Metabolic Surgery for BMI <35: When, If Ever?

1. Metabolic Surgery for BMI <35:When, If Ever? David E. Cummings, M.D. University of Washington, VA Puget Sound, Diabetes & Obesity Center of Excellence, Seattle

2. NIH Consensus Development Panel Criteria for Bariatric Surgery (1991) • BMI > 40 • BMI > 35 and life-threatening obesity-associated cardiopulmonary complications or severe diabetes • Approved: RYGB, VBG, Banding

3. The 1991 NIH Consensus is Outdated • Only considered open operations • No attention to diabetes • Gastric bypass has since been refined • Gastric banding has come into its own • More data on BPD • Gastroplasty is virtually gone • New procedures • Sleeve gastrectomy • Duodenal-jejunal bypass • Ileal interposition • Endoluminal sleeves • Gastric plication, balloons, funnels, etc.

4. National and international guidelines for eligibility for bariatric surgery (adults) The guidelines above are qualified by the following common elements: Appropriate non-surgical weight loss measures have been tried and failed; there is the provision for, and a commitment to, long term follow-up; and individual risk to benefit ratio needs to be evaluated Bariatric Surgical and Procedural Interventions in the Treatment of Obese Patients with Type 2 Diabetes

5. Effect of Bariatric Surgery on Long-Term Mortality Compared With Non-Operated Controls Study Procedure F/U Mortality Reduction MacDonald, 1997 RYGB 9 yr 88% Flum, 2004 RYGB 4.4 yr 33% Christou, 2004 RYGB 5 yr 89% Sowemimo, 2007 RYGB 4.4 yr 63% Dixon, 2007 LAGB 12 yr 72% Adams, 2007 RYGB 8.4 yr 40% Sjostrom, 2007 VBG/other 14 yr 31% RYGB/LAGB Perry, 2008 2 yr 48% P Schauer

6. Swedish Obese Subjects Study Usual Care Total Body Weight Loss (%) Banding Gastroplasty Gastric Bypass Sjöström L, et al. JAMA 307:56 (2012) Years of Follow Up

7. SOS 20-Year Data Reductions in Fatal and Total Heart Attacks and Strokes Sjostrom L, et al. JAMA307:56 (2012)

8. SOS 20-Years: Predictors of Surgical Benefit on CV Events Baseline P Value for Baseline P Value for Feature Surgical Benefit Feature Surgical Benefit 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 .20 Smoking .10 Previous CVD .71 TG .93 SCORE .86 HDL .26 Metabolic synd .73 Cholesterol .28 Glucose .13 ApoB/ApoA-1 .23 Insulin <.001 !! Sjostrom L, et al. JAMA307:56 (2012)

9. SOS 20-Years: Predictors of Surgical Benefit on CV Events Baseline P Value for Baseline P Value for Feature Surgical Benefit Feature Surgical Benefit 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 .20 Smoking .10 Previous CVD .71 TG .93 SCORE .86 HDL .26 Metabolic synd .73 Cholesterol .28 Glucose .13 ApoB/ApoA-1 .23 Insulin <.001 Sjostrom L, et al. JAMA307:56 (2012)

10. SOS 20-Year DataPredictors of Surgical Benefit on CV Events Baseline # Needed to Treat Fold Feature to Prevent CV Event Difference Glucose < Median 150 Glucose > Median 25 6 x Insulin < Median 173 Insulin > Median 21 > 8 x Sjostrom L, et al. JAMA307:56 (2012)

11. SOS 20-Year Data Baseline Insulin, Not BMI or Weight Loss Predict CV Benefits of Surgery Sjostrom L, et al. JAMA307:56 (2012)

12. Swedish Obese Subjects Study Usual Care Multivariate analyses of 20-year data show additional effects of surgery, beyond weight loss, to improve diabetes prevention & remission. Total Body Weight Loss (%) Banding Gastroplasty Gastric Bypass Sjöström L, et al. JAMA 307:56 (2012) Years of Follow Up

13. Does this favorable risk–benefit profile apply to people with BMI <35?

14. Distribution of T2DM According to BMI Thin Normal Overweight Obese I Obese II III >50% of patients with diabetes worldwide have BMI <35 kg/m2 Bays et al. Int J Clinical Prac 61:737 (2007)

15. Surgery to treat DM in less obese patients makes sense if it improves DM through weight-independent mechanisms.

16. Evidence for weight-independent anti-diabetes effects of bariatric surgery.

17. Evidence for Weight-Independent Anti-DM Effects • Fast kinetics of diabetes resolution Poor correlation between amount of weight lost and DM remission rates after RYGB

