Action For Health In Diabetes Study Research Articles

Abstract P153: Intensive Lifestyle Intervention in Type 2 Diabetes Mellitus Results in a More Favorable Sex Hormone Profile in Both Post-Menopausal Females and Older Males (The Look AHEAD Trial Sex Hormone Study)

Background: Prior studies showed an association between some adverse cardiometabolic outcomes and lower testosterone in males and higher estrogen in both males and post-menopausal females. However, few studies of sex hormones focused on people with type 2 diabetes (T2DM), assessed hormone changes over time or applied highly sensitive laboratory assays. Given the importance of lifestyle modification (i.e., diet, exercise and weight loss) in preventing cardiometabolic complications in people with T2DM, we examined the impact of an Intensive Lifestyle Intervention (ILI) on sex hormones over time and differences by sex. Methods: The Look AHEAD (Action for Health in Diabetes) Study was a randomized control trial of 5,145 individuals with BMI ≥25 and T2D to evaluate the effect of ILI compared to the Diabetes Support and Education (DSE) control group on incident cardiovascular events. We selected a sample of 472 males and 426 post-menopausal female participants (mean age 60 years [SD 6.3], 20.5% Black) to examine sex hormones (estradiol - E2, total testosterone - T) and sex hormone binding globulin (SHBG) at baseline and year 1. E2 and T were measured using mass spectrometry analysis and SHBG was measured using an immunoassay. Results: In males, ILI increased SHBG by 17.3% and T by 10.6% compared to the DSE group (Table). In postmenopausal females, ILI increased SHBG by 12.0% and decreased E2 by 23.4% compared to the DSE group (Table). The change in the sex hormone levels from baseline to 1-year follow up was attenuated when adjusted for change in BMI. Conclusion: ILI resulting in weight loss increased T in males and decreased E2 in postmenopausal females and increased SHBG in both sexes. We plan further analysis with a larger sample and longer follow-up to examine the role of weight loss either as a co-occurring metabolic process or as a mediator for the change in sex hormones to better understand the impact of lifestyle changes and sex diffrences.

Weight changes during the COVID-19 shutdown in older individuals with type 2 diabetes: the Look AHEAD Study.

The aimsof this study were as follows: 1) examine weight changes in older adults (mean age=76 years) with type 2 diabetes and overweight or obesity during the COVID-19 shutdown; and 2) compare the behavioral and psychosocial effects of the shutdown in those who had large weight losses (>5%), those who had small weight losses (2%-5%), those who remained weight stable (±2%), or those who gained weight (>2%). Look AHEAD (Action for Health in Diabetes) participants (N=2544) were surveyed during the COVID-19 shutdown (2020), and they self-reported their current weight, reasons for weight change, weight-related behaviors, psychosocial measures, and negative and positive effects of the pandemic on their lives. Comparing self-reported weight during the COVID-19 shutdown with earlier measured weight, Look AHEAD participants lost, on average, 2.2 kg during the COVID-19 shutdown: 47% lost >2%, and only 18% gained >2% (p < 0.0001). Decreases in physical activity and increases in screen time were reported frequently in all weight-change categories. Similarly, there were few differences among the categories on standardized psychosocial measures or self-reported effects of the shutdown on participants' lives. However, when differences were seen, the most negative impact was in those who gained weight. Although weight loss appeared more common than weight gain during the shutdown, the weight-change groups did not differ on most psychosocial and behavioral variables.

Variability of adiposity indices and incident heart failure among adults with type 2 diabetes

BackgroundIt remains unclear how the variability of adiposity indices relates to incident HF. This study evaluated the associations of the variability in several adiposity indices with incident heart failure (HF) in individuals with type 2 diabetes (T2DM).MethodsWe included 4073 participants from the Look AHEAD (Action for Health in Diabetes) study. We assessed variability of body mass index (BMI), waist circumference (WC), and body weight across four annual visits using three variability metrics, the variability independent of the mean (VIM), coefficient of variation (CV), and intraindividual standard deviation (SD). Multivariable Cox regression models were used to generate adjusted hazard ratios (aHR) and 95% confidence intervals (CI) for incident HF.ResultsOver a median of 6.7 years, 120 participants developed incident HF. After adjusting for relevant confounders including baseline adiposity levels, the aHR for the highest (Q4) versus lowest quartile (Q1) of VIM of BMI was 3.61 (95% CI 1.91–6.80). The corresponding aHRs for CV and SD of BMI were 2.48 (95% CI 1.36–4.53) and 2.88 (1.52–5.46), respectively. Regarding WC variability, the equivalent aHRs were 1.90 (95% CI 1.11–3.26), 1.79 (95% CI 1.07–3.01), and 1.73 (1.01–2.95) for Q4 versus Q1 of VIM, CV and SD of WC, respectively.ConclusionsIn a large sample of adults with T2DM, a greater variability of adiposity indices was associated with higher risks of incident HF, independently of traditional risk factors and baseline adiposity levels.Registration-URL:https://clinicaltrials.gov/ct2/show/NCT00000620.

