Study Design

The study methods have been published previously.6,7 The study was conducted at 16 clinical sites in the United States (for details, see the Supplementary Appendix, available with the full text of this article at NEJM.org). It was designed and conducted by the authors, and all analyses were completed by the coordinating center. The study was approved by the institutional review board at each center. The trial was not blinded, but clinical assessors and end-point adjudicators were unaware of study-group assignments. The authors vouch for the accuracy and completeness of the data and all analyses and for the fidelity of this report to the trial protocol, available at NEJM.org.

The study was sponsored by the National Institutes of Health, with additional support from other federal partners and the clinical research centers of several participating institutions. None of the corporate supporters, listed below, had any role in the trial design, data analysis, or reporting of results.

Study Patients

To be eligible for participation in the trial, patients were required to be 45 to 75 years of age and to meet all the following criteria: self-reported type 2 diabetes, as verified by the use of glucose-lowering medication, a physician's report, or glucose levels; a body-mass index (the weight in kilograms divided by the square of the height in meters) of 25.0 or more (27.0 or greater in patients taking insulin); a glycated hemoglobin level of 11% or less; a systolic blood pressure of less than 160 mm Hg; a diastolic blood pressure of less than 100 mm Hg; a triglyceride level of less than 600 mg per deciliter (6.77 mmol per liter); the ability to complete a valid maximal exercise test, suggesting it was safe to exercise; and an established relationship with a primary care provider. Patients could be using any type of glucose-lowering medication, but the percentage of those receiving insulin allowed in the trial was limited to less than 30%. Patients with and those without a history of cardiovascular disease were included to increase the generalizability of the results. Additional eligibility criteria are described elsewhere6 and in the Supplementary Appendix.

Study Interventions

Eligible patients were randomly assigned to participate in an intensive lifestyle intervention (intervention group) or to receive diabetes support and education (control group), with stratification according to clinical site. Curricula for the two study groups were developed centrally and have been described in detail previously6,8 (see the Supplementary Appendix).

The intensive lifestyle intervention was aimed at achieving and maintaining weight loss of at least 7% by focusing on reduced caloric intake and increased physical activity. The program included both group and individual counseling sessions, occurring weekly during the first 6 months, with decreasing frequency over the course of the trial. Specific intervention strategies included a calorie goal of 1200 to 1800 kcal per day (with <30% of calories from fat and >15% from protein), the use of meal-replacement products, and at least 175 minutes of moderate-intensity physical activity per week. A toolbox of strategies was available for patients having difficulty achieving the weight-loss goals (see the Supplementary Appendix).

Diabetes support and education featured three group sessions per year focused on diet, exercise, and social support during years 1 through 4. In subsequent years, the frequency was reduced to one session annually.

All medication adjustments were made by the patient's health care provider, with the exception of temporary changes in glucose-lowering medications made by study staff to reduce the risk of hypoglycemia in the intervention group. Patients and their health care providers received annual reports on the patients' updated cardiovascular risk factors and the goals recommended by the American Diabetes Association.1

Study Assessments

At annual visits, certified staff members who were unaware of study-group assignments measured weight, waist circumference, and blood pressure, along with assessing medication use and obtaining blood for analysis at a central laboratory.6 Maximal-exercise tests were performed in the full cohort before randomization. Submaximal-exercise tests were performed in the full cohort at years 1 and 4 and in a subset of patients at year 2.

During annual visits and telephone calls every 6 months, staff members who were unaware of study-group assignments queried patients about all medical events and hospitalizations. These queries were augmented with searches of national databases for deaths. Hospital and other records were reviewed for potential cardiovascular events, with adjudication according to standard criteria by reviewers who were unaware of study-group assignments (see the Supplementary Appendix).

Study End Points

The primary end point was the first occurrence of a composite cardiovascular outcome. Initially, the composite outcome included death from cardiovascular causes, nonfatal myocardial infarction, and nonfatal stroke, and the anticipated maximal follow-up period was 11.5 years. During the first 2 years of the trial, the primary-event rate in the control group was lower than expected.9 Therefore, hospitalization for angina was added to the primary outcome, and planned follow-up was extended to a maximum of 13.5 years.

Three composite secondary cardiovascular outcomes were also examined: death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke (the original primary outcome); death from any cause, myocardial infarction, stroke, or hospitalization for angina; and death from any cause, myocardial infarction, stroke, hospitalization for angina, coronary-artery bypass grafting, percutaneous coronary intervention, hospitalization for heart failure, or peripheral vascular disease.

Statistical Analysis

We determined that an enrollment of 5000 patients would provide a power of more than 80% to detect a between-group difference of 18% in the rate of major cardiovascular events, with a two-sided alpha level of 0.05, a primary outcome rate of 2% per year in the control group, and a planned maximum follow-up of 13.5 years. The 18% between-group difference was chosen on the basis of reductions in mortality among patients with type 2 diabetes and voluntary weight loss in an observational study,10 effect sizes chosen for trials with similar outcomes,11 feasibility, and public health significance.

On September 14, 2012, on the basis of a futility analysis and recommendation from the data and safety monitoring board, the study's primary sponsors instructed the study investigators to terminate the intervention. All data were censored on this date. At that time, the probability of observing a significant positive result at the planned end of follow-up (i.e., a hazard ratio of 0.82 in the intervention group) was estimated to be 1%.

We used the chi-square test, Fisher's exact test, the Wilcoxon rank-sum test, two-sample t-tests, and Poisson regression to compare the baseline characteristics and key safety outcomes in the two study groups. Physical and laboratory measurements and medication use from baseline through 10 years were modeled with generalized linear regression and generalized estimating equations. The study center was included as a covariate, the covariance was unstructured, and linear contrasts were used to compare groups throughout follow-up. We performed analyses of primary and secondary outcomes using time-to-event methods according to the intention-to-treat principle, as prespecified in the protocol. Kaplan–Meier estimates were used to calculate the cumulative proportion of patients who had an event. First occurrences of primary and secondary outcomes in the two groups were compared with hazard ratios and 95% confidence intervals. Two-sided P values were calculated with likelihood-ratio tests from Cox proportional-hazards regression, with models containing terms for clinical site, history of cardiovascular disease, and study-group assignment. The consistency of intervention effects on the primary outcome among three prespecified subgroups (based on sex, race or ethnic group, and presence or absence of cardiovascular disease at baseline) was evaluated with the use of interaction tests. Results were not adjusted for multiple comparisons, and a P value of less than 0.05 was considered to indicate statistical significance. All statistical analyses were conducted with the use of S-Plus software, version 8.0 (Insightful), or SAS software, version 9.1 (SAS Institute).