ACE/AACE Diabetes Recommendations Implementation Conference ACARBOSE FOR THE PREVENTION OF DIABETES, HYPERTENSION, AND CARDIOVASCULAR DISEASE IN SUBJECTS WITH IMPAIRED GLUCOSE TOLERANCE: THE STUDY TO PREVENT NON-INSULIN-DEPENDENT DIABETES MELLITUS (STOP-NIDDM) TRIAL Jean-Louis Chiasson, MD ABSTRACT Objective: To evaluate, in subjects with impaired glucose tolerance (IGT), the effect of acarbose on the incidence of diabetes, hypertension, and cardiovascular disease. Methods: The Study to Prevent Non-InsulinDependent Diabetes Mellitus (STOP-NIDDM) Trial was an international, multicenter, double-blind, placebo-controlled, randomized investigation, undertaken in 9 participating countries from December 1995 through August 2001. Patients were randomly assigned to receive placebo (N = 715) or acarbose, 100 mg three times a day (N = 714), and underwent follow-up for a mean of 3.3 years. Sixty-one subjects (4%) were excluded from the study because they did not have IGT or had no postrandomization data; thus, 1,368 subjects remained for intent-to-treat analysis. The outcome measures were the development of diabetes based on a single oral glucose tolerance test, the development of hypertension (≥140/90 mm Hg), and the development of major cardiovascular events, including coronary heart disease, cardiovascular death, stroke, and peripheral vascular disease. Results: Two hundred eleven subjects in the acarbose-treated group and 130 in the placebo group discontinued treatment prematurely; however, they underwent follow-up for assessment of end points. Acarbose treatment resulted in a 25% relative risk reduction in the development of type 2 diabetes (hazards ratio [HR], 0.75; 95% confidence interval [CI], 0.63 to 0.90; P = 0.0015), in a 34% risk reduction in the development of new cases of hypertension (HR, 0.66; 95% CI, 0.49 to 0.89; P = 0.0059), and in a 49% risk reduction in the development of cardiovascular events (HR, 0.51; 95% CI, 0.28 to 0.95; P = 0.03). A post hoc cost-effectiveness analysis done from the Swedish perspective showed that acarbose treatFrom the Department of Medicine, Université de Montréal and Research Center, Centre Hospitalier de l’Université de Montréal, Montreal, Quebec, Canada. Presented at the American College of Endocrinology and the American Association of Clinical Endocrinologists Diabetes Recommendations Implementation Conference, Washington, DC, January 31 and February 1, 2005. © 2006 AACE. ment was likely to be cost-effective in the management of subjects with IGT. Conclusion: The STOP-NIDDM Trial demonstrated that, in subjects with IGT, acarbose treatment was effective in reducing the risk of type 2 diabetes. It also suggested that it was associated with a reduction in hypertension and cardiovascular disease. (Endocr Pract. 2006;12[Suppl 1]:25-30) Abbreviations: CI = confidence interval; CV = cardiovascular; HR = hazards ratio; IGT = impaired glucose tolerance; OGTT = oral glucose tolerance test; STOP-NIDDM = Study to Prevent Non-Insulin-Dependent Diabetes Mellitus INTRODUCTION The prevalence of type 2 diabetes mellitus is increasing worldwide at an epidemic rate (1). Furthermore, it is associated with high morbidity and excess mortality, particularly from cardiovascular (CV) disease, and as such is exerting tremendous pressure on health-care costs (2,3). For all these reasons, type 2 diabetes is now recognized as one of the major challenges of the 21st century (4). With a better understanding of the pathophysiology of type 2 diabetes and its CV complications, the concept of prevention was tested. It is generally accepted that insulin resistance and a decreased capacity for insulin secretion are major factors involved in the development of type 2 diabetes (5). Whether insulin resistance or decreased insulin secretion is the first defect to appear in time is still under debate. Clearly, however, as long as the beta cells can compensate for the insulin resistance, glucose tolerance will remain normal. Only when the beta cells fail to compensate fully for the insulin resistance or the insulin action will impaired glucose tolerance (IGT) appear (6). All subjects in whom diabetes develops are thought to go through a phase of IGT characterized by postprandial hyperglycemia. Even this moderate postprandial hyperglycemia is sufficient to induce glucose toxicity and contribute to ENDOCRINE PRACTICE Vol 12 (Suppl 1) January/February 2006 25 26 ACE/AACE Diabetes Conference (Chiasson), Endocr Pract. 2006;12(Suppl 1) further impairment of insulin secretion and action and, thus, to accelerate the progression to diabetes (7,8). Several studies have shown that the higher the 2-hour plasma glucose level after a 75-g glucose challenge within the IGT range, the higher the incidence of diabetes (9-11). More than 60% of patients with type 2 diabetes die of CV disease (12,13). Although diabetes is associated with a clustering of CV risk factors such as obesity, high blood pressure, and dyslipidemia, it is now recognized that hyperglycemia per se is a risk factor for CV disease (1417). Accumulating evidence indicates that postprandial hyperglycemia is a stronger risk factor than fasting plasma glucose (18-22) (Fig. 1). In fact, epidemiologic prospective studies have shown that CV diseases manifest years before the development