Roux-and-Y Gastric Bypass and its Metabolic Effects

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1 Roux-and-Y Gastric Bypass and its Metabolic Effects Nicola Di Lorenzo President elect of SICOb Italian Society for Bariatric Surgery and Metabolic Diseases Dept. of General Surgery-Università di Roma Tor Vergata

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3 Bariatric Surgery Efficacy Buchwald H. JAMA, 2004 Procedure % EWL T2DM (Remission) Gastric Banding 47% (n=1848) 48% Gastric Bypass 62% (n=4204) 84% BPD 70% (n=2480) 98%

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5 Bariatric Surgery Efficacy, Benefit 100% Switch Excess Weight Loss Diabetes Resolution Rate 50% Roux-en-Y Banding 10% Risk 30 Day Mortality Adapted from Buckwald H, et al, Bariatric surgery, a systematic review and metaanalysis, JAMA. 2004;292: and Maggard M, et al, Meta-Analysis: Surgical Treatment of Obesity, Ann Intern Med. 2005;142:

6 Surgery decreases long-term mortality and morbidity in morbidly obese patients. Surgery Controls Risk Rate - Cancer 2.03 % 8.49 % Cardiovascular 4.73 % % Endocrinological 9.47 % % Musculoskeletal 4.83 % % Psychiatric 4.35 % 8.20 % Respiratory 2.71 % % Mortality 0.68 % 6.17 % 0.11 Christou et al. Ann Surg 2004;240:416

7 GUT as an endocrine system Gastric Bypass (1967) Rehfeld J, 2004

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9 Metabolic syndrome Complications of obesity are mainly attributable to increase in visceral adipose tissue mass: glucose intolerance, hyperinsulinemia, hypertrigliceridemia. As compared to subcutaneous adipocytes, visceral adipocytes have higher basal lypolisis, higher sensitivity to cathecolamines and poorer sensitivity to insulin.

10 excessive fat availability ENVIRONMENT fat penetration into the muscular cell the muscular cell uses fat instead of glucose as the energy source insulin resistance hyperinsulinemia

11 Adipokines TNF-, IL-6 (markers of inflammation) Angiotensinogen, (potentially involved in raising blood pressure) Plasminogen activator inhibitor-1 (potentially involved in raising blood pressure) Adiponectin: plasma levels are negatively associated with insulin-resistance

12 RYGB and adiponectin (1) Chen et al Obes Surg 2012

13 RYGB and adiponectin (2) Chen et al Obes Surg 2012

14 RYGB and Diabetes resolution Hayes et al Obes Surg 2012

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16 RYGB and Metabolic alterations Reorganization of gastrointestinal anatomy and not merely reduction in calorie intake and weight loss. Exclusion of duodenum and proximal jejunum, triggering changes enteral-insular axis (foregut hypotesis) Earlier arrival of nutrients to ileum (hindgut hypotesis) Tavares de Sa et al Obes Surg 2011

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18 - Pts 14 Vs 15 - Meal Test

19 Meal Test CONCLUSIONS 1. LRYGB and LSG were associated with an early and INSULIN dramatic improvement in glycemic control GHRELIN 2. insulin, GLP-1, and PYY levels increased similarly after either procedure PYY Our results do not support GLP-1 the idea that the proximal small intestine mediates the improvement in glucose homeostasis. (Peterli)

20 The Hindgut Theory The more rapid delivery of undigested nutrients to the distal bowel upregulates the production of L-cell derivatives like Peptide YY, GLP-1 Mason E. Obes Surg , Rubino et.al, Ann Surg, 2006

21 Hindgut theory: Peptide YY Secreted from entire GI tract L cells Mainly distal (ileum, colon and rectum) Food intake stimulates its release fasting reduces it Effects May ameliorate insulin resistance (in mice) Delays pancreatic/gastric secretions/gastric emptying/intestinal transit Bloom SR. et.al. Nature 2006

22 GLP-1 Enteroglucagon Hindgut theory Glucagon Like Peptide 1 Secreted by ileal L-cells in (rapid) response to a meal Actions Potent stimulator of insulin / supresses glucagon Slows gastric emptying Reduces appetite Increases beta cell mass Wynne K. J Clin Endo Met, 2004

23 RYGB and GLP-1 GLP-1 mantains euglycemia by increasing insulin secretion, and an exaggerated GLP-1 response was noted 10 years after RYGB, strongly suggesting a durability of this effect. Dar et al Obes Surg 2012

