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A Mid-Summer’s Night DREAM: Diabetes Prevention (Part 1-Rosiglitazone Arm)

The results of a major study released: The Dream Study (Diabetes Reduction Assessment with ramipril and rosiglitazone Medication) with over 5000 patients Rosiglitazone reduced the risk of developing type 2 diabetes by 62 percent (p<0.0001) relative to placebo among people at high risk of developing type 2 diabetes. New findings from the 25 million dollar Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) trial have shown that rosiglitazone 8 mg for three years substantially reduces the incidence of type 2 diabetes and increases the likelihood of regression to normoglycemia in adults with impaired fasting glucose (IFG) levels, impaired glucose tolerance (IGT), or both [1]. Treatment with the ACE inhibitor ramipril, however, did not prevent reduce the likelihood of progression to diabetes [2].

Dr Hertzel Gerstein (McMaster Health Sciences Center, Hamilton, ON), who presented the results of the rosiglitazone arm of the 2×2 factorial study this week at the European Association for the Study of Diabetes (EASD) 2006 Meeting, told the audience that treatment with rosiglitazone 8 mg reduced the risk of diabetes by 60%, and that for every 1000 patients treated with rosiglitazone, the drug prevents 144 cases of new diabetes mellitus. He noted that cardiovascular-event rates were similar in both treatment arms, although more patients in the rosiglitazone-treatment arm developed heart failure.

In DREAM, eligible patients were randomly assigned to received rosiglitazone 4 mg once daily for the first four months and 8 mg once daily thereafter. Patients were concurrently assigned to treatment with ramipril 15 mg or placebo in the 2×2-factorial designed trial. The primary end point was incident diabetes or death from any cause during the active treatment period.

In the first arm of the DREAM trial, Dr Salim Yusuf (McMaster University Health Sciences Center) presented the results of 5269 adults aged 30 years or more with impaired fasting glucose, impaired glucose tolerance, or both and no previous cardiovascular disease. Patients were recruited from 191 sites in 21 countries and randomly assigned to receive ramipril 15 mg daily or placebo and followed for a median of three years. The primary outcome was a composite of incident diabetes or death.

At the end of three years, although there were reductions in blood pressure as well as a reduction in liver enzymes, there was no significant reduction in the progression to diabetes or death with ramipril. Subgroup analyses presented also revealed no significant benefit. Yusuf said there was an improvement in terms of regression to normoglycemia, confirming the effect of improving glucose levels with the ACE inhibitor.

In terms of cardiovascular-event reduction, a composite of MI, stroke, congestive heart failure, cardiovascular death, new angina, and revascularization, there was no significant improvement with ramipril. Yusuf stressed, however, that the population enrolled in DREAM differed from the HOPE, PEACE, and EUROPA populations, partially explaining the lack of cardiovascular benefit. For every 1000 patients treated, ramipril enhances the regression to normoglycemia in 104 people, he noted.

Still, in terms of the overall findings, Yusuf said the "data do not support a recommended use of ramipril in patients with impaired fasting glucose or impaired glucose tolerance for the prevention of diabetes," although some of these patients, based on other cardiovascular risk factors, might benefit from ACE-inhibitor therapy.

In the rosiglitazone-treatment arm, investigators reported data on the 5269 patients randomized to treatment. The mean age of participants was 54 years, and all were followed for three years. During the course of the study, 18.8% of individuals experienced a primary event. Of these events, 11.6% individuals treated with rosiglitazone and 26.0% given placebo developed the composite primary outcome.

Investigators also report that a larger number of participants receiving rosiglitazone regressed to normoglycemia, defined as a two-hour plasma glucose concentration of <7.8 mmol/L and fasting plasma glucose concentration of <6.1 mmol/L, than individuals treated with placebo. The effect was also observed when a more stringent definition of normal fasting glucose concentration was used. In total, 50.5% individuals in the rosiglitazone group and 30.3% in the placebo group became normoglycemic.

