peroxisome proliferator-activated receptor (PPAR) αγ agonists failed in development as a result of cardiovascular problems in humans or malignancy, in particular bladder tumours, in animals.11 The PROactive secondary prevention study of the PPARαγ agonist pioglitazone was inconclusive for its primary composite cardiovascular endpoint, but showed a reduction for the secondary composite of death, myocardial infarction, and stroke compared with placebo.12
For rosiglitazone, which is a PPARγ agonist, an active-comparator cardiovascular outcome study (RECORD) was designed from the time of marketing authorisation.13 In 2006, the manufacturer (GlaxoSmithKline) submitted to drug regulators a combined analysis of several studies which suggested that, despite large observational studies to the contrary,14, 15 rosiglitazone increased myocardial ischaemia.16 Nissen and Wolski, using similar data sources, reached similar conclusions.17 The RECORD steering committee published an unplanned interim analysis at that time.18
Here, we report the final planned analysis of the RECORD trial, with 7935 (48%) more person-years of follow-up than at interim analysis, and we focus mainly on protocol-defined cardiovascular outcomes. Furthermore, accumulation of around 25 000 person-years of follow-up provides the opportunity to address, through adverse-event reporting, concern over malignancy11 and the issue of limb fractures raised by the ADOPT study.19
Our aim was to assess non-inferiority of rosiglitazone in combination with metformin or sulfonylurea compared with metformin and sulfonylurea dual therapy for cardiovascular outcomes. The primary endpoint was the time to first cardiovascular hospitalisation or cardiovascular death.
Section snippets
Study design
RECORD was a prospective, multicentre, randomised, open-label trial of dual therapy in patients with type 2 diabetes, comparing rosiglitazone plus either metformin or a sulfonylurea with an active control, metformin plus a sulfonylurea. The study design has been described in detail previously.13, 18 Patients with type 2 diabetes on monotherapy with either metformin or sulfonylurea and in less than optimal blood glucose control (haemoglobin A1c [HbA1c] >7·0–9·0%) were randomly assigned to
Results
Of 7428 patients screened, 4458 were randomly allocated to study groups (figure 1). 11 did not take study medication and were excluded from analysis. 2222 people on metformin were assigned to addition of rosiglitazone (1117) or sulfonylurea (1105), and 2225 patients on a sulfonylurea were assigned to addition of rosiglitazone (1103) or metformin (1122). Mean follow-up duration was 5·5 years, which corresponded to 12 338 person-years in the rosiglitazone group and 12 272 person-years in the
Discussion
The aim of the RECORD trial was to assess the overall cardiovascular safety of rosiglitazone, when added to metformin or sulfonylurea treatment, compared with that of an active control of standard dual therapy, metformin plus sulfonylurea.13 The primary endpoint included cardiovascular death or any cardiovascular hospitalisation during follow-up, which occurred in 321 people of the rosiglitazone group and 323 of the active control group. The trial had less statistical power than initially
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