The Look AHEAD Research Group | My Assignment Tutor

Cardiovascular Effects of Intensive Lifestyle Intervention in Type2 DiabetesThe Look AHEAD Research GroupAbstractBACKGROUND—Weight loss is recommended for overweight and obese individuals with type2 diabetes based on short-term studies, but long-term effects on cardiovascular disease remainunknown. We examined whether intensive lifestyle intervention for weight loss decreasedcardiovascular morbidity and mortality in overweight or obese adults with type 2 diabetes.METHODS—We randomly assigned 5,145 overweight or obese individuals with type 2 diabetesrecruited at 16 US centers to intensive lifestyle intervention (the intervention group), whichpromoted weight loss through decreased calorie intake and increased physical activity, or diabetessupport and education (the control group). The primary outcome was the first post-randomizationoccurrence of a composite cardiovascular outcome (cardiovascular death, non-fatal myocardialinfarction, non-fatal stroke, or hospitalized angina) over a planned maximum follow-up of 13.5years.RESULTS—The trial was stopped early based on a futility analysis when median follow-up was9.6 years. Weight loss was greater in the intervention group than the control group throughout(8.6% vs. 0.7% at 1 year; 6.0% vs. 3.5% at study end). Intensive lifestyle intervention alsoproduced greater reductions in hemoglobin A1c and greater initial improvements in fitness and allcardiovascular risk factors, except LDL cholesterol. The primary outcome occurred in 403 patientsin the intervention group and in 418 in the control group (1.83/100 person-years and 1.92/100person-years, respectively; hazard ratio 0.95; 95% CI 0.83 to 1.09, p=0.505).CONCLUSION—In our study, intensive lifestyle intervention focused on weight loss did notreduce cardiovascular events in overweight or obese adults with type 2 diabetes. (Funded by theDepartment of Health and Human Services and others; ClinicalTrials.gov number,NCT00017953.)Weight loss is recommended for overweight and obese individuals with type 2 diabetes.1This recommendation is based on short-term studies showing numerous benefits of weightloss, including improvements in glycemic control, cardiovascular disease risk factors,quality of life and other obesity-related comorbidities.2 However, it is unknown whetherweight loss reduces the risk of cardiovascular morbidity and mortality in individuals withtype 2 diabetes. Epidemiological studies in individuals with diabetes provide conflictingresults, perhaps due to confounding from unintentional weight loss.3 A recent metaanalysis4 of cohort studies concluded that moderate intentional weight loss was associatedwith reduced mortality in “unhealthy” individuals, which included individuals with diabetes.The Swedish Obesity Subjects (SOS) study (ClinicalTrials.gov number NCT01479452)reported lower cardiovascular event rates over a mean follow-up of 13.3 years in patientswith type 2 diabetes who underwent bariatric surgery;5 however, this was a non-randomizedstudy, and the results achieved through surgery cannot be generalized to other approaches toweight loss.Thus, a critical question remains: Does an intensive lifestyle intervention designed toproduce weight loss through caloric restriction and increased physical activity decreasecardiovascular morbidity and mortality in overweight and obese adults with type 2 diabetes? NIH Public AccessAuthor ManuscriptN Engl J Med. Author manuscript; available in PMC 2014 July 11. Published in final edited form as:N Engl J Med. 2013 July 11; 369(2): 145–154. doi:10.1056/NEJMoa1212914.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptLook AHEAD (Action for Health in Diabetes) addressed this question in a multicenterrandomized clinical trial.METHODSStudy DesignThe study methods have been published previously.6, 7 Look AHEAD was a randomizedtrial conducted at 16 clinical sites in the United States (see the Supplementary Appendix).The trial was designed and conducted by the authors, and all analyses were completed by thecoordinating center. The study was approved by institutional review boards at each center.The trial was not blinded, but clinical assessors and end point adjudicators were masked totreatment assignment. The authors vouch for the accuracy and completeness of the data andall analyses and for the fidelity of this report to the trial protocol, which is available with thefull text of this article at NEJM.org.The study was sponsored by the National Institutes of Health, with additional support fromother federal partners and the clinical research centers of several participating institutions.Major contributions were provided by the FedEx Corporation; Health ManagementResources; LifeScan, Inc., a Johnson & Johnson Company; Nestle HealthCare Nutrition,Inc.; Hoffmann-La Roche Inc.; Abbott Nutrition; and Unilever North America. None of thecorporate sponsors had any role in the trial design, data analysis, or reporting of results.ParticipantsTo be eligible for participation in the trial, volunteers were required to be 45 to 76 years ofage and to have all of the following: self-reported type 2 diabetes verified by use of glucoselowering medication, physician report, or glucose levels; body-mass index (BMI) of 25.0 kg/m2 or greater (27 kg/m2 or greater in individuals taking insulin); hemoglobin A1c less than11%; systolic blood pressure less than 160 mmHg; diastolic blood pressure less than 100mmHg; triglycerides less than 600 mg/dl; ability to complete a valid maximal exercise testsuggesting it was safe to exercise; and a primary care provider. Participants could be usingany type of glucose-lowering medication, but the percentage of participants using insulinwas limited to less than 30%. Participants with and without a history of cardiovasculardisease were included to increase generalizeability of results. Additional eligibility criteriaare described elsewhere 6 and in the Supplementary Appendix.InterventionsEligible individuals were randomized to either an intensive lifestyle intervention (theintervention