OBJECTIVE PARTICIPANTS to evaluate the effects of: Women who had - PDF document

with thanks to…. The EMPOWIR STUDY TEAM Results of the ‘EMPOWIR’ STUDY ( E nhance the M etabolic P rofile of W omen with Insulin R esistance) NAMS MEETING ME ME and OCTOBER 2018 Philipp Scherer PhD Feras M. Hantash MS PhD Director, Touchstone Diabetes Center Assoc. Scientific Director, Diabetes, CV UT Southwestern Medical Center Disease RUTH FREEMAN MD Nichols Institute, Quest Diagnostics The GCRC at Einstein ALBERT EINSTEIN COLLEGE OF MEDICINE/ CTSA (NIH UL11RR025740) Glaxo Smith Kline MONTEFIORE HOSPITAL Unsolicited, investigator initiated award 2 OBJECTIVE PARTICIPANTS to evaluate the effects of: � Women who had gained 20 or more pounds 1. A unique carbohydrate modified, hypocaloric, of weight after their 20’s were invited to lowfat diet, alone and in combination with participate 2. Metformin (2000mg/day) or 3. Metformin plus low dose Rosiglitazone (4 mg/day), in diverse women with documented elevated insulin level and normal glucose tolerance tests. 3

455 Participants Participant Prevalence of abnormal glucose on assessed for eligibility * Flowchart Glucose tolerance test. 346 excluded (age, BMI) 109 participants assessed with GTT 41 excluded: Number Percent 24 normal 11 IFG, IGT or both 68 included-completed (109) 4 diabetic nutrition workshop 2 incomplete data Normal 23 21.1 22 did not continue: 2 moved Nl Glucose + high Insulin 67 61.5 1 pregnant (AUC >100) 46 participants IFG or IGT 11 24 white , 10 Afr-American, 10.1 6 Hisp, 2 Asian, 4 “other” randomized DM 4 3.7 2 were excluded : 1 with GHD Missing data 4 3.7 1 on high dose steroids 44 included in * 11/07 to 12/10 analysis 5 THE EMPOWIR DIET THE EMPOWIR DIET � Exchange program (40% carbs-40% protein-20% fat) � total daily caloric intake ~ 1200-1500 � elimination of all simple (free) sugars � hallmark postponement of 3 allowable additional daily carbohydrate servings (starches) to 4 PM � easily implemented: measure fats; estimate carbohydrate and protein servings based on visual cues www.Syndromew.com 7 8

