Intensive Weight Loss Intervention and Cancer Risk in Adults with Type 2 Diabetes: Analysis of the Look AHEAD Randomized Clinical Trial.

OBJECTIVE: This study was designed to determine whether intensive lifestyle intervention (ILI) aimed at weight loss lowers cancer incidence and mortality. METHODS: Data from the Look AHEAD trial were examined to investigate whether participants randomized to ILI designed for weight loss would have reduced overall cancer incidence, obesity-related cancer incidence, and cancer mortality, as compared with the diabetes support and education (DSE) comparison group. This analysis included 4,859 participants without a cancer diagnosis at baseline except for nonmelanoma skin cancer. RESULTS: After a median follow-up of 11 years, 684 participants (332 in ILI and 352 in DSE) were diagnosed with cancer. The incidence rates of obesity-related cancers were 6.1 and 7.3 per 1,000 person-years in ILI and DSE, respectively, with a hazard ratio (HR) of 0.84 (95% CI: 0.68-1.04). There was no significant difference between the two groups in total cancer incidence (HR, 0.93; 95% CI: 0.80-1.08), incidence of nonobesity-related cancers (HR, 1.02; 95% CI: 0.83-1.27), or total cancer mortality (HR, 0.92; 95% CI: 0.68-1.25). CONCLUSIONS: An ILI aimed at weight loss lowered incidence of obesity-related cancers by 16% in adults with overweight or obesity and type 2 diabetes. The study sample size likely lacked power to determine effect sizes of this magnitude and smaller.

History of Cardiovascular Disease, Intensive Lifestyle Intervention, and Cardiovascular Outcomes in the Look AHEAD Trial.

OBJECTIVE: To examine the effects of an intensive lifestyle intervention (ILI) on cardiovascular disease (CVD), the Action for Health in Diabetes (Look AHEAD) trial randomized 5,145 participants with type 2 diabetes and overweight/obesity to a ILI or diabetes support and education. Although the primary outcome did not differ between the groups, there was suggestive evidence of heterogeneity for prespecified baseline CVD history subgroups (interaction P = 0.063). Event rates were higher in the ILI group among those with a CVD history (hazard ratio 1.13 [95% CI: 0.90-1.41]) and lower among those without CVD (hazard ratio 0.86 [95% CI: 0.72-1.02]). METHODS: This study conducted post hoc analyses of the rates of the primary composite outcome and components, adjudicated cardiovascular death, nonfatal myocardial infarction (MI), stroke, and hospitalization for angina, as well as three secondary composite cardiovascular outcomes. RESULTS: Interaction P values for the primary and two secondary composites were similar (0.060-0.064). Of components, the interaction was significant for nonfatal MI (P = 0.035). This interaction was not due to confounding by baseline variables, different intervention responses for weight loss and physical fitness, or hypoglycemic events. In those with a CVD history, statin use was high and similar by group. In those without a CVD history, low-density lipoprotein cholesterol levels were higher (P = 0.003) and statin use was lower (P ≤ 0.001) in the ILI group. CONCLUSIONS: Intervention response heterogeneity was significant for nonfatal MI. Response heterogeneity may need consideration in a CVD-outcome trial design.

Randomized trial of lifestyle modification and pharmacotherapy for obesity.

