Use of low-dose combination therapy (rosiglitazone and metformin) reduces the risk of progression to type 2 diabetes by two thirds in people deemed at risk of the disease. This strategy could thus be used to target populations at-risk of diabetes. The findings of the CANOE study are reported in an Article Online First and in an upcoming edition of The Lancet, written by Professor Bernard Zinman, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada, with Stewart Harris, University of Western Ontario and colleagues.
Several studies have conclusively shown that lifestyle changes, and some pharmacological interventions, can substantially reduce the development of type 2 diabetes mellitus in individuals at risk of developing the disease. This includes people with impaired glucose tolerance (IGT) or impaired fasting glucose (IGF) whose glucose levels are close to the thresholds required to diagnose type 2 diabetes.
Rosiglitazone (a thiazolidinedione, also known as Avandia) and metformin have different mechanisms of action (one increasing insulin sensitivity and the other reducing liver glucose production, respectively) and have both been shown to reduce the development of diabetes in patients with IGT. In this case, the authors looked to establish whether this combination at half the maximum dose would provide a robust effect on diabetes prevention, while minimising undesirable side-effects.
In this randomised controlled trial undertaken in two Canadian centres, 207 patients with IGT were randomly assigned to receive combination rosiglitazone (2 mg) and metformin (500 mg) twice daily or matching placebo for a median of 3•9 years. The primary outcome was time to development of diabetes, measured by an oral glucose tolerance test or two fasting plasma glucose values of 7•0 mmol/L or greater.
103 participants were assigned to rosiglitazone and metformin, and 104 to placebo; all were included in the analysis. Vital status was obtained in 198 (96%) participants, and medication compliance (taking at least 80% of assigned medication) was 78% in the metformin and rosiglitazone group and 81% in the placebo group. Type 2 diabetes occurred in significantly fewer individuals in the active treatment group (14/14%) than in the placebo group (41/39%). Thus combination therapy reduced the relative risk of diabetes by 66% compared with placebo. The absolute risk reduction was 26%, meaning only four people at risk required combination therapy to prevent one case of diabetes.
Furthermore, 70 (80%) of patients in the treatment group regressed to normal glucose tolerance compared with 52 (53%) in the placebo group. Insulin sensitivity had further decreased by study end in the placebo group, but was stabilised in the combination treatment group. Both groups experienced a decline in pancreatic beta-cell function (another diabetes indicator) but there was no difference in the rate of decline between the two groups.
Referring to the controversy surrounding the risks of using rosiglitazone, the authors say: "CANOE cannot provide additional definitive data for the controversy relating to the specific cardiovascular safety of rosiglitazone, but findings lend support to the notion that half the maximum dose of rosiglitazone could provide important therapeutic effect, with perhaps fewer adverse consequences. Larger long-term studies assessing low-dose combination therapy with these agents will be needed to establish cardiovascular benefit and risk, and overall long-term safety, including fracture risk. Additionally, assessment of the pharmacoeconomic benefits of this intervention would be beneficial in the context of a high–risk, population-directed approach to diabetes prevention."
They conclude: "Low-dose combination therapy with rosiglitazone and metformin was highly effective in prevention of type 2 diabetes in patients with impaired glucose tolerance, with little effect on the clinically relevant adverse events of these two drugs... These results lend support to the notion of use of low-dose combination therapies as an effective means to manage complex metabolic disorders."
In an accompanying Comment, Dr Thomas A. Buchanan, University of Southern California, Los Angeles, CA, USA, and Dr Anny H. Xiang, Kaiser Permanente Southern California, Pasadena, CA, USA, say that "the concept of combining submaximum doses of effective drugs to maintain efficacy and reduce side-effects is an attractive one".
But they add, noting the lack of effect of combination treatment on halting deterioration of beta cell disease function: "We must halt the progressive beta cell disease if we are to keep patients at low-risk glucose levels over the long haul... We need data on more intensive approaches, including high-dose combination therapy, to provide clinicians with a full range of evidence-based approaches to halt or reverse this progressive disease relatively early in its course."
Professor Bernard Zinman, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada. T) +1 416 586 8747 E) zinman@lunenfeld.ca
Dr Thomas A. Buchanan, University of Southern California, Los Angeles, CA, USA. E) buchanan@usc.edu
For full Article and Comment see: http://press.thelancet.com/diablowdose.pdf
Journal
The Lancet