Supplementary Online Content

Supplementary Online Content Sigal RJ, Alberga AS, Goldfield GS, et al. Effects of aerobic training, resistance training, or both on percentage body fat and cardiometabolic risk markers in obese adolescents: the Healthy Eating Aerobic and Resistance Training in Youth randomized clinical trial. JAMA Pediatr. Published online September 22, 2014. doi:10.1001/jamapediatrics.2014.1392 etable 1. Inclusion and Exclusion Criteria etable 2. Run-in Training Program etable 3. Aerobic Training Program etable 4. Resistance Training Program etable 5. Resistance Training Exercises etable 6. Participants on Medications by Group Assignment etable 7. Overall Adverse Events by Study Group etable 8. Adverse Events by Study Group Related and Unrelated to Participation in the HEARTY Trial etable 9. Per-Protocol Analysis: Percent Body Fat and Lean Body Mass at Baseline and Changes After 6 Months etable 10. Per-Protocol Analysis: Anthropometry and Blood Pressure at Baseline and Changes After 3 and 6 Months etable 11. Cardiometabolic Risk Markers at Baseline and Changes After 3 and 6 Months etable 12. Changes in Cardiorespiratory Fitness (VO 2peak and Treadmill Time) and Muscular Strength (Leg Press, Bench Press and Seated Row) in the Aerobic, Resistance, Combined and Control Groups etable 13. Per-Protocol Analysis: Changes in Energy Intake (3-Day Food Diaries) and Background Physical Activity (7-Day Pedometer Logs) in the Aerobic, Resistance, Combined and Control Groups This supplementary material has been provided by the authors to give readers additional information about their work. 2014 American Medical Association. All rights reserved. 1

etable 1. Inclusion and Exclusion Criteria. Inclusion Criteria 1. Body Mass Index >95 th percentile for age, and sex (http:www.cdc.gov/growthcharts) AND/OR >85 th percentile for age/sex with an additional diabetes risk factor: Fasting glucose >6.0 mmol./l fasting, 2-hour plasma glucose 7.8-11 mmol/l after 75 g oral glucose (impaired glucose tolerance), fasting triglycerides > 1.7 mmol/l, fasting plasma insulin >105 pmol/l, HDL-C<0.9 mmol/l, LDL-C>3.0 mmol/l, total cholesterol/hdl-c >90 th percentile, or first degree relative with type 2 diabetes. 2. Waist circumference was required to be >75 th percentile for age and sex [31] so participants with high BMI primarily because they were muscular would not qualify. 3. Age 14-18 years at time of screening. 4. Post-pubertal (Tanner stage IV or V) [32]. 5. Sedentary for at least 4 prior to enrollment. Exclusion Criteria 1. Participation during the previous 4 in a regular program of exercise or aerobic sports > 2 times per week for at least 20 minutes per session. 2. Diabetes mellitus 3. Body weight over 159 kg, and/or BMI>45 kg/m 2, exceeding capacity of the MRI machine 4. Use of any performance-enhancing medication 5. Use of medication, or herbal supplement likely to affect, body composition, lipids or glucose metabolism. Metformin use was permitted if participants were on metformin prior to enrollment and the dose was not altered throughout the trial. We asked that initiation of, or changes in antihypertensive, lipid- and glucose-lowering medications would not be made during the intervention period unless considered medically imperative. 6. Significant weight change (increase or decrease of >5% during the two before enrollment). 7. Uncontrolled hypertension: Blood pressure >150 mm Hg systolic or >95 mm Hg diastolic in sitting position. 8. Activity restrictions due to disease: unstable cardiac or pulmonary disease, significant arthritis. 9. Other illness (i.e. eating disorders/clinical depression) judged by the subject or study physician to make participation in this study inadvisable. 10. Unwillingness/lack of availability to attend exercise and/or nutrition sessions at scheduled times and locations. 11. Significant cognitive deficit resulting in inability to understand or comply with instructions. 12. Pregnancy at the start of the study, or intention to become pregnant in the next year. 13. Inability to communicate in English or French. 14. Unwillingness of participant and/or guardian to sign informed consent. Adapted from Contemp Clin Trials. 2012;33(4):839-47. Alberga AS, Goldfield GS, Kenny GP, Hadjiyannakis S, Phillips P, Prud homme D, Tulloch H, Gougeon R, Wells GA, Sigal RJ. Healthy Eating, Aerobic and Resistance Training in Youth (HEARTY): Study rationale, design and methods, with permission from Elsevier. 2014 American Medical Association. All rights reserved. 2

etable 2. Run-in training program. Aerobic Training Resistance Training Week # Duration (min/day) Intensity (% HRmax) Frequency (sessions/week) Sets Reps Weight (RM) Frequency (sessions/week) 1 15 65 4 1 15 15 4 2 20 65 4 2 15 15 4 3 25 65 4 2 15 15 4 4 30 65 4 3 15 15 4 Abbreviations: % HRmax= Percentage of the Maximum Heart Rate achieved from the maximal exercise test to assess cardiorespiratory fitness (VO 2peak ); REPS= Repetitions; RM= Repetition Maximum (the 15 th repetition is the last repetition that can be done with proper technique and form) Adapted from Contemp Clin Trials. 2012;33(4):839-47. Alberga AS, Goldfield GS, Kenny GP, Hadjiyannakis S, Phillips P, Prud homme D, Tulloch H, Gougeon R, Wells GA, Sigal RJ. Healthy Eating, Aerobic and Resistance Training in Youth (HEARTY): Study rationale, design and methods, with permission from Elsevier. 2014 American Medical Association. All rights reserved. 3