Correlates of cardiorespiratory fitness among overweight or obese individuals with type 2 diabetes

IntroductionMechanistic studies suggest that type 2 diabetes is independently associated with low cardiorespiratory fitness (CRF). Little is known about the CRF profile in type 2 diabetes; we assessed the correlates...

Changes in the Prevalence of Symptoms of Depression, Loneliness, and Insomnia in U.S. Older Adults With Type 2 Diabetes During the COVID-19 Pandemic: The Look AHEAD Study.

To evaluate changes in the prevalence of depressive symptoms, loneliness, and insomnia among older adults with type 2 diabetes from 2016 to 2020 and to assess risk factors for these conditions including demographics, multimorbidity, BMI, treatment group, and pre-coronavirus 2019 (COVID-19) measure scores. This was a prospective, observational study of participants from the Look AHEAD (Action for Health in Diabetes) cohort study. Data were from two assessments before COVID-19 (visit 1: April 2016-June 2018 and visit 2: February 2018-February 2020) and one assessment during COVID-19 (visit 3: July-December 2020). Surveys were administered to assess depressive symptoms, loneliness, and insomnia. The study included 2829 adults (63.2% female, 60.6% White, mean [SD] age 75.6 [6.0] years). The prevalence of mild or greater depressive symptoms did not change significantly between the two pre-pandemic visits (P = 0.88) but increased significantly from pre- to during COVID-19 (19.3% at V2 to 30.4% at V3; P < 0.001). Higher odds of mild or greater depressive symptoms at V3 were associated with being female (adjusted odds ratio [OR] 1.4 [95% CI 1.1-1.7]), identifying as non-Hispanic White (OR 1.4 [95% CI 1.1-1.7]), having obesity (OR 1.3 [95% CI 1.0-1.5]), and reporting mild or greater depressive symptoms at V1 (OR 4.0 [95% CI 2.9-5.4]), V2 (OR 4.4 [95% CI 3.2-5.9]), or both visits (OR 13.4 [95% CI 9.7-18.4]). The prevalence of loneliness increased from 12.3% at V1 to 22.1% at V3 (P < 0.001), while the prevalence of insomnia remained stable across visits at 31.5-33.3%. The prevalence of mild or greater depressive symptoms in older adults with diabetes was more than 1.6 times higher during COVID-19 than before the pandemic.

Racial/ethnic and socioeconomic disparities in the use of newer diabetes medications in the Look AHEAD study

SummaryBackgroundAmong patients with type 2 diabetes, minority racial/ethnic groups have a higher burden of cardiovascular disease, chronic kidney disease, and hypoglycaemia. These groups may especially benefit from newer diabetes medication classes, but high cost may limit access. We examined the association of race/ethnicity with the initiation of newer diabetes medications (GLP-1 receptor agonists, DPP-4 inhibitors, SGLT-2 inhibitors).MethodsWe conducted a secondary analysis of the Look AHEAD (Action for Health in Diabetes) trial including participants with at least one study visit after April 28, 2005. Cox proportional hazards models were used to estimate the association between race/ethnicity and socioeconomic factors with time to initiation of any newer diabetes medication from April 2005 to February 2020. Models were adjusted for demographic and clinical characteristics.FindingsAmong 4,892 participants, 63.6%, 15.7%, 12.6%, 5.2%, and 2.9% were White, Black, Hispanic, American Indian or Alaskan Native (AI/AN), or other race/ethnicity, respectively. During a median follow-up of 8.3 years, 2,180 (45.2%) participants were initiated on newer diabetes medications. Race/ethnicity was associated with newer diabetes medication initiation (p=.019). Specifically, initiation was lower among Black (HR 0.81, 95% CI 0.70 –0.94) and AI/AN participants (HR 0.51, 95% CI 0.26–0.99). Yearly family income was inversely associated with initiation of newer diabetes medications (HR 0.78, 95% CI 0.62–0.98) comparing the lowest and highest income groups. Findings were mostly driven by GLP-1 receptor agonists.InterpretationThese findings provide evidence of racial/ethnic disparities in the initiation of newer diabetes medications, independent of socioeconomic factors, which may contribute to worse health outcomes.