18. Evidence for Weight-Independent Anti-DM Effects • Fast kinetics of diabetes resolution • Glucose homeostasis improves more with RYGB than with equal weight loss from other means Poor correlation between amount of weight lost and DM remission rates after RYGB

19. Long-Term Follow-Up of Gastric Bypass vs. Gastric Banding Percentage Weight Loss % Weight Loss Band Bypass Time (months) C. le Roux, et al Ann Surg 252:966 (2010)

20. Long-Term Follow-Up of Gastric Bypass vs. Gastric Banding Percentage Weight Loss Percentage With Diabetes Band % With Diabetes % Weight Loss Band Bypass Bypass Time (months) Time (months) C. le Roux, et al Ann Surg 252:966 (2010)

21. Evidence for Weight-Independent Anti-DM Effects • Fast kinetics of diabetes resolution • Glucose homeostasis improves more with RYGB than with equal weight loss from other means • Inconsistent correlation between amount of weight lost and DM remission rates after RYGB DE Cummings

22. Prospective Study of RYGB for Type 2 DM in Caucasians With BMI 30–35 kg/m2 • 66 Caucasian patients • 100% F/U up to 6 years • Median F/U = 5 years • BMI 30–35 kg/m2 • Mild obesity for this population • Type 2 DM • Confirmed with Abs, C-peptide, FHx • Severe diabetes • Mean duration: 13 years • 40% on insulin (the rest on oral DM meds) • HbA1c: 9.7% at start Cohen RV….. Cummings DE

23. Rapid & Durable Improvement in HbA1c A 11 10 9 Hemoglobin A1c (%) 8 7 6 5 0 6 12 24 48 60 72 Cohen RV….. Cummings DE Months After Surgery

24. Rapid & Durable Improvement in Fasting Glucose 170 160 150 Fasting Plasma Glucose (mg/dL) 140 130 120 110 100 90 0 6 12 24 48 60 72 Cohen RV….. Cummings DE Months After Surgery

25. 6-Year Study of RYGB for Type 2 DM in Patients With BMI 30–35 kg/m2 70 88% 60 50 Number Of Patients 40 30 20 11% 10 1% 0 No Change T2DM Remission T2DM Improvement Cohen RV….. Cummings DE

26. 140 0 Resolved -5 130 -10 -15 120 Waist Circumference (cm) -20 Total Body Weight Loss (%) 110 -25 -30 100 -35 -40 90 -45 80 -50 0 6 12 24 48 60 72 0 6 12 24 48 60 72 140 0 Improved -5 130 -10 -15 120 Waist Circumference (cm) -20 Total Body Weight Loss (%) 110 -25 -30 100 -35 -40 90 -45 80 -50 0 6 12 24 48 60 72 0 6 12 24 48 60 72 Cohen RV……. Cummings DE Months After Surgery Months After Surgery

27. Evidence for Weight-Independent Beneficial Effects of RYGB on Glycemia • No relationship at any time point between the amount of weight lost and: • Decrease in fasting blood glucose • Decrease in HbA1c • Improvement beta-cell responsiveness to glucose • Increase in estimated insulin sentivitity (HOMA) • Except at 5 and 6 years Cohen RV…. Cummings DE

28. 10-Year Cardiovascular Risk Before vs. After RYGB Cohen RV…..Cummings DE

29. Evidence for Weight-Independent Anti-DM Effects • Fast kinetics of diabetes resolution • Glucose homeostasis improves more with RYGB than with equal weight loss from other means • Inconsistent correlation between amount of weight lost and DM remission rates after RYGB • Some intestinal bypass operations improve diabetes with little or no weight loss DE Cummings

30. Novel Anti-Diabetic GI Procedures Duodenal-Jejunal Bypass Ileal Interposition Duodenal-Jejunal Bypass Sleeve

31. Evidence for Weight-Independent Anti-DM Effects • Fast kinetics of diabetes resolution • Glucose homeostasis improves more with RYGB than with equal weight loss from other means • Inconsistent correlation between amount of weight lost and DM remission rates after RYGB • Some intestinal bypass operations improve diabetes with little or no weight loss • Hints from hyperinsulinemia DE Cummings

32. Hyperinsulinemia Hypoglycemia After Gastric Bypass: Too much of a good thing for islets? Control Late onset: 1-9 years (typical 2-4) Post-RYGB Service et al. NEJM 353:249 (2005)

