How does gastric bypass cause type 2 diabetes remission? Mechanisms and Use of. Bariatric/Metabolic Surgery. to Treat Type 2 Diabetes.

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1 Mechanisms and Use of Bariatric/Metabolic Surgery to Treat Type 2 Diabetes David E. Cummings, M.D. University of Washington, VA Puget Sound, Diabetes & Obesity Center of Excellence, Seattle Disclosure I am P.I. on the COSMID trial (Comparison of Surgery vs. Medicines for Indian Diabetes), funded by Johnson & Johnson Roux-en-Y Gastric Bypass () Gastric Banding How does gastric bypass cause type 2 diabetes remission? Gastric Bypass Reverses Diabetes ~8% full remission of type 2 DM after Buchwald meta-analysis 22,94 patients Schauer, et al. 1,16 patients Whitgrove, et al. 1,29 patients Pories, et al. 68 patients Buchwald meta-analysis 2 135,246 patients Many others DE Cummings

2 Swedish Obese Subjects Study Usual Care How does it work? Total Body Weight Loss (%) insulin sensitivity with weight loss undoubtedly Banding Gastroplasty plays an important role Gastric Bypass Sjöström L, et al. JAMA 37:56 (212) Commentary: et al. Nature Med 18:358 (212) Years of Follow Up Rapid Resolution of Diabetes After Evidence for Weight-Independent Anti-DM Effects Prospective study of 116 patients 24 with DM on oral meds and/or insulin, 8% F/U % Diabetes Resolved Upon Initial Hospital Discharge 83% DM resolution Schauer PR et al, Ann Surg 238: Overall <5 6-1 >1 Duration of DM Fast kinetics of diabetes resolution Glucose homeostasis improves more with than with equal weight loss from other means Poor correlation between amount of weight lost and DM remission rates after, Rubino F. Nature Med (in press) Long-Term Follow-Up of Gastric Bypass vs. Gastric Banding Percentage Weight Loss Percentage With Diabetes Better Improvement in Diabetes After Than After Equivalent Weight Loss from Other Means vs. LAGB LeRoux C, et al; Pattou F, et al % Weight Loss % With Diabetes Band vs. Dietary Weight Loss LaFerrere B, et al; Meirelles K, et al C. le Roux, et al Time (months) Ann Surg 252:966 (21) Band Bypass Time (months) Bypass Sleeve Gastrectomy with Proximal Intestinal Bypass vs. Sleeve Gastrectomy Alone Lee WJ, et al DE Cummings

3 Evidence for Weight-Independent Anti-DM Effects Fast kinetics of diabetes resolution Glucose homeostasis improves more with than with equal weight loss from other means Inconsistent correlation after between baseline weight or amount of weight loss and rates of DM remission, prevention, & recurrence, as well as hard clinical outcomes, Rubino F. Nature Med (in press) A Long-Term Study of to Treat Type 2 Diabetes in Patients With Only Mild Obesity Cohen RV.. Diabetes Care 35:142 (212) Prospective Study of for Type 2 DM in Patients With BMI 3 35 kg/m 2 Rapid & Durable Improvement in HbA1c After in BMI 3-35 A patients with diabetes 1% F/U up to 6 years 1 1% F/U to 6 yrs 9 BMI 3 35 kg/m 2 Mild obesity for this population Hemoglobin A1c 8 Type 2 DM Confirmed with Abs, C-peptide, FHx (%) 7 Severe diabetes Mean duration: 13 years 4% on insulin (the rest on oral DM meds) HbA1c: 9.7% at start Cohen RV.. Diabetes Care 35:142 (212) Cohen RV.. Diabetes Care 35:142 (212) Years After Surgery Diabetes Remission in 6-Year Study of For Type 2 DM in Patients With BMI 3 35 kg/m % 6 5 Waist Circumference (cm) Resolved Total Body Weight Loss -3 (%) Cohen RV.. Diabetes Care 35:142 (212) Number Of Patients T2DM Remission 11% T2DM Improvement 1% No Change Waist Circumference (cm) Cohen RV.. Diabetes Care 35:142 (212) Months After Surgery Improved Total Body Weight Loss -3 (%) Months After Surgery

4 Do Changes in BMI Correlate With Changes in Glycemia? A Hemoglobin A1c 8 (%) 7 BMI vs. Glycemia Regression Analyses No Relationship Between Change in BMI and Change in HbA1c at 6 Months Change In HbA1c Cohen RV.. Diabetes Care 35:142 (212) Years After Surgery Cohen RV.. Diabetes Care 35:142 (212) Change in BMI (kg/m2) No Relationship Between Change in BMI and Change in FPG at 6 Months No Relationship Between Change in BMI and Change in HbA1c at 1 Year Change In Fasting Plasma Glucose Change In HbA1c Cohen RV.. Diabetes Care 35:142 (212) Change in BMI (kg/m2) Cohen RV.. Diabetes Care 35:142 (212) Change in BMI (kg/m2) No Relationship Between Change in BMI and Change in FPG at 1 Year Lack of Correlation Between Weight Loss and Improved Glycemia mo 6 mo 1 year 2 years 4 years 5 years 6 years Change In Fasting Plasma Glucose HbA1c Correl Coeff P Value Cohen RV.. Diabetes Care 35:142 (212) Change in BMI (kg/m2) Fasting Glu Correl Coeff P Value

