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The increasing prevalence of type 2 diabetes has sparked growing interest in developing safe and successful strategies to prevent the disease. Because of the intimate association among obesity, insulin resistance, and diabetes, most investigations have targeted therapeutic lifestyle change and/or the pharmacological reduction of glucose levels. Several notable trials have shown success in this arena (see table).1–6
The annual progression from prediabetes to diabetes is approximately 10%. Lifestyle change reduces this risk by at least half and has additional health benefits. Yet this success requires intensive support from nurses, dietitians, and exercise coaches—access to whom is largely limited in our clinical practices. Pharmacotherapy has proven to be less effective. In one small study involving women with a history of gestational diabetes, however, therapy with the thiazolidinedione (TZD) troglitazone actually demonstrated a diabetes prevention benefit on the same order as that seen with lifestyle improvements.6
How durable any of these interventions might be over time is not clear. Is diabetes truly being prevented, or is its onset simply being delayed? The price to society related to managing diabetes and its myriad complications is profound, yet there is a paucity of data on the cost-effectiveness of many of the regimens validated in these trials.
IN DRIFTS DREAM
Into this polemic enters the DREAM trial of diabetes prevention, the results of which are reported in this issue of DOC News ("DREAM Results: Drug Delays Diabetes," see page 1).7,8 Briefly, this large, multicenter trial explored the potential for diabetes prevention from the TZD rosiglitazone (Avandia, GlaxoSmithKline) and/or the ACE inhibitor ramipril (Altace, Wyeth). Investigators randomized 5,269 patients with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) and free of known cardiovascular disease such that 25% of patients received daily doses of rosiglitazone (8 mg), ramipril (15 mg), both medications, or two placebos.
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After 3 years, prominent results appeared in the TZD arm, where rosiglitazone reduced the frequency of the primary end point—the development of diabetes or death—by 60% compared with placebo. The prevention of diabetes itself was reduced by an impressive 62%. Moreover, compared with placebo, active therapy markedly increased the chance of "regression" to normal glucose homeostasis by 70%.
Stratified analyses conclude that rosiglitazone prevented diabetes irrespective of baseline characteristics, such as body mass index, sex, ethnicity, or the exact category of pre-diabetes. Not unexpectedly, a more powerful effect was seen in the more obese individuals. The benefit of rosiglitazone demonstrated in DREAM is likely due to its principal mechanism of action—the enhancement of insulin sensitivity and, as a consequence, a reduction in beta-cell work.
With ramipril, in contrast, no significant reduction in the primary end point or in its separate components was demonstrated. The message concerning ramipril is clear: ACE inhibition should no longer be considered a potential diabetes prevention strategy. But what about rosiglitazone?
MEANING FOR PHYSICIANS
Most of us see perhaps dozens of patients each week with mildly elevated glucose levels, whose risk of progressing to diabetes over the next few years is considerable. Many of these individuals decline or cannot sustain the lifestyle alterations required to reduce risk. So, given the potential for a "quick fix" from a once-daily tablet, shouldn't this convenient therapy be made available to all high-risk individuals?
Of course, we must consider the important issues of cost, side effects, and long-term disease outcomes. Clearly, the risks from any preventive measure must be carefully judged against its expected dividends. In the DREAM trial, rosiglitazone was reasonably well tolerated, but its benefits were partially offset by increased weight gain and edema rates.
Mean weight gain with active rosiglitazone therapy was 2.2 kg (4.9 lb), certainly not an enormous amount. However, this appeared not to have fully plateaued by the study's conclusion. Although the investigators correctly underscore that new weight had a predilection for the less metabolically active sites, such as the hips, the broader implications in an aging population of any weight gain, especially if it is progressive, are not fully known.
Regarding cardiovascular disease (CVD), which, as a composite, was a predefined secondary end point in DREAM, there was, somewhat surprisingly, a trend toward increased events in the rosiglitazone group. This appeared to be mainly driven by 14 (0.5%) vs. 2 (0.1%, placebo) cases of heart failure. But even excluding heart failure, the risk of several individual components of the cardiovascular composite (e.g., myocardial infarction, angina, revascularization) was numerically greater in rosiglitazone-treated subjects.