of diabetes (23). Subjects with IGT have a twofold increase in the relative risk of coronary heart disease-related mortality (24). On the basis of those observations, it was postulated that decreasing postprandial hyperglycemia by administration of acarbose in subjects with IGT would prevent or delay the progression to diabetes. Similarly, in this highrisk population for CV disease, it was hypothesized that blunting the postprandial increase in plasma glucose levels would also decrease the risk of CV complications. These hypotheses were tested in the Study to Prevent NonInsulin-Dependent Diabetes Mellitus (STOP-NIDDM) Trial. ACARBOSE FOR PREVENTION OF TYPE 2 DIABETES The STOP-NIDDM Trial was an international, double-blind, placebo-controlled, randomized investigation conducted in a population with IGT, undertaken in Canada, Germany, Austria, Norway, Denmark, Sweden, Finland, Spain, and Israel from December 1995 through August 2001 (25,26). The primary objective was to evaluate the effect of acarbose, through its novel mechanism of action in reducing postprandial hyperglycemia, on the rate of progression of IGT to type 2 diabetes. Overall, 1,429 subjects with IGT were randomly assigned to receive placebo (N = 715) or acarbose, 100 mg three times a day (N = 714). Sixty-one subjects (4%) were excluded from the study because they did not have IGT (N = 17) or had no postrandomization data (N = 44); thus, 682 subjects remained in the acarbose group and 686 in the placebo group for intent-to-treat analysis. The mean duration of follow-up was 3.3 years. Two hundred eleven subjects (31%) in the acarbose group and 130 (19%) in the placebo group discontinued treatment prematurely; however, follow-up of them was continued for assessment of end points. All study subjects had a yearly oral glucose tolerance test (OGTT). On the basis of a single OGTT, diabetes developed in 506 subjects—221 (32%) in the acarbose group and 285 (42%) in the placebo group. On Cox proportional hazards analysis, the hazards ratio (HR) was 0.75 (95% confidence interval [CI], 0.63 to 0.90; P = 0.0015). This 25% relative risk reduction was independent of age, body mass index, and sex. Furthermore, if two OGTTs are used to confirm the diagnosis of diabetes, as is now recommended, the number of subjects with IGT converting to diabetes decreased to 105 (15%) in the acarbose group versus 165 (24%) in the placebo group. With use of the same analysis, the HR was 0.64 (95% CI, 0.49 to 0.85), for an absolute reduction of 8.7% and a relative risk reduction of 36% (Fig. 2). Acarbose treatment was also associated with an increase in the reversion of IGT to normal glucose tolerance (P<0.0001). Relative risk < 7.8 7.8-11 > 11 2.5 2 1 7.0-7.7 > 7.7 Fasting plasma glucose (mmol/L) pl 6.1-6.9 h < 6.1 2- 0 a (m sma m g ol lu /L co ) s > 11 7.8-11 < 7.8 0.5 e 1.5 Fig. 1. Risk of cardiovascular mortality according to fasting plasma glucose and 2-hour plasma glucose levels in the DECODE Study. Adapted from Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe (DECODE) Study Group and the European Diabetes Epidemiology Group (22). Cumulative incidence of diabetes ACE/AACE Diabetes Conference (Chiasson), Endocr Pract. 2006;12(Suppl 1) 27 n = 165 200 160 n = 105 120 80 Acarbose Placebo Hazard ratio = 0.64 (CI 95% 95% 0.49 - 0.85); p = 0.0018 Relative risk = 36% Absolute risk = 8.7% Fig. 2. Effect of acarbose on the cumulative incidence of diabetes in subjects with impaired glucose tolerance, based on two oral glucose tolerance tests to confirm the diagnosis. CI = confidence interval. Adapted from Rabasa-Lhoret R, Chiasson JL. In: DeFronzo RA, Ferrannini E, Kee H, Zimmet P, eds. International Textbook of Diabetes Mellitus. Vol 1. 3rd ed. West Sussex, England: John Wiley & Sons Ltd., 2004: 901-914. Therefore, it was concluded that decreasing postprandial hyperglycemia with acarbose was effective in delaying the development of type 2 diabetes in subjects with IGT. ACARBOSE FOR PREVENTION OF HYPERTENSION AND CV DISEASE Another important objective of the STOP-NIDDM Trial was to test whether decreasing postprandial hyperglycemia in subjects with IGT would also decrease the risk of hypertension and CV complications (27). The main outcome measure was the number of subjects in whom hypertension or major CV events developed. Hypertension was considered present if a blood pressure ≥140/90 mm Hg was reported on 2 separate occasions or if the treating physician prescribed an antihypertensive medication. During the study, hypertension developed in 193 subjects—78 in the acarbose group in comparison with 115 in the placebo group (HR, 0.66; 95% CI, 0.49 to 0.89; P = 0.0059) (Fig. 3). The CV events included coronary heart disease (acute myocardial infarction, new angina, revascularization procedures), CV death, stroke, and peripheral vascular disease. All these events were ascertained by an independent “Cardiovascular Event Adjudicating Committee” composed of 3 independent cardiologists, who were blinded to treatment. Furthermore, all subjects had an electrocardiogram before randomization and at the end of the study; these were reviewed and interpreted by 2 independent cardiologists, also blinded to treatment. Overall, 47 subjects had at least 1 cardiovascular event—32 in the placebo group compared