The Association of Prior Intensive Lifestyle Intervention and Diabetes Support and Education With Frailty Prevalence at Long-Term Follow-Up in the Action for Health in Diabetes Extension Study.

Frailty is common in older adults with obesity and diabetes. We compared prevalence of the frailty phenotype between intervention groups in long-term follow-up of Look Action for Health in Diabetes Study (AHEAD), a randomized trial comparing a multidomain intensive lifestyle intervention (ILI) that promoted weight loss and physical activity with a diabetes support and education (DSE) control group in adults with type 2 diabetes and overweight or obesity. Participants included 2 979 individuals randomized to ILI or DSE in 2001-2004 who completed frailty assessment in Look AHEAD-Extension Wave 1 (2016-2018) at an average age of 72.1 ± 6.2 years. Frailty was assessed using a modified frailty phenotype definition (excluding weight loss) defined as the presence of 3 or more of the following frailty characteristics: weakness, slow gait speed, low physical activity, and exhaustion. Frailty odds by intervention assignment (DSE vs ILI) were estimated using multivariable logistic regression, adjusting for sex, clinic site, and time since randomization. At median follow-up of 14.0 years (interquartile range: 13.8-14.1), frailty prevalence was 10.9% in ILI compared with 11.6% in DSE (odds ratio for frailty in ILI vs DSE = 0.94, 95% confidence interval: 0.75-1.18, p = .60). Frailty was more prevalent in participants who were older, female, non-White, of lower socioeconomic status, and at baseline had a higher body mass index and waist circumference, longer duration of diabetes, history of cardiovascular disease, and metabolic syndrome. Prior randomization to ILI compared with DSE was not associated with a lower prevalence of frailty after a median follow-up of 14.0 years in adults with diabetes and overweight or obesity.

Long-term variability of blood pressure and incidence of heart failure among individuals with Type 2 diabetes.

AimsData on the association of long‐term variability of blood pressure (BP) with incident heart failure (HF) in individuals with Type 2 diabetes are scarce. We evaluated this association in a large community‐based sample of adults with Type 2 diabetes.Methods and resultsA total of 4200 participants with Type 2 diabetes who had available BP measurements at four visits (baseline and 12, 24, and 36 months) in the Look AHEAD (Action for Health in Diabetes) study were included. Variability of systolic BP (SBP) and diastolic BP (DBP) across the four visits was assessed using four metrics. Participants free of HF during the first 36 months were followed for HF events. Cox regression was used to generate hazard ratios (HRs) and 95% confidence intervals (CIs) for HF. Of the 4200 participants, the average age was 59 years [standard deviation (SD): 6.8]; 58.5% were women. Over a median follow‐up of 6.7 years, 129 developed HF events. After adjusting for relevant confounders, the HR of incident HF for the highest vs. lowest quartile of SD of SBP was 1.77 (95% CI 1.01–3.09); the HR for the highest (vs. lowest) quartile of variability independent of the mean of SBP was 1.29 (95% CI 0.78–2.14). The adjusted HR for participants in the highest (compared with the lowest) quartile of SD of DBP was 1.61 (95% CI 1.01–2.59), and the adjusted HR for variability independent of the mean of DBP was 1.65 (95% CI 1.03–2.65).ConclusionsA greater variability in SBP and DBP is independently associated with greater risk of incident HF in individuals with Type 2 diabetes.

