Metabolic Effects of Surgery. Francesco Rubino, MD. Chief, Section of Gastrointestinal Metabolic Surgery Director, Diabetes Surgery Center

Transcription

1 Metabolic Effects of Surgery Francesco Rubino, MD Chief, Section of Gastrointestinal Metabolic Surgery Director, Diabetes Surgery Center Weill Cornell Medical College- New York Presbyterian Hospital New York, NY Bariatric Surgery Metabolic Surgery 1

2 Bariatric Surgery: an obsolete, inaccurate definition From the greek Baros (weight) Mechanically reduction of energy intake (restriction and/or malabsorption) Body weight loss (%EWL) is the primary outcome of bariatric surgery Excess body weight (BMI) is the primary criteria for indication to bariatric surgery Surgically induced weight loss determines improvement/resolution of obesity-related co-morbidities Metabolic Surgery Surgical operations aimed to control metabolic diseases as opposed to BW per se %EWL IS NOT the only (nor the primary) outcome of metabolic surgery Mechanisms of action: Strengthening physiology of glucose homeostasis (or fixing underlying pathophysiology of diabetes/obesity) Energy intake is NOT the only target 2

3 Conventional Bariatric-Metabolic Procedures Adjustable Gastric Banding Roux-en-Y Gastric Bypass Biliopancreatic Diversion Novel Metabolic Procedures DJB Ileal Interposition Duodenal-Jejunal Bypass with Sleeve Gastrectomy 3

4 The Heretical Suggestion: A Surgical Cure For Diabetes? Nicolaus Copernicus ( ) Rates of Remission of Diabetes Adjustable Gastric Banding 48% 84% Roux-en-Y Gastric Bypass Biliopancreatic Diversion >95% Buchwald H. JAMA,

5 «Remission» is at odds with the classic teaching Type 2 Diabetes is a Chronic, Progressive and Irreversible Disease * Any Textbook Is Diabetes only about sugar? What about all 3 endpoints? HTN Hypertriglyceridemia HA1C 5

6 93% of diabetic patients ARE NOT well controlled for glucose, cholesterol and blood pressure (NHANES), % of patients n = % 7% 12.4% 7.8% 17.0% 25.8% 37.2% >8% >10% >9% >8% 7-8% % <7% A1C 0 Only 7% of adult diabetic patients from NHANES achieved: A1C <7% PA <130/80 mm Hg Total Cholesterol < 200 mg/dl Saydah SH et al. JAMA. 2004;291: Gastric Bypass and the 3 Endpoints Klingman et al; Surgery

7 Resolution of Comorbid Conditions GBP Band BPD+DS Diabetes 84% 38% 98% Hyperlipidemia 94% 71% 100% Hypercholesterolemia 95% 78% 100% Hypertriglyceridemia 94% 77% 100% Hypertension 75% 43% 81% Sleep apnea 87% 95% 95% Buchwald H et al, JAMA 2004 Does Tight Glycemic Control Reduce Cardiovascular Disease or Mortality? ACCORD Intensive group: non-fatal MI, hypoglycemia & weight gain Trial stopped b/o mortality in intensive group (Why?) ADVANCE No difference between intensive & conventional treatment in macrovascular disease or mortality (either overall or CV) VADT No differences between intensive & conventional treatment in cardiovascular events Severe hypoglycemia was strong predictor or CVD events & death 7

8 b b b Am J Cardiol 2007;99: Bariatric surgery decreases CHD risk to rates lower than the age- and gender-adjusted estimates for the general population. 8

9 SOS Stuy: Overall Mortality Effect on Long-term Mortality Compared to Non-Operated Controls Study Procedure F/U Mortality Reduction MacDonald,1997 RYGB 9 yrs 88% Flum, 2004 RYGB 4.4yrs 33% Christou, 2004 RYGB 5 yrs 89% Sowemimo, 2007 RYGB 4.4 yrs 50% O brien, 2006 LAGB 12 yrs 73% Adams, 2007 RYGB 8.4 yrs 40% Sjostrom, 2007 VBG/other 14 yrs 31% 9

10 - 92% reduction in diabetes-specific mortality risk after gastric bypass surgery Adams et al, New Engl.J. Medic. Aug % Of all patients with BMI > 40 Kg/m2 have access to bariatric surgery in U.S. Source: ASMBS 10

11 Diabetes Surgery: Cultural Barriers Radical departure from conventional treatment and thinking (Healthy Skepticism) Professional biases /interests Limited awareness of benefits/risk of metabolic surgery/bariatric surgery Misperceptions / Preconceptions Diabetes Surgery: Cultural Barriers Radical departure from conventional treatment and thinking (Healthy Skepticism) Professional biases /interests Limited awareness of benefits/risk of metabolic surgery/bariatric surgery Misperceptions / Preconceptions 11

12 Misperceptions / Preconceptions Bariatric surgery is dangerous/drastic measure (?) AHRQ Data: Bariatric Surgery Utilization and Outcomes in 1998 and % change Number 13, , % Inpatient death 0.89% 0.19% -79% Zhao. AHRQ: Jan