etable 3. Aerobic training program. Week No. Frequency (days/wk) Work load Session 1 & 3 Duration /Intensity (%HR max ) Work load Session 2 & 4 Duration /Intensity (%HR max ) 5 4 20 min 70% 10 min 75% / 10 min 65% 6 4 20 min 70% 15 min 75% / 10 min 65% 7 4 25 min 70% 20 min 75% / 10 min 65% 8 4 25 min 75% 20 min 75% / 10 min 70% 9 4 25 min 75% 20 min 75% / 15 min 70% 10 4 25 min 75% 20 min 75% / 10 min 65% / 5 min 75% 11 4 25 min 75% 20 min 75% / 10 min 65% / 10 min 75% 12 4 25 min 80% 20 min 75% / 10 min 65% / 15 min 75% 13 4 25 min 80% 15 min 80% / 10 min 65% / 10 min 80% 14 4 25 min 80% 20 min 80% / 10 min 65% / 10 min 80% 15 4 30 min 75% 20 min 80% / 10 min 65% / 15 min 80% 16 4 30 min 75% 20 min 80% / 10 min 65% / 15 min 80% 17 4 30 min 75% 20 min 80% / 10 min 65% / 15 min 80% 18 4 30 min 75% 25 min 80% / 10 min 65% / 10 min 80% 19 4 30 min 80% 25 min 80% / 10 min 65% / 10 min 80% 20 4 30 min 80% 25 min 80% / 10 min 65% / 15 min 80% 21 4 35 min 80% 25 min 80% / 10 min 65% / 15 min 80% 22 4 35 min 80% 25 min 80% / 10 min 65% / 10 min 80% 23 4 35 min 80% 20 min 85% / 10 min 65% / 10 min 85% 24 4 35 min 80% 20 min 85% / 10 min 65% / 15 min 85% 25 4 35 min 80% 20 min 85% / 10 min 65% / 15 min 85% 26 4 35 min 80% 20 min 85% / 10 min 65% / 10 min 85% Abbreviations: % HRmax= Percentage of the Maximum Heart Rate achieved from the maximal exercise test to assess cardiorespiratory fitness (VO 2peak ) Adapted from Contemp Clin Trials. 2012;33(4):839-47. Alberga AS, Goldfield GS, Kenny GP, Hadjiyannakis S, Phillips P, Prud homme D, Tulloch H, Gougeon R, Wells GA, Sigal RJ. Healthy Eating, Aerobic and Resistance Training in Youth (HEARTY): Study rationale, design and methods, with permission from Elsevier. 2014 American Medical Association. All rights reserved. 4

etable 4. Resistance training program. Week No. Frequency (days/week) Work load Session 1 & 3 # of Repetitions Per Set Work load Session 2 & 4 # of Repetitions Per Set 1 2 3 1 2 3 5 4 15 15 15 15 15 6 4 15 15 15 15 15 7 4 15 15 15 15 15 8 4 12 12 15 15 9 4 12 12 15 15 10 4 12 12 12 15 15 11 4 12 12 12 15 15 12 4 10 10 10 15 15 13 4 10 10 10 12 12 14 4 10 10 10 12 12 15 4 8 8 8 12 12 16 4 8 8 8 12 12 17 4 8 8 8 12 12 18 4 8 8 8 10 10 19 4 8 8 8 10 10 20 4 8 8 8 10 10 21 4 6 6 6 10 10 22 4 6 6 6 10 10 23 4 6 6 6 10 10 24 4 6 6 6 10 10 25 4 6 6 6 10 10 26 4 6 6 6 10 10 Adapted from Contemp Clin Trials. 2012;33(4):839-47. Alberga AS, Goldfield GS, Kenny GP, Hadjiyannakis S, Phillips P, Prud homme D, Tulloch H, Gougeon R, Wells GA, Sigal RJ. Healthy Eating, Aerobic and Resistance Training in Youth (HEARTY): Study rationale, design and methods, with permission from Elsevier. 2014 American Medical Association. All rights reserved. 5

etable 5. Resistance training exercises. A1 A2 B1 B2 Bench press Chest fly Lateral raise Shoulder shrugs Bicep curl Tricep press Abdominal crunches Incline bench press Incline chest fly Shoulder press Front raise Preacher curl Assisted tricep dips Sit-ups Squat Leg curl Front lateral pull down Seated row Lunge Straight leg raise Abdominal crunches Leg press Leg extension Dumbbell pullover Seated row Lying knee extensions Adapted from Contemp Clin Trials. 2012;33(4):839-47. Alberga AS, Goldfield GS, Kenny GP, Hadjiyannakis S, Phillips P, Prud homme D, Tulloch H, Gougeon R, Wells GA, Sigal RJ. Healthy Eating, Aerobic and Resistance Training in Youth (HEARTY): Study rationale, design and methods, with permission from Elsevier. 2014 American Medical Association. All rights reserved. 6

etable 6. Participants on medications by group assignment. Type of Medication Group N Metformin (N=5) Aerobic 2 Resistance 1 Combined 1 Control 1 Oral Contraceptives (N=46) (Alesse, Diane, Linessa, Marvelon, Minovral, Ortho Evra Patch, Tricyclen, Yasmin, not specified) Stimulants (N=8) (Methylphenidate or Dextroamphetamine in various formulations) Aerobic 12 Resistance 13 Combined 5 Control 16 Aerobic 1 Resistance 1 Combined 3 Control 3 2014 American Medical Association. All rights reserved. 7

etable 7. Overall adverse events by study group*. Adverse Events Combined Training Group (n = 75) Aerobic Training Group (n = 75) Resistance Training Group (n = 78) Serious adverse events & hospitalizations 0 (0) 0 (0) 0 (0) 0 (0) Any injury or musculoskeletal discomfort 17 (23) 12 (16) 15 (19) 10 (13) Injury requiring modification of exercise program or restriction of activity 9 (12) 8 (11) 10 (13) 2 (3) Withdrawal for medical reasons 0 (0) 2 (3) 0 (0) 0 (0) All participants with adverse events 19 (25) 14 (19) 16 (21) 18 (24) Type of Adverse Event Upper body (neck, shoulders, upper back, arms) 7 (9) 3 (4) 4 (5) 6 (8) Lower body (lower back, hips, knees, ankle, feet) 8 (11) 9 (12) 10 13) 4 (5) Musculoskeletal injury due to accident while exercising (dropping weight) 2 (3) 0 (0) 1 (1) 0 (0) Anxiety or depression 0 (0) 1 (1) 0 (0) 3 (4) Headache 0 (0) 0 (0) 0 (0) 1 (1) Fainting 0 (0) 0 (0) 0 (0) 1 (1) Respiratory infection 0 (0) 0 (0) 1 (1) 1 (1) Other 2 (3) 1 (1) 0 (0) 2 (3) *Data are the number (percentage) of participants. Percentages are rounded to the nearest 1%. injuries in the control group related to intervention occurred during run-in (prior to randomization). Includes 1 case each of post-exertional malaise, chest pain, kidney infection, ovarian cyst, accidental drug overdose. Control Group (n = 76) 2014 American Medical Association. All rights reserved. 8

