More Good News about the Prevention of Diabetes
Abstract & Commentary
By Jonathan Abrams, MD, Professor of Medicine, Division of Cardiology, University of New Mexico, Albuquerque. Dr. Abrams serves on the speaker's bureau for Merck, Pfizer, and Parke-Davis.
Type II Diabetes Mellitus effects 7-8% of adults in the United States and 5% worldwide, with increasing prevalence. Cardiologists have become more aware of the critical importance of diabetes in elevating vascular risk. Several interventions have been shown to improve normal glucose homeostasis, including lifestyle (diet and physical activity) and the use of acarbose and metformin. The glitazones have been the subject of considerable attention over the last few years. These promising agents act on PPAR-gamma receptors and, thus, increase hepatic and peripheral insulin sensitivity while preserving insulin secretion. Troglitazone, initially quite promising, was withdrawn because of liver toxicity.
DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) prospectively assessed whether rosiglita-zone (ROSI) is able to reduce the onset of diabetes in subjects with impaired fasting glucose, abnormal glucose tolerance, or both.1 This factorial design trial evaluated the efficacy of ROSI vs placebo over a median 3-year period, as well as that of ramipril.2 The ramipril data are not the subject of this discussion (see reference 2).
DREAM is an international trial carried out from 2001-2003 at 191 sites in 21 countries. Inclusion criteria included impaired fasting glucose (IFG) or an abnormal 2-hour plasma glucose concentration following an oral glucose tolerance test (GTT). A history of diabetes was an exclusion criterion, as was any cardiovascular disease. Twenty-five thousand people were screened; the final protocol was carried out in 5269 patients over the age of 30, with IFG, impaired glucose tolerance, or both, and no cardiovascular disease. Treatment consisted of ROSI 8 mg daily, or placebo. In addition, ramipril and matching placebo were randomly assigned to the study cohort in a 2x2 factorial design protocol. Patients were repeatedly counseled about the importance of healthy diet and lifestyle, and were followed closely for 3 or more years. A GTT was performed at 2 years and at the final visit. The composite primary out-come was new-onset diabetes or death from any cause. Diabetes was diagnosed by an abnormal fasting glucose or an oral GTT. Secondary outcomes included regression to normal fasting and 2-hour post-load glucose. In addition, individual components of a composite of cardiovascular events and renal/cardio-renal outcomes were secondary outcomes. Methodology and statistical analyses are extensive and complex. In April 2005, the impaired glucose tolerance arm was reported as being beneficial in the ROSI cohort. Six months later, the entire study was terminated prematurely because of multiple positive ROSI outcomes.
Results: During the median 3 years of the trial, 19% of individuals experienced a primary outcome, including death (1.2%) and the development of diabetes (17.8%). Overall adherence was reasonably good. Medications were prematurely stopped by 28% of the ROSI group and 24% of the placebo patients. Patient refusal was the most common cause of discontinuation; edema and weight gain resulted in withdrawal (4.8% of ROSI group and 1.9% of the placebo group).
The primary outcome of diabetes or death was markedly reduced in the ROSI group, with a hazard ratio of 0.40 (95%; CI, 0.35-0.46), P ≤ 0.0001, with no reduction in mortality. The frequency of diabetes developing during the study was reduced, with a hazard ratio of 0.38, P ≤ 0.0001; the event curve for the primary outcomes began to diverge by year one. All glucose cohorts had a comparable reduction in primary end point. In patients with abnormal fasting plasma glucose, the hazard ratio was 0.35.
The effect of ROSI was comparable throughout the world, in different ethnic groups, in both genders, and across all ages. Benefits of ROSI were not affected by baseline weight or fat distribution. Furthermore, increasing waist-to-hip ratio in the ROSI group did not predict the development of diabetes, in contrast to placebo patients. High BMI individuals had greater reduction in the primary outcome, 40% with a BMI < 28 and 68% with a BMI greater than 32. More ROSI patients than placebo patients regressed to normal glycemia, with improvement of 2-hour plasma glucose tests or fasting plasma glucose concentrations. Cardiovascular out-comes were few and comparable between placebo and ROSI, except for an increased risk of heart failure in the ROSI patients (6.8% with peripheral edema in the ROSI group vs 4.9% in the placebo group).