24 RYGB in maintenance weight loss Ghrelin has orexigenetic properties (i.e. a stimulating effect on appetite) Obestatin suppresses food intake and decreases gastric emptying. It also plays an important role in regolation of energy homeostasis Fasting ghrelin and obestatin plasma levels are higher in weight-stable patients 3 years after RYGB than in a life-style intervention Martins et al Obes Surg 2011

25 RYGB, ghrelin and obestatin Martins et al Obes Surg 2011

26 Hormonal Changes-Ghrelin Ghrelin is a hormone produced primarily by the gastric fundus suppress the insulin sensitizing hormone adiponectin Blocks hepatic insulin signaling Inhibits insulin secretion By gastric fundus removal, the reduced circulating ghrelin level and its insulinostatic effect will increase the maximal captacity of glucose induced insulin release and enable the islet to secrete more insulin Karamkos et al 2008 Abbatini et al 2009

27 RYGB and genetic obesity Heterozygous mutations in melanocortin-4 receptor (MC4R) are the most frequent genetic cause of obesity Lifestyle interventions based on exercise, behaviour and nutrition therapy in children with MC4R mutations are not effective in providing long-term weight loss, in contrast to children without MC4R mutations RYGB induces weight loss independently of this mutations

28 RYGB weight loss Aslan et al Obes Surg 2011

29 RYGB and Body Composition Azevedo de Aquino et al Obes Surg 2012

30 RYGB vs Routine Medical Management

31 RYGB and CVD Donadelli et al Obes Surg 2011

32 RYGB and renal function Zelada Getty et al Obes Surg 2012

33 RYGB and inflammatory markers (1) Brethauer et al Surg Endosc 2011

34 RYGB and inflammatory markers (2) Rojas et al Obes Surg 2011

35 Micronutrient deficiences Rojas et al Obes Surg 2011

36 Micronutrient deficiences Iron deficiency and iron deficiency anemia are the most common findings, as it happens in gastric surgery Iron, zinc and copper are also involved in inflammatory reactions, as anti or prooxidants, so their status appears impaired after RYGB. Rojas et al Obes Surg 2011

37 Bone mineral density RYGB is not detrimental for bone Menopausal women and those with greater lean mass are at higher risk of BMD loss, but progression to osteoporosis is uncommon and the risk of fracture is low. Villarasa et al Obes Surg 2011

38 RYGB and quality of life RYGB has demonstrated to significantly improve QOL when compared to those persons who lost weight without the surgical intervention. Improvement derives both from weight loss and reduction in comorbidities. Patients also reported low depression and high satisfaction after surgery Forbush et al Obes Surg 2011 Myers et al Obes Surg 2012

39 RYGB for T2DM in non severely obese patients Safe and effective to induce remission of T2DM in non severely obese patients, otherwise not elegible for bariatric surgery RYGB should be considered in those patients in which an adequate glycemic control cannot be achieved, despite lyfestyle modifications and the use glucose lowering agents. Boza et al Obes Surg 2011 Huang et al Obes Surg 2011

40 PILOT STUDY GBP effects of GBP on 20 patients type 2 diabetes lasting at least 3 yrs BMI between 30 and 34.9 medical therapy HbA1c minimum 7.5%

41 PILOT STUDY GBP preoperatively and 1, 4, 8, and 12 months after GBP determination of fasting serum glucose level glycosilated hemoglobin (HbA1c) acute insulin response to intravenous glucose load HOMA body weight

42 PILOT STUDY GBP 20 patients (5 F) operated on mean age: 57 yrs (47-69) mean BMI: 32.9 kg/m 2 ( ) mean diabetes duration: 14 yrs: (3-28) insulin therapy: 10 c. 6 patients (2 F) with BMI <32 (mean: 31.1)

43 PILOT STUDY GBP ACCESS: all laparoscopic EARLY COMPLICATIONS 1 intraperitoneal bleeding 1 GI bleeding (both treated conservatively) LATE COMPLICATIONS none

44 PILOT STUDY GBP 11 operated patients never received any antidiabetic medication 6 received low dose single injection of long-acting insulin during the whole first postoperative year with the aim of keeping their serum glucose levels under 200 mg/dl, thus minimizing glucose betatoxicity 3 patients were started on this type of support at the end of the first postoperative year

45 FASTING SERUM GLUCOSE FOLLOWING GBP IN T2DM PATIENTS WITH BMI KG/M 2 (mg/dl) preop (20 c.): 206 ( ) 1-2 months (20 c.): 167 ( ) 4 months (20 c.): 152 (91-312) 8 months (20 c.): 149 (75-250) 12 months (20 c.): 148 (86-247)

