Effect of Ramipril on the Incidence of Diabetes

The DREAM Trial Investigators. N Engl J Med. 2006;355:1-12.

Diabetes mellitus is a chronic disease and a major risk factor for cardiovascular and renal complications. An increase in the prevalence for diabetes also marks a rise in these sequelae, so it is quite important to reduce the incidence of this disease. Previous studies have demonstrated a preventive effect on diabetes using agents that block the renin-angiotensin system. The Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) Trial aimed to assess the preventive effect that ramipril, an angiotensin-converting enzyme (ACE) inhibitor, has on people with impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) as well as a low risk for cardiovascular disease (CVD).

This prospective study consisted of 5,269 individuals, of which 739 had IFG and 4,350 had IGT with or without IFG. Inclusion criteria included the absence of CVD and diabetes, age 30 years or older, and no intolerance of either ACE inhibitors or thiazolidinediones. The main causes for exclusion were ineligibility and refusal to participate. Eligible participants entered a 17-day, single-blind, double-placebo run-in period during which adherence to study medication was assessed; using a 2-by-2 factorial design, those who demonstrated adherence were randomly assigned to receive either ramipril (5 mg daily for the first 2 months, with an increase to 10 mg at the 2-month visit and 15 mg after 1 year) or placebo (rosiglitazone or matching placebo, 4 mg once daily for first 2 months and then 8 mg thereafter). Visits were scheduled for 2 and 6 months after randomization and then every 6 months until the end of the study. Additionally, at every visit study drugs were given, emphasis was placed on adherence and a healthy lifestyle. Electrocardiograms were also recorded at baseline, at 2 years, and at the end of the study. At the 2-year and final visits, oral glucose tolerance tests were performed on people who had not developed diabetes. The primary outcome of the study was a diagnosis of diabetes or death. Diabetes was diagnosed if fasting plasma glucose (FPG) was ≥126 mg/dL or 2-hour plasma glucose (2hPG) was ≥200 mg/dL. Secondary outcomes were composite cardiac and renal events, glucose levels, and regression to normal glucose values. Outcomes were analyzed using Kaplan-Meier curves; additionally, Cox proportional hazard models were used to assess the effect of ramipril on the primary and secondary outcomes. The 2hPG and the median FPG, which were used to estimate the effect of study drugs on glucose levels, were analyzed by Wilcoxon rank-sum analyses.

Study results are summarized in table 1.

Table 1. Summary of Outcomes

Ramipril’s failure to significantly reduce the incidence of diabetes or death was consistent even after controlling for the use of diuretics, beta-blockers, and angiotensin-receptor blockers; these results were the same for individuals with IFG or IGT. Moreover, by the end of the study, more participants on ramipril (42.5%) had regression to normoglycemia than placebo-treated individuals (38.2%; P = .001). Results for plasma glucose values show that the median FPG values were not significantly lower in the ramipril group than placebo; however, the median 2hPG was notably lower in people receiving ramipril compared to those receiving placebo. The number of CVD events as well as hospitalization following the event was similar between groups.

The results from this study show that the use of ramipril for 3 years did not prevent death or decrease the incidence of diabetes in people with IFG or IGT and no history of CVD. However, the medication did result in reversion to normoglycemia in a significant number of people. The differences in these study results compared to previous studies are due to many factors. First, this study was designed primarily to see if ramipril prevented diabetes, as opposed to considering diabetes as a secondary or post hoc outcome. Also, entry in the study mandated fasting glucose and 2hPG values well below the diagnostic threshold for diabetes. Individuals with CVD were not eligible to participate, whereas other studies did not exclude this patient group. Further, this study was placebo-controlled, where previous studies used other antihypertensive agents as the comparison group. Finally, the duration of follow-up was shorter in this trial than previous studies. A limitation of this study lies in the incompleteness of follow-up; information for those who did not reach a primary outcome by the end of the study was available for only 92.6% of participants. Despite these factors, the results suggest that ramipril may have favorable effects on glucose metabolism, a finding that is consistent with other studies on ACE inhibitors used for the same purposes. However, the results do not support routine use of ramipril to prevent diabetes.