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


RESULTS
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.


CONCLUSIONS
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.


BACKGROUND
GlaxoSmithKline plc, UK.
Home
Philip D
PD
Newcastle Diabetes Centre and Newcastle University, Newcastle upon Tyne, UK. philip.home@newcastle.ac.uk
Pocock
Stuart J
SJ
Beck-Nielsen
Henning
H
Curtis
Paula S
PS
Gomis
Ramon
R
Hanefeld
Markolf
M
Jones
Nigel P
NP
Komajda
Michel
M
McMurray
John J V
JJ
D000284:Administration, Oral; D000789:Angina, Unstable / Q000453:epidemiology; D001835:Body Weight; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004232:Diuretics / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D004363:Drug Utilization; D005260:Female; D050723:Fractures, Bone / Q000453:epidemiology; D006442:Glycated Hemoglobin / Q000032:analysis; D006333:Heart Failure / Q000453:epidemiology*; D006760:Hospitalization / Q000706:statistics & numerical data; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008297:Male; D008687:Metformin / Q000627:therapeutic use; D008875:Middle Aged; D009203:Myocardial Infarction / Q000401:mortality*; D009369:Neoplasms / Q000453:epidemiology; D011446:Prospective Studies; D000077154:Rosiglitazone; D012737:Sex Factors; D020521:Stroke / Q000401:mortality*; D013453:Sulfonylurea Compounds / Q000627:therapeutic use; D045162:Thiazolidinediones / Q000627:therapeutic use*
D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D004232:Diuretics; D006442:Glycated Hemoglobin; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007004:Hypoglycemic Agents; D008687:Metformin; D000077154:Rosiglitazone; D013453:Sulfonylurea Compounds; D045162:Thiazolidinediones; C517652:hemoglobin A1c protein, human