Clinical Trials
The Diabetes Control and Complications Trial (DCCT).

Background Long-term microvascular and neurologic complications cause major morbidity and mortality in patients with insulin-dependent diabetes mellitus (IDDM). We examined whether intensive treatment with the goal of maintaining blood glucose concentrations close to the normal range could decrease the frequency and severity of these complications.
Methods A total of 1441 patients with IDDM -- 726 with no retinopathy at base line (the primary-prevention cohort) and 715 with mild retinopathy (the secondary-intervention cohort) were randomly assigned to intensive therapy administered either with an external insulin pump or by three or more daily insulin injections and guided by frequent blood glucose monitoring or to conventional therapy with one or two daily insulin injections. The patients were followed for a mean of 6.5 years, and the appearance and progression of retinopathy and other complications were assessed regularly.

Results In the primary-prevention cohort, intensive therapy reduced the adjusted mean risk for the development of retinopathy by 76 percent (95 percent confidence interval, 62 to 85 percent), as compared with conventional therapy. In the secondary-intervention cohort, intensive therapy slowed the progression of retinopathy by 54 percent (95 percent confidence interval, 39 to 66 percent) and reduced the development of proliferative or severe nonproliferative retinopathy by 47 percent (95 percent confidence interval, 14 to 67 percent). In the two cohorts combined, intensive therapy reduced the occurrence of microalbuminuria (urinary albumin excretion of 40 mg per 24 hours) by 39 percent (95 percent confidence interval, 21 to 52 percent), that of albuminuria (urinary albumin excretion of 300 mg per 24 hours) by 54 percent (95 percent confidence interval, 19 to 74 percent), and that of clinical neuropathy by 60 percent (95 percent confidence interval, 38 to 74 percent). The chief adverse event associated with intensive therapy was a two-to-threefold increase in severe hypoglycemia.
Conclusions Intensive therapy effectively delays the onset and slows the progression of diabetic retinopathy, nephropathy, and neuropathy in patients with IDDM.


The Effect of Intensive Treatment of Diabetes on the Development and Progression of Long-Term Complications in Insulin-Dependent Diabetes Mellitus

The Diabetes Control and Complications Trial Research Group


ABSTRACT

Background Long-term microvascular and neurologic complications cause major morbidity and mortality in patients with insulin-dependen.
diabetes mellitus (IDDM). We examined whether intensive treatment with the goal of maintaining blood glucose concentrations close to the normal range could decrease the frequency and severity of these complications.
Methods A total of 1441 patients with IDDM -- 726 with no retinopathy at base line (the primary-prevention cohort) and 715 with mild retinopathy (the secondary-intervention cohort) were randomly assigned to intensive therapy administered either with an external insulin pump or by three or more daily insulin injections and guided by frequent blood glucose monitoring or to conventional therapy with one or two daily insulin injections. The patients were followed for a mean of 6.5 years, and the appearance and progression of retinopathy and other complications were assessed regularly.

Results In the primary-prevention cohort, intensive therapy reduced the adjusted mean risk for the development of retinopathy by 76 percent (95 percent confidence interval, 62 to 85 percent), as compared with conventional therapy. In the secondary-intervention cohort, intensive therapy slowed the progression of retinopathy by 54 percent (95 percent confidence interval, 39 to 66 percent) and reduced the development of proliferative or severe nonproliferative retinopathy by 47 percent (95 percent confidence interval, 14 to 67 percent). In the two cohorts combined, intensive therapy reduced the occurrence of microalbuminuria (urinary albumin excretion of 40 mg per 24 hours) by 39 percent (95 percent confidence interval, 21 to 52 percent), that of albuminuria (urinary albumin excretion of 300 mg per 24 hours) by 54 percent (95 percent confidence interval, 19 to 74 percent), and that of clinical neuropathy by 60 percent (95 percent confidence interval, 38 to 74 percent). The chief adverse event associated with intensive therapy was a two-to-threefold increase in severe hypoglycemia.

Conclusions Intensive therapy effectively delays the onset and slows the progression of diabetic retinopathy, nephropathy, and neuropathy in patients with IDDM.
Insulin-dependent diabetes mellitus (IDDM) is accompanied by long-term microvascular, neurologic, and macrovascular complications. Although the daily management of IDDM is burdensome and the specter of metabolic decompensation ever-present, long-term complications, including retinopathy, nephropathy, neuropathy, and cardiovascular disease, have caused the most morbidity and mortality since the introduction of insulin therapy1,2. The prevention and amelioration of these complications have been major goals of recent research.
Although studies in animal models of diabetes3,4,5 and epidemiologic studies6,7,8 implicate hyperglycemia in the pathogenesis of long-term complications, previous clinical trials have not demonstrated a consistent or convincing beneficial effect of intensive therapy on them9,10,11. A recent publication from the Stockholm Diabetes Intervention Study demonstrated a more uniform beneficial effect of intensive therapy in patients wit
established complications, despite the apparent crossover of most conventionally treated patients to intensive therapy during the trial12. The Diabetes Control and Complications Trial was a multicenter, randomized clinical trial designed to compare intensive with conventional diabetes therapy with regard to their effects on the development and progression of the early vascular and neurologic complications of IDDM13,14,15. The intensive-therapy regimen was designed to achieve blood glucose values as close to the normal range as possible with three or more daily insulin injections or treatment with an insulin pump. Conventional therapy consisted of one or two insulin injections per day. Two cohorts of patients were studied in order to answer two different, but related, questions: Will intensive therapy prevent the development of diabetic retinopathy in patients with no retinopathy (primary prevention), and will intensive therapy affect the progression of early retinopathy (secondary intervention)? Although retinopathy was the principal study outcome, we also studied renal, neurologic, cardiovascular, and neuropsychological outcomes and the adverse effects of the two treatment regimens.


Methods
Study Design

The trial design and methods have been described elsewhere13,14,15,16,17,18,19,20,21,22,23,24,25. Neither the investigators nor the patients were aware of the outcome data unless predetermined criteria, such as the development of severe retinopathy requiring laser therapy, were met. The physician and the patient were then made aware of the specific condition, and appropriate management was arranged.
A total of 1441 patients were recruited at 29 centers from 1983 through 198915. In June 1993, after an average follow-up of 6.5 years (range, 3 to 9), the independent data monitoring committee16 determined that the study results warranted terminating the trial.


Eligibility Criteria and Base-Line Characteristics

The major criteria for eligibility included insulin dependence, as evidenced by deficient C-peptide secretion; an age of 13 to 39 years; and the absence of hypertension, hypercholesterolemia, and severe diabetic complications or medical conditions13,15,25. To be eligible for the primary-prevention cohort, patients were required to have had IDDM for one to five years, to have no retinopathy as detected by seven-field stereoscopic fundus photography, and to have urinary albumin excretion of less than 40 mg per 24 hours. To be eligible for the secondary-intervention cohort, the patients were required to have had IDDM for 1 to 15 years, to have very-mild-to-moderate nonproliferative retinopathy,13,26 and to have urinary albumin excretion of less than 200 mg per 24 hours. A multicomponent process of informed consent was used to promote the patients' understanding of the study objectives and procedures, emphasizing the necessity of accepting random assignment to either intensive or conventional treatment17. Randomization was stratified according to the primary-prevention and secondary-
intervention cohorts at each center27. The base-line characteristics of the study cohorts are shown in

Table 1 .


The Diabetes Control and Complications Trial Research Group 329 (14): 977, Table 1 September 30, 1993

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Table 1. Base-Line Characteristics of the Two Study Cohorts.

Treatment and Follow-up

Conventional therapy consisted of one or two daily injections of insulin, including mixed intermediate and rapid-acting insulins, daily self-monitoring of urine or blood glucose, and education about diet and exercise13,25. Conventional therapy did not usually include daily adjustments in the insulin dosage. The goals of conventional therapy included the absence of symptoms attributable to glycosuria or hyperglycemia; the absence of ketonuria; the maintenance of normal growth, development, and ideal body weight; and freedom from severe or frequent hypoglycemia. Women who became pregnant or were planning a pregnancy received intensive therapy until the time of delivery, after which they resumed conventional treatment. Patients in the conventional-therapy group were examined every three months.

Intensive therapy included the administration of insulin three or more times daily by injection or an external pump. The dosage was adjusted according to the results of self-monitoring of blood glucose performed at least four times per day, dietary intake, and anticipated exercise. The goals of intensive therapy included preprandial blood glucose concentrations between 70 and 120 mg per deciliter (3.9 and 6.7 mmol per liter), postprandial concentrations of less than 180 mg per deciliter (10 mmol per liter), a weekly 3-a.m. measurement greater than 65 mg per deciliter (3.6 mmol per liter), and hemoglobin A1c (glycosylated hemoglobin), measured monthly, within the normal range (less than 6.05 percent). The patients initially chose either multiple injections or pump therapy and could subsequently change to the other method if their glycemic goals were not achieved or if such was their preference. The patients in the intensive-therapy group visited their study center each month and were contacted even more frequently by telephone to review and adjust their regimens.


Outcome Measures

Seven-field stereoscopic fundus photographs were taken by certified photographers every six months and were centrally assessed by graders unaware of the treatment-group assignments. The graders used the protocol of the Early Treatment Diabetic Retinopathy Study (ETDRS)28. The overall levels of severity of retinopathy were determined for each patient according to the ETDRS interim scale,26 in which a scale of 25 steps is used to represent the overall extent of retinopathy in both eyes. In the primary-prevention cohort, the development of clinically important retinopathy was defined as a change of at least three steps from base line that was sustained for at least six months. Similarly, a sustained three-step change was used to define progression of retinopathy in the secondary-intervention cohort. This definition was chosen because of its reproducibility and because it represented a measure of clinically important worsening. Proliferative retinopathy and severe nonproliferative retinopathy were chosen as additional outcomes, because they indicate the need for frequent follow-up and possibly photocoagulation29. The measures of nephropathic, neuropathic, neuropsychological, macrovascular, and quality-of-life outcomes have been described in detail elsewhere13,18,19,20,21,22,23,24,25.


Statistical Analysis

The Wilcoxon rank-sum test was used to compare the two treatment groups within each cohort with regard to ordinal and numerical variables, and the contingency chi-square test was used for comparisons of categorical variables30. For a stratified analysis of proportions, the adjusted log relative risk comparing the results in the two treatment groups within each cohort was calculated by least-squares analysis31. Event rates are presented as the number of events per 100 patient-years based on the ratio of the observed number of events to the total number of patient-years of exposure. The life-table method was used to estimate the cumulative incidence of events,32 with adjustment for periodically timed assessments33. The difference between cumulative incidence curves was tested by the Mantel (log-rank) test32. The average relative risks for the two treatment groups within each cohort over the entire observation period were estimated by proportional-hazards analysis,32 with stratification or adjustment of the model for base-line variables. The imbalance in the base-line distribution of categories of retinopathy (Table 1) was adjusted for in the estimates of the reduction in the risk of retinopathy in the secondary-intervention cohort. The adjusted percentages of reduction in risk with intensive therapy were calculated by subtracting the average adjusted relative risk of intensive as compared with conventional therapy from 1 and multiplying by 100. The relative risk in the combined cohort was estimated by stratification according to the primary and the secondary cohorts. In the case of recurrent events, the relative risk was computed as the ratio of the crude event rates. The variance of the event rate and of the log relative risk included an adjustment for overdispersion34. A log-linear Poisson regression model was used to assess the relation between the risk of events and the time-dependent covariate measured periodically during the trial34. The time-dependent covariate values were also grouped according to decile, and the crude rate of the event was computed within the categories of the covariate. All outcomes were analyzed on the basis of the original treatment assignments. All results nominally significant at P<0.05 are indicated.