etable 8. Adverse events by study group related and unrelated to participation in the HEARTY trial.* Adverse Events [n (percent)] Combined Training Group (n = 75) Aerobic Training Group (n = 75) Resistance Training Group (n = 78) Control Group (n = 76) Relationship to exercise intervention related unrelated related unrelated related unrelated related unrelated Serious adverse events & Hospitalizations 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Any injury or musculoskeletal discomfort 7 (9) 10 (13) 3 (4) 9 (12) 6 (8) 9 (12) 1 (1) 9 (12) Upper body injury (neck, shoulders, upper back, arms) Lower body injury (lower back, hips, knees, ankle, feet) Musculoskeletal injury due to accident while exercising (dropping weight) Injury required modification of exercise program or restriction of activity 3 (4) 4 (5) 0 (0) 3 (4) 1 (1) 3 (4) 1 (1) 5 (7) 2 (3) 6 (8) 3 (4) 6 (8) 4 (5) 6 (8) 0 (0) 4 (5) 2 (3) 0 (0) 0 (0) 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) 3 (4) 6 (8) 1 (1) 7 (9) 3 (4 ) 7 (9) 1 (1) 1 (1) All participants with Medical AEs 2 (3) 0 (0) 0 (0) 2 (3) 0 (0) 1 (1) 0 (0) 8 (11) Mental Health (anxiety, depression) 0 (0) 0 (0) 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) 3 (4) Neurological (headache, fainting) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 2 (3) Respiratory (cold/flu, pneumonia) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (1) 0 (0) 1 (1) Other 2 (3) 0 (0) 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) 2 (3) Withdrawal for medical reasons 0 (0) 0 (0) 0 (0) 2 Z (3) 0 (0) 0 (0) 0 (0) 0 (0) *Data are the number (percentage) of participants. Percentages are rounded to the nearest 1%. Injuries in the control group related to intervention occurred during run-in (prior to randomization). Includes 1 case each of post-exertional malaise, chest pain, kidney infection, ovarian cyst, accidental drug overdose. Z Fractured hip from a fall at school (1 participant) and fractured forearm while playing football (1 participant). 2014 American Medical Association. All rights reserved. 9

etable 9. Per-protocol analysis: Percent body fat and lean body mass at baseline and changes after 6. Variable N Baseline 6 Within-group change from baseline to 6 Intergroup difference in change from baseline to 6 Mean (SE) Mean (95% Confidence Interval) Percent body fat (%) Aerobic 35 48.7 (0.8) 47.5 (0.9) -1.2 (-2.0, -0.5)** Resistance 23 49.4 (1.0) 47.7 (1.1) -1.6 (-2.5, -0.8)*** Combined 29 50.1 (0.9) 47.7 (1.0) -2.4 (-3.2, -1.6)*** Control 57 48.3 (0.7) 48.0 (0.7) -0.3 (-0.9, 0.3) Aerobic vs. control -0.9 (-1.9, 0) Resistance vs. control -1.4 (-2.4, -0.3) Combined vs. aerobic -1.2 (-2.2, -0.1) Combined vs. resistance -0.7 (-1.9, 0.5) Total body fat mass (kg) Aerobic 35 46.3 (1.9) 44.8 (2.0) -1.5 (-3.0, 0.1) Resistance 23 49.9 (2.3) 49.1 (2.4) -0.7 (-2.7, 1.2) Combined 29 48.0 (2.0) 45.0 (2.2) -3.0 (-4.7, -1.3)*** Control 57 46.8 (1.5) 47.2 (1.5) 0.4 (-0.8, 1.6) Aerobic vs. control -1.8 (-3.8, 0.2) Resistance vs. control -1.4 (-2.4, -0.3) Combined vs. aerobic -1.5 (-3.9, 0.8) Combined vs. resistance -2.3 (-4.9, 0.3) Total body lean mass (kg) Aerobic 35 48.5 (1.1) 49.2 (1.0) 0.8 (-0.2, 1.7) Resistance 23 50.3 (1.3) 52.3 (1.2) 2.0 (0.9, 3.2)*** Combined 29 47.1 (1.2) 48.3 (1.1) 1.2 (0.2, 2.2)* Control 57 49.5 (0.8) 50.5 (0.8) 1.1 (0.3, 1.8)** Aerobic vs. control -0.3 (-1.5, 0.9) Resistance vs. control 1.0 (-0.4, 2.3) Combined vs. aerobic 0.5 (-0.9, 1.8) Combined vs. resistance -0.8 (-2.3, 0.7) Within-group change: *p<0.05, **p<0.01, ***p<0.001. Between-group difference in change: p<0.05, p<0.01, p<0.001. Data from two participants from the Control group were excluded from the per-protocol analysis in this table due to technically inadequate MRI images. All participants included in the per protocol analysis contributed data at baseline and 6 2014 American Medical Association. All rights reserved. 10