Microvascular disease and cardiovascular outcomes among individuals with type 2 diabetes

AimTo evaluate the associations of microvascular disease (MVD) with incident cardiovascular disease (CVD) in individuals with type 2 diabetes. MethodsA total of 4098 participants with type 2 diabetes and without CVD were assessed for MVD (diabetic kidney disease, retinopathy or neuropathy) in the Look AHEAD (Action for Health in Diabetes) study. Cox models were used to generate hazard ratios (HRs) for: (1) CVD composite (myocardial infarction, stroke, hospitalization for angina and/or death from cardiovascular causes), (2) coronary artery disease (CAD), (3) stroke, and (4) CVD-related deaths. ResultsOf 4098 participants, 34.7% (n = 1424) had MVD at baseline. Over a median of 9.5 years, 487 developed the CVD composite, 410 CAD events, 100 stroke, and 54 CVD-related deaths. After adjusting for relevant confounders, MVD was associated with increased risks of CVD composite (HR 1.34, 95% CI 1.11–1.61), CAD (HR 1.24, 95% CI 1.01–1.52), stroke (HR 1.55, 95% CI 1.03–2.33), and cardiovascular mortality (HR 1.26, 95% CI 0.72–2.22). HRs for CVD composite by type of MVD were 1.11 (95% CI 0.89–1.38), 1.63 (95% CI 1.22–2.17) and 1.16 (95% CI 0.92–1.46) for diabetic kidney disease, retinopathy, and neuropathy, respectively. ConclusionsOur findings underscore the relevance of MVD in CVD risk assessment in type 2 diabetes.

Long-Term Variability of Blood Pressure, Cardiovascular Outcomes, and Mortality: The Look AHEAD Study.

We evaluated the associations of visit-to-visit blood pressure (BP) variability with incident cardiovascular disease (CVD) and deaths in adults with type 2 diabetes. We analyzed 4,152 participants in Look AHEAD (Action for Health in Diabetes) free of CVD events and deaths during the first 36 months of follow-up. Variability of systolic BP (SBP) and diastolic BP (DBP) across 4 annual visits was assessed using the intraindividual SD, variation independent of the mean, and coefficient of variation. Cox regression was used to generate the adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for CVD (myocardial infarction [MI], stroke, or CVD-related deaths) and mortality. Over a median of 6.6 years, there were 220 MIs, 105 stroke cases, 62 CVD-related deaths, and 236 deaths. After adjustment for confounders including average BP, the aHRs for the highest (vs. lowest) tertile of SD of SBP were 1.98 (95% CI 1.01-3.92), 1.25 (95% CI 0.90-1.72), 1.26 (95% CI 0.96-1.64), 1.05 (95% CI 0.75-1.46), and 1.64 (95% CI 0.99-2.72) for CVD mortality, all-cause mortality, CVD, MI, and stroke, respectively. The equivalent aHRs for SD of DBP were 1.84 (95% CI 0.98-3.48), 1.43 (95% CI 1.03-1.98), 1.19 (95% CI 0.91-1.56), 1.14 (95% CI 0.82-1.58), and 0.97 (95% CI 0.58-1.60), respectively. In a large sample of individuals with type 2 diabetes, a greater variability in SBP was associated with higher cardiovascular mortality and CVD events; a higher variability in DBP was linked to increased overall and cardiovascular mortality.

Metabolic Dyslipidemia and Cardiovascular Outcomes in Type 2 Diabetes Mellitus: Findings From the Look AHEAD Study.

