Rosiglitazone in the prevention of type 2 diabetes

• background
  • previous studies have suggested that blockade of the renin-angiotensin system may prevent diabetes in people with cardiovascular disease or hypertension
• the Diabetes Reduction Assesment with Ramipril and Rosiglitazone Medication (DREAM) investigators undertook a double-blind, randomized clinical trial with a 2-by-2 factorial design
  • randomly assigned 5269 participants without cardiovascular disease but with impaired fasting glucose levels (after an 8-hour fast) or impaired glucose tolerance to receive ramipril (up to 15 mg per day) or placebo (and rosiglitazone or placebo)
    • followed them for a median of 3 years
    • the primary endpoint of the study was the effects of ramipril on the development of diabetes or death, whichever came first. Secondary outcomes included regression to normoglycemia
      • results
        • incidence of the primary outcome did not differ significantly between the ramipril group (18.1%) and the placebo group (19.5%; hazard ratio for the ramipril group, 0.91; 95% confidence interval [CI], 0.81 to 1.03; P=0.15)
        • participants receiving ramipril were more likely to have regression to normoglycemia than those receiving placebo (hazard ratio, 1.16; 95% CI, 1.07 to 1.27; P=0.001)
        • at the end of the study, the median fasting plasma glucose level was not significantly lower in the ramipril group (102.7 mg per deciliter [5.70 mmol per liter]) than in the placebo group (103.4 mg per deciliter [5.74 mmol per liter], P=0.07), though plasma glucose levels 2 hours after an oral glucose load were significantly lower in the ramipril group (135.1 mg per deciliter [7.50 mmol per liter] vs. 140.5 mg per deciliter [7.80 mmol per liter], P=0.01)
        • with respect to use of rosiglitazone
          • the use of rosiglitazone resulted in a significant and substantial reduction in diabetes or death (11.4%, vs. 26.2% in the placebo group; hazard ratio, 0.40; 95% CI, 0.35 to 0.46)
      • the study authors concluded, that among persons with impaired fasting glucose levels or impaired glucose tolerance, the use of ramipril for 3 years does not significantly reduce the incidence of diabetes or death but does significantly increase regression to normoglycemia
  • an Editorial (2) concludes that "...Given the primary findings of the DREAM trial, ramipril cannot be recommended for the prevention of type 2 diabetes. For patients who take ACE inhibitors for another indication (such as hypertension, congestive heart failure, or a high risk of cardiovascular events), improvement in glycemia may turn out to be yet another benefit. For now, ongoing attention to diet and exercise remains our best hope for reducing the rising rate of diabetes..."

Notes

• thiazolidinediones are peroxisome-proliferator–activated receptor gamma agonists, which are known to improve insulin sensitivity. The concept that they would prevent or delay progression from abnormal glucose metabolism to diabetes is not new
  • for example the Troglitazone in Prevention of Diabetes (TRIPOD) study showed that troglitazone significantly reduced the incidence of diabetes among women at high risk, although reports of hepatotoxicity led to the withdrawal of that medication

Reference:

1. DREAM trial investigators. Effect of ramipril on the incidence of diabetes. N Engl J Med. 2006 Oct 12;355(15):1551-62
2. Editorial. Angiotensin-converting-enzyme inhibitors for impaired glucose tolerance--is there still hope? N Engl J Med. 2006 Oct 12;355(15):1608-10.
3. Buchanan TA, Xiang AH, Peters RK, et al. Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk Hispanic women. Diabetes 2002;51:2796-803.