etable 10. Per-protocol analysis: Anthropometry and blood pressure at baseline and changes after 3 and 6. Within-group Change from Baseline to 6 Intergroup difference in change from baseline to 6 Mean (SE) Mean (95% Confidence Interval) Total body weight (kg) Aerobic 35 97.2 (2.7) 96.5 (2.7) 96.0 (2.8) -1.2 (-3.3, 0.9) Resistance 22 103.8 (3.4) 102.7 (3.4) 103.1 (3.5) -0.7 (-3.3, 1.9) Combined 29 97.7 (3.0) 95.5 (3.0) 94.4 (3.1) -3.3 (-5.5,-1.0)** Control 56 98.8 (2.1) 99.3 (2.1) 99.8 (2.2) 1.0 (-0.7, 2.6) Aerobic vs. control -2.2 (-4.7, 0.4) Resistance vs. control -1.7 (-4.7, 1.3) Combined vs. aerobic -2.1 (-5.1, 0.9) Combined vs. resistance -2.6 (-5.9, 0.8) Body Mass Index (kg/m 2 ) Aerobic 35 34.5 (0.8) 33.7 (0.8) 33.6 (0.8) -1.0 (-1.7, -0.3)** Resistance 22 35.7 (1.0) 35.1 (1.0) 34.8 (1.0) -0.9 (-1.7, -0.1)* Combined 29 34.9 (0.8) 33.6 (0.8) 33.0 (0.9) -2.0 (-2.7, -1.2)*** Control 56 34.5 (0.6) 34.2 (0.6) 34.3 (0.6) -0.1 (-0.7, 0.4) Aerobic vs. control -0.8 (-1.7, 0.0) Resistance vs. control -0.8 (-1.7, 0.2) Combined vs. aerobic -1.0 (-2.0, 0.0) Combined vs. resistance -1.1 (-2.2, 0.0) Waist circumference (cm) Aerobic 35 96.2 (1.7) 92.7 (1.7) 92.4 (1.8) -3.7 (-5.5, -2.0)*** Resistance 22 103.2 (2.1) 99.5 (2.1) 98.4 (2.2) -4.8 (-6.9, -2.7)*** Combined 29 97.4 (1.8) 91.6 (1.9) 90.5 (2.0) -6.9 (-8.8, -5.0)*** Control 56 96.5 (1.3) 94.8 (1.3) 95.7 (1.4) -0.8 (-2.0, 0.6) Aerobic vs. control -2.9 (-5.2, -0.8) Resistance vs. control -4.0 (-6.5, -1.6) Combined vs. aerobic -3.1 (-5.6, -0.7) Combined vs. resistance -2.1 (-4.8, 0.7) Systolic blood pressure (mmhg) Aerobic 35 116 (2) 109 (1) 109 (1) -7 (-10, -4)*** Resistance 22 120 (2) 113 (2) 115 (2) -5 (-10, -1)* Combined 29 111 (2) 106 (2) 111 (2) -1 ( -5, 3) Control 56 113 (1) 109 (1) 110 (1) -3 (-6, 0)* 2014 American Medical Association. All rights reserved. 11

etable 10. Per-protocol analysis: Anthropometry and blood pressure at baseline and changes after 3 and 6 (continued). Within-group Change from Baseline to 6 Intergroup difference in change from baseline to 6 Systolic blood pressure (mmhg) Aerobic vs. control -4 (-8, 0) Resistance vs. control -2 (-7, 3) Combined vs. aerobic 6 ( 1, 11) Combined vs. resistance 5 (-1, 10) Diastolic blood pressure (mmhg) Aerobic 35 75 (1) 74 (1) 71 (1) -4 (-7, -1)* Resistance 22 78 (2) 75 (2) 75 (2) -3 (-7, 1) Combined 29 75 (1) 73 (1) 72 (1) -3 (-6, 0) Control 56 75 (1) 74 (1) 73 (1) -2 (-4, 0) Aerobic vs. control -2 (-5, 2) Resistance vs. control -1 (-5, 4) Combined vs. aerobic 1 (-4, 5) Combined vs. resistance 0 (-5, 5) Within-group change: *p<0.05, **p<0.01, ***p<0.001. Between-group difference in change: p<0.05, p<0.01, p<0.001. 2014 American Medical Association. All rights reserved. 12

etable 11. Cardiometabolic risk markers at baseline and changes after 3 and 6. Within-group Change from Baseline to 6 Intergroup difference in change from baseline to 6 Mean (SE) Mean (95% Confidence Interval) Intention-to-treat analysis Fasting glucose (mg/dl) Aerobic 75 90.6 (0.9) 90.1 (0.9) 90.8 (1.1) 0.3 (-1.8, 2.4) Resistance 77 89.3 (0.8) 90.2 (0.8) 89.3 (1.1) 0.0 (-2.2, 2.2) Combined 75 88.4 (0.9) 88.7 (0.8) 87.4 (1.0) -1.0 (-3.0, 1.1) Control 76 91.0 (0.9) 90.3 (0.9) 89.2 (1.0) -1.9 (-3.9, 0.2) Aerobic vs. control 2.1 (-0.8, 5.1) Resistance vs. control 1.8 (-1.2, 4.8) Combined vs. aerobic -1.2 (-4.2, 1.7) Combined vs. resistance -0.9 (-3.9, 2.0) 2 hour- (post-load) glucose (mg/dl) Aerobic 75 103.3 (2.5) - 99.8 (3.1) -3.5 (-10.1, 3.2) Resistance 78 108.4 (2.4) - 108.7 (3.3) 0.3 ( -6.5, 7.1) Combined 75 102.7 (2.5) - 99.9 (3.0) -2.8 ( -9.2, 3.7) Control 74 104.2 (2.5) - 102.2 (3.1) -2.0 ( -8.6, 4.5) Aerobic vs. control -1.4 (-10.7, 7.8) Resistance vs. control 2.4 ( -7.0, 11.7) Combined vs. aerobic 0.7 ( -8.4, 9.9) Combined vs. resistance -3.1 (-12.4, 6.2) Fasting insulin (µiu/ml) ǂ Aerobic 73 12.2 (0.8) 13.8 (1.0) 14.1 (1.1) 1.9 ( 0.1, 4.0)* Resistance 76 14.5 (0.9) 13.6 (0.9) 13.7 (1.1) -0.8 (-2.7, 1.3) Combined 75 12.2 (0.8) 12.6 (0.9) 13.1 (1.0) 0.9 (-0.8, 2.9) Control 73 12.9 (0.8) 12.4 (0.9) 12.7 (1.0) -0.2 (-1.9, 1.7) Aerobic vs. control 17.5 ( -3.4, 43.1) Resistance vs. control -4.2 (-21.6, 17.0) Combined vs. aerobic -6.9 (-23.3, 13.0) Combined vs. resistance 14.2 ( -6.2, 39.2) 2014 American Medical Association. All rights reserved. 13

