MNT: Weight Management (2015)
- To determine the independent and combined effects of diet induced weight loss and exercise on markers of chronic inflammation by using a single-blind randomized controlled intervention trial in older, overweight and obese men and women with knee osteoarthritis
- To determine the effects of 18 mo of exercise (EX) and diet-induced weight loss (WL) alone and in combination (WL+EX) on self-reported physical function and disability.
- Older (at least 60 years of age)
- Overweight or obese (body mass index at least 28kg/m2)
- Sedentary (less than 20 minutes of formal exercise per week for past six months)
- In the Winston-Salem area.
- Younger tha 60 years of age
- Not overweight or obese (BMI at or below 28kg/m2)
- Not sedentary (more than 20 minutes of formal exercise per week for the past six months).
Screening visits included a medical history review, physical examination, fasting blood profile and 12-lead resting electrocardiogram to exclude subjects who:
- Did not have radiographic evidence of tibiofemoral osteoarthritis
- Did not have knee pain
- Had contraindications for participation in an exercise program, severe hypertension, recent stroke, chronic obstructive pulmonary disease, type 1 diabetes, psychiatric disease, renal disease, liver disease, active cancer other than skin cancer or anemia
- Had cognitive impairment (Mini Mental State Examination score of less than 24)
- Consumed at least 14 alcoholic drinks per week.
- Recruitment: Recruited from the community surrounding Winston-Salem through mass mailings and media advertisements. The subjects were initially screened by telephone for major eligibility criteria before progressing to two screening visits in the Geriatric Research Clinic.
- Design: Randomized controlled intervention trial
- Blinding used: Single blinding (all staff involved in data collection were blinded to the treatment assignment of the participants).
Intervention
- Four treatment groups:
- Exercise
- Diet-induced weight loss
- Exercise and diet-induced weight loss
- Control group.
- Stratified by race: non-Hispanic white or African American
- Variable block randomization method
- 18-month intervention divided into three phases:
- Intensive (Months One to Four)
- Major emphasis was to heighten awareness of the need to change eating habits to lower energy intake
- One introductory individual session was followed by 16 sessions (three group sessions and one individual session per month)
- Each group session included problem-solving, the review of a specific topic and food-tasting of several well-balanced, low-fat, nutritious foods prepared with widely available ingredients
- The individual sessions were used to review individual progress, solve problems, answer questions and set goals
- Body weight was measured weekly for both the WL and WL+EX Groups and
was recorded to the nearest 0.05kg.
- Transition (Months Five to Six)
- Eight weeks of biweekly contacts (three group and one individual session)
- Goals for this phase included:
- Assisting the participants who had not reached their weight goals to re-establish new goals
- Maintaining and preventing relapse in the participants who had reached their weight-loss goals.
- Maintenance (Months Seven to 18)
- Included monthly meetings and phone contacts every two weeks
- Newsletters were mailed regularly that provided pertinent nutritional information and notice of upcoming meetings
- Goals included:
- Assisting participants who had reached their weight loss goals to maintain their weight loss
- Providing counsel for participants who had a difficult time losing weight and adhering to the intervention.
- Intensive (Months One to Four)
- Adherence to the intervention was based on attendance at scheduled sessions and monthly weight assessments.
Statistical Analysis
- Performed by using SAS software, version 8
- Descriptive statistics were calculated for each treatment group (WL, EX, WL+EX and Control) for each assessment (baseline, six months and 18 months)
- Raw values are reported as means ±SDs unless otherwise indicated
- Logarithmic transformation of CRP, IL-6, TNF-a, sTNFR1 and sTNFR2 was used to satisfy the model assumptions (normally distributed errors and linear relations): The only cytokine not transformed was IL-6sR
- Repeated-measures analysis of covariance was used to model each outcome variable separately by using the SAS mixed procedure
- Since the primary focus was on change, the outcome used was the change from baseline
- A random effect of subject was included that accounted for the within-subject correlation at the repeated measurements
- The baseline value of the outcome variable, diet-induced weight loss (yes or no), exercise (yes or no), sex, race (white vs. non-white), follow-up assessment (six vs. 18 months) and baseline BMI were included as fixed effects in the model
- There was no evidence of a weight loss-exercise interaction (P>0.19 in all cases); thus, no interaction term was included
- A supplementary analysis included six- and 18-month BMI in the model to assess whether the treatments had an effect above and beyond that explained by a change in BMI
- To describe the models, adjusted means are reported as means ±SEs for categorical predictors and slopes are reported for continuous predictors
- Spearman’s rank correlation coefficient was used to examine the relations between change from baseline in cytokines and changes from baseline in BMI at six and 18 months
- No adjustment for multiple comparisons or for number of variables was made.
