Incidence of diabetes following ramipril or rosiglitazone withdrawal

Abstract

Objective: To examine the impact of withdrawing rosiglitazone and ramipril medication on diabetes incidence after closeout of the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) trial.

Research design and methods: The 3,366 DREAM subjects at trial end who had not developed diabetes while taking double-blind study medication were transferred to single-blind placebo for 2 to 3 months before undergoing an oral glucose tolerance test. Glycemic status was analyzed for the trial plus washout period and for the washout period alone.

Results: Following median (interquartile range) 71 (63-86) days drug withdrawal, overall glycemic status remained modestly improved in those allocated ramipril during the trial with an 11% increase in regression to normoglycemia, compared with placebo. In those previously allocated rosiglitazone, glycemic status remained substantially improved with a 49% reduction of new-onset diabetes or death and a 22% increase in regression to normoglycemia, compared with placebo. However, during the washout phase alone the incidence of diabetes or death was identical for those allocated previously to ramipril or placebo, or to rosiglitazone or placebo.

Conclusions: In people allocated to ramipril compared with those not allocated ramipril during the trial, the postwashout normoglycemia incidence was higher. In people allocated to rosiglitazone compared with those not allocated rosiglitazone during the trial, the postwashout incidence of diabetes was significantly lower and the incidence of normoglycemia was higher. During the washout period, diabetes incidence was the same for ramipril versus placebo and for rosiglitazone versus placebo. Rosiglitazone delays disease progression during treatment but the process resumes at the placebo rate when the drug is stopped.

Trial registration: ClinicalTrials.gov NCT00095654.

Figure 1

Three possible scenarios showing the relative proportions of subjects with new-onset diabetes at the end of a diabetes prevention trial, after the trial plus a drug washout period, and after the washout period alone. Scenario 1 illustrates a treatment that merely masks the appearance of diabetes by suppressing glucose levels. Scenario 2 demonstrates slowing the development of diabetes while the treatment is being given. Scenario 3 shows sustained benefit even after the treatment has been withdrawn.

Figure 2

Proportions of subjects with new-onset diabetes at the end of the trial, after the trial plus drug washout, and after the washout period (median 71 days) alone for ramipril vs. placebo (A) and rosiglitazone vs. placebo arms of the trial (B).