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

2. Why operate? Evidences in the obese population: Decreased long term mortality, CV, all cause and T2DM related (Sjostrom,2004; Christou,2004; Flum, 2004;Adams, 2007) Evidences of resolution without direct relation to weight loss in some bariatric operations ( Laferrere,2008;Lee,2008;Patou 2008) Surgery over the GI tract can improve T2DM control

3. 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 10 to 15% of T2DM are normal weight (Mokad, in JAMA,2000) 70% of morbidly obese patients have NO T2DM!!

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

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

6. 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 patients 19 patients Mean 37 years old Mean 37 years old Mean BMI 40 (range 35-44) Mean BMI 40 (range 35-44) Select co-morbidity Select co-morbidity n=5 T2DM - At 3 weeks, 5/5 T2DM patients off meds with normal FPG n=5 T2DM - At 3 weeks, 5/5 T2DM patients off meds with normal FPG n=8 HTN n=8 HTN n=2 OSA n=2 OSA n=11 hyperlipidemia n=11 hyperlipidemia A dePaula et.al. SOARD, 2006

7. 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

8. De Paula II/SGII RCT- IT with and without duodenal exclusion Adding a duodenal exclusion improves results (ASMBS,2009)

9. IT + Duodenal Exclusion improves(DSG)T2DM more than without excluding the duodenum SOARD, in press

10. Ileal Interposition- De Paula It’s effective, although complex a procedure : ~ 10% of pts with BMI 20-22 were operated(may be criticized) 3.5% mortality Revisions (unpublished data) described for several reasons major operation, tough patients, ~ 7.5% of major complications

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

12. 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

13. 1st Protocol - Original Intact Stomach DJB 46 pts 46 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)

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

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

16. 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

17. 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

18. 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

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

20. 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

21. Sleeved DJB or Short DS 100 cm 150 cm

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

23. 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)

24. 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

25. Sleeved DJB or Short DS RESULTS First 30 pts @ 12mo Follow up TBWL 9.7% +- 2.6% 22 insulin users Follow-upMean A1cInsulinUnchangedControl, A1c<7 Less meds Resolution No meds,A1c<7 12 mo 6.3+-0.4*NONE 3% ( 1 pt) 24% (10 pts) 63% (19 pts) * 11 ( 37%) pts with A1c less than 6 97% between Control &Resolution

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

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

28. 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*

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

30. 120 min Mixed meal challenge preop to 12 months - * p<0,05 242+-23 196+-11 140+-13 161+-14 Preop 3 mo6 mo12 mo

31. CIT n= 30, in mm, * p<0.05 preop3 mo12 mo 0,71±0,160,69±0,110,60±0,14* *p<0.05 vs. preop

32. BP(mmHg) n= 30, *p<0,05 preop 6 mo12 mo PAS 131,1±14,5 123±11,* 120 ±13,8* PAD 88,7±7.4 80±12,* 71 ±12,7*

33. Lipid Profile Preop6 mo12 mo HDL 41 ±9,5 44 ±6,7 48,7 ±9,8 LDL 181 ±23,7 127 ±13,5 101 ±12,7* Tryglycerides 337 ±54,3 210 ±31,9 111 ±14,3* * p<0.05

34. 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

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

36. 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

37. 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 !

38. DJB-literature

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

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

41. 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

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

43. T2DM surgery in lower BMIs BMIs below 30 : “Different” patient Ileal interposition may be a good option, but carries a higher mortality and morbidity rates, as is a complex procedure in a complex patient. MORE DATA NEEDED. 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!!

44. 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 !!

45. 45 Increased Insulin Resistance Plasmatic Insulin Blood sugar Beta cell failure T2DM symptoms Timing for Surgery Time T2DM Surgery

46. Climbing the Everest We’re here! Need to get to the top!! Serious studies demanded!