Timing of Measurements
Measurements taken at baseline, six months and 18 months:
- Body weight was measured and blood was collected in the morning (between 7:00 a.m. and 9:00 a.m.) via venipuncture after the participants had fasted overnight
- Information concerning comorbid conditions was obtained from a medical history, information on medication use was collected and a physical examination was performed.
Dependent Variables
- Fasting serum concentrations of IL-6, TNF-a, soluble IL-6 receptor (IL-6sR), soluble TNF-a receptor 1 (sTNFR1), soluble TNF-a receptor 2 (sTNFR2) and CRP were measured by enzyme-linked immunosorbent assays
- All samples were measured in duplicate and the average of the two values was used for
data analyses - Duplicate samples that did not provide a CV under 15% were re-analyzed and all values were averaged for data analyses
- All cytokines were measured by using Quantikine immunoassay kits (high-sensitivity for IL-6 and TNF-a) from R&D Systems (Minneapolis)
- The inter- and intraassay CVs for IL-6 were 7.3% and 3.5%, respectively
- The inter- and intraassay CVs for TNF-a were 11.8% and 6.2%%, respectively
- The inter- and intraassay CVs for the soluble receptor assays were less than 5%
- The inter- and intraassay CVs for the CRP assay (ALPCO, Windham, NH) were 8% and 6.7%, respectively.
- All samples were measured in duplicate and the average of the two values was used for
Independent Variables
- Diet program
- Goal was to produce and maintain an average weight loss of 5% of baseline body
weight for the duration of the 18-month intervention - Subjects were initially counseled to decrease their energy intake by 500kcal per day, thus allowing for a loss of approximately 0.5kg body weight per week.
- Goal was to produce and maintain an average weight loss of 5% of baseline body
- Exercise program
- The three-day-per-week exercise program consisted of an aerobic phase (15 minutes), a resistance-training phase (15 minutes), a second aerobic phase (15 minutes) and a cool-down phase (15 minutes)
- The first four months of the 18-month intervention was facility-based. After the first four months, participants who wished to exercise at home underwent a two-month transition phase in which they alternated between the facility and the home
- After the first four months of facility-based exercise, 64% of the subjects in the two exercise groups remained in the facility-based program, 24% opted for the home-based program and 12% of the subjects chose a combined facility-home-based program
- The participants were provided with an aerobic exercise prescription that included walking within a heart rate range of 50% to 75% of heart rate reserve
- The resistance training portion of the program consisted of two sets of 12 repetitions of the following exercises: Leg extension, leg curl, heel raise and step-up
- Cuff weights and weighted vests were used to provide resistance
- A one- to 1.5-minute rest interval separated each exercise
- After two orientation sessions, the participants began with the lowest possible resistance
- Weight was increased after the participant performed two sets of 12 repetitions for two consecutive days
- For the participants in the home-based program, weights were exchanged at the participant’s request or after a determination was made to increase weight during face-to-face or telephone contact
- Telephone contacts were made bi-weekly during the first two months of home-based exercise, tri-weekly during the following two months and monthly thereafter
- Exercise and attendance logs were used to gather data and monitor progress
- Exercise compliance was defined as the number of exercise sessions completed divided
by the total number of prescribed sessions.