Results
Adherence and Metabolic Control

The entire cohort of 1441 patients was followed for a mean of 6.5 years (range, 3 to 9), a total of more than 9300 patient-years. Ninety-nine percent of the patients completed the study, and more than 95 percent of all scheduled examinations were completed. Eleven patients died, and 32 patients, 8 of whom were lost to follow-up, were assigned to inactive status for some time during the trial because of unavailability for study or the investigator's decision that continuation of their treatment would be hazardous. Overall, the average percentage of time spent receiving the assigned treatment was 97 percent. This includes 95 women assigned to conventional therapy who received intensive therapy during pregnancy or while planning a pregnancy. The adherence to assigned treatment and the effectiveness of intensive therapy in lowering blood glucose concentrations are reflected in the substantial difference over time between the glycosylated hemoglobin values of the intensive-therapy group and those of the conventional-therapy group (Figure 1A). Glycosylated hemoglobin reached a nadir at six months in the patients receiving intensive therapy. A statistically significant difference in the average glycosylated hemoglobin value was maintained after base line between the intensive-therapy and conventional-therapy groups in both cohorts (P<0.001). Although 44 percent of the patients receiving intensive therapy achieved the goal of a glycosylated hemoglobin value of 6.05 percent or less at least once during the study, less than 5 percent maintained an average value in this range. The blood glucose concentrations achieved with each treatment, as measured with quarterly seven-point capillary-blood glucose profiles, are shown in Figure 1B. The mean (±SD) value for all glucose profiles in the intensive-therapy group was 155 ±30 mg per deciliter (8.6 ±1.7 mmol per liter), as compared with 231 ±55 mg per deciliter (12.8 ±3.1 mmol per liter) in the conventional-therapy group (P<0.001).


Figure 1. Measurements of Glycosylated Hemoglobin and Blood Glucose in Patients with IDDM Receiving Intensive or Conventional Therapy. 

Panel A shows the medians of all quarterly glycosylated hemoglobin values, with the 25th and 75th percentiles of the yearly values indicated by the vertical lines. The differences between treatments were statistically significant (P<0.001) from three months until the end of the study. Panel B shows the medians of the quarterly mean values for the seven capillary-blood glucose measurements in a 24-hour period in each patient, with the 25th and 75th percentiles indicated by the vertical lines. The differences between treatments were statistically significant (P<0.001) at each of the seven testing times.


Retinopathy
Primary-Prevention Cohort

The cumulative incidence of retinopathy, defined as a change of three steps or more on fundus photography that was sustained over a 6-month period, was similar in the two treatment groups until approximately 36 months, when the incidence curves began to separate (Figure 2A). From five years onward, the cumulative incidence of retinopathy in the intensive-therapy group was approximately 50 percent less than in the conventional-therapy group. During a mean of six years of follow-up, retinopathy as defined above developed in 23 patients in the intensive-therapy group and 91 patients in the conventional-therapy group. Intensive therapy reduced the adjusted mean risk of retinopathy by 76 percent (95 percent confidence interval, 62 to 85 percent) (Table 2). The reduction in risk increased with time. Too few patients in the primary-prevention cohort had proliferative or severe nonproliferative retinopathy (two in the intensive-therapy group and four in the conventional-therapy group) or clinically important macular edema (one and four, respectively), or required photocoagulation (three and two patients, respectively) for reliable conclusions to be drawn.



Figure 2. Cumulative Incidence of a Sustained Change in Retinopathy in Patients with IDDM Receiving Intensive or Conventional Therapy. 

A sustained change in the severity of retinopathy was defined as a change observed by fundus photography of at least three steps from base line that was sustained for at least six months. In the primary-prevention cohort (Panel A), intensive therapy reduced the adjusted mean risk of the onset of retinopathy by 76 percent during the course of the study, as compared with conventional therapy (P<0.001). In the secondary-intervention cohort (Panel B), intensive therapy reduced the adjusted mean risk of progression of retinopathy by 54 percent as compared with conventional therapy (P<0.001). The numbers of patients in each therapy group who were evaluated at years 3, 5, 7, and 9 are shown below the graphs. 



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Table 2. Development and Progression of Long-Term Complications of Diabetes in the Study Cohorts and Reduction in Risk with Intensive as Compared with Conventional Therapy.


Secondary-intervention Cohort

The patients in the intensive-therapy group had a higher cumulative incidence of sustained progression of retinopathy by three steps or more during the first year than did those in the conventional-therapy group, but a lower cumulative incidence beginning at 36 months and continuing for the rest of the study (Figure 2B). Intensive therapy reduced the average risk of such progression by 54 percent (95 percent confidence interval, 39 to 66 percent) during the entire study period (77 patients in the intensive-therapy group and 143 patients in the conventional-therapy group). Intensive therapy reduced the adjusted risk of proliferative or severe nonproliferative retinopathy by 47 percent (P = 0.011) and that of treatment with photocoagulation by 56 percent (P = 0.002) (Table 2).


Consistency of Retinopathy Results

The cumulative incidence of sustained progression of retinopathy by three steps or more was analyzed within subgroups of patients to determine whether the reduction in risk with intensive therapy was consistent among subgroups. The subgroups were defined on the basis of base-line covariates, including age (adults vs. adolescents), sex, duration of IDDM, percentage of ideal body weight, level of retinopathy, mean blood pressure, presence of clinical neuropathy, screening glycosylated hemoglobin value, and albuminuria. A consistent reduction in the risk of retinopathy with intensive therapy was evident in all subgroups in both the primary-prevention and the secondary-intervention cohorts. The difference in retinal outcome between intensive and conventional therapy was also consistent among clinics.


Nephropathy

In both cohorts, microalbuminuria (defined as urinary albumin excretion, measured annually, of 40 mg per 24 hours) or albuminuria (urinary albumin excretion of 300 mg per 24 hours) developed in fewer patients in the intensive-therapy group than in the conventional-therapy group (Figure 3). Intensive therapy reduced the mean adjusted risk of microalbuminuria by 34 percent (P = 0.04) in the primary-prevention cohort and by 43 percent (P = 0.001) in the secondary-intervention cohort (Table 2). The risk of albuminuria was reduced by 56 percent (P = 0.01) in the secondary-intervention cohort. Advanced nephropathy, as defined by urinary albumin excretion of 300 mg or more per 24 hours and a rate of creatinine clearance below 70 ml per minute per 1.73 m2 of body-surface area, developed in very few patients (two in the intensive-therapy group and five in the conventional-therapy group).



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Figure 3. Cumulative Incidence of Urinary Albumin Excretion 300 mg per 24 Hours (Dashed Line) and 40 mg per 24 Hours (Solid Line) in Patients with IDDM Receiving Intensive or Conventional Therapy. 

In the primary-prevention cohort (Panel A), intensive therapy reduced the adjusted mean risk of microalbuminuria by 34 percent (P<0.04). In the secondary-intervention cohort (Panel B), patients with urinary albumin excretion of 40 mg per 24 hours at base line were excluded from the analysis of the development of microalbuminuria. Intensive therapy reduced the adjusted mean risk of albuminuria by 56 percent (P = 0.01) and the risk of microalbuminuria by 43 percent (P = 0.001), as compared with conventional therapy.


The cumulative incidence of microalbuminuria was analyzed among selected subgroups in the 1368 patients in both cohorts in whom urinary albumin excretion was less than 40 mg per 24 hours at base line. The effect of intensive treatment in reducing risk was maintained within the subgroups defined according to age, sex, duration of IDDM, mean blood pressure, base-line glycosylated hemoglobin value, dietary protein intake, and history of smoking.


Neuropathy

Clinical neuropathy was defined as an abnormal neurologic examination that was consistent with the presence of peripheral sensorimotor neuropathy plus either abnormal nerve conduction in at least two peripheral nerves or unequivocally abnormal autonomic-nerve testing9,10. In the patients in the primary-prevention cohort who did not have neuropathy at base line, intensive therapy reduced the appearance of neuropathy at five years by 69 percent (to 3 percent, vs. 10 percent in the conventional-therapy group; P = 0.006) (Table 2). Similarly, in the secondary-intervention cohort, intensive therapy reduced the appearance of clinical neuropathy at five years by 57 percent (to 7 percent, vs. 16 percent; P<0.001) (Table 2). All three components of the definition of clinical neuropathy were reduced similarly by intensive therapy (Figure 4).


Figure 4. Prevalence of Abnormal Clinical Neurologic Examinations, Abnormal Results of Nerve-Conduction Studies, and Abnormal Autonomic-Nerve Studies at Five Years in Patients Receiving Intensive (Solid Bars) or Conventional (Hatched Bars) Therapy. 

Abnormal results of nerve-conduction studies were defined as abnormal results of neurophysiologic tests in at least two peripheral nerves. The analysis included all patients from either cohort who did not have the abnormality in question at base line.


Macrovascular Disease

The relative youth of the patients made the detection of treatment-related differences in rates of macrovascular events unlikely. However, intensive therapy reduced the development of hypercholesterolemia, defined as a serum concentration of low-density lipoprotein cholesterol greater than 160 mg per deciliter (4.14 mmol per liter), by 34 percent (95 percent confidence interval, 7 to 54 percent) in the combined cohort (P = 0.02). When all major cardiovascular and peripheral vascular events were combined, intensive therapy reduced, albeit not significantly, the risk of macrovascular disease by 41 percent (to 0.5 event per 100 patient-years, vs. 0.8 event; 95 percent confidence interval, -10 to 68 percent).


Adverse Events and Safety

Mortality did not differ significantly between the treatment groups (seven deaths in the intensive-treatment group and four in the conventional-treatment group) and was less than expected on the basis of population-based mortality studies35. As reported elsewhere,36 the incidence of severe hypoglycemia, including multiple episodes in some patients, was approximately three times higher in the intensive-therapy group than in the conventional-therapy group (P<0.001). In the intensive-therapy group, there were 62 hypoglycemic episodes per 100 patient-years in which assistance was required in the provision of treatment, as compared with 19 such episodes per 100 patient-years in the conventional-therapy group. This included 16 and 5 episodes of coma or seizure per 100 patient-years in the respective groups. There were no deaths, myocardial infarctions, or strokes definitely attributable to hypoglycemia, and no significant differences between groups with regard to the number of major accidents requiring hospitalization (20 in the intensive-therapy group and 22 in the conventional-therapy group). However, there were two fatal motor vehicle accidents, one in each group, in which hypoglycemia may have had a causative role. In addition, a person not involved in the trial was killed in a motor vehicle accident involving a car driven by a patient in the intensive-therapy group who was probably hypoglycemic. There were 54 hospitalizations, usually brief, to treat severe hypoglycemia in 40 patients in the intensive-therapy group, as compared with 36 hospitalizations in 27 patients in the conventional-therapy group, including 7 and 4 hospitalizations, respectively, to treat hypoglycemia-related injuries.

