Fitness, Fatness, and Survival in Adults With Prediabetes
Fitness, Fatness, and Survival in Adults With Prediabetes
The ACLS is a prospective epidemiological investigation of participants that began in the 1970s. All patients underwent extensive health examinations at the Cooper Clinic in Dallas, Texas. Participants in the current study were drawn from a cohort of 17,967 men and women with pre-DM or impaired fasting glucose (defined as 100 mg/dL ≤ fasting plasma glucose < 126 mg/dL) and who completed a maximal exercise tolerance test at least once during 1974–2002. Participants were unpaid volunteers, sent by their employers, health care providers, or self-referred, and gave informed consent to join the study. The Cooper Institute Institutional Review Board reviewed and approved the study protocol annually.
Participants were excluded from the final analysis if they were underweight (BMI <18.5 kg/m) (n = 125); had a history of DM (n = 57), myocardial infarction (n = 26), stroke (n = 6), or cancer (n = 70); had an abnormal resting or exercise electrocardiogram (ECG) (n = 168); died during the first year of follow-up (n = 34); or had missing data on any one of the three adiposity measures (n = 437). These criteria resulted in 17,044 participants (1,910 women), aged 20–82 years, who were followed until date of death or 31 December 2003. Participants were predominantly white, well educated, and within the middle to upper socioeconomic strata. Additional information on study methods and characteristics of this cohort has previously been published.
A standardized medical examination by a physician, including personal and family histories, was completed for all participants before exercise testing. Blood pressure was measured with standard auscultatory methods after the participant had been seated for five minutes. Hypertension was defined as systolic blood pressure ≥140 mm Hg and/or diastolic blood pressure ≥90 mmHg or a physician diagnosis. Abnormal exercise ECG responses included rhythm and conduction disturbances and ischemic ST-T wave abnormalities as previously described in detail. Previously, we found 90% agreement between the ECG interpretation recorded in our database and a group of three physicians who read a random sample of 357 patient records. Fasting plasma glucose and total cholesterol levels were determined in the Cooper Clinic clinical chemistry laboratory, which participates in and meets the quality-control standards of the Centers for Disease Control and Prevention Lipid Standardization Program. DM was defined as a fasting glucose concentration of ≥126 mg/dL, previous physician diagnosis, or use of insulin. Hypercholesterolemia was defined as a total cholesterol concentration of ≥240 mg/dL or previous physician diagnosis. Personal history of myocardial infarction, stroke, hypertension, diabetes and cancer, family history of CVD, smoking habits, alcohol intake, and physical activity habits was obtained from a standardized questionnaire.
Symptom-limited maximal treadmill exercise testing was performed based on a modified Balke protocol as previously described. The test end point was volitional exhaustion or termination by the physician for medical reasons. Total test time correlates highly (r ≥ 0.92) with directly measured maximal oxygen uptake in both men and women. For standardized interpretation of exercise test performance, maximal METs (1 MET = 3.5 mL O2 uptake/kg/min) were estimated based on the final treadmill speed and grade. CRF was grouped for our primary analysis using age- and sex-specific tertiles of the maximal exercise duration.
Measures of adiposity included BMI, which was calculated from measured weight in kilograms divided by the square of measured height in meters; %BF, which was assessed with hydrostatic weighing, with the sum of seven skinfold measures, or with both assessments, following standardized protocols (a detailed description of our hydrodensiometry procedures has previously been published; and WC, which was measured at the level of the umbilicus. BMI exposure groups were based on standard clinical definitions: normal-weight BMI (18.5–24.9 kg/m), overweight (25.0–29.9 kg/m), and obese (≥30.0 kg/m). For groups based on %BF and WC, we used sex-specific tertiles from this population.
All participants were followed for mortality from the baseline date to the date of death or 31 December 2003. We used the National Death Index as the primary data source for mortality surveillance, augmented with official death certificates obtained from the department of vital records within the decedent's state of residence. The National Death Index has been shown to be an accurate method of ascertaining deaths in observational studies, having high sensitivity (96%) and specificity (100%). CVD mortality was determined using ICD-9 codes 390–449.9 before 1999 and ICD-10 codes 100–178 from 1999–2003.
