Rosiglitazone Evaluated for Cardiovascular Outcomes in Oral Agent Combination Therapy for Type 2 Diabetes - RECORD

Jun 10, 2009
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Trial Sponsor:
GlaxoSmithKline plc, UK.
Date Published:
01/01/2009
Date Updated:
06/10/2009
Original Posted Date:
06/10/2009
References

Description:

The goal of the trial was to evaluate the effect of rosiglitazone plus metformin or sulfonylurea compared with metformin plus sulfonylurea on cardiovascular (CV) outcomes in patients with type 2 diabetes who had inadequate glycemic control while receiving metformin or sulfonylurea monotherapy.

Hypothesis:

Rosiglitazone would be noninferior for CV outcomes in combination with metformin or sulfonylurea, compared with metformin and sulfonylurea dual therapy.

Study Design

Study Design:

Patients Screened: 7,428
Patients Enrolled: 4,447
Mean Follow Up: 5.5 years
Mean Patient Age: 58 years
Female: 48

Patient Populations:

  • Type 2 diabetes, as defined by the World Health Organization criteria
  • Age 40-75 years
  • A body mass index >25.0
  • HbA1c level of >7.0% and ≤9.0% while receiving maximum doses of metformin or a sulfonylurea

Exclusions:

  • Current use of other glucose-lowering agents
  • Hospitalization for a major CV event in the prior 3 months
  • Planned CV intervention
  • Heart failure
  • Clinically significant hepatic disease
  • Renal impairment
  • Uncontrolled hypertension

Primary Endpoints:

  • Hospitalization or death from CV causes, evaluated for noninferiority

Secondary Endpoints:

  • Death from CV causes and from any cause
  • MI
  • Congestive heart failure resulting in hospitalization or death
  • Composite of death from CV causes, MI, or stroke

Drug/Procedures Used:

Following a 4-week run-in period, type 2 diabetics with inadequate glycemic control (hemoglobin [HbA1c], 7-9%) was randomized to rosiglitazone plus metformin or sulfonylurea (n = 2,220; 4 mg/day starting dose of rosiglitazone, uptitrated to 8 mg after 8 weeks) or to metformin plus sulfonylurea (control group; n = 2,227). In the rosiglitazone group, for patients previously on metformin at study entry, sulfonylurea was used for the study regimen; for patients previously on a sulfonylurea at study entry, metformin was used for the study regimen. The criterion for rescue therapy by addition of a third oral agent (if in the rosiglitazone group) or transfer to insulin (in the metformin plus sulfonylurea group) was a confirmed HbA1c of 8.5% or more.

Concomitant Medications:

At 5 years: Statins (50%), fibrates (11%), angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers (63%), antiplatelet agents (36%)

Principal Findings:

A total of 4,447 patients were randomized; 2,222 people on metformin were assigned to addition of rosiglitazone (1,117) or sulfonylurea (1,105), and 2,225 patients on a sulfonylurea were assigned to addition of rosiglitazone (1,103) or metformin (1,122). Baseline characteristics were similar between the two groups.

Mean fasting plasma glucose was 177 mg/dl and mean HbA1c was 7.9%. Patients had had a diabetes diagnosis for an average of 7 years at enrollment. Ischemic heart disease at baseline was present in 16% of patients. The mean duration of diabetes was about 5 years. Mean baseline low-density lipoprotein (LDL) cholesterol was 128 mg/dl. Mean HbA1c at 5 years was lowered more in people randomly assigned to rosiglitazone (0.28-0.44%), whereas body weight and high-density lipoprotein cholesterol increased more, and LDL cholesterol was further reduced than in the groups randomly assigned to either sulfonylurea or metformin.

Compared with metformin and sulfonylurea, rosiglitazone was noninferior for the combined primary endpoint of adjudicated hospitalization or CV death (14.5% for both, hazard ratio [HR] 0.99, 95% confidence interval [CI] 0.85-1.16, p = 0.93). All-cause, CV mortality, and myocardial infarction (MI) were similar between the rosiglitazone and active control arms as well (6.0% vs. 7.0%, p = 0.19; 2.7% vs. 3.2%, p = 0.32; and 2.8% vs. 2.5%, p = 0.47, respectively). The incidence of heart failure was higher in the rosiglitazone arm (2.7% vs. 1.3%, HR 2.1, 95% CI 1.35-3.27, p = 0.001).

Overall cancer rates were similar between the two arms (5.7% vs. 6.6%, p = 0.20). Hypoglycemia seemed to be more frequent in the rosiglitazone arm (0.7% vs. 0.3%, p = 0.08). The risk of bone fractures was also higher in the rosiglitazone arm (10.1% vs. 5.9%, p < 0.001), especially in women.

Interpretation:

Among patients with type 2 diabetes who had inadequate glycemic control while receiving metformin or sulfonylurea, treatment with rosiglitazone plus metformin or sulfonylurea was noninferior to metformin and sulfonylurea in reducing the risk of hospitalization or CV death at a mean of 5.5 years. The absence of a large difference in MI between the two arms is reassuring, since a recent large meta-analysis suggested an excess of MI with rosiglitazone.

There is, however, a higher risk of congestive heart failure and bone fractures with the use of rosiglitazone. A similar higher risk of bone fractures was noted with pioglitazone, another PPAR gamma agonist, in the PERISCOPE trial.

References:

Home PD, Pocock SJ, Beck-Nielsen H, et al. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet 2009;373:2125-35.

Home PD, Pocock SJ, Beck-Nielsen H, et al. Rosiglitazone evaluated for cardiovascular outcomes—an interim analysis. N Engl J Med 2007;357:28-38.

Keywords: Myocardial Infarction, Neoplasms, Myocardial Ischemia, Insulin, Cholesterol, LDL, Diabetes Mellitus, Type 2, Body Weight, Thiazoles, Fractures, Bone, Hypoglycemia, Sulfonylurea Compounds, Drug Combinations, Hemoglobins, Body Mass Index, PPAR gamma, Blood Glucose, Metformin, Heart Failure, Hypoglycemic Agents, Cholesterol, HDL, Confidence Intervals, Thiazolidinediones, Fasting


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