Despite the higher risk of severe hypoglycemia with intensive therapy, there was no difference between the two therapy groups in the occurrence of clinically important changes in neuropsychological function12. In addition, there were no significant differences in the mean total scores on the trial's quality-of-life questionnaire,13 despite the added demands of intensive therapy. Weight gain was a problem with intensive therapy,37 with an increase of 33 percent in the mean adjusted risk of becoming overweight, a condition defined as a body weight more than 120 percent above the ideal (12.7 cases of overweight per 100 patient-years in the intensive-therapy group vs. 9.3 in the conventional-therapy group). At five years, patients receiving intensive therapy had gained a mean of 4.6 kg more than patients receiving conventional therapy. The event rates for diabetic ketoacidosis were 1.8 and 2.0 episodes per 100 patient-years in the conventional-therapy and intensive-therapy groups, respectively (P>0.7).


Discussion

Intensive therapy of patients with IDDM delays the onset and slows the progression of clinically important retinopathy, including vision-threatening lesions, nephropathy, and neuropathy, by a range of 35 to more than 70 percent. The large number of patients studied, the inclusion of a primary-prevention cohort, and the long follow-up period in this study provided the opportunity to demonstrate the effects of treatment in patients with a range of ages, durations of diabetes, degrees of severity of retinopathy, and base-line glycosylated hemoglobin values.
The most consistent finding in previous trials was transient worsening of retinopathy with intensive therapy,9,38,39 a result now confirmed by this trial. This early worsening, consisting of the development of soft exudates or intraretinal microvascular abnormalities, occurred mainly in the secondary-intervention cohort during the first year of therapy (22 percent of the patients in the intensive-therapy group and 13 percent of those in the conventional-therapy group). The abnormalities often disappeared by 18 months (Figure 2B). Early worsening should not deter clinicians from using intensive therapy, because the patients with early worsening who were so treated ultimately had a 74 percent reduction (95 percent confidence interval, 46 to 88 percent) in the risk of subsequent progression as compared with patients with early worsening who received conventional therapy (P<0.001).

Intensive insulin therapy reduced the risk of albuminuria and microalbuminuria by 54 percent and 39 percent, respectively, in the combined cohort. A reduction in the progression to albuminuria was suggested by a previous study of 36 patients with IDDM who had generally higher levels of urinary albumin excretion at base line than the patients in the present trial40. Whether the decrease in the development of both microalbuminuria and albuminuria will result in a decrease in the development of renal insufficiency will be clarified by follow-up of the entire study cohort. The ability of intensive therapy to reduce the development of neuropathy suggests that neuropathy may be preventable. Finally, the tantalizing possibility that intensive therapy may reduce macrovascular disease requires further investigation.
In contrast to the clear-cut efficacy of intensive insulin therapy in reducing long-term complications, the risk of severe hypoglycemia was three times higher with such therapy. Relatively few patients required hospitalization or medical attention for hypoglycemia or resultant injuries, and serial neuropsychological testing showed no changes in cognitive function. Although we are mindful of the potential for severe injury, we believe that the risk of severe hypoglycemia with intensive therapy is greatly outweighed by the reduction in microvascular and neurologic complications.

Was the benefit of intensive therapy a result of the lowered glycemia, and can we choose a glycemic target that will preserve the benefits of intensive therapy but reduce the risk of severe hypoglycemia? We cannot answer these questions directly, because it was not practical to assign patients to multiple treatment groups with different levels of glycemia. Nevertheless, because of the clinical importance of the question, we analyzed the relation between the rate of development of retinopathy and glycemic exposure, expressed as the glycosylated hemoglobin value over time. These secondary analyses showed a continuously increasing risk of sustained progression by three steps with increasing mean glycosylated hemoglobin values (Figure 5A), even after adjustment for temporal effects and potential confounding factors. Similarly, the risk of severe hypoglycemia increased continuously with lower monthly glycosylated hemoglobin values (Figure 5B). These secondary analyses do not support the existence of a specific target value for glycosylated hemoglobin at which the benefits of intensive therapy are maximized and the risks minimized.


Figure 5. Risk of Sustained Progression of Retinopathy (Panel A) and Rate of Severe Hypoglycemia (Panel B) in the Patients Receiving Intensive Therapy, According to Their Mean Glycosylated Hemoglobin Values during the Trial. 

Progression of retinopathy was defined as in the legend to Figure 2. In Panel A, the glycosylated hemoglobin values used were the mean of the values obtained every six months. In Panel B, the mean of the monthly values was used. Squares indicate the crude rates within deciles of the mean glycosylated hemoglobin values during the trial; each square corresponds to more than 400 patient-years. The solid lines are regression lines estimated as a function of the log of the mean glycosylated hemoglobin value in Panel A and the log of the glycosylated hemoglobin value in Panel B; the dashed lines are 95 percent confidence intervals.


On the basis of these results, we recommend that most patients with IDDM be treated with closely monitored intensive regimens, with the goal of maintaining their glycemic status as close to the normal range as safely possible. Because of the risk of hypoglycemia, intensive therapy should be implemented with caution, especially in patients with repeated severe hypoglycemia or unawareness of hypoglycemia. The risk-benefit ratio with intensive therapy may be less favorable in children under 13 years of age and in patients with advanced complications, such as end-stage renal disease or cardiovascular or cerebrovascular disease. Patients with proliferative or severe nonproliferative retinopathy may be at higher risk for accelerated progression of their retinopathy after the start of intensive therapy41 and should be followed closely by their ophthalmologists. Finally, although we did not study patients with non-insulin-dependent diabetes mellitus (NIDDM), hyperglycemia is associated with the presence or progression of complications in NIDDM,42,43 as it is in IDDM. If the main conclusions of this trial with regard to the benefits of reducing glycemia are extended to patients with NIDDM, careful regard for age, capabilities, and coexisting diseases will be necessary. We therefore advise caution in the use of therapies other than diet that are aimed at achieving euglycemia in patients with NIDDM.

Intensive therapy was successfully carried out in the present trial by an expert team of diabetologists, nurses, dietitians, and behavioral specialists, and the time, effort, and cost required were considerable. Because the resources needed are not widely available, new strategies are needed to adapt methods of intensive treatment for use in the general community at less cost and effort. Meanwhile, the health care system should provide the support necessary to make intensive therapy available to those patients who will benefit.
Supported under cooperative agreements and a research contract with the Division of Diabetes, Endocrinology, and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Diseases and by the National Heart, Lung, and Blood Institute, the National Eye Institute, the National Center for Research Resources, and various corporate sponsors (listed in Diabetes Care 1987;10:1-19).


Source Information

A complete list of the persons and institutions participating in the Diabetes Control and Complications Trial Research Group appears in the Appendix.
Address reprint requests to the DCCT Research Group, Box NDIC/DCCT, Bethesda, MD 20892.


References
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  25. DCCT Research Group. DCCT manual of operations. Springfield, Va.: Department of Commerce, National Technical Information Service, 1993. (Publication no. 93-183382.) 
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  28. Early Treatment Diabetic Retinopathy Study Research Group. Grading diabetic retinopathy from stereoscopic color fundus photographs -- an extension of the modified Airlie House classification: ETDRS report no. 10. Ophthalmology 1991;98:786-806.[Abstract] 
  29. Early Treatment Diabetic Retinopathy Study Research Group. Early photocoagulation for diabetic retinopathy: ETDRS report number 9. Ophthalmology 1991;98:Suppl:766-785.[Abstract] 
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  31. Kleinbaum DG, Kupper LL, Morgenstern H. Epidemiologic research: principles and quantitative methods. Belmont, Calif.: Lifetime Learning, 1982:359. 
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  33. Tygstrup N, Lachin JM, Juhl E, eds. The randomized clinical trial and therapeutic decisions. New York: Marcel Dekker, 1982:174. 
  34. McCullagh P, Nelder JA. Generalized linear models. 2nd ed. New York: Chapman & Hall, 1989:194-200, 429-30. 
  35. Dorman JS, Laporte RE, Kuller LH, et al. The Pittsburgh insulin-dependent diabetes mellitus (IDDM) morbidity and mortality study: mortality results. Diabetes 1984;33:271-276.[Abstract] 
  36. DCCT Research Group. Epidemiology of severe hypoglycemia in the Diabetes Control and Complications Trial. Am J Med 1991;90:450-459.[Medline] 
  37. DCCT Research Group. Weight gain associated with intensive therapy in the Diabetes Control and Complications Trial. Diabetes Care 1988;11:567-573.[Abstract] 
  38. Lauritzen T, Frost-Larsen K, Larsen HW, Deckert T. Effect of 1 year of near-normal blood glucose levels on retinopathy in insulin-dependent diabetics. Lancet 1983;1:200-204.[Medline] 
  39. Dahl-Jorgensen K, Brinchmann-Hansen O, Hanssen KF, Sandvik L, Aagenaes O. Rapid tightening of blood glucose control leads to transient deterioration of retinopathy in insulin dependent diabetes mellitus: the Oslo study. BMJ 1985;290:811-815.[Medline] 
  40. Feldt-Rasmussen B, Mathiesen ER, Deckert T. Effect of two years of strict metabolic control on progression of incipient nephropathy in insulin-dependent diabetes. Lancet 1986;2:1300-1304.[Medline] 
  41. Lawson PM, Champion MC, Canny C, et al. Continuous subcutaneous insulin infusion (CSII) does not prevent progression of proliferative and preproliferative retinopathy. Br J Ophthalmol 1982;66:762-766.[Medline] 
  42. Klein R, Klein BE, Moss SE, Davis MD, DeMets DL. The Wisconsin epidemiologic study of diabetic retinopathy. III. Prevalence and risk of diabetic retinopathy when age at diagnosis is 30 or more years. Arch Ophthalmol 1984;102:527-532.[Abstract] 
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Heart Outcomes Prevention Evaluation ( HOPE )
Effects of an Angiotensin-Converting-Enzyme Inhibitor, Ramipril, on Cardiovascular Events in High-Risk Patients

The Heart Outcomes Prevention Evaluation Study Investigators


ABSTRACT

Background Angiotensin-converting-enzyme inhibitors improve the outcome among patients with left ventricular dysfunction, whether or not they have heart failure. We assessed the role of an angiotensin-converting-enzyme inhibitor, ramipril, in patients who were at high risk for cardiovascular events but who did not have left ventricular dysfunction or heart failure.
Methods A total of 9297 high-risk patients (55 years of age or older) who had evidence of vascular disease or diabetes plus one other cardiovascular risk factor and who were not known to have a low ejection fraction or heart failure were randomly assigned to receive ramipril (10 mg once per day orally) or matching placebo for a mean of five years. The primary outcome was a composite of myocardial infarction, stroke, or death from cardiovascular causes.

The trial was a two-by-two factorial study evaluating both ramipril and vitamin E. The effects of vitamin E are reported in a companion paper.
Results A total of 651 patients who were assigned to receive ramipril (14.0 percent) reached the primary end point, as compared with 826 patients who were assigned to receive placebo (17.8 percent) (relative risk, 0.78; 95 percent confidence interval, 0.70 to 0.86; P<0.001). Treatment with ramipril reduced the rates of death from cardiovascular causes (6.1 percent, as compared with 8.1 percent in the placebo group; relative risk, 0.74; P<0.001), myocardial infarction (9.9 percent vs. 12.3 percent; relative risk, 0.80; P<0.001), stroke (3.4 percent vs. 4.9 percent; relative risk, 0.68; P<0.001), death from any cause (10.4 percent vs. 12.2 percent; relative risk, 0.84; P=0.005), revascularization procedures (16.0 percent vs. 18.3 percent; relative risk, 0.85; P=0.002), cardiac arrest (0.8 percent vs. 1.3 percent; relative risk, 0.63; P=0.03), heart failure (9.0 percent vs. 11.5 percent; relative risk, 0.77; P<0.001), and complications related to diabetes (6.4 percent vs. 7.6 percent; relative risk, 0.84; P=0.03).
Conclusions Ramipril significantly reduces the rates of death, myocardial infarction, and stroke in a broad range of high-risk patients who are not known to have a low ejection fraction or heart failure.