BACKGROUND: Weight-loss medications are recommended as an adjunct to a comprehensive program of diet, exercise, and behavior therapy but are typically prescribed with minimal or no lifestyle modification. This practice is likely to limit therapeutic benefits. METHODS: In this one-year trial, we randomly assigned 224 obese adults to receive 15 mg of sibutramine per day alone, delivered by a primary care provider in eight visits of 10 to 15 minutes each; lifestyle-modification counseling alone, delivered in 30 group sessions; sibutramine plus 30 group sessions of lifestyle-modification counseling (i.e., combined therapy); or sibutramine plus brief lifestyle-modification counseling delivered by a primary care provider in eight visits of 10 to 15 minutes each. All subjects were prescribed a diet of 1200 to 1500 kcal per day and the same exercise regimen. RESULTS: At one year, subjects who received combined therapy lost a mean (+/-SD) of 12.1+/-9.8 kg, whereas those receiving sibutramine alone lost 5.0+/-7.4 kg, those treated by lifestyle modification alone lost 6.7+/-7.9 kg, and those receiving sibutramine plus brief therapy lost 7.5+/-8.0 kg (P<0.001). Those in the combined-therapy group who frequently recorded their food intake lost more weight than those who did so infrequently (18.1+/-9.8 kg vs. 7.7+/-7.5 kg, P=0.04). CONCLUSIONS: The combination of medication and group lifestyle modification resulted in more weight loss than either medication or lifestyle modification alone. The results underscore the importance of prescribing weight-loss medications in combination with, rather than in lieu of, lifestyle modification.

Changes in Fasting and Prandial Gut and Adiposity Hormones Following Vertical Sleeve Gastrectomy or Roux-en-Y-Gastric Bypass: an 18-Month Prospective Study.

BACKGROUND: Vertical sleeve gastrectomy (VSG) and Roux-en-Y gastric bypass (RYGB) produce substantial weight loss, both primarily through gastric restriction but with potentially different hormonal signaling. This prospective, observational study compared changes in gut-derived hormones in VSG, RYGB, and weight-stable participants at 6 and 18 months post-surgery. METHODS: Sixty-four obese, non-diabetic women, including 18 VSG, 23 RYGB, and 23 weight-stable controls completed assessments at baseline and 6 months, before and after consuming a mixed-nutrient meal; blood sampling occurred for 180 min post-meal. Fifty-one participants completed the 18-month outcome. Change from baseline in post-prandial area under the curve (over 180 min) for GLP-1, PYY3-36, ghrelin, and leptin was measured at 6 and 18 months post-surgery. RESULTS: At 18 months, VSG and RYGB participants lost a mean (±SEM) of 25.5 ± 2.3% and 34.2 ± 4.2% of initial weight, respectively (p < 0.156), which both differed (p < 0.001) from the +1.7 ± 1.0% gain in the control group. Fasting ghrelin declined significantly more in VSG than RYGB participants at both months 6 (p = 0.0199) and 18 (p = 0.0003). In response to the mixed-nutrient meal, GLP-1 and PYY3-36 demonstrated an exaggerated post-prandial response that was significantly greater in RYGB than VSG at 6 months (p < 0.0001 and p = 0.0062, respectively) but not 18 months (p = 0.0296 and p = 0.1210). CONCLUSIONS: VSG and RYGB both produced substantial weight losses at 18 months. The data suggest a role of gastrointestinal hormones as mediators of weight loss.

Changes in neural responsivity to highly palatable foods following roux-en-Y gastric bypass, sleeve gastrectomy, or weight stability: An fMRI study.

OBJECTIVE: This prospective, observational fMRI study examined changes over time in blood oxygen level dependent (BOLD) response to high- and low-calorie foods (HCF and LCF) in bariatric surgery candidates and weight-stable controls. METHODS: Twenty-two Roux-en-Y gastric bypass (RYGB) participants, 18 vertical sleeve gastrectomy (VSG) participants, and 19 weight-stable controls with severe obesity underwent fMRI before and 6 months after surgery/baseline. BOLD signal change in response to images of HCF vs. LCF was examined in a priori regions of interest. RESULTS: RYGB and VSG participants lost 23.6% and 21.1% of initial weight, respectively, at 6 months, and controls gained 1.0%. Liking ratings for HCF decreased significantly in the RYGB and VSG groups but remained stable in the control group. BOLD response in the ventral tegmental area (VTA) to HCF (vs. LCF) declined significantly more at 6 months in RYGB compared to control participants but not in VSG participants. Changes in fasting ghrelin correlated positively with changes in VTA BOLD signal in both RYGB and VSG but not in control participants. CONCLUSIONS: Results implicate the VTA as a critical site for modulating postsurgical changes in liking of highly palatable foods and suggest ghrelin as a potential substrate requiring further investigation.