33. Diabetes Surgery Summit Rome 2007

34. 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 Rubino, Schauer, Kaplan, & Cummings, Ann Surg 2010 & Ann Rev Med 2010

35. Societies Changing Their Names in ~2007 to Include “Metabolic Surgery” • American Society for Metabolic and Bariatric Surgery • Brazilian Society for Bariatric and Metabolic Surgery • Italian Society for Surgery of Obesity and Metabolic Diseases • Venezuelan Society of Bariatric & Metabolic Surgery • International Federation for Surgery of Obesity and Metabolic Diseases • Asia-Pacific Metabolic & Bariatric Surgery Society

36. 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 • Gastric bypass should be considered to treat type 2 diabetes in patients with BMI ≥ 30 kg/m2 Rubino, Schauer, Kaplan, & Cummings, Ann Surg 2010 & Ann Rev Med 2010

37. Basal Premixed Basal Bolus insulin Management Algorithm for Metabolic Control in Type 2 Diabetes Lifestyle Modification • diet modification • weight control • physical activity Metformin Bariatric Surgery BMI > 35 eligible BMI > 40 prioritised Sulphonylurea Bariatric Surgery BMI > 30 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. Acarbose DPP-4 inhibitor Glitazone Insulin Bariatric Surgical and Procedural Interventions in the Treatment of Obese Patients with Type 2 Diabetes

38. Studies of “Metabolic Surgery” for BMI <35 Fried M, et al (2010) Obes Surg 20:776

39. Database Analysis of RYGB for DM in BMI <35 • Queried ASMBS COE BOLD database • 66,264 pts • Identified 235 pts with BMI 30-35 and DM who had bariatric surgery • 109 AGB • 109 RYGB Demaria EJ, et al, Ann Surg 252:559 (2010)

40. Database Analysis of RYGB for DM in BMI <35 • Weight Loss (at 12 mo) • LABG: BMI 33 → 29 • RYGB: BMI 33 → 23 • “Clinical DM Remission” (at 12 mo) • LAGB 36% • RYGB 75% • Morbidity (90-day, minor) • LAGB: 3% • RYGB: 18% • Mortality (at 90-day): 0% Demaria EJ, et al Ann Surg 252:559 (2010)

41. Political Realities Impelling RCTs • NIH is unlikely to consider revising the 1991 consensus guidelines until substantially more Class A evidence is available • The 1991 conference followed shortly after several RCTs of RYGB vs. VBG • Insurance companies are unlikely to pay for operations performed outside of NIH guidelines

42. It’s very hard to find educated patients in true equipoise about surgical vs. non-surgical options

43. Randomized controlled trials are needed. And they’re on their way!

44. CROSSROADS Trial (an RCT)Calorie Reduction Or Surgery: Seeking Remission for Obesity And Diabetes Cummings, Flum, Arterburn

45. CROSSROADS Trial • RCT of T2DM Rx in BMI 30−40 • Standard RYGB & Medical Care OR • Intensive Medical−Lifestyle Rx • Aerobic exercise • Diet (low-calorie, low-fat) • State-of-the-art DM Rx per ADA/EASD

46. Active RCT’s: Bariatric Surgery and T2DM

47. Starting with the most diabetes-susceptible populations makes sense.

48. Asian Indians Have Increased Diabetes Risk at Lower BMI Levels Asian Indian Chiu M et al. Diabetes Care 34:1741, 2011 Chinese Black Diabetes Incidence per 1000 person-years White Body Mass Index (kg/m2)

49. Prospective Study of RYGB for Type 2 DM in Asian Indians With BMI < 35 kg/m2 • BMI 22–35 kg/m2 • “Overweight” to “Obese” by Indian-specific WHO criteria • Type 2 DM • Confirmed with Abs, C-peptide, FHx • Severe diabetes • Mean duration: 9 years • 80% on insulin (the rest on oral DM meds) • HbA1c: 10.1% • Other features • Dyslipidemia: 93% • Hypertension: 60% Shah S….. Cummings DE SOARD 2010

50. 14 10.1 12 10 6.1 8 6 4 % Off All DM Meds 0% 80% 100% 100% 100% 2 0 Gastric Bypass in Asian Indians With DM & BMI <35 kg/m2 HbA1c (%) 0 1 3 6 9 Shah S….. Cummings DE, SOARD 2010 Months After Surgery