Although dyslipidemia, diabetes, smoking, and hypertension are major risk factors for cardiovascular disease, they do not fully account for the risk. Therefore, other risk factors must be identified in order to reduce mortality and morbidity even further. Epidemiologic and experimental data suggest that activation of the renin-angiotensin-aldosterone system has an important role in increasing the risk of cardiovascular events.1 Angiotensin-converting-enzyme inhibitors block the activation of the renin-angiotensin system and could retard the progression of both heart failure and atherosclerosis. In a meta-analysis of three studies1,2,3 that included more than 9000 patients with low ejection fractions, treatment with angiotensin-converting-enzyme inhibitors reduced the risk of myocardial infarction by 23 percent. This finding, which has not been widely accepted, was independent of the ejection fraction, the cause of heart disease, concomitant use of medications, diabetes status, and blood pressure, suggesting that angiotensin-converting-enzyme inhibitors may have a role in preventing myocardial infarction in a broad range of patients, not just those with low ejection fractions. Angiotensin-converting-enzyme inhibitors may also reduce the risk of stroke, by lowering blood pressure, and may prevent complications related to diabetes.4 These hypotheses require direct confirmation in prospective, randomized clinical trials.
Therefore, in a high-risk population, we evaluated the effects of an angiotensin-converting-enzyme inhibitor, ramipril, in preventing the primary outcome, which was a composite of death from cardiovascular causes, myocardial infarction, or stroke, as well as each outcome separately. Secondary outcomes included death from any cause, the need for revascularization, hospitalization for unstable angina or heart failure, and complications related to diabetes. Other outcomes included worsening angina, heart failure, and the development of diabetes.


Methods
Study Design

The double-blind, two-by-two factorial, randomized Heart Outcomes Prevention Evaluation study evaluated ramipril and vitamin E in 9541 patients. A substudy compared a low dose of ramipril (2.5 mg per day) with a full dose (10 mg per day) or placebo; there were 244 patients in each group. The results of the placebo-controlled study of full-dose ramipril are given here. The effects of vitamin E are reported in a companion paper.5 The design of the study has been reported previously6; a brief summary follows.


Patients

Men and women who were at least 55 years old were eligible for the study if they had a history of coronary artery disease, stroke, peripheral vascular disease, or diabetes plus at least one other cardiovascular risk factor (hypertension, elevated total cholesterol levels, low high-density lipoprotein cholesterol levels, cigarette smoking, or documented microalbuminuria).6 Patients were excluded if they had heart failure, were known to have a low ejection fraction (<0.40), were taking an angiotensin-converting-enzyme inhibitor or vitamin E, had uncontrolled hypertension or overt nephropathy, or had had a myocardial infarction or stroke within four weeks before the study began. All patients provided written informed consent. In this large study it was impractical to measure left ventricular function in all patients. Instead, echocardiograms were obtained at three centers in 496 patients who were enrolled in a substudy. Of these patients, 2.6 percent had an ejection fraction of less than 0.40. A subsequent review of the charts of randomized patients showed that ventricular function had been evaluated before randomization in 5193. Only 421 of these patients (8.1 percent) had a low ejection fraction, and none had heart failure before randomization. We performed a separate analysis of the 4772 patients who were documented to have a normal ejection fraction.

All 10,576 eligible patients participated in a run-in phase in which they received 2.5 mg of ramipril orally once daily for 7 to 10 days followed by matching placebo for 10 to 14 days. A total of 1035 patients were subsequently excluded from randomization because of noncompliance (<80 percent of pills taken), side effects, abnormal serum creatinine or potassium levels, or withdrawal of consent. Of the 9541 remaining patients, 4645 were randomly assigned to receive 10 mg of ramipril once per day, 4652 were randomly assigned to receive matching placebo, and 244 were randomly assigned to receive a low dose (2.5 mg per day) of ramipril. Treatment was scheduled to last five years.

At randomization, patients were assigned to receive ramipril (or matching placebo) at a dose of 2.5 mg once a day for one week, 5 mg for the next three weeks, and then 10 mg. In addition, all patients were randomly assigned to receive 400 IU of vitamin E per day or matching placebo. Follow-up visits occurred at one month and six months and every six months thereafter. At each visit, data were collected on the outcome events, compliance, and side effects leading to a discontinuation of study medications. All primary and secondary events were documented and were centrally adjudicated with the use of standardized definitions.5


Organization of the Study

Patients were recruited from December 1993 to June 1995 at 129 centers in Canada, 27 centers in the United States, 76 centers in 14 western European countries, 30 centers in Argentina and Brazil, and 5 centers in Mexico. The review board at each institution approved the protocol. The study was organized and coordinated by the Canadian Cardiovascular Collaboration Project Office at McMaster University in Hamilton, Ontario. Adjunct offices were located in London, United Kingdom; S?o Paulo, Brazil; and Rosario, Argentina. An independent steering committee oversaw the study.


Outcomes

The primary study outcome was a composite of myocardial infarction, stroke, or death from cardiovascular causes. Each of these outcomes was also analyzed separately. Secondary outcomes were death from any cause, the need for revascularization, hospitalization for unstable angina or heart failure, and complications related to diabetes (whether or not hospitalization was required). Other outcomes were worsening angina, cardiac arrest, heart failure (whether or not hospitalization was required), unstable angina with electrocardiographic changes, and the development of diabetes. These outcomes are defined in a companion paper.5


Statistical Analysis

The study was originally designed to follow participants for a mean of 3.5 years. However, before the end of this period, the steering committee (whose members were unaware of any of the results) recommended increasing the duration of follow-up to five years to account for the impact of a possible lag before treatment had its full effect. Assuming an event rate of 4 percent per year for five years, we calculated that 9000 patients would be required for the study to have 90 percent power to detect a 13.5 percent reduction in the relative risk with a two-sided alpha level of 0.05 and with data analyzed on an intention-to-treat basis. Survival curves were estimated according to the Kaplan-Meier procedure, and treatments were compared with use of the log-rank test. Because of the factorial design, all analyses were stratified for the randomization to vitamin E or placebo. Subgroup analyses were conducted with the use of tests for interactions in the Cox regression model. This model was used to estimate the effects of treatment after stratification for randomization to vitamin E or its placebo.

An independent data and safety monitoring board monitored the progress of all aspects of the study. Four formal interim analyses were planned. The statistical monitoring boundary indicating that ramipril had a beneficial effect was a difference in the primary outcome of 4 SD between groups during the first half of the study and of 3 SD during the second half. The respective boundaries indicating that ramipril had a harmful effect were 3 SD and 2 SD. On March 22, 1999, the monitoring board recommended termination of the study because of the clear evidence of a beneficial effect of ramipril (consistent crossing of the monitoring boundaries in two consecutive reviews). At that time, the data showed a 20 percent reduction in the relative risk of the primary outcome (95 percent confidence interval, 12 percent to 28 percent; z statistic, -4.5; P<0.001). The results of the study were disclosed to the investigators at two meetings held on April 17 and April 24, 1999.
The cutoff date for all events included in the main analysis was set for April 15, 1999, and final visits were scheduled to be completed by June 30, 1999. Vital status was ascertained for 9535 of the 9541 randomized patients (99.9 percent) at the end of the study.


Results
Characteristics of the Patients

The base-line characteristics of the 9297 patients who underwent randomization are shown in Table 1. There were 2480 women, 5128 patients who were at least 65 years old, 8162 who had cardiovascular disease, 4355 who had hypertension, and 3577 who had diabetes.


Compliance

Among the patients who were randomly assigned to the ramipril group, 87.4 percent were taking ramipril or an open-label angiotensin-converting-enzyme inhibitor at one year, 85.0 percent were doing so at two years, 82.2 percent were doing so at three years, 75.1 percent were doing so at four years, and 78.8 percent were doing so at the final follow-up visit. The percentage of patients who were receiving 10 mg of ramipril per day was 82.9 percent at one year, 74.6 percent at two years, 70.9 percent at three years, 62.4 percent at four years, and 65.0 percent at the last visit. Among the patients who were randomly assigned to receive placebo, 3.4 percent were receiving an angiotensin-converting-enzyme inhibitor at one year, 6.0 percent were doing so at two years, 8.1 percent were doing so at three years, 10.8 percent were doing so at four years, and 12.3 percent were doing so at five years. The most common reasons for discontinuing treatment are outlined in Table 2. More patients in the ramipril group than in the placebo group stopped treatment because of cough (7.3 percent vs. 1.8 percent) or hypotension or dizziness (1.9 percent vs. 1.5 percent). By contrast, more patients in the placebo group than in the ramipril group stopped treatment because of uncontrolled hypertension (3.9 percent vs. 2.3 percent) or because of a clinical event - a primary or secondary outcome (8.9 percent vs. 6.6 percent). The percentage of patients who were receiving nonstudy angiotensin-converting-enzyme inhibitors for heart failure was 5.4 percent in the ramipril group and 7.2 percent in the placebo group; 1.3 percent and 1.3 percent, respectively, were receiving such drugs because of proteinuria, and 4.8 percent and 6.4 percent for control of hypertension. The use of open-label angiotensin II-receptor antagonists in both groups was low (1.6 percent in the ramipril group and 1.8 percent in the placebo group), but the reasons for such use were similar to those for angiotensin-converting-enzyme inhibitors.



Blood Pressure

The mean blood pressure at entry was 139/79 mm Hg in both groups. The mean blood pressure was 133/76 mm Hg in the ramipril group and 137/78 mm Hg in the placebo group at one month, 135/76 mm Hg and 138/78 mm Hg, respectively, at two years, and 136/76 mm Hg and 139/77 mm Hg, respectively, at the end of the study.


Primary Outcomes and Deaths from Any Cause

A total of 651 patients in the ramipril group (14.0 percent) died of cardiovascular causes or had a myocardial infarction or stroke, as compared with 826 patients in the placebo group (17.8 percent; relative risk, 0.78; 95 percent confidence interval, 0.70 to 0.86; P<0.001) (Figure 1 and Table 3). Treatment with ramipril also reduced the risk of the primary outcome among patients who were receiving vitamin E (338 patients who received both agents reached the end point, as compared with 421 patients who received only vitamin E; relative risk, 0.79; P=0.001) or its placebo (313 patients who received ramipril and the vitamin E placebo reached the end point, as compared with 405 patients who received the vitamin E placebo alone; relative risk, 0.76; P<0.001; P=0.79 for the comparison of the two relative risks). In addition, there were significant reductions in risk when each of these end points was analyzed separately: 282 patients in the ramipril group died of cardiovascular causes, as compared with 377 patients in the placebo group (relative risk, 0.74; 95 percent confidence interval, 0.64 to 0.87; P<0.001); 459 patients in the ramipril group had a myocardial infarction, as compared with 570 patients in the placebo group (relative risk, 0.80; 95 percent confidence interval, 0.70 to 0.90; P< 0.001); and 156 patients in the ramipril group had a stroke, as compared with 226 patients in the placebo group (relative risk, 0.68; 95 percent confidence interval, 0.56 to 0.84; P<0.001). The risk of death from any cause was also significantly reduced by treatment with ramipril (relative risk, 0.84; 95 percent confidence interval, 0.75 to 0.95; P=0.005).