46 FASTING SERUM GLUCOSE FOLLOWING BPD IN T2DM PATIENTS WITH BMI KG/M 2 (mg/dl) preop (15 c.): 234 ( ) 1-2 months (15 c.): 155 (85-391) 4 months (15 c.): 131 (89-193) 8 months (15 c.): 132 (75-209) 12 months (15 c.): 126 (83-181)

47 fasting serum glucose in T2DM patients with BMI between 30 and 35 after BPD AND GBP mg/dl after BPD after GBP

48 fasting serum glucose in T2DM patients with BMI between 30 and 35 after BPD and GBP mg/dl after BPD after GBP BPD vs. GBP at 4 mos p <0.02 at 8 mos p <0.01 at 12 mos p<0.01

49 HbA1c in T2DM patients with BMI kg/m 2 following GBP preop (20 c.): 9.5 ( ) 1-2 months (20 c.): 7.5 ( ) 4 months (20 c.): 7.0 ( ) 8 months (20 c.): 6.8 ( ) 12 months (20 c.): 7.0 ( )

50 HbA1c in T2DM patients with BMI kg/m 2 following BPD preop (15 c.): 9.5 ( ) 1-2 months (15 c.): 7.2 ( ) 4 months (15 c.): 6.2 ( ) 8 months (15 c.): 5.8 ( ) 12 months (15 c.): 5.9 ( )

51 HbA1c in T2DM with BMI between 30 and 35 after BPD and GBP % after BPD after GBP BPD vs. GBP at 4 mos p <0.02 at 8 mos p <0.01 at 12 mos p<0.01

52 HbA1c level in T2DM patients with BMI kg/m 2 prior to and after GBP HbA1c > 7 % HbA1c >6.1-7 % HbA1c 6 % preop. 1 month 4 months 8 months 12 months 18 months

53 type 2 diabetes patients with BMI serum cholesterol values after GBP mean (mg/dl) abnormal values prior to GBP /20 (55%) at 1 month after GBP 174 4/20 (20%) at 4 months after GBP 173 6/20 (30%) at 8 months after GBP 171 4/20 (20%) at 1 year after GBP 177 5/20 (25%)

54 type 2 diabetes patients with BMI serum cholesterol values after BPD mean abnormal prior to BPD (mg/dl) 195 values 8/15 (53 %) at 1 month after 140 0/15 (0%) BPD at 4 months after 141 0/15 (0%) BPD at 8 months after 138 0/15 (0%) BPD at 1 year after BPD 147 0/15 (0%)

55 serum total cholesterol in T2DM patients with BMI between 30 and 35 after BPD and GBP after BPD after GBP mg/dl

56 type 2 diabetes patients with BMI serum triglycerides values after GBP mean (mg/dl) abnormal values prior to GBP /20 (80%) at 1 month after GBP /20 (60%) at 4 months after GBP 166 7/20 (35%) at 8 months after GBP 131 8/20 (40%) at 1 year after GBP 141 3/20 (15%)

57 type 2 diabetes patients with BMI serum triglycerides values after BPD mean abnormal prior to BPD (mg/dl) 254 values 8/15 (53 %) at 1 month after 222 8/15 (53%) BPD at 4 months after 171 8/15 (53%) BPD at 8 months after 166 9/15 (60%) BPD at 1 year after BPD 150 8/15 (53%)

58 mean serum triglyceride values in T2DM patients with BMI after BPD and GBP mg/dl after BPD after GBP

59 T2DM patients with BMI serum triglycerides after GBP and BPD after BPD after GBP % of patients with values > 150 mg/dl

60 T2DM patients with BMI between 30 and 35 kg/m 2 after GBP: individual BMI changes kg/m 2 mean: preop months 24.7

61 T2DM patients with BMI between 30 and 34.9 kg/m 2 after BPD: individual BMI changes mean: preop months 26.4 kg/m prior to at 1-2 months at 4 months at 8 months at 1 year

62 CONCLUSIONS 1 BPD seems more effective than GBP in T2DM resolution also in the range of BMI 30-35

63 CONCLUSIONS 2 patients with BMI <30 have no risk of excessive weight loss they are much more resistant to surgical therapy, and need further careful evaluation they would take great advantage of early intervention

64 THANK YOU FOR YOUR ATTENTION