Treatment with rosiglitazone did result in significant weight gain and increases in body mass index, but not in abdominal fat, the increase in fat was in the hips. Gerstein noted, a "well-known side effect of these drugs." He added that the results were consistent across various subgroups, including men and women, those of different ages, those from different geographic locales, and those with varying baseline glycemic abnormalities.

One of the big questions that emerged during the course of the DREAM presentation was whether or not glucose lowering prevents hard cardiovascular end points, such as those listed as secondary end points in the DREAM study. According to Yusuf, who argued that societal change is one of the most important factors for the prevention of type 2 diabetes, rapidly increasing in the industrialized nations, "It is up to the diabetes community to show that glucose lowering prevents cardiovascular disease."

Commenting on the results of the DREAM study during the meeting, Dr Nicholas Wareham (Cambridge University, UK), who wrote an editorial accompanying the publication of the results in the Lancet, said the study shows that the progression to diabetes in people with impaired glucose regulation can be diminished [2]. Moreover, the relative risk reduction of rosiglitazone seen in DREAM was similar to that obtained by lifestyle interventions, as well as similar to that seen in two previous trials of troglitazone, a drug that has since been withdrawn.

Focusing on the issue of preventing future cardiovascular events, Wareham noted that the DREAM study was underpowered to estimate the effect of glucose lowering on cardiovascular disease events, partly because the trial recruited individuals free of cardiovascular disease. However, he said that an estimation of the likely effect on events, based on data from observational studies, is that, with each 1.1 mmol/L difference in fasting glucose concentration associated with a 20% difference in cardiovascular disease risk, "the difference of 0.5 mmol/L seen in DREAM should lower risk by about 8.6%."

"If this estimate were the true value, the number needed to treat people like those in DREAM for three years to prevent one cardiovascular disease event would be 554, which is very high," he writes in the Lancet and stressed during the EASD presentation.

One of the major issues of treatment with rosiglitazone is whether or not the treatment effect lasts longer than the intervention, data that were not presented, although DREAM investigators plan to present washout data at an upcoming meeting. Wareham noted that data from the troglitazone arm of the Diabetes Prevention Program suggest that the risk returns to untreated levels when the drug is withdrawn, an occurrence that is not observed with lifestyle interventions.
Publishers Note: The results from the Dream Trial for the prevention of Diabetes are very similar to the results from the Diabetes Prevention Trial where the risk for developing diabetes was reduced with LifeStyle Modification by 58%. Even though the patients in the Dream Trial were counseled on diet and exercise it was not as aggressive as in the DPPT trials.

According to Wareham, "despite the impressive risk reduction for progression to diabetes, the lack of data on long-term benefits and side effects and the high cost of therapy mean that healthcare funders are unlikely to see rosiglitazone as an appropriate agent for individuals with impaired glucose regulation but low absolute cardiovascular risk. Unfortunately, the greater benefits in higher-risk individuals would have to be balanced against the likely increased risk of heart failure."

1. DREAM investigators. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet 2006; DOI:10.1016/S0140-6736(06)69420-8. Available at: www.thelancet.com,
2. The DREAM Trial Investigators. Effect of ramipril on the incidence of diabetes. N Engl J Med 2006;355. DOI: 10.1056/NEJMoa065061. Available at: http://www.nejm.org.
3. Tuomilehto J, Wareham N. Glucose lowering and diabetes prevention: are they the same? Lancet 2006; DOI:10.1016/S0140-6736(06)69421-X. Available at: Available at: www.thelancet.com

Ingelfinger JR, and Solomon CG. Angiotensin-converting-enzyme inhibitors for impaired glucose tolerance–is there still hope? N Engl J Med 2006: DOI: 10.1056/NEJMe068213. Available at: http://www.nejm.org.

The DREAM trial’s rosiglitazone results were published online September 15, 2006 in the Lancet. The trial’s ramipril outcomes were released online September 15, 2006 in the New England Journal of Medicine and are slated for the publication’s October 12, 2006 issue.