An open-label efficacy trial of escitalopram for night eating syndrome.

OBJECTIVE: Night eating syndrome (NES) has become increasingly recognized as a disorder in need of effective treatments. Selective serotonin reuptake inhibitors have shown efficacy in previous trials, so we sought to expand our understanding of the efficacy of escitalopram in the current trial. METHOD: Thirty-one adults with NES participated in a 12-week open-label trial of escitalopram. Outcome measures included the Night Eating Symptom Scale (NESS), percent of daily intake after the evening meal (% intake) and number of nocturnal ingestions/week (NI), weight, total awakenings/week, mood, and quality of life. Mixed-effects models were used to assess change over time. RESULTS: Significant reductions were observed from week 0 to week 12 for the NESS (30.2 to 15.2), % intake (46% to 17%), NI (5.8 to 1.2), weight (90.2 to 88.6 kg), awakenings (8.1 to 2.7), and BDI-II (12.1 to 7.7). Outcomes did not differ significantly by gender, age, race, or psychiatric co-morbidity status. Eighteen of 31 completed 12 weeks of treatment. DISCUSSION: This open-label trial of escitalopram showed significant reductions in symptoms associated with NES. Randomized controlled trials are warranted to test these findings. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT01401595.

Four-year change in cardiorespiratory fitness and influence on glycemic control in adults with type 2 diabetes in a randomized trial: the Look AHEAD Trial.

OBJECTIVE: To examine an intensive lifestyle intervention (ILI) compared with diabetes support and education (DSE) on 4-year change in fitness and physical activity (PA), and to examine the effect of change in fitness and PA, adjusting for potential confounders, on glycemic control in the Look AHEAD Trial. RESEARCH DESIGN AND METHODS: Subjects were overweight/obese adults with type 2 diabetes mellitus (T2DM) with available fitness data at 4 years (n = 3,942).This clinical trial randomized subjects to DSE or ILI. DSE subjects received standard care plus information related to diet, PA, and social support three times per year. ILI subjects received weekly intervention contact for 6 months, which was reduced over the 4-year period, and were prescribed diet and PA. Measures included weight, fitness, PA, and HbA1c. RESULTS: The difference in percent fitness change between ILI and DSE at 4 years was significant after adjustment for baseline fitness and change in weight (3.70 vs. 0.94%; P < 0.01). At 4 years, PA increased by 348 (1,562) kcal/week in ILI vs. 105 (1,309) kcal/week in DSE (P < 0.01). Fitness change at 4 years was inversely related to change in HbA1c after adjustment for clinical site, treatment, baseline HbA1c, prescribed diabetes medication, baseline fitness, and weight change (P < 0.01). Change in PA was not related to change in HbA1c. CONCLUSIONS: A 4-year ILI increased fitness and PA in overweight/obese individuals with T2DM. Change in fitness was associated with improvements in glycemic control, which provides support for interventions to improve fitness in adults with T2DM.

Effect of the look AHEAD study intervention on medication use and related cost to treat cardiovascular disease risk factors in individuals with type 2 diabetes.

