1. Surgery for T2DM in BMIs < 35 The Center of Excelence for the Surgical Treatment of Obesity and Metabolic Disorders Hospital Oswaldo Cruz, São Paulo, Brasil Ricardo Cohen MD FACS

2. Cuántos procedimientos mas se han descrito y/o puesto en práctican en IMCs < 35 LAGB O’brien/Dixon 1 (non-diabetic) Dixon/O’brien 2 (diabetic) Fielding et al Italian Registry Gastric Bypass Fobi et al Cohen et al Lee WJ et al BPD - Scopinaro, Chielini

3. Type 2 Diabetes: An operable Intestinal Disease? Why operate? Evidences in the obese population: Dr Pories already showed everything! Evidences of resolution without direct relation to weight loss in some bariatric operations (Laferrere,2008;Lee,2008;Patou 2008) Previous speakers did the job!!

4. Surgery over the GI tract can improve T2DM control 10 to 15% of T2DM are normal weight (Mokad, in JAMA,2000)10 to 15% of T2DM are normal weight (Mokad, in JAMA,2000) 70% of morbidly obese patients have NO T2DM!!70% of morbidly obese patients have NO T2DM!! If it seems that there is a surgical induced antidiabetic effect, and most diabetics in the world are NOT morbidly obese, most of them are NOT under control, why not offer this option to some selected patients??? 45 % with BMI BELOW 30

5. Options AGB RYGBBPD

6. 13 | Glycemia as an Endpoint YearAuthorNLevelTherapy ControlOutcome 2008Dixon J60A LAGB (BMI 30-40 kg/m2) Medical management 72% Resolution of Type 2 DM 2006O’Brien PE79A LAGB (BMI 30-34 kg/m 2 ) Medical management Reduction in metabolic syndrome 93%- surgery vs. 46%- medical management 2008Lee WJ158CRYGBP < 35 kg/m 2 RYGBP >35 kg/m 2 76.5% success in BMI<35 kg/m2; 88.9% success in BMI 35–45 kg/m2, 2006Cohen R37CRYGBP < 35 kg/m 2 97% Resolution of Type 2 DM 2009Chiellini C5CBPD < 35 kg/m 2 Low energy diet 100% Resolution of Type 2 DM; no improvement in diet group

7. April 2002- Feb 2008 127 patients 28 - 63 years-old ( mean of 44) 98 women WE HAVE STARTED WITH THE LRYGB

8. BMI30-3131.1-3232.1-3333.1-3434.1-34.9 Pts 24(19%)33(26%)39(31.5%)19(15%)12(8.5%) T2DM1310201310 127 Patients 66 T2DM(52%) Effect of RYGB in patients with BMI < 35 kg/m 2

9. Uncontrolled T2DM after 12 mo of agressive medical and behavioral treatment History of T2DM from 2 to 20 years Fasting C peptide over 1 that increases after a meal challenge LRYGB was indicated when:

10. RYGB, BMI 30-35 Cohen at al.

11. A1c

12. RYGB, BMI 30-35 Cohen at al. EWL, 72 months follow up

13. RYGB, BMI 30-35 Cohen at al.

14. No mortality No leaks 1 reoperation due to intestinal obstruction 4.5% of minor complications ( port site hematomas, vomiting)

15. Duodenal- Jejunal Bypass with sleeve gastrectomy Ileal interposition Sleeve gastrectomy Novel procedures

16. T2DM & THE METABOLIC EFFECTS OF BARIATRIC SURGERY Novel Surgical Options Ileal Interposition +/- Sleeve Gastrectomy Ileal Interposition +/- Sleeve Gastrectomy Physiologic Basis = Enteroinsular AxisPhysiologic Basis = Enteroinsular Axis HighlightsHighlights Complex MIS procedureComplex MIS procedure 3 GI anastomosis3 GI anastomosis Scant worldwide experienceScant worldwide experience

17. T2DM & THE METABOLIC EFFECTS OF BARIATRIC SURGERY Novel Surgical Options “First in Man” Ileal interposition & Sleeve Gastrectomy “First in Man” Ileal interposition & Sleeve Gastrectomy 19 patients19 patients Mean 37 years oldMean 37 years old Mean BMI 40 (range 35-44)Mean BMI 40 (range 35-44) Select co-morbiditySelect co-morbidity –n=5 T2DM - At 3 weeks, 5/5 T2DM patients off meds with normal FPG –n=8 HTN –n=2 OSA –n=11 hyperlipidemia A dePaula et.al. SOARD, 2006