5 Tests of Beta-Cell Function Long After A 11 Effects on Hemoglobin 1 9 C-Peptide Testing With Standardized Meal Insulin Secretion A1c (%) Cohen RV.. Diabetes Care 35:142 (212) Years After Surgery Improved β Cell Function for Up to 6 Years After 25 Cohen RV.. Diabetes Care 35:142 (212) 2 15 Glucose (mg/dl) C-Peptide 4 3 (ng/ml) 2 1 Fasting Post-Meal Before After β-cell sensitivity to glucose by 446% Effects on Roughly Estimated Insulin Sensitivity Change in Roughly Estimated Insulin Resistance After 12 HOMA-IR Effects on Metabolic Syndrome and Predicted CVD Risk Cohen RV.. Diabetes Care 35:142 (212) Years After Surgery

6 Systolic Blood Pressure (mmhg) Total 16 Cholesterol 14 (mg/dl) 12 1 Low Density Lipoprotein (mg/dl) Diastolic Blood Pressure (mmhg) Cohen RV.. Diabetes Care 35:142 (212) Years After Surgery High Density Lipoprotein (mg/dl) Cohen RV.. Diabetes Care 35:142 (212) Years After Surgery Triglycerides (mg/dl) Years After Surgery 1-Year Cardiovascular Risk Before vs. After Cardio- Pre-Surgery Post-Surgery Absolute 95% Relative Vascular (n=66) (n=66) Mean Risk Mean Risk Risk Confidence Risk P Value Event (%) ± SD (%) ± SD Reduction Interval Reduction CHD 35.3 ± ± % %.1 Fatal CHD 26.2 ± ± % %.1 Stroke 5. ±.4 2.5± % %.1 Fatal Stroke.7 ±.3.4 ±.2.3% %.9 Diabetes Incidence per 1 person-years Chiu M et al. Diabetes Care 34:1741, 211 Asian Indians Have Increased Diabetes Risk at Lower BMI Levels Asian Indian Chinese Black White Cohen RV.. Diabetes Care 35:142 (212) Body Mass Index (kg/m2) BMI & Diabetes in Taiwan NTUH Prospective Study of for Type 2 DM in Asian Indians With BMI < 35 kg/m 2 BMI kg/m 2 Overweight to Obese by Indian-specific WHO criteria Number WJ Lei, et al. J Gastrointest Surg 12: BMI % % >35 <2% 2,555 cases Type 2 DM Confirmed with Abs, C-peptide, FHx Severe diabetes Mean duration: 9 years 8% on insulin (the rest on oral DM meds) HbA1c: 1.1% Other features Dyslipidemia: 93% Hypertension: 6% Shah S, Todkar J.. SOARD 6:332

7 Gastric Bypass in Asian Indians With Type 2 DM & BMI <35 kg/m 2 Gastric Bypass in Asian Indians With Type 2 DM & BMI <35 kg/m Fasting Blood Glucose (mg/dl) Fasting Blood Glucose (mg/dl) Shah S, Todkar J.. SOARD 6: % on insulin Months After Surgery Shah S, Todkar J.. SOARD 6:322 5 % 8% 1% 1% 1% Months After Surgery % Off All DM Meds Gastric Bypass in Asian Indians With Type 2 DM & BMI <35 kg/m 2 Gastric Bypass in Asian Indians With Type 2 DM & BMI <35 kg/m 2 Shah S, Todkar J.. SOARD 6:332 HbA1c (%) % 8% 1% 1% 1% Months After Surgery % Off All DM Meds 3 25 Fasting 2 Blood 15 Glucose (mg/dl) 1 5 Shah S.. No correlations between amount of weight loss and % 8% improved 1% 1% 1% glycemia 1% 1% 1% Months After Surgery % Off All DM Meds UKPDS Risk Engine 1-Year Cardiovascular Risk Predictions (%) Coronary 1 Heart 8 6 Disease 4 2 Fatal Coronary Heart Disease Stroke Fatal Stroke Pre-Op Post-Op Shah, Todkar Cummings SOARD 6:332 COSMID Randomized Controlled Trial Comparison Of Surgery vs. Medicines for Indian Diabetes Shah SS, Todkar J, Kim K,

