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Rosiglitazone Reduced the Incidence of Diabetes in Patients With Impaired Glucose Tolerance

	STUDY

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DREAM (Diabetes REduction Assessment with ramipril and rosiglitizone Medication) Trial Investigators; Gerstein HC, Yusuf S, Bosch J, Pogue J, Sheridan P, Dinccag N, Hanefeld M, Hoogwerf B, Laakso M, Mohan V, Shaw J, Zinman, B, Holman RR: Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet368 : 1096-1105,2006[Medline]

	SUMMARY

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Design. A randomized, placebo-controlled, double-blind trial.

Subjects. Adults > 30 years of age with impaired fasting glucose (IFG; fasting plasma glucose [FPG] > 110 mg/dl and < 126 mg/dl and 2-hour plasma glucose < 200 mg/dl during oral glucose tolerance test [OGTT]) or impaired glucose tolerance (IGT; FPG < 126 mg/dl and 2-hour plasma glucose 140-200 mg/dl and no previous history of diabetes or cardiovascular disease).

Methods. Potentially eligible patients entered a placebo run-in period; those who were successful in taking 80% of doses were then randomized to rosiglitazone and 4 mg/day for 2 months then 8 mg/day. Follow-up visits were scheduled at 2 months, 6 months, and then every 6 months thereafter. FPG was used for monitoring; those with results suggestive of diabetes were scheduled for an OGTT to determine the presence or absence of diabetes. The main outcome of interest was incident diabetes or death, as assessed by blinded outcome adjudicators.

Results. A total of 5,269 patients were enrolled. The mean age was 54.7 years, and 59% were women. Most participants (86%) had IGT with or without IFG; 14% had IFG only. Median followup was 3.0 years. The incidence of diabetes was 10.6% in the intervention group and 25.0% in the control group (hazard ratio [HR] 0.38, 95% CI 0.33-0.44). Deaths did not differ between groups. The median FPG was 9 mg/dl lower in the intervention group. Adverse effects were uncommon, but incidence of heart failure (0.5 vs. 0.1%, HR 7.0, 95% CI 1.6-30.9) and incidence of total cardiovascular events (2.9 vs. 2.1%, 1.37, 0.97-1.94) were increased in the intervention group. Intervention patients also gained on average 2.2 kg of additional weight compared with control subjects.

Conclusions. Rosiglitazone reduces the incidence of diabetes and mean FPG levels but is associated with a small excess risk of heart failure and with weight gain.

	COMMENTARY

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The DREAM trial suggests that rosiglitazone can be effective in reducing the risk of clinical diabetes among patients with IGT or IFG. The observed reduction in the risk of developing clinical diabetes was large in magnitude: seven patients would need to be treated to prevent one case of incident diabetes. Rosiglitazone was also associated with an increased risk of heart failure, although the underlying incidence of heart failure was low in this population.

These findings add to existing evidence suggesting that lifestyle intervention,¹ and to a lesser extent metformin or acarbose,² can delay or prevent progression to diabetes. They also add to accumulating evidence about the increased risk of heart failure with thiazolidinediones.³ A separate arm of the DREAM trial also examined the effect of ACE inhibitors on diabetes incidence, but it did not find a reduction in incidence.⁴

What are the clinical implications of these trials? First, it should be recognized that the end point of diabetes prevention is a somewhat artificial construct. The adverse microvascular and macrovascular effects of elevated plasma glucose levels behave in a linear or exponential manner and do not change dramatically when patients' FPG or OGTT results pass the threshold we have defined as "diabetes." As such, the net beneficial effects of "diabetes prevention" in this context may be more modest than the large reduction in the hazard ratio seems to suggest.

The benefits of prevention must be balanced against any adverse effects and costs of interventions used to achieve it. Lifestyle interventions, such as the changes in dietary and physical activity patterns used in the Diabetes Prevention Program, may have important collateral benefits beyond the reductions in diabetes incidence. Increased effort should be devoted to identifying effective and relatively inexpensive ways to implement such programs in wider practice.⁵

For now, the best choice of pharmacological agent (if any) to be used as an adjunct to lifestyle intervention or when lifestyle change is not effective in patients with IGT remains unclear. Further evidence from head-to-head studies and economic analyses is required.

	Footnotes

 
Michael Pignone, MD, MPH, is an associate professor of medicine at the University of North Carolina Department of Medicine in Chapel Hill and an associate editor of Clinical Diabetes.

	REFERENCES

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¹ Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM, the Diabetes Prevention Program Research Group: Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 346: 393-403,2002[Abstract/Free Full Text]

² Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M: Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet 359:2072 -2077, 2002[Medline]

³ Dormandy J, Charbonnel B, Eckland DJ, Erdmann E, Massi-Benedetti M, Moules IK, Skene AM, Tan MH Lefebvre PJ, Murray GD, Standl E, Wilcox RG, Wilhelmsen L, Betteridge J, Birkeland K, Golay A, Heine RJ, Koranyi L, Laakso M, Mokan M, Norkus A, Pirags V, Podar T, Scheen A, Scherbaum W, Schernthaner G, Schmitz O, Skrha J, Smith U, Taton J, 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. Lancet366 : 1279-1289,2005[Medline]

⁴ DREAM Trial Investigators: Effect of ramipril on the incidence of diabetes. N Engl J Med 355:1551 -1562, 2006[Abstract/Free Full Text]

⁵ Herman WH, Hoerger TJ, Brandle M, Hicks K, Sorensen S, Zhang P, Hamman RF, Ackermann RT, Engelgau MM, Ratner RE, Diabetes Prevention Program Research Group: The costeffectiveness of lifestyle modification or metformin in preventing type 2 diabetes in adults with impaired glucose tolerance. Ann Intern Med 142: 323-332,2005[Abstract/Free Full Text]

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This Article Extract Full Text (PDF) Purchase Article View Shopping Cart Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Pignone, M. Search for Related Content PubMed Articles by Pignone, M. Social Bookmarking                What's this?