BackgroundMetabolic dyslipidemia (high triglyceride) and low high‐density lipoprotein cholesterol (HDL‐C) is highly prevalent in type 2 diabetes mellitus (T2DM). The extent to which diabetes mellitus–related abnormalities in the triglyceride–HDL‐C profile associates with cardiovascular disease (CVD) risk is incompletely understood. We evaluated the associations of triglyceride and HDL‐C status with CVD outcomes in individuals with T2DM.Methods and ResultsWe analyzed data from 4199 overweight/obese adults with T2DM free of CVD with available data on triglyceride and HDL‐C at baseline (2001–2004) in the Look AHEAD (Action for Health in Diabetes) study. We used Cox proportional models to estimate hazard ratios (HRs) and 95% CIs of: (1) composite CVD outcome (myocardial infarction, stroke, hospitalization for angina, and/or death from cardiovascular causes); (2) coronary artery disease events; and (3) cerebrovascular accidents (stroke). Of the 4199 participants, 62% (n=2600) were women, with a mean age of 58 years (SD, 7), and 40% (n=1659) had metabolic dyslipidemia at baseline. Over a median follow‐up of 9.5 years (interquartile range, 8.7–10.3), 500 participants experienced the composite CVD outcome, 396 experienced coronary artery disease events, and 100 experienced stroke. Low HDL‐C was associated with higher hazards of the composite CVD outcome (HR, 1.36; 95% CI, 1.12–1.64 [P=0.002]) and coronary artery disease events (HR, 1.46; 95% CI, 1.18–1.81 [P=0.001]) but not stroke (HR, 1.38; 95% CI, 0.90–2.11 [P=0.140]). Compared with patients with normal triglyceride and normal HDL, participants with metabolic dyslipidemia had higher risks of the composite CVD outcome (HR, 1.30; 95% CI, 1.03–1.63 [P=0.025]) and coronary artery disease events (HR, 1.48; 95% CI, 1.14–1.93 [P=0.003]) but not stroke (HR, 1.23; 95% CI, 0.74–2.05 [P=0.420]).ConclusionsIn a large sample of overweight/obese individuals with T2DM, metabolic dyslipidemia was associated with higher risks of CVD outcomes. Our findings highlight the necessity to account for metabolic dyslipidemia in CVD risk stratification among patients with T2DM.RegistrationURL: https://www.lookaheadtrial.org; Unique identifier: NCT00017953.

Cardiorespiratory Fitness and Atherosclerotic Cardiovascular Outcomes by Levels of Baseline-Predicted Cardiovascular Risk: The Look AHEAD Study

BackgroundWe evaluated the associations of cardiorespiratory fitness with atherosclerotic cardiovascular disease (ASCVD) by levels of baseline-predicted ASCVD risk among adults with type 2 diabetes. MethodsWe analyzed data from 4203 adults with type 2 diabetes in the Look AHEAD (Action for Health in Diabetes) study. Cardiorespiratory fitness was assessed using maximal exercise testing and categorized into low, moderate, and high; baseline-predicted. ASCVD risk was calculated using the American College of Cardiology/American Heart Association Pooled Cohort Equation. We used Cox regression models to estimate hazard ratios (HR) and 95% confidence intervals (CI) for ASCVD events (fatal and nonfatal myocardial infarction and stroke). ResultsOver a median of 9.6 years, there were 295 ASCVD events. The effect of fitness on outcomes was different across levels of 10-year predicted ASCVD risk (P for interaction < .001). Among participants with a baseline-predicted risk of 7.5% to 20%, the HR of low (vs high) fitness group was 1.94 (95% CI, 1.12-3.35) for ASCVD events. Fitness was not significantly associated with ASCVD events in the groups with baseline-predicted risk <7.5% (HR 1.53; 95% CI, 0.49-4.76) or ≥20% (HR 1.40; 95% CI, 0.88-2.24). A similar pattern was observed for myocardial infarction and stroke separately. ConclusionsIn a large sample of type 2 diabetes individuals, the association of low fitness with incident ASCVD was modified by the baseline-predicted 10-year ASCVD risk. Our findings suggest the utility of assessing fitness in ASCVD risk stratification in type 2 diabetes, especially among those with intermediate predicted 10-year risk of ASCVD.

Long-term variability of glycemic markers and risk of all-cause mortality in type 2 diabetes: the Look AHEAD study

IntroductionGlycemic variability may predict poor outcomes in type 2 diabetes. We evaluated the associations of long-term variability in glycosylated hemoglobin (HbA1C) and fasting plasma glucose (FPG) with cardiovascular disease (CVD)...

Effects of Weight Loss on Obstructive Sleep Apnea Severity. Ten-Year Results of the Sleep AHEAD Study.