Figure 1. Kaplan-Meier Estimates of the Composite Outcome of Myocardial Infarction, Stroke, or Death from Cardiovascular Causes in the Ramipril Group and the Placebo Group.


The relative risk of the composite outcome in the ramipril group as compared with the placebo group was 0.78 (95 percent confidence interval, 0.70 to 0.86).


Figure 1. Kaplan-Meier Estimates of the Composite Outcome of Myocardial Infarction, Stroke, or Death from Cardiovascular Causes in the Ramipril Group and the Placebo Group.


Secondary and Other Outcomes

Significantly fewer patients in the ramipril group than in the placebo group underwent revascularization (742 vs. 852; relative risk, 0.85; P=0.002), and there was a trend toward fewer hospitalizations for heart failure in the ramipril group (141 vs. 160; relative risk, 0.88; P=0.25) (Table 4). However, treatment with ramipril had no effect on the likelihood of hospitalization for unstable angina. In addition, significantly fewer patients in the ramipril group than in the placebo group had a cardiac arrest (37 vs. 59; relative risk, 0.62; P=0.02), worsening angina (1107 vs. 1220; relative risk, 0.89; P=0.004), heart failure (417 vs. 535; relative risk, 0.77; P<0.001), a new diagnosis of diabetes (102 vs. 155; relative risk, 0.66; P<0.001), or complications related to diabetes (299 vs. 354; relative risk, 0.84; P=0.03).


Figure 2. The Beneficial Effect of Treatment with Ramipril on the Composite Outcome of Myocardial Infarction, Stroke, or Death from Cardiovascular Causes Overall and in Various Predefined Subgroups.

Cerebrovascular disease was defined as stroke or transient ischemic attacks. The size of each symbol is proportional to the number of patients in each group. The dashed line indicates overall relative risk.


Temporal Trends

The reduction in the risk of the composite outcome with ramipril therapy was evident within one year after randomization (169 patients reached the end point in the ramipril group, as compared with 198 in the placebo group; relative risk, 0.85; 95 percent confidence interval, 0.70 to 1.05) and was significant at two years (326 vs. 398 patients; relative risk, 0.82; 95 percent confidence interval, 0.70 to 0.94). The relative risk was 0.78 in the second year, 0.73 in the third year, and 0.74 in the fourth year, when the data on patients who were still alive at the end of the preceding year were analyzed.


Discussion

Our findings show that ramipril, an angiotensin-converting-enzyme inhibitor, is beneficial in a broad range of patients without evidence of left ventricular systolic dysfunction or heart failure who are at high risk for cardiovascular events. Treatment with ramipril reduced the rates of death, myocardial infarction, stroke, coronary revascularization, cardiac arrest, and heart failure as well as the risk of complications related to diabetes and of diabetes itself.
Our findings indicate that the spectrum of patients who would benefit from treatment with an angiotensin-converting-enzyme inhibitor is quite broad and complement those of previous studies of patients with low ejection fractions3 or heart failure and acute myocardial infarction.7 The underlying rationale for our study was that the inhibition of angiotensin-converting enzyme would prevent events related to ischemia and atherosclerosis, in addition to those related to heart failure and left ventricular dysfunction (although patients with these two conditions were excluded from the study). We therefore included a broad range of patients with any manifestation of coronary artery disease (e.g., a history of myocardial infarction or revascularization, unstable angina, or stable angina), a history of cerebrovascular disease or peripheral vascular disease, or diabetes and one cardiovascular risk factor, and ramipril was beneficial in all these subgroups.

A total of 3577 patients in our study had diabetes, 1135 of whom had no clinical manifestations of cardiovascular disease, and the event rate in this group was about half that in the other patients (10.2 percent vs. 18.7 percent). Nonetheless, overall, treatment with ramipril was beneficial in patients with diabetes.
The magnitude of the benefit of treatment with ramipril with respect to the primary outcome was at least as large as that observed with other proven secondary prevention measures, such as treatment with beta-blockers,8 aspirin,9 and lipid-lowering agents,10 during four years of treatment. In addition, there were reductions in the rates of revascularization, heart failure, complications related to diabetes, and new cases of diabetes. The rapid and sustained response to ramipril and the continuing divergence in results between the ramipril group and the placebo group indicate that longer-term treatment may yield even better results. Ramipril was also well tolerated.

The benefits of ramipril were observed among patients who were already taking a number of effective treatments, such as aspirin, beta-blockers, and lipid-lowering agents, indicating that the inhibition of angiotensin-converting enzyme offers an additional approach to the prevention of atherothrombotic complications. Only a small part of the benefit could be attributed to a reduction in blood pressure, since the majority of patients did not have hypertension at base line (according to conventional definitions) and the mean reduction in blood pressure with treatment was extremely small (3/2 mm Hg). A reduction of 2 mm Hg in diastolic blood pressure might at best account for about 40 percent of the reduction in the rate of stroke and about one quarter of the reduction in the rate of myocardial infarction.11 Howev-er, the results of recent studies, such as the Hypertension Optimal Treatment study,12 suggest that for high-risk patients (e.g., those with diabetes), it may be beneficial to lower blood pressure even if it is already within the "normal" range. Moreover, a recent reanalysis of 20 years of blood-pressure data from the Framingham Heart Study13 suggests that the degree of benefit expected from a decrease in blood pressure may have been underestimated. Despite these considerations, it is likely that angiotensin-converting-enzyme inhibitors exert additional direct mechanisms on the heart or the vasculature that are important. These may include antagonizing the direct effects of angiotensin II on vasoconstriction,1 the proliferation of vascular smooth-muscle cells,1 and rupture of plaques14; improving vascular endothelial function1; reducing left ventricular hypertrophy; and enhancing fibrinolysis.1

We also observed a reduction in the incidence of heart failure in patients with no evidence of impairment of left ventricular systolic dysfunction. These data complement those of a study of patients with a low ejection fraction15 and studies of patients after myocardial infarction,1,2,3,7,16,17 which demonstrated that treatment with angiotensin-converting-enzyme inhibitors prevents heart failure, and the studies of patients with documented low ejection fractions and heart failure, which indicated that angiotensin-converting-enzyme inhibitors reduced the rate of hospitalization for heart failure.17 Both these results and our findings suggest that angiotensin-converting-enzyme inhibitors will be beneficial for patients who are at high risk for heart failure, irrespective of the degree of left ventricular systolic dysfunction.
We believe that the extent to which our results may have been affected by the inclusion of patients with undiagnosed low ejection fractions is very small, because a large substudy of 496 consecutive patients at three centers indicated that only 2.6 percent had an ejection fraction of less than 0.40, an extensive review of charts identified only 8.1 percent of patients with a low ejection fraction before randomization, and treatment was clearly beneficial in the subgroup of 4772 patients who were documented to have preserved ventricular function (relative risk, 0.73; 95 percent confidence interval, 0.63 to 0.84; P<0.001) and in those with no history of myocardial infarction (relative risk, 0.77; 95 percent confidence interval, 0.65 to 0.91; P=0.002).

We observed a marked reduction in the incidence of complications related to diabetes and new cases of diabetes. These effects may be mediated by improved insulin sensitivity, a decrease in hepatic clearance of insulin, an antiinflammatory effect, improved blood flow to the pancreas,18 or an effect on abdominal fat.19 The results are also consistent with the results of the recent Captopril Prevention Project study,20 which indicated a lower rate of newly diagnosed diabetes in patients who were randomly assigned to receive captopril than in those who were assigned to receive a diuretic or beta-blocker, and with the results of other trials, which reported that treatment with an angiotensin-converting-enzyme inhibitor slowed the progression of nephropathy among patients with type 2 diabetes21 as well as those without diabetes.22 Our findings clearly demonstrate that ramipril, a long-acting angiotensin-converting-enzyme inhibitor, reduces the rates of death, myocardial infarction, stroke, revascularization, cardiac arrest, heart failure, complications related to diabetes, and new cases of diabetes in a broad spectrum of high-risk patients. Treating 1000 patients with ramipril for four years prevents about 150 events in approximately 70 patients.

Funded by the Medical Research Council of Canada, Hoechst-Marion Roussel, AstraZeneca, King Pharmaceuticals, Natural Source Vitamin E Association and Negma, and the Heart and Stroke Foundation of Ontario. Dr. Yusuf was supported by a Senior Scientist Award of the Medical Research Council of Canada and a Heart and Stroke Foundation of Ontario Research Chair.
We are indebted to N. Bender, B. Rangoonwala, A. Ljunggren, G. Olsson, W. Whitehill, J.C. Dairon, J. Ghadiali, B. Carter, J.P. St. Pierre, W. Schulz, M. Jensen, L. Rios-Nogales, M. Bravo, J. Bourgouin, C. Vint-Reed, and F. Schutze for support and to Karin Dearness for secretarial help. * The investigators are listed in the Appendix.


Source Information

The writing group (Salim Yusuf, D.Phil., Peter Sleight, D.M., Janice Pogue, M.Sc., Jackie Bosch, M.Sc., Richard Davies, Ph.D., and Gilles Dagenais, M.D.) assumes responsibility for the overall content and integrity of the manuscript.
Address reprint requests to Dr. Salim Yusuf at the Canadian Cardiovascular Collaboration Project Office, Hamilton General Hospital, 237 Barton St. E., Hamilton, ON L8L 2X2, Canada, or at hope@ccc.mcmaster.ca.




Diabetes Prevention Program ( DDP )

Reduction in the Incidence of Type 2 Diabetes with Lifestyle Intervention or Metformin

Diabetes Prevention Program Research Group


ABSTRACT

Background Type 2 diabetes affects approximately 8 percent of adults in the United States. Some risk factors - elevated plasma glucose concentrations in the fasting state and after an oral glucose load, overweight, and a sedentary lifestyle - are potentially reversible. We hypothesized that modifying these factors with a lifestyle-intervention program or the administration of metformin would prevent or delay the development of diabetes. Methods We randomly assigned 3234 nondiabetic persons with elevated fasting and post-load plasma glucose concentrations to placebo, metformin (850 mg twice daily), or a lifestyle-modification program with the goals of at least a 7 percent weight loss and at least 150 minutes of physical activity per week. The mean age of the participants was 51 years, and the mean body-mass index (the weight in kilograms divided by the square of the height in meters) was 34.0; 68 percent were women, and 45 percent were members of minority groups. Results The average follow-up was 2.8 years. The incidence of diabetes was 11.0, 7.8, and 4.8 cases per 100 person-years in the placebo, metformin, and lifestyle groups, respectively. The lifestyle intervention reduced the incidence by 58 percent (95 percent confidence interval, 48 to 66 percent) and metformin by 31 percent (95 percent confidence interval, 17 to 43 percent), as compared with placebo; the lifestyle intervention was significantly more effective than metformin. To prevent one case of diabetes during a period of three years, 6.9 persons would have to participate in the lifestyle-intervention program, and 13.9 would have to receive metformin. Conclusions Lifestyle changes and treatment with metformin both reduced the incidence of diabetes in persons at high risk. The lifestyle intervention was more effective than metformin. Type 2 diabetes mellitus, formerly called non-insulin-dependent diabetes mellitus, is a serious, costly disease affecting approximately 8 percent of adults in the United States.1 Treatment prevents some of its devastating complications2,3 but does not usually restore normoglycemia or eliminate all the adverse consequences. The diagnosis is often delayed until complications are present.4 Since current methods of treating diabetes remain inadequate, prevention is preferable. The hypothesis that type 2 diabetes is preventable5,6 is supported by observational studies and two clinical trials of diet, exercise, or both in persons at high risk for the disease7,8 but not by studies of drugs used to treat diabetes.5 The validity of generalizing the results of previous prevention studies is uncertain.9 Interventions that work in some societies may not work in others, because social, economic, and cultural forces influence diet and exercise. This is a special concern in the United States, where there is great regional and ethnic diversity in lifestyle patterns and where diabetes is especially frequent in certain racial and ethnic groups, including American Indians, Hispanics, African Americans, Asians, and Pacific Islanders.10 The Diabetes Prevention Program Research Group conducted a large, randomized clinical trial involving adults in the United States who were at high risk for the development of type 2 diabetes. The study was designed to answer the following primary questions: Does a lifestyle intervention or treatment with metformin, a biguanide antihyperglycemic agent, prevent or delay the onset of diabetes? Do these two interventions differ in effectiveness? Does their effectiveness differ according to age, sex, or race or ethnic group?