Control Variables
- Control Group
- Served as a Comparison Group and was designed to provide attention, social interaction and health education
- Met monthly for one hour for the first three months and discussed topics concerning osteoarthritis, obesity and exercise
- Question and answer sessions followed each presentation
- Monthly phone contact was maintained during Months Four to Six and bi-monthly contact was maintained during Months Seven through 18: During each phone contact, information on pain, medications, illnesses and hospitalization was obtained.
Initial N
316 subjects.
Attrition (Final N)
- 252 (80%) completed the study (returned for the final data collection visit)
- Blood was available for analysis from 272 subjects at baseline, 242 subjects at six months and 219 subjects at 18 months
- Analyses were conducted on data from subjects with a baseline blood sample and at least one follow-up sample.
Age
Dietary Weight Loss Group | Exercise Group | Dietary weight loss + Exercise Group | Control Group | |
N | 71 | 67 | 64 | 70 |
Age (years) | 68±52 | 69±6 | 68±7 | 69±6 |
Ethnicity
Dietary Weight Loss Group | Exercise Group | Dietary weight loss + Exercise Group | Control Group | |
N | 71 | 67 | 64 | 70 |
Non-White (%) | 27 | 20 | 21 | 19 |
Other relevant demographics:
Dietary Weight Loss Group | Exercise Group | Dietary weight loss + Exercise Group | Control Group | |
N | 71 | 67 | 64 | 70 |
Women (%) | 74 | 74 | 74 | 65 |
Baseline CRP (mcg/ml) | 6.0±6.5 | 6.8±7.8 | 6.5±7.9 | 5.9±6.0 |
Baseline IL-6 (pg/ml) | 4.7±3.4 | 4.4±3.1 | 4.9±3.0 | 4.7±3.2 |
Baseline IL-6sR (pg/ml) | 35,197±8,911 | 34,581±9,596 | 35,156±11,075 | 38,040±10,764 |
Baseline TNF-a (pg/ml) | 2.5±1.8 | 3.4±4.8 | 3.4±6.4 | 3.8±7.5 |
Baseline sTNFR1 (pg/ml) | 1,409±470 | 1,433±404 | 1,395±397 | 1,464±421 |
Baseline sTNFR2 (pg/ml) | 2,674±842 | 2,760±807 | 2,656±792 | 2,850±1,127 |
Anthropometrics
Dietary Weight Loss Group | Exercise Group | Dietary weight loss + Exercise Group | Control Group | |
N | 71 | 67 | 64 | 70 |
Baseline Body Weight (kg) | 95.6±15.2 | 92.4±14.6 | 91.8±17.4 | 95.7±18.8 |
Baseline BMI (kg/m2) | 34.4±4.9 | 34.6±5.8 | 33.9±5.6 | 34.5±5.3 |
Location
Winston-Salem, NC.
Key Findings
N | Change BMI Spearman's correlation coefficient |
P-Value | ||
Change CRP | Six months | 242 | 0.11 | 0.08 |
18 months | 214 | 0.07 | 0.30 | |
Change IL-6 | Six months | 229 | -0.06 | 0.36 |
18 months | 208 | 0.00 | 0.95 | |
Change IL-6sR | Six months | 231 | 0.04 | 0.59 |
18 months | 210 | -0.12 | 0.09 | |
Change TNF-a | Six months | 232 | 0.16 | 0.02 |
18 months | 210 | -0.06 | 0.40 | |
Change sTNFR1 | Six months | 240 | 0.25 | <0.0001 |
18 months | 219 | 0.18 | 0.007 | |
Change sTNFR2 | Six months | 240 | 0.18 | 0.006 |
18 months | 219 | 0.11 | 0.10 |
Other Findings
- Subjects in the WL Group lost 5.7% of their baseline body weight and reduced their BMI by 2.0 during the 18-month intervention
- Subjects in the WL+EX Group lost 4.4% of their baseline body weight and reduced their BMI by 1.48 (P<0.0001 relative to the Control Group)
- Body weight did not change significantly in the EX Group (-2.6%) relative to the Control Group (-1.3%).