Rationale: Weight loss is recommended to treat obstructive sleep apnea (OSA).Objectives: To determine whether the initial benefit of intensive lifestyle intervention (ILI) for weight loss on OSA severity is maintained at 10 years.Methods: Ten-year follow-up polysomnograms of 134 of 264 adults in Sleep AHEAD (Action for Health in Diabetes) with overweight/obesity, type 2 diabetes mellitus, and OSA were randomized to ILI for weight loss or diabetes support and education (DSE).Measurements and Main Results: Change in apnea-hypopnea index (AHI) was measured. Mean ± SE weight losses of ILI participants of 10.7 ± 0.7, 7.4 ± 0.7, 5.1 ± 0.7, and 7.1 ± 0.8 kg at 1, 2, 4, and 10 years, respectively, were significantly greater than the 1-kg weight loss at 1, 2, and 4 years and 3.5 ± 0.8 kg weight loss at 10 years for the DSE group (P values ≤ 0.0001). AHI was lower with ILI than DSE by 9.7, 8.0, and 7.9 events/h at 1, 2, and 4 years, respectively (P values ≤ 0.0004), and 4.0 events/h at 10 years (P = 0.109). Change in AHI over time was related to amount of weight loss, baseline AHI, visit year (P values < 0.0001), and intervention independent of weight change (P = 0.01). OSA remission at 10 years was more common with ILI (34.4%) than DSE (22.2%).Conclusions: Participants with OSA and type 2 diabetes mellitus receiving ILI for weight loss had reduced OSA severity at 10 years. No difference in OSA severity was present between ILI and DSE groups at 10 years. Improvement in OSA severity over the 10-year period with ILI was related to change in body weight, baseline AHI, and intervention independent of weight change.

Weight Change 2 Years After Termination of the Intensive Lifestyle Intervention in the Look AHEAD Study.

This study evaluated weight changes after cessation of the 10-year intensive lifestyle intervention (ILI) in the Look AHEAD (Action for Health in Diabetes) study. It was hypothesized that ILI participants would be more likely to gain weight during the 2-year observational period following termination of weight-loss-maintenance counseling than wouldparticipants in the diabetes support and education (DSE) control group. Look AHEAD was a randomized controlled trial that compared the effects of ILI and DSE on cardiovascular morbidity and mortality in participants with overweight/obesity and type 2 diabetes. Look AHEAD was converted to an observational study in September 2012. Two years after the end of the intervention (EOI), ILI and DSE participants lost a mean (SE)of 1.2 (0.2) kg and 1.8 (0.2) kg, respectively (P = 0.003). In addition, 31% of ILI and 23.9% of DSE participants gained ≥ 2% (P < 0.001) of EOI weight, whereas 36.3% and 45.9% of the respective groups lost ≥ 2% of EOI weight (P = 0.001). Two years after the EOI, ILI participants reported greater use of weight-control behaviors than DSE participants. Both groups lost weight during the 2-year follow-up period, but more ILI than DSE participants gained ≥ 2% of EOI weight. Further understanding is needed of factors that affected long-term weight change in both groups.

347-OR: The Long-Term Effects of an Intensive Lifestyle Intervention on Medicare Outcomes

Research Objective: Interventions for type 2 diabetes (T2D) often focus on lifestyle, including diet and physical activity. The Look AHEAD (Action for Health in Diabetes) study is one of the largest randomized trials of an intensive lifestyle intervention (ILI). Starting in 2001, 5145 adults with overweight/obesity and T2D were randomized to ILI or conventional diabetes support and education. The ILI led to persistent reductions in weight (8.6% in first year), improved diabetes control, and reduced self-reported hospitalizations and prescription drug use during the 12-year intervention. However, it is unclear whether benefits persisted beyond the intervention. We linked Look AHEAD participants to Medicare data to estimate the long-term effects of ILI on health care use. Study Design: We estimated differences in healthcare use between ILI and control groups during 2012-2015 (immediately after the intervention), adjusting for baseline characteristics. We focused on measures of healthcare use that were available for traditional Medicare and private Medicare Advantage enrollees, including hospitalizations, emergency visits, and prescription drug use. We also estimated whether the ILI affected disability-related Medicare eligibility. Population Studied: We linked 2,796 participants to Medicare data out of 3,246 consenting to linkages after the Look AHEAD intervention phase. Principal Findings: We found significantly lower annual Part D drug costs for the ILI group between 2012-2015 (-$401, p=0.029). Annual emergency department visits and hospitalizations were not significantly different between intervention groups in 2012-2015. A similar percentage of ILI and control group participants were initially eligible for Medicare before age 65 due to disability. Conclusions: The ILI led to reductions in prescription drug use and costs that persisted beyond the intervention, but did not affect long-term hospitalizations, emergency visits, or eligibility for Medicare through disability. Disclosure P.J. Huckfeldt: Employee; Spouse/Partner; U.S. Department of Veterans Affairs. C. Frenier: None. N.M. Pajewski: None. M. Espeland: Research Support; Self; National Institutes of Health. Other Relationship; Self; Boehringer Ingelheim International GmbH, Ironwood Pharmaceuticals, Inc. A.L. Peters: Advisory Panel; Self; Abbott, Becton, Dickinson and Company, Bigfoot Biomedical, Eli Lilly and Company, Lexicon Pharmaceuticals, Inc., Livongo Health, MannKind Corporation, Medscape, Merck &amp; Co., Inc., Omada Health, Inc., OptumRx, Inc., Sanofi US, Zafgen, Inc. Research Support; Self; AstraZeneca, Dexcom, Inc., Jaeb Center for Health Research, MannKind Corporation, National Institute of Diabetes and Digestive and Kidney Diseases. Speaker's Bureau; Self; Novo Nordisk Inc. R. Casanova: None. L.J. Cheskin: None. D. Goldman: Advisory Panel; Self; ACADIA Pharmaceuticals. Consultant; Self; Precision Health Economics. Stock/Shareholder; Self; Precision Medicine Group, Inc. Other Relationship; Self; Aspen Health Strategy Group, Celgene Corporation. Funding National Institute of Diabetes and Digestive and Kidney Diseases (R01DK107552)