Methods

We conducted a clinical trial involving persons at 27 centers who were at high risk for diabetes. The methods have been described in detail elsewhere,6 and the protocol is available at http://www.bsc.gwu.edu/dpp. The institutional review board at each center approved the protocol, and all participants gave written informed consent.


Participants

Eligibility criteria included an age of at least 25 years, a body-mass index (the weight in kilograms divided by the square of the height in meters) of 24 or higher (22 or higher in Asians), and a plasma glucose concentration of 95 to 125 mg per deciliter (5.3 to 6.9 mmol per liter) in the fasting state ( 125 mg per deciliter in the American Indian clinics) and 140 to 199 mg per deciliter (7.8 to 11.0 mmol per liter) two hours after a 75-g oral glucose load. These concentrations are elevated but are not diagnostic of diabetes according to the 1997 criteria of the American Diabetes Association.11 Before June 1997, the criterion for plasma glucose in the fasting state was 100 to 139 mg per deciliter (5.6 to 7.7 mmol per liter), or 139 mg per deciliter in the American Indian clinics. Eligible persons were excluded if they were taking medicines known to alter glucose tolerance or if they had illnesses that could seriously reduce their life expectancy or their ability to participate in the trial. Recruitment was designed to enroll approximately half the participants from racial or ethnic minority groups. A four-step screening and recruitment process was developed to identify eligible participants.6,12,13


Interventions

Eligible participants were randomly assigned to one of three interventions: standard lifestyle recommendations plus metformin (Glucophage) at a dose of 850 mg twice daily, standard lifestyle recommendations plus placebo twice daily, or an intensive program of lifestyle modification. The study initially included a fourth intervention, troglitazone, which was discontinued in 1998 because of the drug's potential liver toxicity.6 The results in the troglitazone group are not reported here.

Treatment with metformin was initiated at a dose of 850 mg taken orally once a day, with placebo tablets also given once a day initially. At one month, the dose of metformin was increased to 850 mg twice daily, unless gastrointestinal symptoms warranted a longer titration period. The initiation of treatment with half a tablet was optional. Adherence to the treatment regimen was assessed quarterly on the basis of pill counts and structured interviews. The standard lifestyle recommendations for the medication groups were provided in the form of written information and in an annual 20-to-30-minute individual session that emphasized the importance of a healthy lifestyle. Participants were encouraged to follow the Food Guide Pyramid14 and the equivalent of a National Cholesterol Education Program Step 1 diet,15 to reduce their weight, and to increase their physical activity.

The goals for the participants assigned to the intensive lifestyle intervention were to achieve and maintain a weight reduction of at least 7 percent of initial body weight through a healthy low-calorie, low-fat diet and to engage in physical activity of moderate intensity, such as brisk walking, for at least 150 minutes per week. A 16-lesson curriculum covering diet, exercise, and behavior modification was designed to help the participants achieve these goals. The curriculum, taught by case managers on a one-to-one basis during the first 24 weeks after enrollment, was flexible, culturally sensitive, and individualized. Subsequent individual sessions (usually monthly) and group sessions with the case managers were designed to reinforce the behavioral changes.


Outcome Measures

The primary outcome was diabetes, diagnosed on the basis of an annual oral glucose-tolerance test or a semiannual fasting plasma glucose test, according to the 1997 criteria of the American Diabetes Association: a value for plasma glucose of 126 mg per deciliter (7.0 mmol per liter) or higher in the fasting state or 200 mg per deciliter (11.1 mmol per liter) or higher two hours after a 75-g oral glucose load.11 In addition to the semiannual measurements, fasting plasma glucose was measured if symptoms suggestive of diabetes developed. The diagnosis required confirmation by a second test, usually within six weeks, according to the same criteria. If diabetes was diagnosed, the participants and their physicians were informed and glucose-tolerance tests were discontinued, but fasting plasma glucose was measured every six months, with glycosylated hemoglobin measured annually. As long as the fasting plasma glucose concentration was less than 140 mg per deciliter, participants were asked to monitor their blood glucose and to continue their assigned study treatment. If the fasting plasma glucose concentration reached or exceeded 140 mg per deciliter, the study medication was discontinued and the participant was referred to his or her physician for treatment. Measurements of glucose and glycosylated hemoglobin (HbA1c) were performed centrally. All tests were performed without interrupting the assigned treatment, except that placebo or metformin was not taken on the morning of the test. The investigators and the participants were unaware of the results of these measurements and were informed only if the results exceeded the specified threshold for a change in the treatment.

Self-reported levels of leisure physical activity were assessed annually with the Modifiable Activity Questionnaire.16 The physical-activity level was calculated as the product of the duration and frequency of each activity (in hours per week), weighted by an estimate of the metabolic equivalent of that activity (MET) and summed for all activities performed, with the result expressed as the average MET-hours per week for the previous year. Usual daily caloric intake during the previous year, including calories from fat, carbohydrate, protein, and other nutrients, was assessed at base line and at one year with the use of a modified version of the Block food-frequency questionnaire.17


Statistical Analysis and Early Closure

Random treatment assignments were stratified according to the clinical center. Assignments to metformin and placebo were double-blinded. The study design and analysis followed the intention-to-treat principle. Nominal (unadjusted) P values and confidence intervals are reported.
The blinded treatment phase was terminated one year early, in May 2001, on the advice of the data monitoring board, on the basis of data obtained through March 31, 2001, the closing date for this report. By then, we had obtained evidence of efficacy on the basis of 65 percent of the planned person-years of observation. To maintain a type I error level of 0.05 for significance in pairwise comparisons of the risk of diabetes between groups, with adjustment for repeated interim analyses, the group-sequential log-rank test18 required a P value of less than 0.0159. For pairwise comparisons of other outcomes, a Bonferroni-adjusted criterion of P<0.0167 was used. The study design provided 90 percent power to detect a 33 percent reduction from an incidence of 6.5 cases of diabetes per 100 person-years, with a 10 percent rate of loss to follow-up per year.

The time to the outcome was assessed with the use of life-table methods.19 Modified product-limit curves for the cumulative incidence of diabetes were compared with the use of the log-rank test. The estimated cumulative incidence at three years and the Greenwood estimate of the standard error were used to calculate the number of persons who would need to be treated in order to prevent one case of confirmed diabetes during a period of three years and the associated 95 percent confidence interval. Risk reduction, heterogeneity among strata, and interactions between treatment assignments and covariates were assessed by proportional-hazards regression. Fixed-effects models with the assumption of normally distributed errors20 were used to assess differences over time in body weight and plasma glucose and glycosylated hemoglobin values among the three groups.


Results
Study Cohort and Follow-up

From 1996 to 1999, we randomly assigned 3234 study participants to one of the three interventions (1082 to placebo, 1073 to metformin, and 1079 to the intensive lifestyle intervention). Base-line characteristics, including all measured risk factors for diabetes, were similar among the three study groups (Table 1). 12 The participants were followed for an average of 2.8 years (range, 1.8 to 4.6). At the close of the study, 99.6 percent of the participants were alive, of whom 92.5 percent had attended a scheduled visit within the previous five months.


Adherence to Interventions

Fifty percent of the participants in the lifestyle-intervention group had achieved the goal of weight loss of 7 percent or more by the end of the curriculum (at 24 weeks), and 38 percent had a weight loss of at least 7 percent at the time of the most recent visit; the proportion of participants who met the goal of at least 150 minutes of physical activity per week (assessed on the basis of logs kept by the participants) was 74 percent at 24 weeks and 58 percent at the most recent visit. Dietary change was assessed only at one year. Daily energy intake decreased by a mean (±SE) of 249±27 kcal in the placebo group, 296±23 kcal in the metformin group, and 450±26 kcal in the lifestyle-intervention group (P<0.001). Average fat intake, which was 34.1 percent of total calories at base line, decreased by 0.8±0.2 percent in the placebo and metformin groups and by 6.6±0.2 percent in the lifestyle-intervention group (P<0.001). The proportion of participants who took at least 80 percent of the prescribed dose of the study medication was slightly higher in the placebo group than in the metformin group (77 percent vs. 72 percent, P<0.001). Ninety-seven percent of the participants taking placebo and 84 percent of those taking metformin were given the full dose of one tablet (850 mg in the case of metformin) twice a day; the remainder were given one tablet a day to limit side effects.

Changes in weight and leisure physical activity in all three groups and adherence to the medication regimen in the metformin and placebo groups are shown in Figure 1. Participants assigned to the lifestyle intervention had much greater weight loss and a greater increase in leisure physical activity than did participants assigned to receive metformin or placebo. The average weight loss was 0.1, 2.1, and 5.6 kg in the placebo, metformin, and lifestyle-intervention groups, respectively (P<0.001).


Figure 1. Changes in Body Weight (Panel A) and Leisure Physical Activity (Panel B) and Adherence to Medication Regimen (Panel C) According to Study Group.

Each data point represents the mean value for all participants examined at that time. The number of participants decreased over time because of the variable length of time that persons were in the study. For example, data on weight were available for 3085 persons at 0.5 year, 3064 at 1 year, 2887 at 2 years, and 1510 at 3 years. Changes in weight and leisure physical activity over time differed significantly among the treatment groups (P<0.001 for each comparison).


Incidence of Diabetes

The cumulative incidence of diabetes was lower in the metformin and lifestyle-intervention groups than in the placebo group throughout the follow-up period (Figure 2). The crude incidence was 11.0, 7.8, and 4.8 cases per 100 person-years for the placebo, metformin, and lifestyle-intervention groups, respectively (Table 2). The incidence of diabetes was 58 percent lower (95 percent confidence interval, 48 to 66 percent) in the lifestyle-intervention group and 31 percent lower (95 percent confidence interval, 17 to 43 percent) in the metformin group than in the placebo group. The incidence of diabetes was 39 percent lower (95 percent confidence interval, 24 to 51 percent) in the lifestyle-intervention group than in the metformin group. The results of all three pairwise group comparisons were statistically significant by the group-sequential log-rank test. None of these results were materially affected by adjustment for base-line characteristics. The estimated cumulative incidence of diabetes at three years was 28.9 percent, 21.7 percent, and 14.4 percent in the placebo, metformin, and lifestyle-intervention groups, respectively. On the basis of these rates, the estimated number of persons who would need to be treated for three years to prevent one case of diabetes during this period is 6.9 (95 percent confidence interval, 5.4 to 9.5) for the lifestyle intervention and 13.9 (95 percent confidence interval, 8.7 to 33.9) for metformin.


Figure 2. Cumulative Incidence of Diabetes According to Study Group. The diagnosis of diabetes was based on the criteria of the American Diabetes Association.11 The incidence of diabetes differed significantly among the three groups (P<0.001 for each comparison).