Mean differences BW, WC, and BP by study group Metformin plus Placebo Metformin Rosiglitazone Mean Mean Mean Baseline 6 months Difference Baseline 6 months Difference Baseline 6months Difference (se) (se) (se) (se) (se) (se) (P value) ( P value) ( P value) Weight 185.4 176.2 -9.3 187.5 177.2 -10.3 180.3 170.8 -9.4 (lbs) (0.049) (0.002) (0.032) (6.2) (6.2) (5.2) (4.7) (7.0) (8.7) Waist 39.3 36.7 -2.6 36.6 35.6 -1.0 36.5 34.3 -2.2 (Inches) (0.002) (0.036) (0.6) (0.9) (0.7) (0.8) (0.143) (0.9) (1.4) Systolic BP 117.5 113.8 -3.6 114.3 107.2 -7.2 118.7 114.2 -4.5 (mm Hg) ( 0.001) (2.9) (2.9) (0.265) (3.4) (3.0) (6.0) (4.7) (0.389) Diastolic BP 75.9 71.7 -4.2 75.3 72.7 -2.5 76.9 74.3 -2.6 (mm Hg) (2.6) (2.3) (0.025) (2.0) (2.3 ) (0.162 ) (4.2) (3.8 ) (0.562) 10 Mean differences in metabolic parameters Mean differences in lipid profile Metformin plus Placebo Metformin Rosiglitazone Metformin plus Metformin Place b o Rosiglitazone Mean Mean Mean Baseline 6 months Difference Baseline 6 months Difference Baseline 6 months Difference Mean Mean Mean (se) (se) (se) (se) (se) (se) Baseline 6 months Difference Baseline 6 months Difference Baseline 6 months Difference ( P value) ( P value) ( P value) ( P value) ( P value) ( P value) Fasting Total 176.1 183.6 7.5 190.3 202.0 11.8 204.6 224.2 19.7 Glucose 88.8 84.9 - 3.8 89.9 84.0 - 5.9 83.9 80.8 - 3.1 cholesterol (5.3) (7.0) (0.360) (7.5) (7.0) (0.206) (12.0) (12.6) (0.030) (mg/dl) (0.034) (1.3) (2.2) (0.150) (2.3) (1.8) (2.4) (1.4) (0.308) (mg/dl) Fasting HDL 49.3 56.5 7.2 61.6 70.1 8.5 57.7 68.3 8.2 Insulin 11.2 8.1 - 3.1 12.5 8.0 - 4.5 8.7 6.3 - 2.4 (mg/dl) (0.016) (0.030) (2.3) (3.5) (5.8) (5.8) (3.2) (6.2) (0.150) ( μ U/ml) ( 0.026) (1.4) (1.3) (0.181) (2.0) (1.2) (1.5) (0.9) (0.063) LDL 105.6 108.1 2.5 111.2 111.3 0.1 126.6 132.1 6.0 (mg/dl) (5.0) (5.6) (0.602) (7.9) (6.5) (0.991) (10.1) (8.8) (0.373) 5.4 5.3 - 0.1 5.4 5.3 0 5.4 5.4 0 HbA1c (0.1) (0.1) (0.309) (0.1) (0.1) (0.631) (0.1) (0.1) (0.645) Triglycerides 96.0 97.1 0.52 88.0 103.1 15.1 88.3 112.4 24.2 (%) (mg/dl) (10.1) (11.7) (0.648) (11.3) (13.0) (0.094) (11.9) (20.5) (0.103) 2.3 1.5 -0.8 2.5 1.6 - 0.9 1.9 1.3 - 0.6 HOMA -R (0.2) (0.054) (0.013) (0.) (0.142) (.4) (.3) (.3) (0.2) Adiponect 9.3 10.6 1.3 10.6 10.9 0.3 11.1 18.5 7.4 in (1.3) (1.2) (0.092) (1.4) (1.7) (0.730) (1.0) (1.5) (<0.001) ( μ g/ml) 12 11

Changes in body weight and leptin in 15 subjects with progressive weight loss at 3 major study intervals * Ghrelin Results in 22 subjects. Body weight (kg) Leptin (ng/ml) � Ethnicity Randomization visit (mean ± SE) 80.16 ± 2.15 26.15 ± 2.01 6 month 77.51 ± 2.21 25.99 ± 2.61 32% caucasian, 12 month 76.14 ± 1.75 27.57 ± 2.65 41% African American Mean difference 1 -2.65 ± 1.00 - 0.17 ± 1.40 18% Hispanic 9% other P value - 6 months 1 0.019 0.907 Age 46.2 Mean difference 2 - 3.23 ± 1.12 1.39 ± 0.99 BMI 31.1 P value - 12 months 2 0.013 0.183 Ghrelin at baseline - 1392(113.8) pg/ml Mean difference 3 - 0.2078 ± 0.6138 1.58 ± 1.31 P value - 6mos vs.12 mos. 3 0.740 0.249 6months – 1149 (75) P 0.031 reduction in 20/22 subjects . 1. Randomization vs . 6 month visit 2. Randomization vs. 12 month visit * N Engl J Med 366;4 , Jan 26,2012 (letter) 3. 6 month vs. 12 month visit 13 Adiponectin results Group Baseline 6 months P value Placebo 9.3 (1.3) 10.6(1.2) 0.092 Metformin 10.6 (1.4) 10.9 (1.7) 0.730 SUMMARY HYPOTHESIS SUMMARY HYPOTHESIS Metformin + 11.1 (1.0) 18.5 (1.5) 0.001 rosiglitazone EErrError Bars: 95% CI

EErrError Bars: 95% CI EErrError Bars: 95% CI Conclusion 1. Weight gain in adult women is often associated with insulin resistance 2. Fasting insulin was reduced after 6 months on dietary intervention and metformin 3. A modified diet with delayed CHO intake can result in significant wgt reduction 4. Leptin did not fall in this wgt loss study 5. Ghrelin was reduced 6. Adiponectin was reduced only in met-rosi group