etable 11. Cardiometabolic risk markers at baseline and changes after 3 and 6 (continued). Within-group Change from Baseline to 6 Intergroup difference in change from baseline to 6 HbA1c (%) Aerobic 75 5.16 (0.03) - 5.15 (0.03) -0.01 (-0.08, 0.06) Resistance 77 5.20 (0.03) - 5.16 (0.03) -0.03 (-0.10, 0.03) Combined 74 5.18 (0.03) - 5.16 (0.03) -0.02 (-0.08, 0.05) Control 76 5.17 (0.03) - 5.15 (0.03) -0.02 (-0.09, 0.04) Aerobic vs. control 0.01 (-0.08, 0.10) Resistance vs. control -0.01 (-0.11, 0.08) Combined vs. aerobic -0.01 (-0.10, 0.09) Combined vs. resistance 0.02 (-0.08, 0.11) Total cholesterol (mg/dl) Aerobic 75 162.2 (3.6) 158.7 (3.7) 159.2 (3.9) -3.0 ( -8.7, 2.7) Resistance 78 165.0 (3.5) 162.3 (3.6) 159.7 (3.9) -5.3 (-11.0, 0.5) Combined 75 163.3 (3.6) 159.4 (3.7) 155.6 (3.8) -7.6 (-13.2, -2.1)** Control 76 169.8 (3.5) 170.3 (3.8) 170.0 (3.9) 0.2 ( -5.4, 5.9) Aerobic vs. control -3.2 (-11.1, 4.6) Resistance vs. control -5.5 (-13.4, 2.5) Combined vs. aerobic -4.6 (-12.4, 3.1) Combined vs. resistance -2.4 (-10.2, 5.5) LDL-Cholesterol (mg/dl) Aerobic 75 99.4 (3.1) 94.5 (3.3) 95.2 (3.4) -4.2 ( -9.3, 0.9) Resistance 78 99.6 (3.0) 98.1 (3.2) 93.9 (3.4) -5.7 (-10.9, -0.5)* Combined 75 100.2 (3.1) 96.0 (3.2) 92.2 (3.3) -8.0 (-13.0, -3.0)** Control 75 102.5 (3.0) 103.5 (3.3) 101.2 (3.4) -1.2 ( -6.3, 3.9) Aerobic vs. control -3.0 (-10.1, 4.1) Resistance vs. control -4.5 (-11.7, 2.7) Combined vs. aerobic -3.7 (-10.7, 3.3) Combined vs. resistance -2.2 ( -9.3, 4.9) HDL-Cholesterol (mg/dl) Aerobic 75 41.7 (1.1) 42.2 (1.2) 41.9 (1.3) 0.2 (-1.5, 1.9) Resistance 78 43.1 (1.1) 43.3 (1.1) 43.9 (1.3) 0.9 (-0.9, 2.6) Combined 75 42.4 (1.1) 42.2 (1.1) 43.6 (1.2) 1.3 (-0.4, 2.9) Control 76 43.5 (1.1) 44.5 (1.2) 44.1 (1.3) 0.6 (-1.1, 2.3) 2014 American Medical Association. All rights reserved. 14

etable 11. Cardiometabolic risk markers at baseline and changes after 3 and 6 (continued). Within-group Change from Baseline to 6 Intergroup difference in change from baseline to 6 Aerobic vs. control -0.4 (-2.8, 2.0) Resistance vs. control 0.3 (-2.1, 2.7) Combined vs. aerobic 1.0 (-1.3, 3.4) Combined vs. resistance 0.4 (-2.0, 2.8) Non-HDL cholesterol (mg/dl) Aerobic 75 120.5 (3.5) 116.4 (3.7) 117.3 (3.7) -3.2 ( -8.3, 1.9) Resistance 78 121.9 (3.4) 119.1 (3.6) 115.9 (3.7) -6.0 (-11.2, -0.7)* Combined 75 120.9 (3.5) 117.1 (3.7) 112.0 (3.6) -8.9 (-13.9, -3.9)*** Control 76 126.3 (3.5) 125.9 (3.7) 126.1 (3.7) -0.2 ( -5.3, 4.9) Aerobic vs. control -3.0 (-10.1, 4.1) Resistance vs. control -5.8 (-12.9, 1.4) Combined vs. aerobic -5.7 (-12.7, 1.3) Combined vs. resistance -2.9 (-10.0, 4.2) Triglycerides (mg/dl) ǂ Aerobic 75 96.4 (5.4) 95.8 (5.9) 98.9 (5.9) 2.5 ( -7.4, 13.6) Resistance 78 102.4 (5.6) 93.2 (5.7) 100.7 (6.1) -1.7 (-12.0, 9.9) Combined 75 91.8 (5.1) 95.1 (5.8) 89.6 (5.2) -2.2 (-11.1, 7.6) Control 76 106.8 (5.9) 101.0 (6.4) 113.3 (6.7) 6.6 ( -4.8, 19.2) Aerobic vs. control -3.3 (-16.6, 12.0) Resistance vs. control -7.3 (-20.2, 7.6) Combined vs. aerobic -4.9 (-17.9, 10.0) Combined vs. resistance -0.8 (-14.5, 15.0) Per-protocol analysis Fasting glucose (mg/dl) Aerobic 35 89.5 (1.3) 89.8 (1.0) 90.2 (1.3) 0.7 (-2.1, 3.5) Resistance 21 90.8 (1.6) 89.9 (1.2) 89.6 (1.7) -1.2 (-4.8, 2.4) Combined 29 88.4 (1.4) 88.5 (1.0) 89.2 (1.5) 0.8 (-2.3, 3.8) Control 56 90.6 (1.0) 90.6 (0.8) 89.7 (1.1) -1.7 (-4.0, 0.5) Aerobic vs. control 2.4 (-1.1, 6.0) Resistance vs. control 0.5 (-3.7, 4.7) Combined vs. aerobic 0.1 (-4.1, 4.2) Combined vs. resistance 2.0 (-2.8, 6.7) 2014 American Medical Association. All rights reserved. 15