Overall, fasting plasma glucose concentrations fell in the ROSI patients, more so than with placebo; the 2-hour plasma GTT levels were reduced. Small differences in blood pressure were present, favoring ROSI. ALT measurements were lower in the ROSI cohort than in placebo. At the final visit, mean body weight was increased by 2.2 kg more in the ROSI group than placebo, P ≤ 0.0001. However, ROSI patients had a lower waist-to-hip ratio because of increase in hip circumference and no effect on waist circumference. ROSI patients were more likely to regress to normoglycemia than placebo. The primary end points of the ramipril arm of the study did not differ from placebo.2
The authors of the DREAM trial conclude that this large international study demonstrated that ROSI 8 mg daily, along with lifestyle recommendations, "substantially reduces the risk of diabetes or death by 60% in individuals at risk for diabetes. The absolute risk difference between treatment groups of 14.4% means that for every 7 people with impaired fasting glucose or impaired glucose tolerance prescribed … for 3 years, one will be prevented from developing diabetes." ROSI also increased the likelihood of regression to normal glycemia by 70-80%, compared to placebo. The authors point out that the ROSI results are comparable to that achieved by lifestyle interventions, and greater than that achieved by metformin or acarbose. This trial supports data from smaller clinical trials with troglitazone. High BMI or abdominal fat distribution patients on ROSI had a comparable 3-4% incidence of the primary outcome; thus, "the observation of higher risk reduction with higher baseline obesity." ROSI appeared to diminish the relationship between increasing obesity and higher risk of diabetes. A number of potential explanations are provided in the discussion regarding how ROSI might exert its beneficial effects, including increased adiponectin, decreased inflammatory cytokines, and alterations in fat accumulation in non-visceral compartments.
Cardiovascular events were not altered in the study. The authors believe that the relatively short observation period and low event rates "preclude drawing reliable conclusions with regard to the cardiovascular effects of ROSI." There was a small increase in non-fatal heart failure in ROSI patients; fluid overload was less than in previous reports, perhaps due to "a reduced susceptibility of lower risk people to heart failure." The authors note that 8% of adults worldwide have impaired glucose tolerance or impaired fasting glucose, with 5-10% of these individuals developing diabetes. They conclude that adding ROSI to basic lifestyle recommendations will substantially reduce the risk of developing diabetes by about two-thirds, offering a novel, preventive approach that could be more effective and sustainable than lifestyle approaches alone. Finally, the improvement in glycemic control, with a 70-80% regression to normo-glycemia, "suggests that it is treating dysglycemia as well as reducing the frequency of diabetes." (Note: an accompanying editorial emphasizes the benefits of lifestyle modification as "the mainstay for the prevention of type 2 diabetes.")3
Commentary
Cardiologists have been bombarded with discussions of diabetes and metabolic syndrome over the past 5-6 years. The American College of Cardiology has a targeted diabetes initiative; there are many discussions of diabetes related to increased cardiovascular risk or overt cardiovascular disease in lectures and especially in the current literature. At this juncture, however, cardiologists have not taken on the mantle of primary treatment of diabetes, with respect to hyperglycemia. Glitazones were initially viewed as having great promise, but these drugs were considerably set back by the troglitazone fiasco some years ago. It is unlikely that many cardiologists will perform oral glucose tolerance tests but, certainly, assessing fasting plasma glucose can and should become part of our practice.
It would be of great interest to see whether the DREAM trial influences guidelines for the treatment of diabetes. Because patients were selected for low risk of cardiovascular disease, and there were no cardiovascular end point differences between placebo and ROSI, it is unlikely that practicing cardiologists will begin to prescribe ROSI. However, if favorable event data is forthcoming, suggesting that with abnormal glycemia, this very important risk factor can be ameliorated by ROSI treatment, it could become appropriate for the cardiology community to utilize ROSI, as well as metformin. The core of diabetes prevention remains lifestyle interventions (diet and exercise), which have been shown to unequivocally delay or prevent the new onset of diabetes. It may be that the combination of ROSI with vigorous lifestyle modifications will have an even greater impact on the prevention of diabetes and improvement of glycemia in high-risk individuals.
DREAM, a complex study, is somewhat difficult to digest, with respect to many less critical issues. However, the robust reduction in new onset diabetes and improved glycemic control with ROSI, and a relatively benign adverse event profile, opens up a new avenue for the cardiovascular community to join in the critical fight against diabetes.
References
1. Gertsein HC, et al. Effect of Rosiglitazone on the Frequency of Diabetes in Patients with Impaired Glucose Tolerance or Impaired Fasting Glucose: A Randomised Controlled Trial. Lancet. 2006;368:1096-1105.
2. Effect of Ramipril on the Incidence of Diabetes: N Engl J Med. 2006;355:1551-1562.
3. Tuomilehto J, Wareham N. Glucose lowering and diabetes prevention: Are they the same?. Lancet. 2006;368:1218-1219.
Type II Diabetes Mellitus effects 7-8% of adults in the United States and 5% worldwide, with increasing prevalence. Cardiologists have become more aware of the critical importance of diabetes in elevating vascular risk.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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