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Mount Sinai Hospital
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June 16, 2010 (Toronto, ON)
In a pioneering study, researchers including Lunenfeld Senior Investigator Dr. Bernie Zinman have shown that use of low-dose combination therapy reduces the risk of progression to type 2 diabetes by two thirds, in people at risk of developing the disease. The study was published online on June 3 in the prestigious scientific journal The Lancet.
“The idea behind the trial was that by combining lower doses of two drugs, we might see the benefits of both, without the side effects typically associated with these medications,” said Dr. Zinman.  
The CAnadian Normoglycemia Outcomes Evaluation (CANOE) trial was a double-blind, randomized controlled study of 207 patients in two Canadian centres (Toronto and London) who exhibited elevated levels of blood sugar and impaired glucose tolerance (IGT), known pre-conditions of diabetes.
Patients received either a combination of two diabetes medications, rosiglitazone and metformin, at low doses (2 mg and 500 mg respectively) twice daily, or placebo, for median periods of three to nine years. The primary outcome of the study was time to the development of diabetes, measured by an oral glucose tolerance test or two fasting plasma glucose values of 7.0 mmol/L or greater.    
Both rosiglitazone and metformin are drugs that, in the past, were typically prescribed individually in patients with diabetes, depending on the severity and progression of their illness. Rosiglitazone helps the body better use insulin, while metformin helps the liver reduce its production of glucose. While each medication has been shown to reduce the development of diabetes in at-risk patients, this therapeutic benefit has also been associated with significant adverse effects, which undermined their use as potential preventative measures for diabetes progression.
Dr. Zinman and his team designed the CANOE study to assess the effects of combining the two medications at half the maximum dose, to determine if a robust effect on diabetes prevention can be achieved with minimal undesirable side effects.
In the study, 103 patients received low-dose combination therapy, and 104 received placebo. After analysis, it was shown that type 2 diabetes occurred in significantly fewer individuals in the active treatment group (14/13.6%) than in the placebo group (41/39.4%). 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 the patients in the treatment group regressed to normal glucose tolerance, compared with 52 (53%) in the placebo group. Sensitivity to insulin (a measure of the responsiveness of the body to control glucose in response to insulin) further decreased in the placebo group by the end of the study, but was stabilized 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.
“This is the first time that low-dose combination therapy was proven to have such a beneficial effect in diabetes, in the context of disease prevention,” said Dr. Zinman. “Our study shows positive complementary effects, with minimal adverse effects.”
Some of the recent media attention on the study has focused on the controversy surrounding the use of rosiglitazone (Avandia®), due to its apparent links to cardiovascular disease and increased fracture risk. The CANOE study did not show any cardiac-related side effects or fluid retention (a potential marker of future heart effects) from combination therapy after four years. Patients in the active treatment group experienced an increase in diarrhea compared with those in the placebo group, but no difference in other gastrointestinal symptoms, swollen ankles, fluid retention or hypoglycemia.  
“Our study was a relatively small one, and was not designed to assess cardiac outcomes,” said Dr. Zinman. “Trials of that nature typically include thousands of patients.” Dr. Zinman noted that 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.     
Diabetes has reached epidemic proportions worldwide and is a leading cause of heart disease, stroke, blindness, kidney failure and limb amputation. Several studies have shown that lifestyle changes and appropriate pharmacologic therapy can significantly reduce the development of type 2 diabetes in people at risk of the disease. This includes people with IGT or impaired fasting glucose (IFG), whose glucose levels are close to the thresholds required to diagnose type 2 diabetes.
“We need to do whatever we can to curb this epidemic,” said Dr. Zinman. “The most effective way to prevent the complications of diabetes is to prevent diabetes in the first place.”
In an editorial accompanying the study in The Lancet, Drs. Thomas Buchanan and Anny Xiang noted that the low-dose combination therapy did not appear to affect the progression of beta-cell disease in this particular study, indicating that additional interventions that promote the health of these insulin-producing cells are likely to yield further improvements in outcomes.
In related studies, Dr. Zinman, Director of the Leadership Sinai Centre for Diabetes, is working with Mount Sinai Hospital colleagues Dr. Ravi Retnakaran (Clinician-Scientist) and Dr. Anthony Hanley (Staff Scientist, with primary appointment to the Department of Nutritional Sciences) to better understand beta-cell failure in individuals at high risk for diabetes. These studies will help define appropriate interventions to halt the progressive deterioration of pancreatic beta-cell insulin secretion seen in type 2 diabetes, and will result in improved metabolic control.

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