8 What about the relationship between body weight and diabetes prevention? Cumulative Diabetes Incidence Over 15 Years in SOS Surgery & Control Participants Without Diabetes at Kaplan-Meier Cumulative Incidence Surgery reduces incidence of new diabetes by ~8% Follow-Up Time (years) Number at Risk Control 1,771 1,513 1,76 44 Surgery 1,658 1,561 1, Control (392 events) Surgery (11 events) What baseline patient characteristics best predicted surgical prevention of diabetes? Commentary: Rubino F &. Nature Rev Endo 212 Carlsson LM Sjöström L. New Engl J Med 367:695 (212) Interactions Between Indicated Risk Factors and Treatment 14 Interaction P Value 14 Interaction P Value 14 Interaction P Value Incidence rate per 1 p-y (95% CI) Glucose.7 12 IFG Yes/No < Incidence rate per 1 p-y (95% CI) Insulin < Incidence rate per 1 p-y (95% CI) BMI < Control Surgery What about the relationship between weight or weight and diabetes recurrence after initial remission? Blood Glucose (mg/dl) Serum Insulin (mu/l) BMI (kg/m 2 ) Values (deciles) Commentary: Rubino F &. Nature Rev Endo 212 Carlsson LM Sjöström L. New Engl J Med 367:695 (212)

9 Long-term Remission & Relapse of T2DM after Recurrence of T2DM After Initial Remission 35% relapse at 5 years 4,434 patients with T2DM undergoing Analyzed over 13 years (retrospectively) Initial Remission (within 5 yrs) 77% off DM meds & A1c <6.5 % of Initial Remitters Still in Remission Median duration of remission = 8.3 years Arterburn DE et al. Obes Surg 23:93 (213) Arterburn DE et al. Obes Surg 23:93 (213) Years Since Initial Remission Relapse Not Clearly Due to Weight Regain Lowess Smoothed BMI (kg/m2) Pre-op BMI did not predict remission or relapse No Remission of T2DM Prolonged Remission What about the relationship between body weight and hard cardiovascular Recurrence of T2DM outcomes after surgery? Arterburn DE et al. Obes Surg 23:93 (213) Years Since Surgery SOS 2-Year Data Reductions in Fatal and Total Heart Attacks and Strokes SOS 2-Years: Predictors of Surgical Benefit on CV Events P Value for P Value for Feature Surgical Benefit Feature Surgical Benefit Commentary:, et al. Nature Med 18:358 (212) Sjostrom L, et al. JAMA 37:56 (212) BMI.58 Gender.92 Body weight.96 Age.76 Waist hip.73!! Systolic bp.31 Waist circum.86 Diastolic bp.71 Hip circum.38 Diabetes.2 Smoking.1 Previous CVD.71 TG.93 SCORE.86 HDL.26 Metabolic synd.73 Cholesterol.28 Glucose.13 ApoB/ApoA-1.23 Insulin <.1 Commentary:, et al. Nature Med 18:358 (212) Sjostrom L, et al. JAMA 37:56 (212)

10 Inadequacy of BMI as a Stand-Alone Surgical Criterion SOS has shown that BMI does not predict the benefits from surgery with respect to: Diabetes prevention.but baseline fasting Cancer insulin and/or glucose Myocardial infarctions levels (reflecting insulin Strokes resistance) predict almost Death all of these benefits! The benefits of surgery seem more related to effects on glucose homeostasis than on body weight. SOS: NEJM 27, JAMA 212, NEJM 212 Evidence for Weight-Independent Anti-DM Effects Novel Anti-Diabetic GI Procedures Fast kinetics of diabetes resolution Glucose homeostasis improves more with than with equal weight loss from other means Inconsistent correlation between amount of weight lost and DM remission rates after Duodenal-Jejunal Bypass Duodenal-Jejunal Bypass Sleeve Some intestinal bypass operations improve diabetes with little or no weight loss, Rubino F. Nature Med (in press) Ileal Interposition Evidence for Weight-Independent Anti-DM Effects Fast kinetics of diabetes resolution Hyperinsulinemia Hypoglycemia After Gastric Bypass: Too much of a good thing for islets? Glucose homeostasis improves more with than with equal weight loss from other means Inconsistent correlation between amount of weight lost and DM remission rates after Some intestinal bypass operations improve diabetes with little or no weight loss Control Post- Late onset: 1-26 years (typical 2-4) Hints from hyperinsulinemia, Rubino F Nature Med (in press) Commentary: NEJM 353:3 (25) Service et al. NEJM 353:249 (25)

11 Ossabaw Pig 4 Average Beta Cell Area per Total Pancreas Area 3.5 Insulin Positive Area per Pancreas Section Area (%) Cummings, Flum, Sturek Flum DR, Hull RL, Farm Pigs Ossabaw Controls Sham GJ Surgery GJD Surgery What Causes s Weight-Independent Anti-Diabetes Effects? Changes in Gut Hormones? Ghrelin Ghrelin Peptide hormone produced primarily by stomach & proximal small intestine Powerfully stimulates appetite and food intake in many species, including humans, Overduin J J Clin Invest 27

