Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial

doi:10.1016/S0140-6736(09)60953-3

The Lancet

Volume 373, Issue 9681, 20–26 June 2009, Pages 2125-2135

https://doi.org/10.1016/S0140-6736(09)60953-3 Get rights and content

Summary

Background

Rosiglitazone is an insulin sensitiser used in combination with metformin, a sulfonylurea, or both, for lowering blood glucose in people with type 2 diabetes. We assessed cardiovascular outcomes after addition of rosiglitazone to either metformin or sulfonylurea compared with the combination of the two over 5–7 years of follow-up. We also assessed comparative safety.

Methods

In a multicentre, open-label trial, 4447 patients with type 2 diabetes on metformin or sulfonylurea monotherapy with mean haemoglobin A_1c (HbA_1c) of 7·9% were randomly assigned to addition of rosiglitazone (n=2220) or to a combination of metformin and sulfonylurea (active control group, n=2227). The primary endpoint was cardiovascular hospitalisation or cardiovascular death, with a hazard ratio (HR) non-inferiority margin of 1·20. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00379769.

Findings

321 people in the rosiglitazone group and 323 in the active control group experienced the primary outcome during a mean 5·5-year follow-up, meeting the criterion of non-inferiority (HR 0·99, 95% CI 0·85–1·16). HR was 0·84 (0·59–1·18) for cardiovascular death, 1·14 (0·80–1·63) for myocardial infarction, and 0·72 (0·49–1·06) for stroke. Heart failure causing admission to hospital or death occurred in 61 people in the rosiglitazone group and 29 in the active control group (HR 2·10, 1·35–3·27, risk difference per 1000 person-years 2·6, 1·1–4·1). Upper and distal lower limb fracture rates were increased mainly in women randomly assigned to rosiglitazone. Mean HbA_1c was lower in the rosiglitazone group than in the control group at 5 years.

Interpretation

Addition of rosiglitazone to glucose-lowering therapy in people with type 2 diabetes is confirmed to increase the risk of heart failure and of some fractures, mainly in women. Although the data are inconclusive about any possible effect on myocardial infarction, rosiglitazone does not increase the risk of overall cardiovascular morbidity or mortality compared with standard glucose-lowering drugs.

Funding

GlaxoSmithKline plc, UK.

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 A_1c [HbA_1c] >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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Fast track — ArticlesRosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Study design

Results

Discussion

Am J Cardiol

Lancet

Clin Ther

J Am Coll Cardiol

Intensive blood-glucose control with sulfonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33)

Lancet

Rosiglitazone RECORD study: glucose control outcomes at 18 months

Diabet Med

Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial

Diabet Obes Metab

Global guideline for Type 2 diabetes

European public assessment report for Actos

European public assessment report for Avandia

Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34)

Lancet

Pleiotropic actions of peroxisome proliferator–activated receptors in lipid metabolism and atherosclerosis

Arterioscler Thromb Vasc Biol

Effect of the addition of rosiglitazone to metformin or sulfonylureas versus metformin/sulfonylurea combination therapy on ambulatory blood pressure in people with type 2 diabetes: a randomized controlled trial (the RECORD study)

Cardiovasc Diabetol

Fast track — Articles
Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial