results & commentary
New findings from the Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) trial have shown that rosiglitazone 8 mg for 3 years substantially reduces the incidence of type 2 diabetes and increases the likelihood of regression to normoglycemia in adults with impaired fasting glucose levels, impaired glucose tolerance, or both. Treatment with the angiotensin-converting enzyme (ACE) inhibitor ramipril, however, did not reduce the likelihood of progression to diabetes.

Hertzel Gerstein, MD, from McMaster University Health Sciences Center in Hamilton, Ontario, Canada, who presented the results of the rosiglitazone group of the 2 x 2 factorial study at the 42nd annual meeting of the European Association for the Study of Diabetes (EASD) in Copenhagen, Denmark, told the audience that treatment with rosiglitazone 8 mg reduced the risk for diabetes by 60% and that for every 1000 patients treated with rosiglitazone, the drug prevents 144 cases of new diabetes mellitus. Dr. Gerstein noted that cardiovascular event rates were similar in both treatment groups, although more patients in the rosiglitazone-treatment group developed heart failure.

Ramipril Not Recommended to Prevent Progression to Diabetes

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

In outlining the rationale for the study, Jackie Bosche, MD, from McMaster University Health Sciences Center, told the assembled EASD audience that previous studies have suggested that ACE inhibitors and thiazolidinediones decrease the progression to diabetes.

In the Heart Outcomes Prevention Evaluation (HOPE) trial, for example, there was a 34% reduction in the risk for progression to diabetes with ACE inhibitor treatment, as well as a 17% reduction observed in the Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) trial. In a recent meta-analysis of the HOPE, PEACE, and the European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease (EUROPA) trials, there was an observed 14% reduction in the risk for progression to diabetes.

In the first group of the DREAM trial, Salim Yusuf, MD, from McMaster University Health Sciences Center, presented the results of 5269 adults aged 30 years or older with impaired fasting glucose or 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 up for a median of 3 years. The primary outcome was a composite of incident diabetes or death.

At the end of 3 years, although there were reductions in blood pressure, as well as a reduction in liver enzymes, but there was no significant reduction in the progression to diabetes or death with ramipril. Subgroup analyses presented also revealed no significant benefit. Dr. 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 myocardial infarction, stroke, congestive heart failure, cardiovascular death, new angina, and revascularization, there was no significant improvement with ramipril. Dr. 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, Dr. Yusuf noted.

Still, in terms of the overall findings, Dr. 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.

Better Results With Rosiglitazone

In the rosiglitazone-treatment group, investigators reported data on the 5269 patients randomized to treatment. The mean age of participants was 54 years, and all were followed up for 3 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 vs individuals treated with placebo regressed to normoglycemia, defined as a 2-hour plasma glucose concentration of less than 7.8 mmol/L and fasting plasma glucose concentration of less than 6.1 mmol/L. 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.

Table. Primary and Other Outcomes*


(n = 2635)

(n = 2634)

Hazard Ratio
(95% CI)


Composite primary endpoint



(0.35 - 0.46)

< .0001




(0.33 - 0.44)

< .0001

Diagnosed by fasting plasma glucose/
oral glucose tolerance test



(0.33 - 0.44)

< .0001

Clinician diagnosed



(0.33 - 0.66)

< .0001




(0.55 - 1.49)


Regression (fasting plasma glucose,
< 6.1 mmol/L)



(1.57 - 1.87)

< .0001

Regression (fasting plasma glucose,
< 5.6 mmol/L)



(1.65 - 2.04)

< .0001

Cardiovascular events composite



(0.97 - 1.94)


Confirmed heart failure



(1.60 - 30.9)


*CI indicates confidence interval. Primary endpoint is a composite of myocardial infarction, stroke, congestive heart failure, cardiovascular death, new angina, and revascularization.

Source: Lancet. Published online September 15, 2006.

Treatment with rosiglitazone did result in significant weight gain and increases in body mass index, Dr. 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.

As noted, there was an increase in confirmed heart failure, although investigators could not explain why the finding occurred. According to Dr. Yusuf, "if we accept the increased risk of heart failure with this drug, then it is on us to understand why."

Lower Glucose and Next Steps

One of the big questions that emerged during the course of the DREAM presentation was whether glucose lowering prevents hard cardiovascular endpoints, such as those listed as secondary endpoints in the DREAM study. According to Dr. 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, Nicholas Wareham, MD, from Cambridge University in Cambridge, England, who wrote an editorial accompanying the publication of the results in The Lancet, said the study shows that that the progression to diabetes in people with impaired glucose regulation can be diminished. 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 2 previous trials of troglitazone, a drug that has since been withdrawn.