12 GHRELIN GH ACTH & Cortisol Epinephrine Glucagon? Adiponectin Counter-regulatory GLUCOSE Human Plasma Ghrelin Levels Rise & Fall Shortly Before & After Every Meal Plasma Ghrelin (pg/ml) B L D Insulin Action 4 Insulin Secretion 3 n = 1 Food Intake Cummings, et al. Diabetes 5: Time of Day Plasma Ghrelin Increases After Diet-Induced Weight Loss B L D Roux-en-Y Gastric Bypass 6 Plasma Ghrelin (pg/ml) 5 Ingested food bypasses most of the 4 After Wgt Loss Before Wgt Loss 3 n = 13 ghrelin-producing cells Cummings, et al. NEJM 346:1623 Clock Time 8 B L D Pro-Diabetic Ghrelin Levels 7 Plasma Ghrelin (pg/ml) Normal Weight Wgt-Reduced Obese Normal Weight Matched Obese Increased GLP-1 Secretion 2 Gastric Bypass Detection Limit 1 Gastric Bypass Clock Time, et al. NEJM 346:1623

13 & Overduin J J Clin Invest 117:13 STOMACH Ghrelin Leptin GRP, NMB FOOD PANCREAS Amylin Enterostatin Glucagon Insulin PP & Overduin J J Clin Invest 117:13 STOMACH Ghrelin Leptin GRP, NMB FOOD PANCREAS Amylin Enterostatin Glucagon Insulin PP DUODENUM CCK, GIP DUODENUM CCK, GIP JEJUNUM APOAIV JEJUNUM APOAIV ILEUM GLP-1 Oxyntomodulin PYY insulin secretion food intake COLON GLP-1 Oxyntomodulin PYY ILEUM GLP-1 Oxyntomodulin PYY insulin secretion food intake COLON GLP-1 Oxyntomodulin PYY Plasma GLP-1 Increases After in Humans GLP-1 GLP-1 After Test Meal 2 GLP-1 After Plasma GLP-1 (pm) Time from test meal (minutes Pre-op avg Post-op avg Released in correct location to engage neural (e.g., vagal) pathways to improve glucose homeostasis GLP-1 After Test Meal GLP-1 After Test Meal Plasma GLP-1 (% change from ) Time from test meal (minutes pre-op avg post-op avg Carlson M, Heap A, Associated with increased incretin effect Occurs immediately, lasts for years DE Cummings Plasma GLP-1 (pmol/l) Plasma GLP-1 Increases After in Ossabaw Pigs Days 14 Days 6 Days 14 Days GLP-1 Cells per High-Power Filed of Mucosa GLP-1 Cells in Distal Ileum After in Ossabaw Pigs Flum DR, Time from Test Meal (minutes) Flum DR, Hull RL, Before Surgery(n=4) Surgery After Necropsy(n=7) Surgery

14 Duodenal (Jejunal) Bypass: DJB No Change in GLP-1 After DJB in Ossabaw Pigs DJB Plasma GLP-1 (pmol/l) Days 6 Days 6 Days 14 Days 1 5 Flum DR, Time from Test Meal (minutes) Gastro-Jejunostomy: GJ No Change in GLP-1 After Gastrojejunostomy in Ossabaw Pigs GJ Plasma GLP-1 (pmol/l) Days 6 Days 6 Days 14 Days 1 5 Flum DR, Time from Test Meal (minutes) Plasma PYY Increases After in Ossabaw Pigs No Change in PYY After DJB in Ossabaw Pigs DJB 4 4 Plasma GLP-1 (pmol/l) Days 14 Days 14 Days 6 Days Plasma GLP-1 (pmol/l) Days 6 Days 6 Days 14 Days Flum DR, Time from Test Meal (minutes) Flum DR, Time from Test Meal (minutes)

15 No Change in PYY After Gastrojejunostomy in Ossabaw Pigs Plasma PYY During Test Meal GJ 5 & Overduin J J Clin Invest 117:13 45 GJ FOOD 4 Plasma GLP-1 (pmol/l) Days 6 Days 6 Days 14 Days insulin secretion Flum DR, Time from Test Meal (minutes) ILEUM GLP-1 PYY Oxyntomodulin All after COLON GLP-1 PYY Oxyntomodulin Ileal Interposition A Simple Model body weight 1-cm distal transection Gastric Band TIME muscle insulin sensitivity Vascularly intact Innervated Isoperistaltic GLP-1 insulin secretion TIME body weight muscle insulin sensitivity, Rubino F Nature Medicine (in press 214) & Overduin J J Clin Invest 117:13 FOOD Does this explain everything? No. GLP 1 loss of function experiments in humans & rodents show insulin secretion GLP 1 only accounts for some ILEUM GLP-1 PYY Oxyntomodulin All after COLON GLP-1 PYY Oxyntomodulin of the glycemic effects of. Kaplan LM, et al. (212) Planas J, et al. (212) Salehi M, et al. Diabetes (211)

