Surgery for T2DM in BMIs < 35. Novel Procedures

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. Surgery over the GI tract can improve T2DM control • 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)

3. Surgery over the GI tract can improve T2DM control • 10 to 15% of T2DM are normal weight (Mokad, in JAMA,2000) • 70% of morbidly obese patients have NO T2DM!! 45 % with BMI BELOW 30 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???

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

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

6. T2DM & THE METABOLIC EFFECTS OF BARIATRIC SURGERYNovel Surgical Options • “First in Man” Ileal interposition & Sleeve Gastrectomy • 19 patients • Mean 37 years old • Mean BMI 40 (range 35-44) • Select 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

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 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complex a procedure : • ~ 10% of pts with BMI 20-22 were operated(may be criticized) • 3.5% mortality • Revisions (unpublished data) described for several reasons • major operation, tough patients, ~ 7.5% of major complications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. 9 30 8 29 7 BMI (kg/m2) HbA1c (%) 28 6 27 5 4 26 0 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 Time Post Surgery (month) Time Post Surgery (month) R Cohen et.al SOARD, 2007

13. 1st Protocol - Original Intact Stomach DJB • 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. Surgical treatment of T2DM • Analysis of 46 patients with@ 12 mo follow-up

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

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

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

20. Moving Forward • Increased the biliary limb lenght ADA 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.

21. Sleeved DJB orShort DS 150 cm 100 cm

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

23. Sleeved DJB orShort 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 orShort 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 orShort DS • RESULTS • First 30 pts @ 12mo Follow up • TBWL 9.7% +- 2.6% • 22 insulin users 97% between Control &Resolution * 11 ( 37%) pts with A1c less than 6

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? Change in body composition? Delta BMI A1c<7, NO MEDS

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+-19 142+-23 123+-9 101 +-13*

30. 120 min Mixed meal challenge preop to 12 months - * p<0,05 242+-23 196+-11 161+-14 140+-13 Preop 3 mo 6 mo 12 mo

31. CIT • n= 30, in mm, * p<0.05 *p<0.05 vs. preop

32. BP(mmHg)n= 30, *p<0,05

33. Lipid Profile * p<0.05

34. Short DS and low BMI T2DMPredictors of Success(A1c<7) • There isNOsignificance, 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. DJB-literature

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 AlgorithmWe want to be “an arrow”!!! Metabolic Surgery BMI > 30 Psychologic stability 12 month history of uncontrolled DM/Metabolic Syndrome

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

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