Focusing on the issue of preventing future cardiovascular events, Dr. 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, 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," Dr. Wareham writes in The Lancet, and stressed during the EASD presentation.
One of the major issues of treatment with rosiglitazone is whether 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. Dr. Wareham noted that data from the troglitazone group 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.

According to Dr. 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 health-care 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."

Clinical Context

Impaired fasting glucose or impaired glucose tolerance affects up to 8% of adults worldwide, and 5% to 10% of these individuals will develop type 2 diabetes mellitus annually. While lifestyle interventions can reduce the risk of developing diabetes by approximately 50%, such interventions may be difficult for patients to sustain. Also, acarbose and metformin can also prevent progression to diabetes, although their effects are probably less than that of lifestyle interventions.

Previous research on thiazolidinediones has suggested that these medications may also prevent progression to type 2 diabetes. The authors of the current trial test this hypothesis among a cohort of subjects with impaired fasting glucose, impaired glucose tolerance, or both disorders.

Study Highlights

  • Potential study participants were at least 30 years old. Adults were screened with a 75-g oral glucose tolerance test, and those with impaired fasting glucose (fasting glucose level between 6.1 and 7.0 mmol/L and 2-hour plasma glucose concentration, < 7.8 mmol/L after glucose tolerance test) or impaired glucose tolerance (fasting glucose level between < 7.0 mmol/L and 2-hour plasma glucose concentration between 7.8 and 11.1 mmol/L after glucose tolerance test) were eligible for study participation. Patients with known diabetes were excluded from study participation.
  • All study subjects received advice on lifestyle intervention to prevent diabetes. Participants were randomized to receive rosiglitazone, which was titrated to a dose of 8 mg daily, or matching placebo.
  • The primary study outcome was the composite of incident diabetes and mortality due to any cause. Subjects were diagnosed as having diabetes if the fasting glucose was 7 mmol/L or more on at least 2 occasions or if 2-hour glucose tolerance testing revealed a glucose level of 11.1 mmol/L or more on at least 2 occasions. Clinical diagnoses of diabetes were also accepted. The authors also followed regression to normal glucose levels and cardiovascular events. The median follow-up period was 3 years.
  • 5269 adults were randomized into the study. The mean age of subjects was 54.7 years, and 59.2% of the cohort was female. Baseline characteristics were similar between the rosiglitazone and placebo groups. 57% of participants had impaired glucose tolerance, 14% had impaired fasting glucose, and 29% had both disorders.
  • The primary outcome was met by 18.8% of the overall study cohort, including 1.2% of subjects who died. Rosiglitazone therapy was associated with a reduced hazard ratio of 0.40 for the primary outcome when compared with placebo, and this significant difference was derived almost entirely from a reduced risk for incident diabetes. The difference between rosiglitazone and placebo in the primary outcome was evident by 1 year of treatment.
  • Rosiglitazone was similarly effective in the primary outcome among subjects with impaired fasting glucose and impaired glucose tolerance, and it was more effective at higher levels of body mass index.
  • Mean fasting glucose levels were 0.5 mmol/L lower in the rosiglitazone vs placebo groups. Rosiglitazone therapy was also associated with slightly lower values for blood pressure and serum alanine aminotransferase levels. Rosiglitazone therapy was also associated with a mean body weight increase of 2.2 kg vs placebo, but subjects receiving rosiglitazone had a lower waist-to-hip ratio.
  • Rates of regressing to fasting serum glucose levels less than 6.1 mmol/L were 50.5% and 30.3% in the rosiglitazone and placebo groups, respectively, a significant difference.
  • Rates of all cardiovascular outcomes were similar between treatment groups, but more subjects receiving rosiglitazone developed heart failure (0.5% vs 0.1% in the rosiglitazone vs placebo groups, respectively).

Pearls for Practice

  • Patients with impaired fasting glucose or impaired glucose tolerance may develop type 2 diabetes mellitus at a rate of 5% to 10% per year. Lifestyle changes, metformin, and acarbose may prevent this progression to overt diabetes.
  • The current study demonstrates that rosiglitazone 8 mg daily can reduce the risk of progression to type 2 diabetes as well as improve fasting glucose levels and regression to normoglycemia among adults with impaired fasting glucose or impaired glucose tolerance or both. However, rosiglitazone treatment was associated with a slightly higher risk for heart failure than placebo.

Study results in Lancet. Published online September 15, 2006.