13 Mortality Rates Following Common Operations in U.S. Hospitals Number of Hospitals performing operation National Average Mortality rate( %) ] Average Hospital caseloads Median Aortic Aneur CABG Craniot Esophag Resect Hip Replac Panc Ped. Heart Surger y Dimick JB, Welch HG, Birkmeyer JD. Surgical mortality as an indicator of hospital quality. JAMA 2004,292, SRC: Bariatric Surgery Mortality 0.3% (55,567 patients) Lap Chole:

14 Morbidity of Bariatric Surgery Agency for Healthcare Research and Quality (AHRQ) Medical Care May 2009 Overall Complication Rate is 15% (all types of complications) 21% decline from 2002 to 2006 (from 24% to 15%) Post-surgical infection rate dropped by 58% Hernias, Leaks, Respiratory Failure and pneumonia fell btw 29 and 50% Ulcers, Hemorrhage, deep-vein thrombosis, PE, MI unchanged But their risk ranges between 2.4 and 0.1% Increased use of Laparoscopy, increased surgeon experience and use of restrictive procedures Billroth 1 Billroth 2 14

15 DIABETES SURGERY: INDICATIONS 15

16 Incidence of MI in 7 years (%) Non-diabetics n = 1373 Diabetics n = % p < p < % 20.2% % 5 0 No DM, No MI No DM, MI DM, No MI DM, MI Haffner, et al. N Engl J Med 1998; 339:

17 Mechanisms of Diabetes Control by Metabolic Surgery Misperceptions / Preconceptions Bariatric surgery enforces life-style changes and mechanically reduce nutrient absorption and/or intake of nutrients 17

18 The Old Dogma 1. Restriction 2. Malabsorption 18

19 DISCOVERY OF GASTROINTESTINAL HORMONES 1967 Gastric Bypass Rehfeld J,

20 Misperceptions / Preconceptions Common belief that weight loss itself improves diabetes is not scientifically correct Is diabetes control dependent on the intervention that causes weight loss or weight loss per se? Intervention: Decreased caloric intake and intensive physical activity (NOT WEIGHT LOSS!!) 20

21 January 2004 Diabetes Resolution is a Direct Effect of Surgery, not Unique of Obese Individuals P<0.001 Rubino et al. Ann Surg

22 Troy S, et al Cell Metab 8:177, DJB 2. Banding > 3. Sham > Pair-fed with DJB animals Significantly better glucose tolerance in DJB mice BMI BMI-%fat relationship varies with age, gender and race/ethnicity BMI is not an equivalent measure of fatness across groups BMI does not accurately reflect the risk of patients with established diabetes BMI does not predict successful outcome of surgery 22

23 Dixon et al Jama, January 2008 BMI (total: 60 pts- 13 pts <35) RCT LAGB+conv/behav. Rx vs conv/behav rx alone Complete remission (Hb6<0): 73 vs yr Weight loss: 20.7 vs 1.7%% No major complic in both groups 23

24 Survey- DSC-Weill Cornell- IFSO Patient number by procedure DJB RYGB 157 BPD GB SG Total= 237 patients BPD without SG 24

25 10 9 HA1c comparison before and after surgery HA1c (%) DJB RYGB BPD GB SG Procedure Type HA1c Preop HA1c postop: 3 months HA1c postop: 1 year Authors: Menchaca, Frenzen, Lee, Shah, Resa, Patolia, Castagneto, Berry, Muffazal, Ramos-Neto Surgery, Gynecology & Obstetrics; February

26 BMI > 35 Evidence for Weight-Independent Mechanisms of Surgical Control of Diabetes 26

27 Rapid Improvement of Diabetes After RYGB units insulin Blood Glucose (mg/dl) Days After Surgery Adapted from Pories W, 1980 Rapid Improvement of Diabetes After RYGB units insulin 400 Blood Glucose (mg/dl) insulin Days After Surgery Adapted from Pories W,

28 Glucose levels (mg/dl) Just Starvation & Weight Loss? OGTT GK rats GK DJB 600 GK Sham Pair-feeding Time (min) 28

29 Mechanisms of Diabetes Control after GI Surgery: Weight Loss? Effects on Glucose Homeostasis of Equivalent Weight Loss from RYGB vs. Diet Type 2 diabetes patients matched for BMI, age, degree of diabetes RYGB Diet Studied at 9.7 kg Studied at 9.2 kg Laferrère et al JCEM 93:2479,

30 Glucose (mg/dl) More Improved Glucose Tolerance After RYGB Than After Equivalent Dietary Weight Loss OGTT Before RYGB Before Diet After Diet After RYGB Sleeve Gastrectomy vs. Gastric Bypass ~A Randomized Trial for T2DM Treatment Indication Courtesy of Dr Lee Taiwan Established T2DM patients Moderate obesity,bmi Y/O HbA1C>8% Sleeve Gastrectomy Sleeved Gastric Bypass (Minigastric Bypass) 30

