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Commentaries on both new and classic studies of importance for the treatment of diabetes are posted here monthly.

The DREAM Trial

Comment on:

DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) Trial Investigators; Gerstein HC, Yusuf S, Bosch J, et al. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet. 2006;368:1096-1105.

Background

Diabetes affects almost 240 million adults worldwide. However, diagnosis is often delayed. Once there is “pre-diabetes” (impaired fasting glucose [IFG] or impaired glucose tolerance [IGT]), there is a 10% annual progression to diabetes. Several strategies are under study to reduce the onset of diabetes, mainly by lifestyle intervention or drugs. The most relevant randomized controlled trials done to date on the reduction of Type 2 diabetes risk are summarised in Table 1, together with the therapeutic intervention and the main results.

The DREAM study investigated the effect of a thiazolidinedione (rosiglitazone) and an angiotensin-converting enzyme inhibitor (ramipril) on the incidence of Type 2 diabetes.

Methods and Key Results

A total of 5269 adults aged 30 years or older with IFG, IGT, or both and with no previous cardiovascular disease were randomly assigned to rosiglitazone (8 mg daily; n=2635) or placebo (n=2634). Follow-up was a median of 3 years. At baseline, most of the individuals had isolated IGT (57%), only a minority had isolated IFT (14%), and the rest had both. The primary outcome was a composite of incident diabetes or death. Analyses were done by intention to treat. (Trial registration: ClinicalTrials.gov, number NCT00095654.)

The dropout rate was around 2.2% in the rosiglitazone group and 1.7% in the placebo group. About 24% of individuals in the rosiglitazone group and 20% in the placebo group did not take their medication at the last visit. A total of 306 (11.6%) individuals in the rosiglitazone group and 686 (26.0%) in the placebo group developed the composite outcome, giving a hazard ratio (HR) of 0.40 (95% CI: 0.35 to 0.46; P<0.0001). A total of 1330 (50.5%) individuals in the rosiglitazone group and 798 (30.3%) in the placebo group became normoglycaemic (HR: 1.71, 95% CI: 1.57 to 1.87; P<0.0001). Subgroup analysis showed a more powerful effect in people with a high body mass index and an elevated waist/hip ratio. Side effects were minimal, and in particular, there was no significant difference in the cardiovascular event rates between the rosiglitazone and placebo groups, although 14 (0.5%) participants in the rosiglitazone group and 2 (0.1%) in the placebo group developed heart failure (P=0.01). The rosiglitazone group gained 2.2 kg more than the placebo group, showing a predilection for an increase in the hip circumference (less metabolically active fat).

Clinical Implications

The DREAM study demonstrated that rosiglitazone in combination with a healthy diet and physical activity can reduce the risk of developing diabetes by 60%. This relative risk reduction with rosiglitazone on progression to diabetes was similar to that reported for lifestyle changes and in accordance with the known results of troglitazone (another glitazone now withdrawn for use) in previous prevention studies. This effect was greater than that reported for acarbose or metformin (see Table 1). The results suggest that for every 1000 individuals treated with rosiglitazone during 3 years, about 144 cases of diabetes will be prevented, with an excess of 4 to 5 cases of congestive heart failure.

Table 1:  Some randomized controlled trials on progression to Type 2 diabetes

RRR=relative risk reduction; TRIPOD=Troglitazone in Prevention of Diabetes; XENDOS=Xenical in the Prevention of Diabetes in Obese Subjects.

Side effects were minimal, but similar to the PROspective pioglitAzone Clinical Trial In macroVascular Events (ProActive), an increased risk for heart failure was found in the DREAM study. Although the frequency of heart failure was much lower in the present study, where participants were free of pre-existing heart disease, the risk was 7 times higher (CI: 1.60 to 30.9) in the rosiglitazone than in the placebo group.

The fact that nearly a quarter of the participants did not take their medication at the final visit illustrates the difficulties in maintaining lifelong preventive interventions in an asymptomatic setting.

Knowing the hypoglycaemic effect of the glitazones, rosiglitazone might simply have masked the progression of diabetes by reducing hyperglycaemia in newly onset diabetes. Moreover, we do not know whether the preventive effect of rosiglitazone lasts after the treatment is stopped. These hypotheses will be tested in the post-trial washout period and will be published in short time.

In summary, the clear risk reduction in progression to diabetes with rosiglitazone should be balanced with the present lack of data on long-term benefits and with the side effects (especially heart failure) and the high cost of therapy. Moreover, more research is needed to know whether starting these (or other) interventions in the pre-diabetic phase would result in preventing end-organ complications.

Most clinicians will continue to emphasize in the first place the clear benefits of moderate caloric restriction by a healthy diet in combination with a modest increase in physical activity. Rosiglitazone can (as can metformin) be an option in the very high-risk patient, especially if progression of the glucose intolerance is seen.

For readers interested in the effect of ramipril (the other drug investigated in the DREAM study), its use did not significantly reduce diabetes risk. However, a longer or larger trial might have yielded significant results as indicated by the finding that significantly more individuals in the ramipril group than in the placebo group had normal fasting glucose levels and glucose tolerance.

Further Reading

DREAM Trial Investigators; Bosch J, Yusuf S, Gerstein HC, et al. Effect of ramipril on the incidence of diabetes. N Engl J Med. 2006;355:1551-1562.

Fonseca VA, Kahn SE. Of Hopes and DREAMS: The Quest to Prevent Type 2 Diabetes. J Clin Endocrinol Metab. 2006;91:4762-4763. Epub 2006 Oct 24.

Heneghan C, Thompson M, Perera R. Prevention of diabetes. BMJ. 2006;333:764-765.

Ingelfinger JR, Solomon CG. Angiotensin-converting-enzyme inhibitors for impaired glucose tolerance—is there still hope? N Engl J Med. 2006;355:1608-1610.

Tuomilehto J, Wareham N. Glucose lowering and diabetes prevention: are they the same? Lancet. 2006;368:1218-1219.

References

Dormandy JA, Charbonnel B, Eckland DJ, et al; PROactive investigators. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005;366:1279-1289.

Knowler RC, Hamman RF, Edelstein SL, et al; Diabetes Prevention Program Research Group. Prevention of type 2 diabetes with troglitazone in the Diabetes Prevention Program. Diabetes. 2005;54:1150-1156.

Lindstrom J, Ilanne-Parikka P, Peltonen M, et al; Finnish Diabetes Prevention Study Group. Sustained reduction in the incidence of type 2 diabetes by lifestyle intervention: follow-up of the Finnish Diabetes Prevention Study. Lancet. 2006;368:1673-1679.

Padwal R, Majumdar SR, Johnson JA, Varney J, McAlister FA. A systematic review of drug therapy to delay or prevent type 2 diabetes. Diabetes Care. 2005;28:736-744.

This Website Feature is funded by an unrestricted educational grant from Pfizer Inc.

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