etable 11. Cardiometabolic risk markers at baseline and changes after 3 and 6 (continued). Within-group Change from Baseline to 6 Intergroup difference in change from baseline to 6 2 hour-(post-load) glucose (mg/dl) Aerobic 34 105.0 (3.6) - 98.2 (3.4) -6.7 (-14.2, 0.7) Resistance 22 111.5 (4.5) - 103.4 (4.2) -8.1 (-17.3, 1.0) Combined 29 99.5 (4.0) - 90.6 (3.7) -8.9 (-16.9, -0.8)* Control 54 106.8 (2.9) - 102.1 (2.7) -4.7 (-10.6, 1.2) Aerobic vs. control -2.0 (-11.4, 7.3) Resistance vs. control -3.4 (-14.3, 7.4) Combined vs. aerobic -2.1 (-13.0, 8.7) Combined vs. resistance -0.7 (-12.8, 11.4) Fasting insulin (µiu/ml) ǂ Aerobic 34 11.4 (1.1) 11.7 (1.1) 12.6 (1.3) 1.2 (-1.0, 3.9) Resistance 21 19.1 (2.2) 13.3 (1.5) 13.9 (1.8) -5.2 (-8.2, -1.4)** Combined 29 11.8 (1.2) 10.5 (1.0) 11.4 (1.2) -0.4 (-2.5, 2.2) Control 53 14.5 (1.1) 13.2 (1.0) 13.5 (1.1) -0.9 (-2.8, 1.3) Aerobic vs. control 18.2 ( -7.1, 50.3) Resistance vs. control -22.4 (-41.5, 2.9) Combined vs. aerobic -12.5 (-33.7, 15.4) Combined vs. resistance 33.2 ( -2.7, 82.3) HbA1c (%) Aerobic 35 5.20 (0.04) - 5.17 (0.04) -0.04 (-0.12, 0.05) Resistance 21 5.25 (0.06) - 5.15 (0.05) -0.10 (-0.21, 0.01) Combined 29 5.13 (0.05) - 5.12 (0.05) -0.01 (-0.11, 0.08) Control 56 5.21 (0.04) - 5.17 (0.03) -0.04 (-0.11, 0.03) Aerobic vs. control 0.00 (-0.10, 0.11) Resistance vs. control -0.06 (-0.19, 0.07) Combined vs. aerobic 0.03 (-0.10, 0.15) Combined vs. resistance 0.09 (-0.05, 0.23) Total cholesterol (mg/dl) Aerobic 35 160.4 (5.5) 154.7 (5.6) 157.2 (5.5) -3.2 (-10.6, 4.2) Resistance 22 167.1 (6.9) 165.6 (7.0) 159.5 (6.9) -7.6 (-16.8, 1.5) Combined 29 166.6 (6.1) 157.0 (6.1) 157.4 (6.0) -9.2 (-17.3, -1.1)* Control 56 169.5 (4.4) 170.3 (4.4) 169.6 (4.3) 0.1 ( -5.8, 6.0) 2014 American Medical Association. All rights reserved. 16

etable 11. Cardiometabolic risk markers at baseline and changes after 3 and 6 (continued). Within-group change from baseline to 6 Intergroup difference in change from baseline to 6 Aerobic vs. control -3.3 (-12.4, 5.8) Resistance vs. control -7.7 (-18.3, 2.9) Combined vs. aerobic -6.0 (-16.6, 4.6) Combined vs. resistance -1.5 (-13.5, 10.4) LDL-Cholesterol (mg/dl) Aerobic 35 98.0 (4.9) 92.1 (5.0) 95.1 (4.8) -3.0 ( -9.6, 3.7) Resistance 22 101.7 (6.1) 100.0 (6.3) 94.0 (6.1) -7.6 (-15.9, 0.6) Combined 29 99.4 (5.4) 92.0 (5.5) 90.3 (5.5) -9.2 (-16.5, -1.9)* Control 55 102.9 (3.9) 103.3 (4.0) 100.5 (3.8) -2.3 ( -7.7, 3.0) Aerobic vs. control -0.7 ( -8.9, 7.6) Resistance vs. control -5.3 (-14.9, 4.3) Combined vs. aerobic -6.2 (-15.7, 3.4) Combined vs. resistance -1.5 (-12.3, 9.2) HDL-Cholesterol (mg/dl) Aerobic 35 42.2 (1.7) 42.2 (1.7) 41.7 (1.8) -0.5 (-2.8, 1.7) Resistance 22 41.7 (2.2) 42.7 (2.1) 43.3 (2.3) 1.6 (-1.2, 4.4) Combined 29 45.6 (1.9) 44.8 (1.9) 47.4 (2.0) 1.8 (-0.7, 4.3) Control 56 40.7 (1.4) 42.3 (1.3) 41.8 (1.4) 1.1 (-0.7, 2.9) Aerobic vs. control -1.7 (-4.4, 1.1) Resistance vs. control 0.5 (-2.8, 3.7) Combined vs. aerobic 2.3 (-0.9, 5.6) Combined vs. resistance 0.2 (-3.5, 3.9) Non-HDL cholesterol (mg/dl) Aerobic 35 118.2 (5.4) 112.3 (5.6) 115.5 (5.3) -2.7 ( -9.3, 4.0) Resistance 22 125.4 (6.9) 122.7 (7.1) 116.2 (6.7) -9.2 (-17.5, -0.9)* Combined 29 121.0 (6.0) 112.3 (6.2) 110.1 (5.9) -10.9 (-18.3, -3.6)** Control 56 128.8 (4.3) 128.1 (4.5) 127.8 (4.2) -1.0 ( -6.4, 4.3) Aerobic vs. control -1.6 ( -9.9, 6.6) Resistance vs. control -8.2 (-17.8, 1.4) Combined vs. aerobic -8.3 (-17.9, 1.3) Combined vs. resistance -1.7 (-12.5, 9.0) 2014 American Medical Association. All rights reserved. 17