Effects of a long-term lifestyle modification programme on peripheral neuropathy in overweight or obese adults with type 2 diabetes: the Look AHEAD study

Aims/hypothesisThe aim of this study was to evaluate the effects on diabetic peripheral neuropathy (DPN) of a long-term intensive lifestyle intervention (ILI) programme designed to achieve and maintain weight loss.MethodsBeginning in 2001, a total of 5145 overweight or obese people with type 2 diabetes, aged 45–76 years, participating in the multicentre Look AHEAD (Action for Health in Diabetes) study were randomised to ILI (n = 2570) or to a diabetes support and education (DSE) control group (n = 2575) using a web-based management system at the study coordinating centre at Wake Forest School of Medicine (Winston-Salem, NC, USA). Randomisation was stratified by clinical centre and was not revealed to the clinical staff responsible for obtaining data on study outcomes. Because of the nature of the study, patients and the local centre interventionists were not blinded to the study group assignments. In addition, the coordinating centre staff members responsible for data management and statistical analyses were not blinded to the study group assignments. The interventions were terminated in September 2012, 9–11 years after randomisation, but both groups continued to be followed for both primary and secondary outcomes. Neuropathy evaluations included the Michigan Neuropathy Screening Instrument (MNSI) questionnaire completed at baseline in 5145 participants (ILI n = 2570, DSE n = 2575) and repeated annually thereafter and the MNSI physical examination and light touch sensation testing conducted in 3775 participants (ILI n = 1905, DSE n = 1870) 1–2.3 years after discontinuation of the intervention.ResultsAt baseline, the MNSI questionnaire scores were 1.9 ± 0.04 and 1.8 ± 0.04 in the ILI and DSE groups, respectively (difference not statistically significant). After 1 year, when weight loss was maximal in the ILI group (8.6 ± 6.9%) compared with DSE (0.7 ± 4.8%), the respective MNSI scores were 1.7 ± 0.04 and 2.0 ± 0.04 (p ≤ 0.001). Subsequently, the scores increased gradually in both groups, but remained significantly lower in the ILI group for the first 3 years and at the end of follow-up. In both groups, there was a significant association between changes in the MNSI scores and changes in body weight, HbA1c and serum lipids. There were no significant between-group differences in the proportions of participants with MNSI physical examination scores ≥2.5, considered to be indicative of diabetic neuropathy. The light touch sensation measured separately in either the right or left big toes (halluces) did not differ between ILI and DSE, but when the data were combined for both toes, light touch was better preserved in the ILI group.Conclusions/interpretationILI resulted in a significant decrease in questionnaire-based DPN, which was associated with the magnitude of weight loss. In both the ILI and DSE groups, changes in the MNSI score were also related to changes in HbA1c and lipids. There were no significant effects of ILI on physical examination measures of DPN conducted 1–2.3 years after termination of the active intervention, except for light touch sensation, which was significantly better in the ILI group when measurements were combined for both toes. However, a potential limiting factor to the interpretation of the physical examination data is that no baseline studies are available for comparison.Trial registration:ClinicalTrials.gov NCT00017953.Funding:This work was funded by the National Institutes of Health through cooperative agreements with the National Institute of Diabetes and Digestive and Kidney Diseases.