with 15 in the acarbose group (Fig. 4). Therefore, decreasing postprandial hyperglycemia was associated with a 49% relative risk reduction in the incidence of CV events (HR, 0.51; 95% CI, 0.28 to 0.95; P = 0.03). Among the CV events, the major reduction was in the risk of acute myocardial infarction—12 cases in the placebo group compared with 1 in the acarbose group (HR, 0.09; 95% CI, 0.01 to 0.72; P = 0.02). In addition, the electrocardiograms confirmed 8 silent myocardial infarctions that were not diagnosed clinically; 1 was in the acarbose group and 7 in the placebo group. Thus, a total of 2 myocardial infarctions occurred in the acarbose group versus 19 in those taking placebo (P<0.001 by the Fisher exact test). These data suggest that acarbose could decrease the risk of CV disease in subjects with IGT. The STOP-NIDDM Trial is the first prospective intervention study to show that acarbose treatment was associated with a reduction in the incidence of new cases of hypertension and CV disease in subjects with IGT. These observations are compatible with the hypothesis that postprandial hyperglycemia is a risk factor for CV disease. COST-EFFECTIVENESS OF ACARBOSE IN MANAGEMENT OF SUBJECTS WITH IGT Using the STOP-NIDDM Trial population, the costeffectiveness of the use of acarbose in the treatment of subjects with IGT was assessed in Sweden, one of the countries that participated in this study (unpublished data). The cost-effectiveness was based on the effect of acarbose in reducing the risk of the development of diabetes (25%), of hypertension (34%), and of CV disease (49%). The cost 28 ACE/AACE Diabetes Conference (Chiasson), Endocr Pract. 2006;12(Suppl 1) n = 115 No. of subjects 120 110 100 90 n = 78 80 Acarbose Placebo Hazard ratio = 0.66 (CI 95% 95% 0.49 - 0.89); p = 0.0059 Fig. 3. Effect of acarbose on the cumulative incidence of hypertension in subjects with impaired glucose tolerance. CI = confidence interval. From Chiasson et al (27). Reprinted with permission. was calculated on the basis of Swedish costs for baseline laboratory tests, for physician visits every 6 months, and for treatment and follow-up for type 2 diabetes without complications, hypertension, and CV events (during a 40month period) irrespective of who pays or benefits. When all the intent-to-treat population was included, the cost for the 40-month period was similar for both groups, slightly in favor of placebo (4.310 euro compared with 4.528 euro for the acarbose group). This analysis does not take into account the long-term follow-up with the delay in the appearance of complications, which very likely would favor acarbose treatment. Furthermore, when subgroups with a high risk for diabetes or a high risk for CV events (or both) based on the formula of Stern et al (28) and the formula of Anderson et al (29), respectively, were analyzed, acarbose treatment was cost saving; the cost of acarbose was more than fully offset by savings attributable to reduced probability of clinical events. Although this study was conducted from a Swedish perspective, because of the relative homogeneity in terms of clinical practice and economic development in the 9 countries participating in the STOP-NIDDM Trial, we predict that the cost-effectiveness results for Sweden are likely to be applicable to the other participating countries as well. with IGT was also associated with reduction in the risk of developing hypertension. Third, the study also suggested that decreasing postprandial hyperglycemia in subjects with IGT could also reduce the risk of CV disease. This result, however, needs to be confirmed in a well-designed prospective intervention study statistically powered to yield a definitive answer to this important question. Finally, it can be predicted that acarbose is likely to be cost-effective in the management of subjects with IGT. On the basis of the STOP-NIDDM Trial observations, as well as those of other trials on the prevention of type 2 diabetes, it can be recommended that intervention should probably predate the actual diagnosis of diabetes. All these intervention studies have shown that, in a high-risk population with IGT, diabetes could be prevented or at least delayed. Consequently, the diabetes-specific complications should be delayed by appropriate management, and such intervention should theoretically be cost-effective over time. Of foremost importance, if the risk of CV complications can be decreased in this high-risk population, as suggested in the STOP-NIDDM Trial, that outcome would definitely justify early intervention before the development of diabetes. CONCLUSION ACKNOWLEDGMENT On the basis of the STOP-NIDDM Trial experience, several conclusions can be drawn. First, the study demonstrated that reducing postprandial hyperglycemia with acarbose in subjects with IGT was associated with a significant reduction in the risk of developing diabetes. Second, acarbose treatment in this high-risk population We acknowledge the contribution of the coordinating nurses and dietitians in all medical centers that participated in this study. We are grateful to Susanne Bordeleau for preparation of the manuscript and illustrations. The STOPNIDDM Trial was funded by an unrestricted research grant from Bayer AG. 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