etable 11. Cardiometabolic risk markers at baseline and changes after 3 and 6 (continued). Within-group change from baseline to 6 Intergroup difference in change from baseline to 6 Triglycerides (mg/dl) ǂ Aerobic 35 93.3 (7.3) 86.2 (7.9) 93.9 (7.3) 0.6 (-11.8, 15.0) Resistance 22 111.9 (11.0) 101.0 (11.7) 102.1 (10.0) -9.8 (-26.4, 10.0) Combined 29 98.8 (8.6) 90.8 (9.1) 89.9 (7.7) -9.0 (-22.0, 6.2) Control 56 114.2 (7.1) 108.0 (7.8) 118.7 (7.3) 4.5 (-8.2, 18.7) Aerobic vs. control -3.1 (-18.9, 15.7) Resistance vs. control -12.2 (-28.7, 8.0) Combined vs. aerobic -9.6 (-26.6, 11.2) Combined vs. resistance -0.3 (-21.1, 25.9) Within-group change: *p<0.05, ** p<0.01, *** p<0.001. Between-group difference in change: p<0.05, p<0.01, p<0.001 ǂ Values were log-transformed for analysis; geometric means are presented. Abbreviations: HbA1c= Hemoglobin A1c, HDL-C= High density lipoprotein cholesterol, LDL= Low density lipoprotein cholesterol. The numbers of participants who underwent phlebotomy for the tests in this table intention-to-treat analyses in the Aerobic, Resistance, Combined and Control groups respectively were 61, 65, 65 and 54 at 3, and 55, 50, 58 and 56 at 6. In the per-protocol analyses, the numbers of participants were the same at baseline and 6. Note: We did not conduct an Oral Glucose Tolerance Test at 3 to assess 2 hour- (post load) glucose nor did we measure HbA1c at 3. 2014 American Medical Association. All rights reserved. 18

etable 12. Changes in cardiorespiratory fitness (VO 2peak and treadmill time) and muscular strength (leg press, bench press and seated row) in the aerobic, resistance, combined and control groups. Within-group change from baseline to 6- Between-group difference in change from baseline to 6- Mean (SE) Mean (95% Confidence Interval) Intention-to-treat analysis VO 2peak (mlo 2 /kg/min) Aerobic 75 30.6 (0.5) - 33.4 (0.7) 2.7 (1.6, 3.9)*** Resistance 78 30.0 (0.5) - 30.9 (0.7) 0.9 (-0.2, 2.0) Combined 75 30.6 (0.5) - 32.2 (0.6) 1.6 (0.5, 2.7)** Control 76 30.6 (0.5) - 30.9 (0.7) 0.2 (-0.8, 1.3) Aerobic vs. control 2.5 (0.9, 4.1) Resistance vs. control 0.7 (-0.9, 2.3) Combined vs. aerobic -1.1 (-2.7, 0.4) Combined vs. resistance 2.5 (0.9, 4.1) Treadmill time (minutes) Aerobic 75 10.0 (0.2) 11.0 (0.2) 1.1 (0.6, 1.6)*** Resistance 78 10.1 (0.2) 10.8 (0.2) 0.8 (0.3, 1.2)** Combined 75 10.2 (0.2) 11.2 (0.2) 1.0 (0.5, 1.4)*** Control 76 10.0 (0.2) 10.2 (0.2) 0.2 (-0.3, 0.6) Aerobic vs. control 0.9 (0.3, 1.6) Resistance vs. control 0.6 (-0.1, 1.3) Combined vs. aerobic -0.1 (-0.8, 0.5) Combined vs. resistance 0.2 (-0.5, 0.9) Leg press (kg) Aerobic 64 93.6 (4.2) 127.3 (6.8) 135.5 (8.1) 41.9 (28.5, 55.3)*** Resistance 66 99.8 (4.1) 157.6 (6.5) 172.7 (7.9) 72.8 (59.7, 86.0)*** Combined 63 109.7 (4.2) 160.9 (6.7) 174.1 (8.0) 64.4 (51.2, 77.6)*** Control 60 104.1 (4.3) 125.8 (6.9) 126.7 (7.9) 22.5 (9.3, 35.7)*** Aerobic vs. control 19.4 (0.5, 38.2) Resistance vs. control 50.3 (31.7, 68.9) Combined vs. aerobic 22.5 (3.7, 41.4) Combined vs. resistance -8.4 (-27.0, 10.2) 2014 American Medical Association. All rights reserved. 19

etable 12. Changes in cardiorespiratory fitness (VO 2peak and treadmill time) and muscular strength (leg press, bench press and seated row) in the aerobic, resistance, combined and control groups (continued). Within-group change from baseline to 6- Between-group difference in change from baseline to 6- Bench press (kg) Aerobic 63 26.9 (1.2) 30.5 (1.5) 31.0 (1.7) 4.1 (1.3, 6.9)** Resistance 65 28.7 (1.2) 38.0 (1.4) 40.4 (1.7) 11.7 (9.0, 14.5)*** Combined 64 28.5 (1.2) 39.0 (1.5) 41.0 (1.6) 12.5 (9.8, 15.1)*** Control 61 29.0 (1.2) 30.7 (1.5) 32.4 (1.7) 3.3 (0.6, 6.1)* Aerobic vs. control 0.8 (-3.1, 4.7) Resistance vs. control 8.4 (4.6, 12.2) Combined vs. aerobic 8.3 (4.5, 12.2) Combined vs. resistance 0.7 (-3.1, 4.5) Seated row (kg) Aerobic 63 39.5 (1.3) 43.7 (1.4) 44.8 (2.2) 5.4 (1.1, 9.6)* Resistance 65 41.6 (1.3) 49.4 (1.4) 51.5 (2.1) 9.9 (5.8, 14.0)*** Combined 63 40.9 (1.3) 49.4 (1.4) 55.1 (2.1) 14.2 (10.2, 18.2)*** Control 61 40.9 (1.3) 45.8 (1.5) 47.7 (2.1) 6.8 (2.8, 10.9)** Aerobic vs. control -1.5 (-7.4, 4.4) Resistance vs. control 3.0 (-2.7, 8.8) Combined vs. aerobic 8.9 (3.0, 14.7) Combined vs. resistance 4.3 (-1.4, 10.1) Per-protocol analysis VO 2peak (mlo 2 /kg/min) Aerobic 33 31.7 (0.8) - 34.3 (0.9) 2.6 (1.2, 3.9)*** Resistance 22 30.6 (1.0) - 31.6 (1.1) 1.0 (-0.7, 2.6) Combined 29 30.5 (0.9) - 32.6 (0.9) 2.2 (0.7, 3.6)** Control 51 30.3 (0.6) - 30.7 (0.7) 0.3 (-0.7, 1.4) Aerobic vs. control 2.2 (0.5, 4.0) Resistance vs. control 0.6 (-1.3, 2.6) Combined vs. aerobic -0.4 (-2.4, 1.6) Combined vs. resistance 1.2 (-1.0, 3.4) 2014 American Medical Association. All rights reserved. 20

