EASD: ACE-Inhibitor Diabetes Prevention DREAM Is Over

COPENHAGEN, Sept. 15 -- The ACE-inhibitor Altace (ramipril) does not prevent type 2 diabetes in patients with impaired glucose metabolism, found a major randomized trial.

The disappointing results were revealed in the DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) trial, reported at the European Association for the Study of Diabetes meeting here today and published simultaneously as an early online release by the New England Journal of Medicine.

The study pitted Altace against placebo, with and without Avandia (rosiglitazone), in more than 5,200 patients without cardiovascular disease but with impaired fasting glucose or impaired glucose tolerance. Altace did not reduce the incidence of diabetes or death, the investigators wrote. The investigators also reported separate, favorable results from the Avandia portion of the trial here and in The Lancet.

Patients who received Altace did, however, did have a significant improvement in terms of regression toward normoglycemia, wrote Hertzel C. Gerstein, M.D., of McMaster University in Hamilton, Ontario, and colleagues, on behalf of the DREAM investigators.

"Given the primary findings of the DREAM trial, ramipril cannot be recommended for the prevention of type 2 diabetes," wrote Julie R. Ingelfinger, M.D., and Caren G. Solomon, M.D., M.P.H., both deputy editors of NEJM, in an accompanying editorial.

Previous studies had dropped tantalizing clues that ACE-inhibitors might prevent type 2 diabetes in patients with cardiovascular risk factors.

An analysis of data from the Heart Outcomes Prevention Evaluation (HOPE) trial, which asked whether Altace or vitamin E could reduce the risk of cardiovascular events in high-risk patients, showed that Altace reduced the risk of newly diagnosed diabetes by 34% compared with placebo, Dr. Inglefinger and Dr. Solomon pointed out.

"A subsequent meta-analysis of 12 randomized trials also showed reductions in the risk of diabetes in subjects receiving ACE inhibitors, as well as in those receiving angiotensin-receptor blockers (27% and 23%, respectively), suggesting that this effect might be related generally to inhibition of the renin-angiotensin system," they wrote.

In the double-blind DREAM trial, investigators in 21 countries enrolled 5,269 participants without cardiovascular disease but with either impaired 8-hour fasting glucose levels or impaired response to a glucose challenge tests.

The participants were randomly assigned, in a two-by-two factorial design, to either Altace or placebo, plus Avandia or placebo, and were followed for a median of three years.

The primary endpoint of the trial was the effect of Altace on death or the development of diabetes (whichever came first).

Secondary endpoints included glucose levels and regression to normal glucose levels, defined as a fasting plasma glucose level

The investigators have yet to analyze data on the other secondary outcomes, which included a composite of cardiac and renal events, defined as either cardiovascular events (clinical or silent MI, stroke, death from cardiovascular events, revascularization procedures, heart failure, newly diagnosed angina with objective evidence of ischemia, or ventricular arrhythmia requiring resuscitation) or renal events, as determined by measurements in urine and blood at a central laboratory.

They found that after three years there were no significant differences in either the development of diabetes or in deaths between the Altace and placebo groups at 18.1% vs. 19.5% among the placebo group. The hazard ratio for the Altace group was 0.91 (95% confidence interval, 0.81 to 1.03, P=0.15).

They also found that patients receiving Altace were slightly but significantly 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 study end, oral glucose tolerances, but not fasting plasma glucose levels, were lower among patients who received the ACE-inhibitor versus placebo.

In patients on Altace, median plasma glucose levels 2 hours after an oral glucose load were 135.1 mg/dL (7.50 mmol/L), compared with 140.5 mg/dL (7.80 mmol/L) for patients on placebo (P=0.01).

Median fasting plasma glucose levels (after an eight-hour fast) in the Altace group was102.7 mg/dL (5.70 mmol/L), compared with 103.4 mg/dL (5.74 mmol/L) in the placebo group (P=0.07).

Although Altace did not have an effect on the primary outcomes of type 2 diabetes or death, the finding that the drug helped more patients return to normoglycemia suggests that a reduction in the rate of new diabetes cases might appear in a longer or larger study, the DREAM investigators wrote.

"How can the absence of a significant effect of ramipril on the incidence of diabetes in the DREAM trial be reconciled with prior findings that this drug and other inhibitors of the renin-angiotensin system reduce the risk of diabetes?" Dr. Inglefinger and Dr. Solomon asked in their editorial.

"As the DREAM investigators note, previous trials included subjects with hypertension and subjects with, or at high risk for, cardiovascular disease, populations that differed from those in the DREAM trial - and did not include standard assessments of glucose levels," they wrote.

However, while ACE-inhibitors may eventually be shown to offer a diabetes-prevention benefit, for the moment at-risk patients will have to rely on the old standbys of diet and exercise, the editorialists concluded.