C-Reactive Protein
- CRP concentrations decreased more in subjects in the WL Group than in subjects who did not undergo weight loss (i.e., those in the EX and Control Groups): Change in delta log CRP, -0.26±0.07mcg compared with 0.04±0.07mcg per ml; P=0.01
- There was a significant effect of sex, such that CRP decreased more in men than in women (delta log CRP, -0.29±0.09mcg compared with -0.02±0.06mcg per ml; P=0.0062), but there was no significant effect of race (P=0.88).
Interleukin 6 and Soluble Interleukin 6 Receptor
- There was a significant main effect of WL (P=0.009) but not EX (P=0.86) on changes in IL-6 concentrations: IL-6 concentrations decreased more in subjects in the WL Group than in subjects who did not undergo weight loss (delta log IL-6, -0.13±0.04pg compared with -0.01±0.04pg per ml)
- There was an overall effect of race: IL-6 concentrations decreased more in non-white than in white subjects (delta log IL-6, -0.13±0.06pg compared with -0.01±0.03pg per ml; P=0.042)
- There was a marginally significant racial difference, however, IL-6sR concentrations decreased more in non-white than in white subjects (delta log IL-6sR, -2,205±747pg compared with -639±367pg per ml; P=0.055)
Tumor necrosis factor a and soluble tumor necrosis factor receptors
- In the WL Group, TNF-a concentrations decreased more in non-white than in white subjects (delta log TNF-a, -0.20±0.08pg compared with -0.01±0.04pg per ml; P =0.017)
- Diet-induced WL resulted in a significant reduction in sTNFR1 concentrations, compared with no WL (delta log sTNFR1, -0.070±0.017pg compared with -0.013±0.017pg per ml; P=0.007)
- sTNFR1 concentrations decreased more in non-white than in white subjects (delta log sTNFR1, -0.084±0.02pg compared with 0.002±0.01pg per ml; P=0.001)
- There was a marginally significant racial difference: sTNFR2 concentrations decreased more in non-white than in white subjects (delta log sTNFR2, -0.046±0.02pg compared with 0.001±0.01pg per ml; P=0.07).
Ratios of cytokines to cytokine receptors
There were no significant effects of WL, EX, sex or race on IL-6/IL-6sR, TNF-a/sTNFR1, TNF-a/sTNFR2 or TNF-a/R1+R2, except that race was significant at 0.0494 as a predictor of TNF-a/sTNFR2 (with white subjects having higher ratios).
Association between changes in BMI and changes in markers of inflammation
Changes in the soluble TNF-a receptors but not in CRP or other cytokines correlated directly with changes in BMI.
Secondary analysis showed
- BMI was marginally significant (beta=0.029, P=0.057) as a predictor of CRP concentrations, but there was still a significant effect of WL on changes in CRP (P=0.020).
- BMI was not a significant predictor of IL-6 concentrations (beta=-0.004, P=0.60) and there was still a significant effect of WL (P=0.008)
- BMI was a strong predictor of sTNFR1 concentrations (beta=0.0092, P=0.007), but there was still a significant effect of WL (P=0.019).
- The results of the present randomized controlled trial in older, obese men and women with knee osteoarthritis showed that 18 months of a dietary weight-loss intervention reduced circulating concentrations of CRP, IL-6 and sTNFR1
- Except for sTNFR1, the effect of the intervention was independent of changes in body weight
- Additional studies with larger sample sizes are needed to explore the possibility of sex and race differences in the response of these inflammatory biomarkers to weight loss
- In addition, more trials are needed to assess the effects of different modes and intensities of exercise on inflammation.