OBJECTIVE: To examine the effect of a lifestyle intervention to produce weight loss and increased physical fitness on use and cost of medications to treat cardiovascular disease (CVD) risk factors in people with type 2 diabetes. RESEARCH DESIGN AND METHODS: Look AHEAD is a multicenter randomized controlled trial of 5,145 overweight or obese individuals with type 2 diabetes, aged 45-76 years. An intensive lifestyle intervention (ILI) involving group and individual meetings to achieve and maintain weight loss through decreased caloric intake and increased physical activity was compared with a diabetes support and education (DSE) condition. Medications prescribed to treat diabetes, hypertension, and hyperlipidemia were compared at baseline and 1 year. Medication costs were conservatively estimated using prices from a national online pharmacy. RESULTS: Participants randomized to an ILI had significantly greater improvements in CVD risk parameters and reduced medication use and cost compared with those assigned to DSE. At 1 year, average number of medications prescribed to treat CVD risk factors was 3.1 +/- 1.8 for the ILI group and 3.6 +/- 1.8 for the DSE group (P < 0.0001), with estimated total monthly medication costs of $143 and $173, respectively (P < 0.0001). DSE participants meeting optimal care goals at 1 year were taking an average of 3.8 +/- 1.6 medications at an estimated cost of $194/month. ILI participants at optimal care required fewer medications (3.2 +/- 1.7) at lower cost ($154/month) (P < 0.001). CONCLUSIONS: At 1 year, ILI significantly improved CVD risk factors, while at the same time reduced medication use and cost. Continued intervention and follow-up will determine whether these changes are maintained and reduce cardiovascular risk.

Changes in symptoms of depression with weight loss: results of a randomized trial.

Recent studies of rimonabant have re-awakened interest in the possible adverse psychiatric effects of weight loss, as well as of weight loss medications. This study examined changes in symptoms of depression in 194 obese participants (age = 43.7 +/- 10.2 years; BMI = 37.6 +/- 4.1 kg/m(2)) in a 1-year randomized trial of lifestyle modification and medication. Participants were assigned to (i) sibutramine alone; (ii) lifestyle modification alone; (iii) sibutramine plus lifestyle modification (i.e., combined therapy); or (iv) sibutramine plus brief therapy. Participants completed the Beck Depression Inventory-II (BDI-II) at baseline and weeks 6, 10, 18, 26, 40, and 52. At 1 year, participants in combined therapy lost the most weight and those in sibutramine alone the least (12.1 +/- 8.8% vs. 5.5 +/- 6.5%; P < 0.01). Mean BDI-II scores across all participants declined from 8.1 +/- 6.9 to 6.2 +/- 7.7 at 1 year (P < 0.001), with no significant differences among groups. Despite this favorable change, 13.9% of participants (across the four groups) reported potentially discernible increases (>or= 5 points on the BDI-II) in symptoms of depression at week 52. They lost significantly less weight than participants in the rest of the sample (5.4 +/- 7.8% vs. 9.0 +/- 7.8%, respectively; P < 0.03). The baseline prevalence of suicidal ideation was 3.6%. Seven new cases of suicidal ideation were observed during the year, with three in lifestyle modification alone. Further research is needed to identify characteristics of obese patients at risk of negative mood changes (and suicidal ideation) in response to behavioral and pharmacologic therapies.

Metabolic syndrome and health-related quality of life in obese individuals seeking weight reduction.

BACKGROUND: No previous research has examined the association between metabolic syndrome (MetSyn) and health-related quality of life (HRQoL) using standard criteria for defining MetSyn. We hypothesized that MetSyn would be associated with lower HRQoL on measures of physical and mental health. METHODS AND PROCEDURES: Participants were 361 individuals in two randomized weight loss trials. MetSyn was defined by the National Cholesterol Education Panel criteria. The Medical Outcomes Study, Short Form-36 (SF-36) was used to assess HRQoL. Differences in HRQoL and in clinical and psychosocial characteristics were compared among participants with and without MetSyn. Multiple regression was used to determine predictors of HRQoL. RESULTS: MetSyn was associated with lower scores on the physical function and general health subscales of the SF-36 and on the physical component summary (PCS) score. This association remained after controlling for age or depression but was eliminated by controlling for BMI. MetSyn was not associated with lower mental quality of life, a higher depression score, tobacco or alcohol use, or a higher rate of psychosocial stressors. DISCUSSION: Individuals with MetSyn reported lower HRQoL. This appeared to be an effect of increased weight, rather than a unique effect of MetSyn. Larger studies are needed to assess whether MetSyn may have an independent effect on HRQoL.