The results of the RECORD study are reported in an article published Online First and in a future edition of The Lancet. The findings are presented at the same time at the American Diabetes Association (ADA) meeting in New Orleans, USA. They indicate that the use of rosiglitazone (Avandia) together with regular diabetes treatments (metformin or a sulfonylurea) to reduce blood glucose in type 2 diabetics does not raise the risk of cardiovascular disease or death. On the other hand, the research establishes that using rosiglitazone multiplies by more than two the risk of heart failure, and increases the risk of fracture, mostly in women.

Being part of a group of drugs called thiazolidinediones, rosiglitazone is an efficient agent to control blood glucose, as confirmed by many studies. However its use has been reduced over concern about adverse effects. Research has implied an increased risk of heart attacks caused by rosiglitazone. Professor Philip Home, from The Medical School, Newcastle University, UK, and collaborators evaluated 4,447 patients in a randomized trial. All participants had type 2 diabetes and were already given either metformin or a sulfonylurea with a mean haemoglobin A1c concentration (HbA1c) of 7.9 percent. In the first group, 2,220 patients received in addition rosiglitazone, and in the control group 2,227 patients received a combination of metformin and sulfonylurea. Cardiovascular hospitalization or cardiovascular death was the main endpoint.

Results showed that 321 people reached the primary endpoint with rosiglitazone compared to 323 in the control group. Therefore, there was no statistically important distinction. Also, the researchers found that heart failure causing admission to hospital or death occurred in 61 people in the rosiglitazone group and 29 in the control group. As a consequence, the risk of heart failure was multiplied by two for rosiglitazone patients. In patients receiving rosiglitazone, the risk of arm and lower leg fractures was increased by 57 percent. The risk of bone fracture was higher for women (82 percent) than that for men (23 percent).

The authors explain: “It is good to have robust evidence that this useful medication does perform similarly to other glucose-lowering medications in regard of cardiovascular events. It is also good to see it perform better in controlling blood glucose in the longer term. The data on fractures and heart failure are known class effects, and here the study provides useful data to help clinicians and people with diabetes decide when it is not safe to use rosiglitazone.”

They write in conclusion: “What are the clinical implications for the future use of rosiglitazone? Rosiglitazone is not recommended for people with a history of heart failure or with previous problems that might have led to myocardial dysfunction. Rosiglitazone should be used with caution in women at high risk of fractures. Although our evidence is insufficient to rule out a small increased risk of myocardial infarction caused by rosiglitazone when compared with other glucose-lowering agents, rosiglitazone does not increase overall cardiovascular morbidity or mortality.”

In a supplementary note, Dr Ravi Retnakaran and Dr Bernard Zinman, of Mount Sinai Hospital, Toronto, and of the University of Toronto, Canada, remark that half-maximum doses of rosiglitazone (or a related drug called pioglitazone) given in combination therapy could be considered, since it is generally acknowledged that half-doses give better-than-half results, while restricting side-effects. They write in conclusion: “This combination therapy is currently being assessed for the prevention of diabetes in individuals with impaired glucose tolerance. If the efficacy of this strategy is confirmed, we might be able to find the optimal way to use this class of medications in the treatment of type 2 diabetes.”

“Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial”
Philip D Home, Stuart J Pocock, Henning Beck-Nielsen, Paula S Curtis, Ramon Gomis, Markolf Hanefeld, Nigel P Jones, Michel Komajda, John J V McMurray, for the RECORD Study Team
DOI: 10.1016/S0140-6736(09)60953-3

Written by Stephanie Brunner (B.A.)