18. Ileal interposition- De Paula, 2008 Conclusions: Laparoscopic II-SG and II-DSG seem to be promising procedures for the control of the metabolic syndrome and type 2 diabetes mellitus. Excluding the duodenum may improve results. A longer follow-up period is needed. Surg Endosc

19. De Paula II/SGII Adding a duodenal exclusion improves results (SOARD,2010) RCT II +Duodenal Exclusion x Ileal interposition WITHOUT Duodenal Exclusion

20. Ileal Interposition- De Paula It’s effective, although complex a procedure : ~ 10% of pts with BMI 20-22 were operated(some LADA included, probably) 3.5% mortality Revisions for intestinal obstruction 6% major complications ( leaks and important intracavitary bleeding) malnutrition (my experience in revising Il Int)- sleeve too tight?; interposed ileum problems?

21. Sleeve gastrectomy in lower BMIs There were only 3 T2DM pts, with 2 resolutions and 1 improvement, related to weight loss

22. 4 9 8 7 6 5 01234567890123456789 HbA 1c (%) Time Post Surgery (month) 26 30 29 28 27 01234567890123456789 BMI (kg/m2) Time Post Surgery (month) R Cohen et.al SOARD, 2007

23. 1st Protocol - Original Intact Stomach DJB 46 pts46 pts -April 2007-March 2008 -27 men -Hx of T2DM – 2 to 10 years -BMI 22-34.9 -Fasting C peptide>1 -LADA ruled out ( negative antibodies)

24. Analysis of 46 patients with @ 12 mo follow-upAnalysis of 46 patients with @ 12 mo follow-up Surgical treatment of T2DM

25. Outcomes Classification Resolution - No meds/insulin, HbA1c<7Resolution - No meds/insulin, HbA1c<7 Control - Less meds/no insulin, HbA1c<7Control - Less meds/no insulin, HbA1c<7 Improvement- Less meds/no insulin, HbA1c< baselineImprovement- Less meds/no insulin, HbA1c< baseline Non response - Same or worst than baselineNon response - Same or worst than baseline

26. Outcomes Classification Resolution Control Improvement No response 10 cases4 cases3 cases7 cases Between resolution and Improvement = 70% 41 % of pts are OFF MEDS All insulin users, including non responders are OFF insulin

27. Delta BMI x A1c and FPG Delta BMI HAS NO IMPACT in the negative variation of A1c AND FPG from preop to 12 months FP G No relation between weight loss/gain and DM resolution

28. We have learned and moved forward, seeking for better results The role of Ghrelin The role of the biliary limb lenght Results were less dramatic than those in the obese population

29. GHRELIN ↑ GH ↑ ACTH & Cortisol ↑ Epinephrine ↑ Glucagon? ↓ Adiponectin ↓ Insulin Action ↓ Insulin Secretion ↑ Food Intake ↑ GLUCOSE Counter-regulatory Courtesy of DE Cummings Ghrelin is Diabetogenic

30. Moving Forward Increased the biliary limb lenght Data suggests that altered bile acid levels and composition may contribute to improved glucose and lipid metabolism in patients who have had GB with longer biliary limbs. ADA,2007

31. Sleeved DJB or Short DS 100 cm 150 cm

32. BIG TRIALS it’s not all about sugar !!!! 2008;358:580-91.

33. Sleeved DJB or Short DS Endpoints in 24 mo A) Primary Glycemic control - fasting and post prandial A1c<7 B) Secondary Blood pressure Lipids Carothideal Inthima Thickness(CIT)

34. 2nd Protocol - Sleeved DJB or Short DS May 2008 - Jul 2009 78 operated cases Mean BMI = 28.6 ( 25.6-30.4) Mean time of Hx of T2DM - 13.3 y( 4-20 y) Mean preop A1c= 8.2+- 0.9 46 insulin users ( 59%) Ruled out LADA ( negative GAD/ICA) Fasting C peptide over 1, with corrected fasting glycemia below 120 mg/dl Increase of C peptide after a mixed meal challenge

35. Sleeved DJB or Short DS RESULTS First 30 pts @ 12mo Follow up TBWL 9.7% +- 2.6% 22 insulin users Follow- up Mean A1c Insulin UnchangedControl, A1c<7 Less meds Resolution No meds,A1c<7 12 mo6.3+-0.4*NONE3% ( 1 pt) 24% (10 pts) 63% (19 pts) * 11 ( 37%) pts with A1c less than 6 97% between Control &Resolution

36. Is there weight loss relation to T2DM resolution? Although there is some weight loss, there is no direct cause-effect relation !