While the numbers here are small, with none of these comparisons achieving statistical significance, the findings are slightly puzzling and counterintuitive. To date, most studies have suggested a benefit of TZDs on CVD, particularly regarding atherosclerosis. Almost all have been short-term investigations tracking cardiovascular surrogates, such as inflammatory markers, tests of endothelial function, or ultrasound measures of atheroma volume.
Thus far, PROactive is the only randomized trial to assess fully the effects of a TZD (pioglitazone [Actos, Takeda]) on cardiovascular events, albeit in a different group than that assessed in DREAM—the PROactive trial studied patients with type 2 diabetes and established macrovascular disease.9 Although a treatment effect from active therapy on the primary end point was not shown in this study, a modest benefit on the combined risk of mortality, myocardial infarction, and stroke was demonstrated (DOC News, December 2005).
Could the lack of a positive cardiovascular outcome in DREAM simply be a manifestation of decreased statistical power in this healthier group of patients with a very low event rate? Has the effect of insulin resistance and/or mild hyperglycemia in patients free of CVD heretofore been exaggerated? Could differential effects of the two TZDs on lipid profiles have influenced these results?10
In spite of these concerns, the risk-benefit ratio outlined by the DREAM investigators (144 cases of diabetes prevented for every 1,000 people treated with rosiglitazone for 3 years, with an excess of 4–5 cases of heart failure) appears to favor treatment. This is particularly so when one considers the apparent, reasonably mild heart failure encountered and the predictable long-term negative impact of diabetes on our patients' vitality, productivity, and quality of life. Admittedly, this discussion becomes more complex if the effects of rosiglitazone wane over time, only measurably delaying the progression to diabetes.
WEIGHING COSTS AND BENEFITS
Broad application of drug-based diabetes prevention has profound implications for our health care system, considering the tens of millions of new patients that would be potential candidates. Rigorous cost-effectiveness analyses are urgently needed to best evaluate the long-term price to society. Such analyses must take into account the costs of screening, medication, and monitoring.
Since most subjects randomized in DREAM had IGT and not IFG, the 2-hour oral glucose tolerance test (OGTT) would need to become the standard case-finding method. Follow-up studies on an annual to biannual basis also would seem logical. Yet we know that the results of an OGTT can be quite labile. Simpler, cheaper, and arguably more stable diagnostic and surveillance strategies, perhaps involving some combination of fasting glucose and glycated hemoglobin (A1C), might be more reasonable options.
These costs need to be weighed against likely savings from preventing diabetes and, ostensibly, avoiding its long-term complications. Importantly, these assessments must be made against the backdrop of preventive measures already considered part of standard medical practice, such as lipid lowering and antihypertensive therapy.
Important questions remain: Would the impressive benefits of rosiglitazone be enhanced if superimposed on modest lifestyle changes? Can lower, perhaps even better-tolerated doses of rosiglitazone exert a similar effect on diabetes risk? Over time, would a decrease in cardiovascular complications become manifest? Are the effects of rosiglitazone on diabetes prevention applicable to pioglitazone? (Although the PIPOD study seems to suggest so, we need the results of the ACT NOW study, currently under way, to answer this question.11,12)
The complete ramifications of the DREAM trial results must await its full digestion by the medical community and the expected commentaries from our professional organizations, as well as the Food and Drug Administration. Specifically, the American Diabetes Association will need to incorporate the trial's findings into its position statement concerning type 2 diabetes prevention. Our patients are likely best served by our continuing to emphasize the unsurpassed benefits of healthy living, including moderate calorie restriction and modest increases in physical activity. Clearly, some degree of personal responsibility on their part, in conjunction with intelligent social policies, will be necessary for the realization of these goals.
Based on the DREAM findings, however, pharmacological diabetes prevention
should now be considered a real option in those very high-risk patients who
are simply not successful with lifestyle change, especially if progressive
hyperglycemia is observed. 
Acknowledgments
The author thanks Rory McCrimmon, MD, and Sandra Norris, MD, for their input during the preparation of this commentary.
Footnotes
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Note of disclosure: Inzucchi has served on advisory boards and accepted speaker's honoraria from Takeda Pharmaceuticals North America.
References
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