16 Hyperinsulinemic Clamp Studies Early After GI Surgery Biliopancreatic Diversion Ferrannini & Mingrone 25 & 26: Fast Si is not explained by weight loss, whereas slower insulin sensitivity after is explained by weight loss No DM in groups Upper Intestinal Gastric Bypass Campos 29: No Δ Si at 2 weeks c/w caloric restriction Geloneze 21: No Δ Si at 1 month Mingrone 213: Si at 1 mo in DM and non DM No DM Mostly No DM DM & non-dm Nutrient Exclusion Kashyap & Schauer 21: Si at 1 & 4 weeks Cummings & Flum 213: Si at 2 weeks?) All DM DE Cummings Duodenal (Jejunal) Bypass Duodenal (Jejunal) Bypass No gastric restriction No calorie malabsorption No change in food intake No change in body weight Major, durable in glucose tolerance with little or no weight loss in several rat DM models (but not in non-dm rats) Rubino F F Rubino, G Mingrone, S Hu, C Otto, J Liu, D Pacheco, Y Wang, M Speck, Kindel & Tso, others Duodenal-Jejunal Bypass in Humans ( Gastric-Sparing Gastric Bypass ) Does duodenal bypass ameliorate type 2 diabetes in humans? ~1.5 ft ~2.4 ft ~12 18 ft Cohen RV, et al.

17 Prospective Study of DJB for Type 2 DM in Patients With BMI < 35 kg/m 2 Duodenal-Jejunal Bypass in 46 Patients with DM & BMI <35 kg/m 2 46 patients BMI kg/m 2 Severe Diabetes Confirmed type 2: negative GAD, ICA Duration of DM: 2 1 years HbA1c (%) % on insulin Rx 6.5 % on insulin Rx 7% on insulin; others on oral DM meds Mean HbA1c = 8.9% Cohen RV,, et al Months After Surgery Cohen RV,, et al. No Relationship Between Change in Body Weight and Improvement in Glycemia Duodenal Jejunal Bypass (DJB) HbA1c Substantially improves Change in HbA1c glucose homeostasis with little or no weight loss in several rat DM models (but not in non-dm rats) Change in BMI (kg/m 2 ) Data at 1 year Cohen RV,, et al. and in humans F Rubino, G Mingrone, S Hu, C Otto, J Liu, D Pacheco, Y Wang, M Speck, Kindel & Tso R Cohen, A Ramos, G Ferzli, B Geloneze, & many others Duodenal Jejunal Bypass Sleeve Can the same thing be accomplished with an endoscopically implantable device? Food bypasses the duodenum & proximal jejunum, as it does in Substantially improves glucose homeostasis in several rat models of type 2 DM and in humans, before & out of proportion to weight loss GI Dynamics, L Kaplan, F Rubino, R Cohen, others

18 Duodenal (Jejunal) Exclusion Duodenal (Jejunal) Exclusion Gastro-jejunal Anastamosis Lower Intestinal vs. Upper Intestinal Hypothesis? Rubino F,, et al., Ann Surg 244:741 Oral Glucose Tolerance Human Mechanisms Study OGTT GK rats GK DJB Patients: severely obese type 2 diabetics Gastrostomy Tube 6 GK Sham GK GJ Remove DM Meds Glucose levels (mg/dl) Time (min) Tests: meal tolerance tests FS-IVGTT hyperinsulinemic clamps (with tracers) 1 Normal Oral Feeding 2 weeks 2 Gastric Feeding 3 Normal With G-tube Oral Feeding 2 weeks 2 weeks 4 Rubino, Cummings, et al. Ann Surg 244:741 Hyperglycemic Normoglycemic? Hyperglycemic? Normoglycemic? DE Cummings & DR Flum Insulin Sensitivity by Hyperinsulinemic/Euglycemic Clamp Insulin Sensitivity by Clamp (M/I) DE Cummings & DR Flum Duodenal Exclusion 1 Duodenal Passage Duodenal Exclusion 2 Meal Tolerance Test: Insulin Insulin 25 (µu/ml) 2 1 Duod Passage Duod Excl 2 Duod Excl Meal Time (minutes) DE Cummings & DR Flum

19 Meal Tolerance Test: Glucose Acute Insulin Response to Glucose (IVGTT) Glucose (mg/dl) Duod Passage Duod Excl 2 Duod Excl Meal Time (minutes) DE Cummings & DR Flum Insulin µu/ml Duod Passage Duod Exclusion 2 Duod Exclusion Time (minutes) DE Cummings & DR Flum Human Mechanisms Study Patients: severely obese type 2 diabetics Remove DM Meds Tests: meal tolerance tests FS-IVGTT hyperinsulinemic clamps (with tracers) 1 Normal Oral Feeding Gastrostomy Tube Duodenal nutrient passage strongly influences insulin sensitivity, independent of weight change. 2 Gastric Feeding 3 Normal With G-tube Oral Feeding 4 Novel Roles of the Gut to Regulate Insulin Sensitivity 2 weeks 2 weeks 2 weeks Hyperglycemic Normoglycemic? Hyperglycemic? Normoglycemic? DE Cummings & DR Flum Nutrient sensing in the gut regulates food intake Nutrient sensing in the gut regulates insulin secretion Relating to: Wang PY et al. Nature 452:112 Thaler & Cummings Nature 452:941 Relating to: Wang PY et al. Nature 452:112 Thaler & Cummings Nature 452:941