37. Why the more WL, worst outcome? Can anybody tell me why? Delta BMI A1c<7, NO MEDS Change in body composition?

38. Hb A1c preop to 12 months - * p<0,05 8..9+- 0.9 7.1+-0.4 6.9+-0.6 6.3+-0.4 *

39. FPG preop to 12 months - * p<0,05 176+-19 123+-9 101 +-13* 142+-23

40. 120 min Mixed meal challenge preop to 12 months - * p<0,05 242+-23 176+-11 140+-13 161+-14 Preop 3 mo6 mo12 mo

41. CIT n= 30, in mm, * p<0.05 preop3 mo12 mo 0,71±0,160,69±0,11 0,60±0,14* *p<0.05 vs. preop

42. BP(mmHg) n= 30, *p<0,05 PAD, preop- 12 mo preop 6 mo12 mo PAS 131,1±14,5 123±11,9 120 ±13,8 PAD 88,7±7.480±12,571 ±12,7*

43. Lipid Profile Preop6 mo12 mo HDL 41 ±9,544 ±6,748,7 ±9,8 LDL 181 ±23,7127±13,5101 ±12,7* Tryglycerides 337 ±54,3210 ±31,9111 ±14,3* * p<0.05

44. Short DS and low BMI T2DM Predictors of Success(A1c<7) There is NO significance, comparing preop to 3,6, 9 & 12 mo ( **p<0.05) Gender Time of Hx of T2DM ( 2- 20 years) Previous use of insulin Weight loss Homa IR decrease Homa B increase Preop fasting and stimulated C peptide ** p value of Chi-Square test, Exact Fisher test or Mann-Whitney test

45. Delta WC x Success If pts lost > 7% of WC @ 6 mo they tend to succeed (P=0,05, Non parametric Mann-Whitney test)

46. GI Surgery for T2DM Sleeved DJB /Short DS is more effective that “Classic DJB” The only predictor is the loss of more than 7% of WC until the 6th month

47. T2DM history and previous use of insulin(after proper screening)has no effect on success No straight relation between WL and success Why the more WL, less chance for success???? Change of paradigm !

48. DJB-literature

49. RemissionImprovement remission and improved LRYGB100% LSG67%33%100% LAGB50%25%75% LSG+DJB93%7%100%

50. DJB-literature Modest decrease in BMI, with decrease in A1c @ 6 mo

51. T2DM surgery in lower BMIs BMI 30-35, growing support for surgery in uncontrolled T2DM patients. RYGB and BPD seems to have a good role

52. Treatment Algorithm We want to be “an arrow”!!! BMI > 30 Psychologic stability 12 month history of uncontrolled DM/Metabolic Syndrome Metabolic Surgery

53. T2DM surgery in lower BMIs BMIs below 30 : “Different” patient Ileal interposition may be a good option, but carries a high mortality and morbidity rates, as is a complex procedure in a complex patient In De Paula’s randomized trial between II+SG versus II+SG+duodenal diversion,bypassing the duodenum improves results!! Sleeved duodenal exclusion, seems so far a good procedure, BUT WE NEED MORE DATA!!

54. T2DM surgery in lower BMIs Although we believe that we have several SILENT EVIDENCES, that point us that surgery may benefit T2DM in lower BMIs, we need to start speaking NATIVE CONTEMPORARY DIABETOLESE! RANDOMIZED CONTROLLED TRIALS!!! RYGB x Sleeved DJBxBest Med treatment in BMIs 26-35 Work in Progress !!

55. 55 Increased Insulin Resistance Plasmatic Insulin Blood sugar Beta cell failure T2DM symptoms Insulin Resistance plays a major role Time APPARENTLY NOT A GOOD CANDIDATE

56. 56 Increased Insulin Resistance Plasmatic Insulin Blood sugar Beta cell failure T2DM symptoms Timing for Surgery Time T2DM Surgery

57. GI surgery and T2DM 1st Protocol

59. http://www.controlled- trials.com/ISRCTN79580044