Effects of visceral adipose tissue reduction on CVD risk factors independent of weight loss: The Look AHEAD study

ABSTRACTObjectives: To determine if the reduction of visceral adipose tissue (VAT) volume by lifestyle intervention improved risk factors for cardiovascular disease (CVD) independent of weight loss amount. Design: Ancillary study of randomized-controlled trial. Setting: Data analysis using multivariable regression models. Participants: Participants of the Look AHEAD (Action for HEAlth in Diabetes) Fatty Liver Ancillary Study. Main outcome measures: Correlations between changes in VAT and in CVD risk factors, while adjusting for weight loss and treatment (intensive lifestyle intervention [ILI] vs. diabetes support and education [DSE]). Results: Of 100 participants analyzed, 52% were women, and 36% were black, with a mean age of 61.1 years. In the DSE group, mean weight and VAT changed by 0.1 % (p=0.90) and 4.3% (p=0.39), respectively. In the ILI group, mean weight and VAT decreased by 8.0% (p<0.001) and 7.7% (p=0.01), respectively. Across both groups, mean weight decreased by 3.6% (p<0.001), and mean VAT decreased by 1.2% (p=0.22); the decrease in VAT was correlated with the increase in HDL-cholesterol (HDL-C; R=−0.37; p=0.03). There were no correlations between changes in VAT and blood pressure, triglycerides, LDL-C, glucose, or HbA1c. After adjusting for age, race, gender, baseline metabolic values, fitness, and treatment group, changes in HDL-C were not associated with changes in VAT, while weight changes were independently associated with decrease in glucose, HbA1c, and increase in HDL-C. Conclusions: VAT reduction was not correlated with improvements of CVD risk factors in a sample of overweight and obese adults with type 2 diabetes after adjusting for weight loss.

The Look AHEAD Study: Implications for Clinical Practice Go Beyond the Headlines

O N FRIDAY, OCTOBER 19, 2012, THE NATIONAL Institutes of Health (NIH) announced that the lifestyle “intervention was stopped early in NIHfunded study of weight loss in overweight and obese adults with type 2 diabetes after finding no harm, but no cardiovascular benefits.” The primary study question of the long-term Look AHEAD (Action for Health in Diabetes) Study had been answered. An intensive lifestyle intervention program aimed at a 10% weight loss and 175 minutes of physical activity per week did not reduce cardiovascular events (defined as heart attack, stroke, hospitalization for angina, or death) in people with type 2 diabetes compared with a program of diabetes support and education. A review of the primary study results, along with careful consideration of the previously published data, can put the study’s results in perspective and go beyond the headlines.

Eight‐year weight losses with an intensive lifestyle intervention: The look AHEAD study

ObjectiveTo evaluate 8-year weight losses achieved with intensive lifestyle intervention (ILI) in the Look AHEAD (Action for Health in Diabetes) study.Design and MethodsLook AHEAD assessed the effects of intentional weight loss on cardiovascular morbidity and mortality in 5,145 overweight/obese adults with type 2 diabetes, randomly assigned to ILI or usual care (i.e., diabetes support and education [DSE]). The ILI provided comprehensive behavioral weight loss counseling over 8 years; DSE participants received periodic group education only.ResultsAll participants had the opportunity to complete 8 years of intervention before Look AHEAD was halted in September 2012; ≥88% of both groups completed the 8-year outcomes assessment. ILI and DSE participants lost (mean±SE) 4.7±0.2% and 2.1±0.2% of initial weight, respectively (p<0.001) at year 8; 50.3% and 35.7%, respectively, lost ≥5% (p<0.001), and 26.9% and 17.2%, respectively, lost ≥10% (p<0.001). Across the 8 years ILI participants, compared with DSE, reported greater practice of several key weight-control behaviors. These behaviors also distinguished ILI participants who lost ≥10% and kept it off from those who lost but regained.ConclusionsLook AHEAD’s ILI produced clinically meaningful weight loss (≥5%) at year 8 in 50% of patients with type 2 diabetes and can be used to manage other obesity-related co-morbid conditions.Trial Registrationclinicaltrials.gov Identifier: NCT00017953