20 Nutrient sensing in the gut regulates insulin secretion & sensitivity Drawing by Nathan Cummings 5 th grade Relating to: Wang PY et al. Nature 452:112 Thaler & Cummings Nature 452:941 Relating to: Wang PY et al. Nature 452:112, 28 Thaler & Cummings Nature 452:941 In vivo Insulin Tolerance Test: db/db Proteins Injected Glucose (mg/dl) In vitro Soleus Muscle Glucose Uptake Insulin IRS-1 PI3K Intestinal Proteins TSC1/TSC2 Thr 38 -PO 4 Akt Ser 473 -PO 4 mtorc2 PP242 In vivo Insulin Tolerance Test: Wild Type Proteins Injected Glucose (mg/dl) In vitro Myoblast Glucose Uptake GSK3 TSC1/TSC2 Rheb/GTP mtorc1 Salinari et al PLOS ONE (Epub 213) S6K1 Salinari S.Mingrone G. PLOS ONE (Epub 213) Gastric Band Mechanisms Model intestinal nutrient sensing & metab insulin sensitivity GLP-1 insulin secretion TIME body weight muscle insulin sensitivity body weight muscle insulin sensitivity, Rubino F Nature Medicine (in press 214) Weight Independent Anti Diabetes Candidate Mechanisms of GLP 1 (& PYY & OXM) Ghrelin Amylin Duodenal factor Intestinal LCFACoA & CCK Intestinal Gluconeogenesis Bile acids Ceramides in Gut Microbiome Inflamm & oxidative stress Branched Chain AA in blood Reprogram intest glu metab, Rubino F. Nature Med (in press 214)

21 Where does metabolic surgery fit in diabetes care (including less obese T2DM)? NIH Consensus Development Panel Criteria for Bariatric Surgery (1991) BMI > 4 or BMI > 35 with diabetes Surgery to treat DM in less obese patients makes sense if it improves DM through weightindependent mechanisms. Diabetes Surgery Summit Rome 27 Diabetes Surgery Summit Conclusions Gastric bypass improves diabetes via mechanisms beyond reduced food intake & body weight Gastric banding improves diabetes only via its effects on food intake and body weight Societies That Changed Their Names Soon After 27 to Include Metabolic Surgery American Society for Metabolic & Bariatric Surgery Brazilian Society for Bariatric & Metabolic Surgery Italian Society for Surgery of Obesity & Metabolic Diseases Venezuelan Society of Bariatric & Metabolic Surgery Obesity & Metabolic Surgery Society of India International Federation for the Surgery of Obesity & Metabolic Disorders Rubino, Schauer, Kaplan, & Cummings, Ann Surg 21 & Ann Rev Med 21 Asia Pacific Metabolic & Bariatric Surgery Society

22 Diabetes Surgery Summit Conclusions Distribution of T2DM According to BMI Gastric bypass improves diabetes via mechanisms beyond reduced food intake & body weight Gastric banding improves diabetes only via its effects on food intake and body weight Gastric bypass should be considered to treat type 2 diabetes in patients with BMI 3 kg/m 2 Thin Normal Overweight Obese I Obese II III >5% of patients with diabetes worldwide have BMI <35 kg/m 2 Rubino, Schauer, Kaplan, & Cummings, Ann Surg 21 & Ann Rev Med 21 Bays et al. Int J Clinical Prac 61:737 (27) Management Algorithm for Metabolic Control in Type 2 Diabetes ADA EASD Consensus Algorithm for T2DM Treatment Lifestyle Modification diet modification weight control physical activity Metformin Bariatric Surgery Sulphonylurea Acarbose DPP 4 inhibitor Glitazone Insulin Bariatric Surgery BMI > 35 eligible BMI > 4 prioritised Bariatric surgery not mentioned for anyone! BMI > 3 eligible & BMI > 35 prioritized If HbA1c >7.5% despite optimized conventional therapy, especially if weight is increasing, or if other weight responsive comorbidities are not reaching target on conventional therapy. Basal Basal Bolus insulin Premixed Bariatric Surgical and Procedural Interventions in the Treatment of Obese Patients with Type 2 Diabetes Nathan DM, et al. Diabetes Care 32:193, 29 Main Problem Relative paucity of highest quality, longterm outcome date from surgical compared with medical DM care But are RCTs of surgical vs. non surgical care feasible?

