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In patients with pre-diabetes, therapy with rosiglitazone (Avandia, GlaxoSmithKline), when combined with a healthful diet and physical activity, can reduce the risk of developing type 2 diabetes by 62% compared with placebo, according to the results of the Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) trial.
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The largest diabetes-prevention trial to date, DREAM compared the effects of the thiazolidinedione (TZD) rosiglitazone, the ACE inhibitor ramipril (Altace, Wyeth), a combination of the two drugs, and placebo on the progression to diabetes in 5,269 participants with impaired glucose tolerance (IGT) or impaired fasting glucose (IFG) who were treated at medical centers in 21 countries. The results were reported at the European Association for the Study of Diabetes (EASD) 42nd Annual Meeting, held September 14–17 in Copenhagen, Denmark.
"This is the latest effect we've seen for a medication" related to diabetes, says Rury Holman, MD, of University of Oxford in England, who serves as European co-chair of DREAM. "To finally have something that is not only safe but may actually help is really something."
STUDY DESIGN
Participants were randomized to receive placebo, 8 mg rosiglitazone daily, 15 mg ramipril daily, or a combination of the two drugs. All participants received the same counseling about diet and exercise and were assessed every 6 months for 3–5 years. The primary outcome of the study was diagnosis of diabetes or death. Analysis of data revealed that 10.6% of participants who received rosiglitazone progressed to diabetes, compared with 25% in the placebo group. Those who took rosiglitazone had a 60% reduction in diabetes or death (62% reduction in diabetes alone) and were 70% more likely to return to normal glucose levels.
The DREAM trial results were published simultaneously with the EASD presentation, with the rosiglitazone data appearing in The Lancet and the ramipril data appearing in the New England Journal of Medicine.1,2
Ramipril was studied because previous research suggested that the drug might delay the progression to diabetes. Analysis of data from the Heart Outcome Prevention Evaluation (HOPE) trial showed that ramipril reduced newly diagnosed diabetes by 34% in people with hypertension or at high risk of negative cardiovascular outcomes.3 Other studies have suggested such a link, according to experts familiar with the issue.
In the DREAM study, no statistically significant difference in progression to diabetes was observed between those who took ramipril and those who took placebo. Nor was any benefit noted from the combination of rosiglitazone and ramipril.
However, subjects receiving ramipril experienced a "modest effect on regression to normal glycemia," according to Salim Yusef, MD, primary DREAM study investigator and director of the Population Health Research Institute at McMaster University in Hamilton, Ontario.
In addition, researchers began to see differences between the ramipril and placebo groups in the last year of the study, although they did not reach statistical significance. "There may be an emergence of an effect," says primary DREAM investigator Hertzel Gerstein, MD, of McMaster University.
Study investigators speculate that the ramipril results might be different if the study were continued for 1–2 more years, but caution that no conclusions should be drawn from the DREAM data.
Considering that antihypertension drugs such as beta-blockers often are linked to worsening glycemia, news that ramipril has a neutral or possibly weak or delayed beneficial effect strengthens its role in the treatment of people at risk of diabetes and cardiovascular disease, according to Yusef.
"Perhaps the late divergence we see with ramipril may be real," he says. "It may be that the effects are small or late. Think of the glycemic effect as a bonus."
ROSIGLITAZONE'S BENEFICIAL EFFECTS
Rosiglitazone produced a number of beneficial effects, including improvements in liver enzymes and redistribution of body fat. Investigators note that participants in all groups gained weight over time, although those in the placebo group had an increased waist-to-hip ratio, while the measure remained the same among those receiving rosiglitazone.
"Rosiglitazone appears to preferentially stimulate fat deposition on the hips rather than the abdomen, which is associated with lower health risks," Yusef says.
Although some studies suggest that rosiglitazone may have a deleterious effect on the liver, as marked by elevated liver enzymes, "we did not see that at all," Gerstein says. "We found a significant reduction in [liver enzymes] compared to placebo."
DREAM did not include pioglitazone (Actos, Takeda), but Holman says it is likely the delay to diabetes holds true for the whole class of TZDs.
"What we don't know about pioglitazone is the dose, effects, and side effects," Holman says.
DREAM participants tolerated the drugs well, with a very low rate of adverse effects. The incidence of cardiovascular events—defined as a composite of heart attack, stroke, cardiovascular death, heart failure, angina, or revascularization—was very low in all groups. The incidence of congestive heart failure (CHF) was slightly elevated among people who took rosiglitazone—14 cases of CHF (0.5%) compared with 2 cases (0.1%) among those receiving placebo.
REACTION
Many in the medical community greeted news of the DREAM trial results with a positive response. "I think it's exciting," says endocrinologist Steven Kahn, MB, ChB, of Veterans Affairs Puget Sound Health Care System in Seattle. "It adds another possibility to the options we have.
"At this point, the first thing we still need to do is lifestyle changes," he adds. "But if lifestyle changes don't work, one can weigh the benefits of metformin, rosiglitazone, and other choices."
An accompanying editorial in The Lancet questioned whether the observed results can be properly regarded as prevention or treatment, and whether the data are persuasive enough for payers and the Food and Drug Administration.4
"Overall, despite the impressive risk reduction for progression to diabetes, the lack of data on long-term benefits and the high cost of therapy mean that health care funders are unlikely to see rosiglitazone as an appropriate agent for individuals with impaired glucose regulation but low absolute cardiovascular risk," the editorial says.
The question of whether rosiglitazone produces a delay in progression to diabetes that persists after the drug is discontinued is being addressed in a wash-out study that will be reported at the International Diabetes Federation annual meeting in Cape Town, South Africa, in December.
GlaxoSmithKline has no immediate plans to seek approval for an indication for rosiglitazone in prediabetes or to prevent diabetes. To date, no drug has been approved for either purpose.
"It's very early for us to be thinking about that," says
company spokesperson Bernadette King. "This was presented to us when the
rest of the world learned about it. We're taking our time to digest this
information and wait for the wash-out data." 
References
2. DREAM Trial Investigators: Effect of ramipril on the incidence of
diabetes. N Engl J Med. Published online at
http://content.nejm.org/cgi/content/abstract/NEJMoa065061v1
September 15, 2006, DOI: 10.1056/NEJMoa065061. Accessed
September 26, 2006.
3. Heart Outcome Prevention Evaluation Study Investigators: Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: Results of the HOPE study and MICRO-HOPE substudy. Lancet 255:253–259, 2000.
4. Tuomilehto J, Wareham N: Glucose lowering and diabetes prevention: Are they the same? Lancet 368:1218–1219, 2006.[Medline]
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