Table 2. Incidence of Diabetes


Treatment Effects among Subgroups

Incidence rates and risk reductions within subgroups of participants and the results of tests of the homogeneity of risk reduction among subgroups are shown in Table 2; 95 percent confidence intervals for the subgroup data indicate the precision of the risk-reduction estimate for each stratum. The study had inadequate power to assess the significance of effects within the subgroups, nor were such tests planned. Significant heterogeneity indicates that treatment effects differed according to the values of the covariates. Treatment effects did not differ significantly according either to sex or to race or ethnic group (Table 2). The lifestyle intervention was highly effective in all subgroups. Its effect was significantly greater among persons with lower base-line glucose concentrations two hours after a glucose load than among those with higher base-line glucose values. The effect of metformin was less with a lower body-mass index or a lower fasting glucose concentration than with higher values for those variables. Neither interaction was explained by the other variable or by age. The advantage of the lifestyle intervention over metformin was greater in older persons and those with a lower body-mass index than in younger persons and those with a higher body-mass index.


Glycemic Changes

In the first year, there was a similar reduction in the mean fasting plasma glucose values in the metformin and lifestyle-intervention groups, whereas the values rose in the placebo group (Figure 3). The values rose in parallel in all three groups in subsequent years. There was a similar temporal pattern in the values for glycosylated hemoglobin, except that the values in the metformin group were in between those in the lifestyle-intervention and placebo groups. Figure 4 shows the percentage of participants who had normal glucose concentrations (fasting values, post-load values, and both) at each annual examination. Metformin and the lifestyle intervention were similarly effective in restoring normal fasting glucose values, but the lifestyle intervention was more effective in restoring normal post-load glucose values.


Figure 3. Fasting Plasma Glucose Concentrations (Panel A) and Glycosylated Hemoglobin Values (Panel B) According to Study Group.


The analysis included all participants, whether or not diabetes had been diagnosed. Changes in fasting glucose values over time in the three groups differed significantly (P<0.001). Glycosylated hemoglobin values in the three groups differed significantly from 0. 5 to 3 years (P<0.001). To convert the values for glucose to millimoles per liter, multiply by 0.05551.


Figure 4. Participants with Normal Plasma Glucose Values, According to Study Group.


Panel A shows the proportions of participants with normal glucose values in the fasting state (<110 mg per deciliter [6.1 mmol per liter]), Panel B the proportions with normal values two hours after an oral glucose load (<140 mg per deciliter [7.8 mmol per liter]), and Panel C the proportions with normal values for both measurements. Persons in whom a diagnosis of diabetes had been made were considered to have abnormal values, regardless of the actual values at the time. By design, no participants had normal post-load glucose values at base line, but base-line fasting glucose values were normal in 67 percent of persons in the placebo group, 67 percent of those in the metformin group, and 68 percent of those in the lifestyle-intervention group. Metformin and lifestyle intervention were similarly effective in restoring normal fasting glucose concentrations, but lifestyle intervention was more effective in restoring normal post-load glucose concentrations.


Adverse Events

The rate of gastrointestinal symptoms was highest in the metformin group, and the rate of musculoskeletal symptoms was highest in the lifestyle-intervention group (Table 3). Hospitalization and mortality rates were unrelated to treatment. No deaths were attributed to the study intervention.


Discussion

Our results support the hypothesis that type 2 diabetes can be prevented or delayed in persons at high risk for the disease. The incidence of diabetes was reduced by 58 percent with the lifestyle intervention and by 31 percent with metformin, as compared with placebo. These effects were similar in men and women and in all racial and ethnic groups. The intensive lifestyle intervention was at least as effective in older participants as it was in younger participants. The results of our study extend previous data showing that lifestyle interventions can reduce the incidence of diabetes7,8 and demonstrate the applicability of this finding to the ethnically and culturally diverse population of the United States. The risk reduction associated with the lifestyle intervention in our study was the same as that in a study conducted in Finland,8 and was higher than the reductions associated with diet (31 percent), exercise (46 percent), and diet plus exercise (42 percent) in a study in China.7
Our lifestyle intervention was systematic and intensive, with the study participants receiving detailed, individualized counseling. The study, however, was not designed to test the relative contributions of dietary changes, increased physical activity, and weight loss to the reduction in the risk of diabetes, and the effects of these components remain to be determined.

The incidence of diabetes in our placebo group (11.0 cases per 100 person-years) was higher than we had anticipated6 and was higher than the incidence in observational studies,21 perhaps owing to the greater frequency of glucose testing or to the selection of persons at higher risk in our study. The incidence of diabetes in the placebo group was similar among racial and ethnic groups despite differences in these subgroups in observational, population-based studies.10 Racial and ethnic-group differences in the incidence of diabetes were presumably reduced in our study by the selection of persons who were overweight and had elevated fasting and post-load glucose concentrations - three of the strongest risk factors for diabetes.
Previous studies have not demonstrated that drugs used to treat diabetes are effective for its prevention, perhaps because of small samples and the lack of data on adherence to the prescribed regimens.5 In contrast, metformin was effective in our study, although less so than the lifestyle intervention. Metformin was less effective in persons with a lower base-line body-mass index or a lower fasting plasma glucose concentration than in those with higher values for these variables. The reduction in the average fasting plasma glucose concentration was similar in the lifestyle-intervention and metformin groups, but the lifestyle intervention had a greater effect than metformin on glycosylated hemoglobin, and a larger proportion of participants in the lifestyle-intervention group had normal post-load glucose values at follow-up. These findings are consistent with the observation that metformin suppresses endogenous glucose production, the main determinant of fasting plasma glucose concentrations.22

Rates of adverse events, hospitalization, and mortality were similar in the three groups, except that the rate of gastrointestinal symptoms was highest in the metformin group and the rate of musculoskeletal symptoms was highest in the lifestyle-intervention group. Thus, the interventions were safe in addition to being effective.
An estimated 10 million persons in the United States resemble the participants in the Diabetes Prevention Program in terms of age, body-mass index, and glucose concentrations, according to data from the third National Health and Nutrition Examination Survey.23 If the study's interventions were implemented among these people, there would be a substantial reduction in the incidence of diabetes. Ultimately, the benefits would depend on whether glucose concentrations could be maintained at levels below those that are diagnostic of diabetes and whether the maintenance of these lower levels improved the long-term outcome. These questions should be addressed by continued follow-up of the study participants and by analysis of the main secondary outcomes - reductions in risk factors for cardiovascular disease, in the proportion of participants with atherosclerosis, and in the proportion with cardiovascular disease, which is the leading cause of death among patients with type 2 diabetes.24,25 Optimal approaches to identifying candidates for preventive measures remain to be determined. Although elevation of either the fasting or the post-load glucose concentration strongly predicts diabetes,26,27 both were required for eligibility in this study. Whether the results would be similar in persons with an isolated elevation of the fasting or post-load glucose concentration or other risk factors for diabetes is likely but unknown.

In summary, our study showed that treatment with metformin and modification of lifestyle were two highly effective means of delaying or preventing type 2 diabetes. The lifestyle intervention was particularly effective, with one case of diabetes prevented per seven persons treated for three years. Thus, it should also be possible to delay or prevent the development of complications, substantially reducing the individual and public health burden of diabetes.
Supported by the National Institutes of Health through the National Institute of Diabetes and Digestive and Kidney Diseases, the Office of Research on Minority Health, the National Institute of Child Health and Human Development, and the National Institute on Aging; the Indian Health Service; the Centers for Disease Control and Prevention; the General Clinical Research Center Program, National Center for Research Resources; the American Diabetes Association; Bristol-Myers Squibb; and

Parke-Davis. Dr. Hamman owns stock in Bristol-Myers Squibb, which sells metformin in the United States.
We are indebted to the participants in the study for their dedication to the goal of preventing diabetes; to Lipha Pharmaceuticals for the metformin and placebo; to LifeScan, Health-O-Meter, Hoechst Marion Roussel, Merck-Medco Managed Care, Merck, Nike, Slim-Fast Foods, and Quaker Oats for materials, equipment, and medicines for concomitant conditions; and to McKesson BioServices, Mathews Media Group, and the Henry M. Jackson Foundation for support services provided under subcontract with the Coordinating Center.
* The members of the Diabetes Prevention Program Research Group are listed in the Appendix.


Source Information

The writing group (William C. Knowler, M.D., Dr.P.H., Elizabeth Barrett-Connor, M.D., Sarah E. Fowler, Ph.D., Richard F. Hamman, M.D., Dr.P.H., John M. Lachin, Sc.D., Elizabeth A. Walker, D.N.Sc., and David M. Nathan, M.D.) takes responsibility for the content of this article.
Address reprint requests to the Diabetes Prevention Program Coordinating Center, Biostatistics Center, George Washington University, 6110 Executive Blvd., Suite 750, Rockville, MD 20852.


References
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  22. DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med 1999;131:281-303.[ISI][Medline]
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The Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM)

The Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) study is a large-scale, international, multi-centre, randomised, double-blind, controlled, 2x2 factorial design trial which aims to determine if treatment with an ACE inhibitor (ramipril) and/or a thiazolidinedione (rosiglitazone) can delay or prevent the development of type 2 diabetes (T2DM) in people with impaired glucose tolerance (IGT). Recruitment, which commenced in July 2001, will continue until July 2003 aiming to randomise 4000 subjects. Participants will be followed for a minimum of three years with regular assessment to ascertain the occurrence of the primary outcome (new onset T2DM or all cause mortality) as well as predefined secondary outcomes. The study is co-ordinated by the Canadian Cardiovascular Collaboration (CCC) at McMaster University, Hamilton,Canada. European centres are managed by the EuroDREAM project office (see contact details below) at the Diabetes Trials Unit, Oxford Centre for Diabete, Endocrinology & Metabolism, Oxford, UK.


Background

The prevalence of type 2 diabetes mellitus (T2DM) is increasing rapidly with 221 million cases predicted world-wide by the year 2010. As well as increasing the risk of cardiovascular disease (CVD) two to four fold, T2DM is the leading cause of blindness in working age adults, end-stage renal disease and non-traumatic lower extremity amputations. People with dysglycaemia, especially those with impaired glucose tolerance (IGT), are at increased risk of developing both CVD and T2DM. Recent studies, inclduing the DPP, STOP-NIDDM and Finnish DPS, have shown that treating IGT subjects with lifestyle measures, acarbose or metformin can reduce their risk of developing T2DM.


Rationale

The DREAM study is investigating whether treatment with an ACE inhibitor (ramipril) and/or a thiazolidinedione (rosiglitazone) can delay or prevent the development of T2DM. These two agents are of paricular interest as a post hoc analysis of the HOPE study has suggested that ramipril may delay the onset of diabetes whilst the TRIPOD study showed that a reduced rate of progression to diabetes in women given the thiazolidinedione troglitazone subsequent to a diagnosis of gestational diabetes mellitus. Ramipril, which has direct effects on the rennin-angiotensin-kallikrein system, may prevent diabetes through effects on the beta cell and by vascular and metabolic effects on muscle (partially mediated by nitric oxide) that may amplify the effects of insulin. Rosiglitazone improves insulin sensitivity and may have a beta cell cytoprotective effect but does not appear to directly affect the rennin-angiotensin-kallikrein system. As the mechanisms by which either drug may prevent diabetes differ, they are unlikely to interact during a clinical trial and indeed may be complementary.