etable 12. Changes in cardiorespiratory fitness (VO 2peak and treadmill time) and muscular strength (leg press, bench press and seated row) in the aerobic, resistance, combined and control groups (continued). Within-group change from baseline to 6- Between-group difference in change from baseline to 6- Treadmill time (minutes) Aerobic 33 10.4 (0.3) - 11.4 (0.3) 1.1 (0.5, 1.7)*** Resistance 22 9.9 (0.4) - 10.8 (0.4) 0.9 (0.2, 1.6)* Combined 29 10.2 (0.3) - 11.5 (0.3) 1.3 (0.7, 1.9)*** Control 51 9.9 (0.2) - 10.1 (0.3) 0.2 (-0.3, 0.7) Aerobic vs. control 0.9 (0.1, 1.6) Resistance vs. control 0.7 (-0.2, 1.5) Combined vs. aerobic 0.2 (-0.6, 1.1) Combined vs. resistance 0.4 (-0.5, 1.4) Leg press (kg) Aerobic 27 88.5 (6.9) 130.0 (9.6) 136.0 (11.5) 47.5 (29.5, 65.4)*** Resistance 16 111.7 (9.0) 183.2 (12.5) 211.7 (15.0) 100.0 (76.6, 123.3)*** Combined 19 105.3 (8.4) 159.8 (11.5) 175.7 (13.8) 70.3 (48.9, 91.7)*** Control 41 108.2 (5.6) 132.9 (8.0) 132.1 (9.3) 23.9 (9.4, 38.5)** Aerobic vs. control 23.5 (0.4, 46.7) Resistance vs. control 76.0 (48.5, 103.5) Combined vs. aerobic 22.8 (-5.1, 50.8) Combined vs. resistance -29.6 (-61.3, 2.0) Bench press (kg) Aerobic 25 26.0 (2.1) 29.8 (2.4) 30.7 (2.6) 4.7 (1.1, 8.3)* Resistance 17 30.9 (2.5) 42.8 (2.9) 47.7 (3.2) 16.8 (12.4, 21.2)*** Combined 21 25.7 (2.3) 39.8 (2.6) 42.2 (2.9) 16.5 (12.5, 20.4)*** Control 41 30.2 (1.6) 31.8 (1.9) 33.4 (2.0) 3.3 (0.4, 6.1.)* Aerobic vs. control 1.4 (-3.2, 6.0) Resistance vs. control 13.5 (8.3, 18.8) Combined vs. aerobic 11.8 (6.4, 17.2) Combined vs. resistance -0.3 (-6.2, 5.6) 2014 American Medical Association. All rights reserved. 21

etable 12. Changes in cardiorespiratory fitness (VO 2peak and treadmill time) and muscular strength (leg press, bench press and seated row) in the aerobic, resistance, combined and control groups (continued). Within-group change from baseline to 6- Between-group difference in change from baseline to 6- Seated row (kg) Aerobic 26 40.9 (2.1) 45.9 (2.2) 46.9 (3.3) 6.0 (-0.3, 12.4) Resistance 16 45.1 (2.7) 55.0 (2.8) 60.1 (4.2) 15.1 (7.0, 23.1)*** Combined 21 37.4 (2.4) 47.6 (2.5) 58.6 (3.7) 21.3 (14.2, 28.4)*** Control 42 42.9 (1.7) 47.3 (1.8) 49.6 (2.6) 6.7 (1.7, 11.7)** Aerobic vs. control -0.7 (-8.7, 7.4) Resistance vs. control 8.4 (-1.2, 17.9) Combined vs. aerobic 15.3 (5.8, 24.8) Combined vs. resistance 6.2 (-4.5, 17.0) Within-group change: * p<0.05, ** p<0.01, *** p<0.001. Between-group difference in change: p<0.05, p<0.01, p<0.001. Abbreviations: VO 2peak : peak oxygen consumption. Abbreviations: VO 2peak : peak oxygen consumption.8-rm: 8-repetitions maximum. The numbers of participants who completed treadmill testing for VO2peak and treadmill time at 6 in the Aerobic, Resistance, Combined and Control groups respectively were 46, 47, 54 and 51. Treadmill testing was not done at 3. The numbers of participants who completed 8-repetitions maximum (8-RM) strength testing in the Aerobic, Resistance, Combined and Control groups respectively were 49, 55, 52 and 44 at 3, and 40, 43, 46 and 46 at 6. This type of strength testing was initiated Jan. 30, 2006, so participants enrolled earlier did not undergo it. 2014 American Medical Association. All rights reserved. 22

etable 13. Per-protocol analysis: Changes in energy intake (3-day food diaries) and background physical activity (7-day pedometer logs) in the aerobic, resistance, combined and control groups. Within-group change from baseline to 6- Mean (SE) Mean (95% Confidence Interval) Between-group difference in change from baseline to 6- Total energy intake (kilocalories/ day) Aerobic 33 2059 (110) 1975 ( 92) 1861 (80) -198 (-426, 31) Resistance 22 2524 (135) 2066 (112) 2129 (98) -395 (-674, -116)** Combined 28 2113 (121) 2009 (99) 1898 (87) -215 (-463, 33) Control 50 2133 (90) 1916 (75) 1883 (65) -250 (-436, -64)** Aerobic vs. control 52 (-240, 344) Resistance vs. control -145 (-478, 188) Combined vs. aerobic -17 (-352, 318) Combined vs. resistance 180 (-191, 551) Total step counts (steps/day, excluding gym sessions) Aerobic 7 8048(1326) - 6906 (1467) -1142 (-3958, 1674) Resistance 5 8617(1603) - 9732 (1767) 1115 (-2216, 4447) Combined 4 8123(1711) - 9905 (1902) 1782 (-1943, 5507) Control 2 7136(2534) - 10530 (2793) 3394 (-1874, 8662) Aerobic vs. control -4536 (-10509, 1438) Resistance vs. control -2278 (-8512, 3955) Combined vs. aerobic 2923 (-1746, 7593) Combined vs. resistance 666 (-4332, 5664) Within-group change: * p<0.05, ** p<0.01, *** p<0.001. Between-group difference in change: p<0.05, p<0.01, p<0.001. Abbreviations: VO 2peak : peak oxygen consumption 2014 American Medical Association. All rights reserved. 23