Descriptive analyses summarized baseline characteristics of participants by sex and BMI groups. The mean levels of continuous variables were compared using ANOVA, while χ tests compared the distribution of categorical variable values. We used Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% CIs, according to exposure categories: CRF, BMI, %BF, or WC. In multivariable analyses, we adjusted for age, sex, baseline examination year, physical activity (active or inactive), smoking (current smoker or not), alcohol intake (>14 drinks/week or not), hypercholesterolemia, hypertension, and family history of CVD (present or not for each) (model 1). Then, we additionally adjusted for BMI, %BF, and WC when CRF was the exposure or for CRF (treadmill test duration in minutes) when BMI, %BF, or WC was the exposure (model 2).
To determine whether the association between adiposity and mortality in adults with pre-DM differed by age, we used BMI categories as exposure and examined the association in younger adults (<55 years) and older adults (≥55 years). We also examined whether this association varied by follow-up time, analyzing separately those participants who were followed <10 years and ≥10 years. And finally, we also examined this association separately by fasting glucose levels (100–109 vs. 110–125 mg/dL).
The joint effects of adiposity and CRF were examined by using combined groups as previously reported. We created six categories based on categories of BMI (normal-weight BMI, overweight, and obese), WC (tertiles), or %BF (tertiles) and dichotomized these into fit (middle and upper tertiles) and unfit (lower tertile). Reference groups were fit–normal weight, fit–lower WC, and fit–lower BF%, respectively. To further assess the effects of follow-up time and smoking, we repeated these analyses in subjects with ≥10 years of follow-up and in smokers versus nonsmokers. Cumulative hazard plots grouped by exposures suggested no appreciable violations of the proportional hazards assumption. Data analyses were performed using SPSS, version 20.0 (IBM), and all P values are two-sided with an α level of 0.05.
Research Design and Methods
The ACLS is a prospective epidemiological investigation of participants that began in the 1970s. All patients underwent extensive health examinations at the Cooper Clinic in Dallas, Texas. Participants in the current study were drawn from a cohort of 17,967 men and women with pre-DM or impaired fasting glucose (defined as 100 mg/dL ≤ fasting plasma glucose < 126 mg/dL) and who completed a maximal exercise tolerance test at least once during 1974–2002. Participants were unpaid volunteers, sent by their employers, health care providers, or self-referred, and gave informed consent to join the study. The Cooper Institute Institutional Review Board reviewed and approved the study protocol annually.
Participants were excluded from the final analysis if they were underweight (BMI <18.5 kg/m) (n = 125); had a history of DM (n = 57), myocardial infarction (n = 26), stroke (n = 6), or cancer (n = 70); had an abnormal resting or exercise electrocardiogram (ECG) (n = 168); died during the first year of follow-up (n = 34); or had missing data on any one of the three adiposity measures (n = 437). These criteria resulted in 17,044 participants (1,910 women), aged 20–82 years, who were followed until date of death or 31 December 2003. Participants were predominantly white, well educated, and within the middle to upper socioeconomic strata. Additional information on study methods and characteristics of this cohort has previously been published.
Clinical Evaluation
A standardized medical examination by a physician, including personal and family histories, was completed for all participants before exercise testing. Blood pressure was measured with standard auscultatory methods after the participant had been seated for five minutes. Hypertension was defined as systolic blood pressure ≥140 mm Hg and/or diastolic blood pressure ≥90 mmHg or a physician diagnosis. Abnormal exercise ECG responses included rhythm and conduction disturbances and ischemic ST-T wave abnormalities as previously described in detail. Previously, we found 90% agreement between the ECG interpretation recorded in our database and a group of three physicians who read a random sample of 357 patient records. Fasting plasma glucose and total cholesterol levels were determined in the Cooper Clinic clinical chemistry laboratory, which participates in and meets the quality-control standards of the Centers for Disease Control and Prevention Lipid Standardization Program. DM was defined as a fasting glucose concentration of ≥126 mg/dL, previous physician diagnosis, or use of insulin. Hypercholesterolemia was defined as a total cholesterol concentration of ≥240 mg/dL or previous physician diagnosis. Personal history of myocardial infarction, stroke, hypertension, diabetes and cancer, family history of CVD, smoking habits, alcohol intake, and physical activity habits was obtained from a standardized questionnaire.