Subjects

A two year recruitment period aims to randomise 4000 individuals at high risk for T2DM. To be included, subjects must be aged 30 or older and have IGT i.e. a 2 hour plasma glucose post 75 g glucose challenge of 7.8 to 11.0 mmol/L (140 to 199 mg/dl) inclusive.


Key exclusion criteria include:
  • Current use of ACE inhibitors and/or thiazolidinediones
  • Known hypersensitivity to either study medication
  • Prior use of antidiabetic medications except during pregnancy
  • Use of systemic glucocorticoids or niacins
  • Low ejection fraction, uncontrolled hypertension
  • History of diabetes
  • Renal disease
  • Hepatic disease
  • Randomisation
  • Eligible subjects will be randomised in a 2x2 factorial manner to double-blind study medication with:
  • ramipril or matching placebo and, simultaneously, to:
  • rosiglitazone or matching placebo.

  Ramipril
Arm
 
Rosiglitazone
Arm
1,000
ramipril
rosiglitazone
1,000
placebo
rosiglitazone
2,000
rosiglitazone
1,000
ramipril
placebo
1,000
placebo
placebo
2,000
placebo
  2,000
ramipril
2,000
placebo
4,000
subjects
in total

Three Year Follow-Up

All subjects will be followed up for at least 3 years including any who discontinue study medication. Measurements taken at specified visits will include FPG, OGTT, ALT, potassium, creatinine, HbA1c, urinary albumin/creatinine ratio, heart rate, blood pressure, ankle pressure and ECG. Reports of any hospitalisation, death, surgery, or serious adverse events will be collected at every visit.


Study Management and Funding

The DREAM study is an international trial co-ordinated by the Canadian Cardiovascular Collaboration (CCC) at McMaster University, Hamilton, Canada. European centres are managed by the EuroDREAM project office at the Diabetes Trials Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism. The study is funded jointly by the Canadian Institutes of Health Research, Aventis Pharma, King Pharmaceuticals and GlaxoSmithKline.




Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)

Reactions to the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) results from researchers around the world -- and subsequent replies by ALLHAT steering committee members -- have been published together in one issue of JAMA. In the April 23 issue, Jackson T. Wright, Jr, MD, PhD (Case Western Reserve University School of Medicine, Cleveland, Ohio), Barry R. Davis, MD, PhD (University of Texas-Houston Health Science Center, Houston), and Jeffrey A. Cutler, MD (National Heart, Lung, and Blood Institute, Baltimore, Maryland) respond to criticisms and comments on the blood pressure-lowering component of ALLHAT.


Definition of Heart Failure Questioned

Dr. Wright and colleagues particularly reject criticism that the definition of heart failure for ALLHAT was "unduly influential" in the results. In a joint communication, Christopher R. Palmer, PhD, and Morris J. Brown, MD (University of Cambridge, UK), Giuseppe Mancia, MD (University of Milan, Italy), and Luis M. Ruilope, MD (University of Madrid, Spain) maintain that the ALLHAT authors "inappropriately emphasized their results for heart failure, although it was only 1 component of a secondary composite outcome."[3] They point out that the diuretic chlorthalidone, which ALLHAT concluded was the preferred treatment for hypertension, did worse in terms of the primary event rate (11.5% vs 11.3% for amlodipine or 11.4% for lisinopril) and all-cause mortality (17.1% vs 16.5% or 17.0%, respectively). All these endpoints are worthy of more attention than heart failure, which is difficult to diagnose, Dr. Palmer and coauthors maintain. They point to the reported 85% agreement rate for heart failure between the ALLHAT subcommittee and clinical investigators, suggesting that this "represents considerable disagreement," perhaps indicating that the investigators were counting events rather then individuals.

Dr. Palmer and coauthors were all participants in the International Nifedipine GITS Study: Intervention as a Goal in Hypertension Treatment (INSIGHT) trial, a European study that compared the long-acting calcium channel blocker, nifedipine GITS, with the diuretic combination, co-amilozide (hydrochlorothiazide plus amiloride), in hypertensive patients aged >/=55 years.INSIGHT reported that the 2 treatments had similar effects on blood pressure lowering and on primary outcomes of cardiovascular death, MI, heart failure, or stroke, and concluded that "blood pressure, not drug choice, matters," contrary to the message of ALLHAT. The INSIGHT authors note that the incidence of heart failure in INSIGHT was only one tenth that reported in ALLHAT, and classification of nonfatal heart failures as secondary endpoints, as was done in ALLHAT, would have only strengthened their study's conclusion.

The ALLHAT researchers reject the criticisms of the INSIGHT investigators, pointing out that heart failure is the leading cause of hospitalization in the United States and therefore a key secondary outcome. Acknowledging that heart failure events were not designed to be centrally reviewed in the original protocol, Dr. Wright and colleagues note that when large differences were seen between the treatment groups, a staged review was set up of the hospitalized and fatal cases (81% of heart failure cases). These data are being prepared for publication. They also note that ALLHAT enrolled a high-risk population of hypertensive patients. In ALLHAT, 2-year mortality was 20% after diagnosis of heart failure, "certainly more than 'ankle edema'," they remark. They suggest that rather than overdiagnosis in ALLHAT, heart failure might have been underreported in INSIGHT.


Side Effects: New-Onset Diabetes, Suicide Risk, Decreased Tolerance?

Franz Messerli, MD (Ochsner Clinic Foundation, New Orleans, Louisiana) and Michael Weber, MD (SUNY Downstate Medical College, Brooklyn, New York) make the point that although about 10% of all patients in ALLHAT developed new diabetes (fasting blood sugar > 126 mg/dL), the risk of developing diabetes in patients on chlorthalidone was 43% to 65% higher than those on lisinopril and 18% to 30% higher than those on amlodipine. Although the ALLHAT report concluded that this difference did not translate into more cardiovascular events or higher all-cause mortality in the chlorthalidone group, Drs. Messerli and Weber say that the long-term sequelae of the high risk of diabetes may not have developed during the 2-6 years of follow-up in ALLHAT. Since antihypertensive therapy is life-long, it may be better to avoid thiazide-type diuretics, or at least as monotherapy in hypertensive patients at risk for diabetes, they suggest. Dr. Wright and colleagues reply that the incidence of new-onset diabetes in ALLHAT was actually 11.6%, 9.8%, and 8.1% in the chlorthalidone, amlodipine, and lisinopril groups, respectively, and stress that mean follow-up was 4.9 years (range, 4-8 years). "It would be hazardous to project outcomes beyond this period," they declare. They suggest, however, that before any consequences of a 3.5% difference in the incidence of diabetes occurred, a large number of other cardiovascular outcomes might be possible.

The small but statistically significant higher absolute risk of unintentional injury, suicide, or homicide among patients on chlorthalidone vs those on amlodipine is highlighted by William Rifkin, MD (Maimonides Medical Center, Brooklyn, New York). This risk was twice as high in patients randomized to the diuretic as in those randomized to the calcium channel blocker. The difference in risk between chlorthalidone and lisinopril showed a trend in the same direction. Dr. Rifkin suggests that further analysis of "this intriguing finding" might be useful. The ALLHAT authors reply that further analysis will be considered, although they "doubt that it will be fruitful."

Steven A. Yarows, MD (University of Michigan Health System, Ann Arbor), suggests that the reported decreased drug tolerance with lisinopril compared with chlorthalidone in ALLHAT may have been the result of increased usage of secondary agents with higher adverse effects. Dr. Wright and colleagues reply that this possibility cannot be excluded, but on the basis of drug initiation and discontinuation data, it seems unlikely that more patients in the lisinopril group would stop their blinded agent yet remain on add-on drugs with postulated side effects.


ALLHAT Patient Population: Special Characteristics

Taishiro Chikamori, MD (Tokyo Medical University, Tokyo, Japan), points out that more than half the patients (52%) in ALLHAT had preexisting atherosclerotic cardiovascular disease and that there therefore might have been a significant confounding effect of baseline ejection fraction on the primary and secondary endpoints. The ALLHAT authors reply that the percentage of patients with atherosclerotic disease was less than in the Heart Outcomes Prevention Evaluation (HOPE) trial (80%), and that although LV function was not assessed at baseline in ALLHAT, patients with a history of heart failure or LV ejection fraction of < 35% were excluded from the trial. The results of ALLHAT may not be generalizable to a significant proportion of patients with hypertension, according to Jan Laws Houghton, MD (Albany Medical College and Center, Albany, New York). Many of the ALLHAT patients may have salt-sensitive hypertension, for which diuretic therapy would be particularly efficacious. Patients aged < 55 years, who were eligible for ALLHAT, would be less likely to have salt-sensitive disease or evidence of cardiovascular disease, Dr. Houghton notes. While referring to Dr. Houghton's point as "interesting," the ALLHAT authors reply that diuretics have been shown to be beneficial in many subgroups of patients, including younger patients. They stress that the ALLHAT results were mainly consistent among subgroups defined by age, diabetic status, and race.


Renal Function Data

HT Ong, FRCP (HT Ong Heart Clinic, Penang, Malaysia), points to a contradiction in ALLHAT, where glomerular filtration rate (GFR) was best preserved in the patients on amlodipine and declined most in those on chlorthalidone, but this finding was dismissed on the basis of data from the African-American Study of Kidney Disease and Hypertension (AASK) trial. Dr. Ong points out that in AASK, the effect of amlodipine was dependent on the degree of baseline proteinuria. He suggests that patients with hypertensive nephropathy but no significant proteinuria may best be treated with amlodipine, then with an ACE inhibitor when proteinuria subsides to a protein-to-creatinine ratio > 0.22. The ALLHAT investigators note that their patients were at relatively low risk for adverse renal outcomes and that calcium channel blockers in these patients may produce a hemodynamic increase in GFR that does not relate to long-term outcomes as renal function deteriorates. The renal outcomes data in high-risk subgroups will be published separately


Lipid-Lowering Therapy

In the same issue of JAMA, ALLHAT steering committee member Jeffery L. Probstfield, MD (University of Washington Medical Center, Seattle) responds to comments and questions about the lipid-lowering component of ALLHAT. In particular, he refutes a suggestion from William C. Taylor, MD (Beth Israel Deaconess Medical Center, Boston), that "the ALLHAT results confirm that a large proportion of people without known CHD [coronary heart disease] who take medication to lower cholesterol will derive no benefit." Dr. Taylor cites evidence that cholesterol-lowering medications are potentially harmful and states that despite current recommendations,[18] there is no evidence to support prescribing cholesterol-lowering drugs in patients without known CHD, such as young men, elderly men, and women of all ages. Dr. Probstfield reiterates that although the ALLHAT results provided no independent evidence that statin treatment is beneficial in older hypertensive, moderately hypercholesterolemic patients, like another JAMA correspondent, the ALLHAT investigators believe that the disparity between their results and those of similar, long-term, placebo-controlled statin trials, which showed reductions in mortality and CHD events, is due to the far smaller cholesterol difference between the treated and controlled (usual care) patients. The ALLHAT investigators recommend that their results be viewed in the context of other statin trials as consistent with prior recommendations and guidelines on cholesterol lowering.

In answer to other questions, Dr. Probstfield acknowledges that C-reactive protein levels were not measured in ALLHAT, but suggests that they may have been no different from those seen in other, positive statin trials, and that they would not have accounted for the lack of a positive result in this part of the ALLHAT study. He also states that CHD reductions were similar in patients with total cholesterol/HDL cholesterol ratios above and below 5, disputing the suggestion that benefit from treatment may have varied according to this ratio.