Low dose rosiglitazone and metformin lowers progression to type 2 diabetes in high risk people

Low dose rosiglitazone and metformin lowers progression to type 2 diabetes in high risk people

Using a low-dose combination of rosiglitazone and metformin lowers the risk of developing Type 2 diabetes by approximately two-thirds in people at high risk of developing the disease. 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 say this strategy could be targeted at high-risk populations in an article published in the medical journal The Lancer.

There is compelling evidence from previous studies that lifestyle changes, as well as some pharmacological interventions can considerably lower the risk of developing Type 2 diabetes in patients at risk of developing the disease, the authors say. This includes individuals with IGT (impaired glucose tolerance) or IGF (impaired fasting glucose) whose levels of glucose are nearing the thresholds required to diagnose Type 2 diabetes.

Rosiglitazone (a thiazolidinedione, also known as Avandia) and metformin have different mechanisms of action - one raises insulin sensitivity and the other reduces liver glucose production, respectively - and have both been shown to reduce the development of diabetes in patients with IGT. In this case, the researchers aimed to determine whether this combination at half the maximum dose would provide a robust effect on diabetes prevention, while minimising unwanted side-effects.

A randomised controlled trial - called CANOE - involving 207 patients with IGT in two Canadian was carried out. Patients were randomly given either the combination therapy or a matching placebo:

  • 103 participants received combination rosiglitazone (2 mg) and metformin (500 mg) twice daily for 3.9 years
  • 104 participants received a matching placebo for a median of 3•9 years
The primary outcome was how long it took for diabetes to develop, measured by an oral glucose tolerance test or two fasting plasma glucose values of 7•0 mmol/L or greater.

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 considerably fewer patients in the active treatment group (14/14%) than in the placebo group (41/39%). In other words, combination therapy lowered the relative diabetes risk by 66% compared to the placebo. The absolute risk reduction was 26% - only four people at risk required combination therapy to prevent one case of diabetes.

70 (80%) of the patients receiving the active combination therapy regressed to normal glucose tolerance, compared with 52 (53%) in the placebo group.

Insulin sensitivity had further decreased by the end of the study in the placebo group, but was stabilised in the combination treatment group.

All the participants in both groups experienced a drop 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 wrote:

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.

The researchers concluded:

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:

Tthe 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.

"Low-dose combination therapy with rosiglitazone and metformin to prevent type 2 diabetes mellitus (CANOE trial): a double-blind randomised controlled study"

Prof Bernard Zinman MD, Prof Stewart B Harris MD, Jan Neuman MSc, Prof Hertzel C Gerstein MD, Ravi R Retnakaran MD, Janet Raboud PhD, Ying Qi MSc, Anthony JG Hanley PhD

The Lancet, Early Online Publication, 3 June 2010


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