group) or diabetes support and education (the control group); randomizationwas stratified by clinical site. Curricula for both treatment arms were developed centrallyand have been described in detail 6, 8 (see the Supplementary Appendix). Intensive lifestyleintervention aimed at achieving and maintaining at least a 7% weight loss by focusing onreduced caloric intake and increased physical activity. The program included both group andindividual counseling sessions, occurring weekly during the first six months, withdecreasing frequency over the course of the trial. Specific intervention strategies included acalorie goal of 1200 to 1800 kcal/day (with less than 30% of calories from fat and more than15% from protein), use of meal replacement products, and at least 175 minutes per week ofmoderate intensity physical activity. A toolbox of strategies was available for participantshaving difficulty achieving the weight loss goals.Diabetes support and education featured three group sessions per year focused on diet,exercise, and social support during years 1 to 4. In subsequent years the frequency wasreduced to one session annually.Page 2N Engl J Med. Author manuscript; available in PMC 2014 July 11.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptAll medication adjustments were made by the participant’s health care provider, with theexception of temporary changes in glucose-lowering medications made by study staff toreduce the risk of hypoglycemia in the intensive lifestyle intervention group. Participantsand their health care providers received annual reports on the participants’ updatedcardiovascular risk factors and the goals recommended by the American DiabetesAssociation.1Assessments and OutcomesCertified staff, masked to participants’ intervention assignment, measured weight, waistcircumference and blood pressure, assessed medication use, and obtained blood for analysisat the central laboratory annually.6 Maximal exercise tests were performed on the full cohortprior to randomization. Submaximal exercise tests were performed on the full cohort atyears 1 and 4 and on a subset at year 2.During annual visits and 6-month phone calls, participants were queried by staff masked totreatment assignment about all medical events and hospitalizations. These queries wereaugmented with searches of national databases on deaths. Hospital and other records wereobtained for potential cardiovascular events and adjudicated according to standard criteriaby reviewers masked to intervention assignment (see Supplementary Appendix).The primary end point was the first post-randomization occurrence of a compositecardiovascular outcome. Initially, the composite cardiovascular outcome includedcardiovascular death, nonfatal myocardial infarction, and nonfatal stroke, and the anticipatedmaximal follow-up interval was 11.5 years. During the first two years of the trial, theprimary event rate in the control group was lower than expected.9 Therefore, hospitalizedangina was added to the primary outcome and planned follow-up was extended to amaximum of 13.5 years. Three composite secondary cardiovascular outcomes were alsoexamined: cardiovascular death, myocardial infarction, or stroke (the original primaryoutcome); death (all causes), myocardial infarction, stroke, or hospitalized angina; and death(all causes), myocardial infarction, stroke, hospitalized angina, coronary artery bypassgrafting, percutaneous coronary angioplasty, hospitalization for heart failure, or peripheralvascular disease.Statistical AnalysesWith a planned sample size of 5000 participants, Look AHEAD had greater than 80%probability of detecting an 18% difference in major cardiovascular events between the twogroups, assuming a two-sided alpha level of 0.05, a primary outcome rate of 2% per year inthe control group, and a planned maximum follow-up of 13.5 years. The 18% difference waschosen based on reductions in mortality in individuals with type 2 diabetes with voluntaryweight loss in an observational study,10 effect sizes chosen for trials with similaroutcomes,11 feasibility, and public health significance.On September 14, 2012, Look AHEAD’s primary sponsors, based on futility analysis andrecommendation of the data and safety monitoring board, instructed the study investigatorsto terminate the intervention. All data analyses extend to this date. At that time, theprobability of observing a significant positive result at planned end of follow-up, assumingthe actual hazard ratio to be 0.82, was estimated to be 1%.Baseline characteristics and key safety outcomes were compared between study groupsusing chi-square, Fisher’s exact, Wilcoxon rank-sum, two-sample t-tests and Poissonregression. Physical and laboratory measurements and medication use from baseline through10 years were modeled with generalized linear regression and generalized estimatingequations. Center was included as a covariate, covariance was unstructured, and linearPage 3N Engl J Med. Author manuscript; available in PMC 2014 July 11.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscriptcontrasts were used to compare groups throughout post-baseline follow-up and at annualvisits. Analyses of primary and secondary outcomes were performed using time-to-eventmethods according to the intention-to-treat principle as pre-specified in the protocol.Kaplan–Meier estimates were used to calculate the proportion of participants who had anevent over time. First occurrences of primary and secondary outcomes in the two groupswere compared with hazard ratios and 95% confidence intervals. Two-sided p-values werecalculated with likelihood-ratio tests from Cox proportional-hazards regression, with modelscontaining terms for clinical site, history of cardiovascular disease, and interventionassignment. The consistency of intervention effects on the primary outcome among threepre-specified subgroups (sex, race or ethnicity and history of cardiovascular disease) wasevaluated using interaction tests. Results were not adjusted for multiple comparisons andp

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