23 It s very hard to find educated patients in true equipoise about surgical vs. non-surgical options Typical Enrollment Strategies Approach patients in a bariatric surgery clinic Likely to be biased in favor of surgery Approach patients in a medical clinical Likely to be biased in favor of non surgery May be okay for observational studies, but problematic for RCTs CROSSROADS Trial (an RCT) Our approach Calorie Reduction Or Surgery: Seeking Remission for Obesity And Diabetes Cummings, Flum, Arterburn, et al CROSSROADS Trial RCT of T2DM Rx in BMI 3 4 Standard & Medical Care OR Intensive Medical Lifestyle Rx Aerobic exercise Diet (low calorie, low fat) State of the art DM Rx per ADA/EASD

24 Identify Eligible Patients From Databases Use administrative & clinical databases Meet inclusion criteria BMI 3 4 kg/m 2 Type 2 diabetes Has coverage for both Rx arms Have no exclusion criteria Unique, Validated Shared Decision Making Instrument Modified from D. Arterburn

25 Pool of Potentially Eligible Candidates Sent invitation letter to participate in screening call (1%) Non-responders to screening call: (unable to contact, contacted and refused, or deceased) (41%) Contacted for screening call (59%) Ineligible for study (17%) Refused study (2%) Eligible and interested in SDM call (23%) Completed SDM call (15%) Not interested in more info about weight control (17%) Non-responders to SDM call: (unable to contact, contacted and refused) (8%) Prefers non-surgical treatment and not invited to RCT (9%) At equipoise or prefers surgery and invited to RCT (6.4%) Randomized Participants Arterburn D. SOARD 213 (Epub) Randomized (2.4%) Ineligible after surgeon s chart review or refused randomization (4%) Arterburn D. SOARD 213 (Epub) Demographics Participant Characteristics Surgical Medical Lifestyle P Value Age (yr) 52. (8.3) 54.6 (6.3).4 Female sex 8.% 58.8%.3 White race 8.% 64.7%.4 CROSSROADS One Year Results Anthropometrics & Body Composition Fitness Glycemia Body weight (kg) 18.8 (14.9) (16.5).6 Height (cm) (7.9) (1.3).1 BMI (kg/m 2 ) 38.3 (3.7) 37.1 (3.5).3 Waist circumference (cm) (1.2) 12.8 (1.).8 Waist to hip ratio 1. (.1) 1. (.1).8 Body fat by DEXA (%) 47.6 (5.4) 46.1 (6.4).6 Body fat by BEI (%) 41.4 (6.3) 38.6 (8.2).3 VO 2max by ETT 19.6 (2.6) 21.1 (3.6).4 HbA1C (%) 7.7 (1.) 7.3 (.9).4 Fasting plasma glucose (mg/dl) (47.1) (47.7).7 Fasting plasma insulin (uu/ml) 23. (14.7) 26.9 (19.5).6 Use of insulin 6.% 47.1%.5 Duration of known diabetes (yr) 11.4 (4.8) 6.8 (5.2).9 Dyslipidemia 86.7% 82.4% 1. Lipids Blood Pressure Cholesterol (mg/dl) Total (37.2) (31.1).5 LDL 93.1 (28.9) 85.9 (22.7).4 HDL 44.5 (11.5) 42.2 (1.8).6 Triglycerides (mg/dl) (59.4) 23.5 (12.).1 Hypertension 8.% 94.1%.3 Blood pressure (mm Hg) Systolic (2.6) 12.1 (9.6).3 Diastolic 77. (1.2) 74.8 (7.5).9 difference biases against surgical superiority Primary Endpoint: Diabetes Remission at One Year (HbA1c <6.% Off All Diabetes Medications) 6% Changes in Glycemia Significantly greater fall in A1c with surgery Percent In Remission 7. HbA1c (%) Med Lifestyle Surgical 6% Time (months)

26 Changes in Glycemia Changes in Glycemia HbA1c (%) Fasting Glucose Fasting Insulin (µu/ml) HOMA-IR Med-Lifestyle Surgery Med-Lifestyle Surgery Med-Lifestyle Surgery Med-Lifestyle Surgery Changes in Body Composition Changes in Lean Body Mass & Fitness Body Weight (kg) % Fat Mass (DEXA) Lean Body Mass (kg, DEXA) 32 3 VO2 Max (i.e., Fitness) Life Surg Med-Lifestyle Surgery Med-Lifestyle Surgery Med-Lifestyle Surgery Med-Lifestyle Surgery Changes in Blood Pressure Changes in Blood Lipids Systolic BP (mm Hg) Diastolic BP (mm Hg) Total Cholesterol LDL Cholesterol P =.5 Med-Lifestyle Surgery Med-Lifestyle Surgery Med-Lifestyle Surgery Med-Lifestyle Surgery