Cardiorespiratory Fitness
Symptom-limited maximal treadmill exercise testing was performed based on a modified Balke protocol as previously described. The test end point was volitional exhaustion or termination by the physician for medical reasons. Total test time correlates highly (r ≥ 0.92) with directly measured maximal oxygen uptake in both men and women. For standardized interpretation of exercise test performance, maximal METs (1 MET = 3.5 mL O2 uptake/kg/min) were estimated based on the final treadmill speed and grade. CRF was grouped for our primary analysis using age- and sex-specific tertiles of the maximal exercise duration.
Adiposity Measures
Measures of adiposity included BMI, which was calculated from measured weight in kilograms divided by the square of measured height in meters; %BF, which was assessed with hydrostatic weighing, with the sum of seven skinfold measures, or with both assessments, following standardized protocols (a detailed description of our hydrodensiometry procedures has previously been published; and WC, which was measured at the level of the umbilicus. BMI exposure groups were based on standard clinical definitions: normal-weight BMI (18.5–24.9 kg/m), overweight (25.0–29.9 kg/m), and obese (≥30.0 kg/m). For groups based on %BF and WC, we used sex-specific tertiles from this population.
Mortality Surveillance
All participants were followed for mortality from the baseline date to the date of death or 31 December 2003. We used the National Death Index as the primary data source for mortality surveillance, augmented with official death certificates obtained from the department of vital records within the decedent's state of residence. The National Death Index has been shown to be an accurate method of ascertaining deaths in observational studies, having high sensitivity (96%) and specificity (100%). CVD mortality was determined using ICD-9 codes 390–449.9 before 1999 and ICD-10 codes 100–178 from 1999–2003.
Statistical Methods
Descriptive analyses summarized baseline characteristics of participants by sex and BMI groups. The mean levels of continuous variables were compared using ANOVA, while χ tests compared the distribution of categorical variable values. We used Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% CIs, according to exposure categories: CRF, BMI, %BF, or WC. In multivariable analyses, we adjusted for age, sex, baseline examination year, physical activity (active or inactive), smoking (current smoker or not), alcohol intake (>14 drinks/week or not), hypercholesterolemia, hypertension, and family history of CVD (present or not for each) (model 1). Then, we additionally adjusted for BMI, %BF, and WC when CRF was the exposure or for CRF (treadmill test duration in minutes) when BMI, %BF, or WC was the exposure (model 2).
To determine whether the association between adiposity and mortality in adults with pre-DM differed by age, we used BMI categories as exposure and examined the association in younger adults (<55 years) and older adults (≥55 years). We also examined whether this association varied by follow-up time, analyzing separately those participants who were followed <10 years and ≥10 years. And finally, we also examined this association separately by fasting glucose levels (100–109 vs. 110–125 mg/dL).
The joint effects of adiposity and CRF were examined by using combined groups as previously reported. We created six categories based on categories of BMI (normal-weight BMI, overweight, and obese), WC (tertiles), or %BF (tertiles) and dichotomized these into fit (middle and upper tertiles) and unfit (lower tertile). Reference groups were fit–normal weight, fit–lower WC, and fit–lower BF%, respectively. To further assess the effects of follow-up time and smoking, we repeated these analyses in subjects with ≥10 years of follow-up and in smokers versus nonsmokers. Cumulative hazard plots grouped by exposures suggested no appreciable violations of the proportional hazards assumption. Data analyses were performed using SPSS, version 20.0 (IBM), and all P values are two-sided with an α level of 0.05.
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