University/Hospital: | Wake Forest University Claude D Pepper Older Americans Independence Center from the National Institute of Aging (P60 AG10484) and Wake Forest University School of Medicine General Clinical Research Center (M01-RR00211) |
Quality Criteria Checklist: Primary Research
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Relevance Questions | |||
1. | Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies) | Yes | |
2. | Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about? | Yes | |
3. | Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice? | Yes | |
4. | Is the intervention or procedure feasible? (NA for some epidemiological studies) | Yes | |
Validity Questions | |||
1. | Was the research question clearly stated? | Yes | |
1.1. | Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? | Yes | |
1.2. | Was (were) the outcome(s) [dependent variable(s)] clearly indicated? | Yes | |
1.3. | Were the target population and setting specified? | Yes | |
2. | Was the selection of study subjects/patients free from bias? | Yes | |
2.1. | Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study? | Yes | |
2.2. | Were criteria applied equally to all study groups? | Yes | |
2.3. | Were health, demographics, and other characteristics of subjects described? | Yes | |
2.4. | Were the subjects/patients a representative sample of the relevant population? | ??? | |
3. | Were study groups comparable? | Yes | |
3.1. | Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) | Yes | |
3.2. | Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? | Yes | |
3.3. | Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) | Yes | |
3.4. | If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis? | N/A | |
3.5. | If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.) | N/A | |
3.6. | If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? | N/A | |
4. | Was method of handling withdrawals described? | Yes | |
4.1. | Were follow-up methods described and the same for all groups? | ??? | |
4.2. | Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.) | Yes | |
4.3. | Were all enrolled subjects/patients (in the original sample) accounted for? | Yes | |
4.4. | Were reasons for withdrawals similar across groups? | ??? | |
4.5. | If diagnostic test, was decision to perform reference test not dependent on results of test under study? | N/A | |
5. | Was blinding used to prevent introduction of bias? | Yes | |
5.1. | In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? | Yes | |
5.2. | Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.) | Yes | |
5.3. | In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? | N/A | |
5.4. | In case control study, was case definition explicit and case ascertainment not influenced by exposure status? | N/A | |
5.5. | In diagnostic study, were test results blinded to patient history and other test results? | N/A | |
6. | Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described? | Yes | |
6.1. | In RCT or other intervention trial, were protocols described for all regimens studied? | Yes | |
6.2. | In observational study, were interventions, study settings, and clinicians/provider described? | N/A | |
6.3. | Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect? | Yes | |
6.4. | Was the amount of exposure and, if relevant, subject/patient compliance measured? | Yes | |
6.5. | Were co-interventions (e.g., ancillary treatments, other therapies) described? | No | |
6.6. | Were extra or unplanned treatments described? | No | |
6.7. | Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? | Yes | |
6.8. | In diagnostic study, were details of test administration and replication sufficient? | N/A | |
7. | Were outcomes clearly defined and the measurements valid and reliable? | Yes | |
7.1. | Were primary and secondary endpoints described and relevant to the question? | Yes | |
7.2. | Were nutrition measures appropriate to question and outcomes of concern? | Yes | |
7.3. | Was the period of follow-up long enough for important outcome(s) to occur? | Yes | |
7.4. | Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? | Yes | |
7.5. | Was the measurement of effect at an appropriate level of precision? | Yes | |
7.6. | Were other factors accounted for (measured) that could affect outcomes? | No | |
7.7. | Were the measurements conducted consistently across groups? | Yes | |
8. | Was the statistical analysis appropriate for the study design and type of outcome indicators? | Yes | |
8.1. | Were statistical analyses adequately described and the results reported appropriately? | Yes | |
8.2. | Were correct statistical tests used and assumptions of test not violated? | Yes | |
8.3. | Were statistics reported with levels of significance and/or confidence intervals? | Yes | |
8.4. | Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)? | No | |
8.5. | Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? | No | |
8.6. | Was clinical significance as well as statistical significance reported? | Yes | |
8.7. | If negative findings, was a power calculation reported to address type 2 error? | No | |
9. | Are conclusions supported by results with biases and limitations taken into consideration? | Yes | |
9.1. | Is there a discussion of findings? | Yes | |
9.2. | Are biases and study limitations identified and discussed? | Yes | |
10. | Is bias due to study's funding or sponsorship unlikely? | Yes | |
10.1. | Were sources of funding and investigators' affiliations described? | Yes | |
10.2. | Was the study free from apparent conflict of interest? | Yes | |