27 HDL Cholesterol P =.8 Changes in Blood Lipids Triglycerides Average # of Metabolic Meds Taken at 1 Year On GERD Meds Med-Lifestyle 3% Surgery % Med-Lifestyle Surgery Med-Lifestyle Surgery Diabetes HTN Lipids Metab Syndr CROSSROADS: One Year Results Surgery Was Better than Meds Lifestyle for: HbA1c & diabetes meds usage Diabetes remission fasting insulin (but not fasting glucose) HOMA IR body weight % body fat (by DEXA and BIA) systolic blood pressure CROSSROADS: One Year Results Interventions Were Similar for: diastolic blood pressure cholesterol LDL HDL (trend for surgical superiority) triglycerides Adverse Events RCT Interventions Compared N BMI (kg/m 2 ) No major events in either group Substantially more hypoglycemia reported in the medical group Ikramuddin, et al Schauer, et al Mingrone, et al Published RCTs of Surgical vs. Medical and/or Lifestyle Interventions for Diabetes & Obesity Intensive medical-lifestyle care VSG Intensive medical care BPD Conventional medical care 12 With T2DM 15 With T2DM 6 With T2DM Follow-Up Main Findings year Achieved composite goal for T2DM, hypertension, and dyslipidemia : 49% Medical: 19% (O.R. 4.8) year HbA1c <6.% : 42% VSG: 37% Medical: 12% 35 2 years HbA1c <6.5% off diabetes medications : 75% (O.R. 7.5 vs. meds) BPD: 95% (O.R. 9.5 vs. meds) Medical: % One inpatient admission for alcohol abuse in a surgical patient Dixon, et al O Brien, et al LAGB Conventional medical care LAGB Supervised lifestyle intervention 5 RCTs - All 4 ops now in use - Various med-lifestyles 6 With T2DM 5 No T2DM 44 pts BMI down to years HbA1c <6.2% off diabetes medications LAGB: 73% Medical: 13% (O.R. 5.5) >35 2 years >5% excess body weight loss LAGB: 84% Lifestyle: 12% 1 2 yrs, Cohen RV Lancet DM Endo (214)

28 Conclusions from This & Other Recent RCTs Management Algorithm for Metabolic Control in Type 2 Diabetes Bariatric/metabolic surgery is more effective than medical-lifestyle interventions for weight loss, glycemic control, DM remission, & improvements in other CVD risk factors, with acceptable complications, for at least 1-2 years, including in patients with a BMI < 35. Bariatric Surgery BMI > 3 eligible & BMI > 35 prioritized If HbA1c >7.5% despite optimized conventional therapy, especially if weight is increasing, or if other weight responsive comorbidities are not reaching target on conventional therapy. Lifestyle Modification diet modification weight control physical activity Metformin Sulphonylurea Acarbose DPP 4 inhibitor Glitazone Insulin Basal Basal Bolus insulin Bariatric Surgery BMI > 35 eligible BMI > 4 prioritised Premixed Bariatric Surgical and Procedural Interventions in the Treatment of Obese Patients with Type 2 Diabetes NIH-Sponsored Ongoing RCTs Type 2 Diabetes Patient Population SLIMM T2D (Goldfine, Lautz, et al.) Triabetes & Triabetes 2 (Courcoulas, et al.) CROSSROADS (Cummings, Flum, et al.) Stampede II (Schauer, Kirwan, et al.) IDeaLS (Clark, Brancati, et al.) SOLID (Sarwer, et al.) NIH-Sponsored Ongoing RCTs Type 2 Diabetes Patient Population SLIMM T2D (Goldfine, Lautz, et al.) Triabetes & Triabetes 2 (Courcoulas, et al.) CROSSROADS (Cummings, Flum, et al.) Stampede II (Schauer, Kirwan, et al.) IDeaLS (Clark, Brancati, et al.) SOLID (Sarwer, et al.) Obstructive Sleep Apnea Patient Population ABC Trial (Patel, et al.) Obstructive Sleep Apnea Patient Population ABC Trial (Patel, et al.) Proposed UO1 consortium for long-term F/U, Cohen RV Lancet DM Endo (in press), Cohen RV Lancet DM Endo (214) Are we ready for a mega RCT of surgery vs. medical lifestyle care for T2DM with hard endpoints? I think so. U. Washington Joost Overduin Karen Foster Schubert Scott Frayo Ian Townsend Dave Flum Allison Rhodes Skye Stewart Leon Chan Jessica Kuzma David Arterburn Emily Westbrook Jon Purnell Scott Weigle Funding: NIH/NIDDK Elsewhere Contributors Francesco Rubino (Cornell) Ricardo Cohen (Sao Paulo, Brazil) Phil Schauer (Cleveland Clinic) Carel LeRoux (U. London) Shashank Shah (Pune, India) Jaya Todkar (Pune, India) Lars Sjostrom (Sweden) G.I. Dynamics (Boston) Jens Holst (U. Copenhagen)