31 Results Weight loss After 6 months, there was no difference in weight loss between the two groups Weight loss BMI Sleeve Gastric Endpoint Gastrectomy Bypass % A1c < % 93.3% LDL mg/dl Triglycerides mg/dl % at Rx Goals 14% 60% A1c < 7% LDL < 130 TG < 150 Lee WJ et al,

32 Hyperinsulinemia Hypoglycemia After Gastric Bypass: Too much of a good thing for islets? Control Post-RYGB Service et al. NEJM 353:249 (2005) Increase in Postprandial GLP-1 and PYY After RYGB GLP-1 PYY Meal Meal Korner J, et al JCEM 90:359, 2005 Korner J, et al SOARD 3:597,

33 Diabetes Care 2008 online Evidence for weight-independent mechanisms Kinetics of diabetes resolution Glucose homeostasis studies at equivalent weight loss after RYGB vs. other Hints from hyperinsulinemia 33

34 There is increasing evidence that intestinal bypass procedures may have glycemic effects that are independent of, and additive to, their effects on weight. ADA 2009 Standards of Care 34

35 Courtesy of Lee Kaplan Gastric Band Sleeve Gastrex RYGB DJB BPD Gastric Restriction ± Gastrectomy Ileal Interposition Endoluminal Sleeve Altered gastric function? Gastric exclusion Duodenal exclusion Enhanced distal nutrient delivery Malabsorption Partial vagotomy ±? Courtesy of Lee Kaplan Gastric Band Sleeve Gastrex RYGB DJB BPD Gastric Restriction ± Gastrectomy Ileal Interposition Endoluminal Sleeve Altered gastric function? Gastric exclusion Duodenal exclusion Enhanced distal nutrient delivery Malabsorption Partial vagotomy ±? 35

36 Mechanisms of diabetes control after RYGB Nutrients reach the distal ileum within 5 min of the ingestion of food and this stimulates the secretion of GLP-1 by L-cells located in this area «Distal mechanism» Mason E. Obes Surg , Mechanisms of Surgical Treatment of T2D The exclusion of the duodenal nutrient passage may offset an abnormality of gastrointestinal physiology responsible for insulin resistance and type 2 diabetes «Proximal mechanism» 36

37 November 2006 Early Ileal Stimulation Gastro-jejunal Anastomosis Annals of Surgery Nov

38 Glucose levels (mg/dl) Oral Glucose Tolerance OGTT GK rats GK DJB GK Sham GK GJ Time (min) Annals of Surgery Nov 2006 Duodenal Exclusion Annals of Surgery Nov

39 OGTT after Doudenal Exlcusion OGTT AUC Duodenal Pass. Duod. Exclus Duodenal Pass. Duod. Exclus P<0.05 Annals of Surgery Nov 2006 Restoration of Duodenal Passage Annals of Surgery Nov 2006 AUC OGTT X 2 39

40 Exclusion of the proximal small bowel from the flow of nutrients is the primary mediator of diabetes resolution after DJB Annals of Surgery Nov 2006 Implications 40

41 Diabetes Surgery Summit Rome 2007 Reccommendations Endorsed by: ASMBS IFSO TOS IASO 41

42 Bariatric surgery should be considered for adults with BMI > 35 kg/m2 andtype 2 diabetes, especially if the diabetes is difficult to control with lifestyle and pharmacologic therapy. (B) Although small trials have shown glycemic benefit of bariatric surgery in patients with type 2 diabetes and BMI of 30 35kg/m2, there is currently insufficient evidence to generally recommend surgery in patients with BMI35 kg/m2 outside of a research protocol. (E) The long-term benefits, cost effectiveness, and risks of bariatric surgery in individuals with type 2 diabetes should be studied in well-designed randomized controlled trials with optimal medical and lifestyle therapy as the comparator. (E) Surgery should be considered in pts with BMI > 35 and inadequately controlled diabetes. Bariatric surgery should be considered for adults with BMI > 35 kg/m2 and type 2 diabetes, especially if the diabetes is difficult to control with lifestyle and pharmacologic therapy. (B) 42

43 Surgery may be considered as a non-primary alternative in pts with uncontrolled diabetes and BMI in patients with type 2 diabetes and BMI of 30 35kg/m2, there is currently insufficient evidence to generally recommend surgery in patients with BMI35 kg/m2 outside of a research protocol. 42 yo female Type 2 diabetes diagnosed 5 years ago Multiple drugs and insulin with NO benefit HbA1c >8 Hyperlipidemia Hypertension BMI: yo female Joint Pain BMI 37 43

44 Re-thinking Diabetes 44

45 The Heretical Suggestion: Is Diabetes an Intestinal Disease? Nicolaus Copernicus ( ) 45

46 Surgical Control of Diabetes 1. Enhancing a positive mechanism that improves glucose homeostasis 2. Fixing alterations of glucose homeostasis Distal Mechanism GLP1 PYY 46

47 DJB in non-diabetic rats Annals of Surgery Nov

48 DJB in non-diabetic rats P=0.02 Annals of Surgery Nov 2006 Billroth 1 Billroth 2 48

49 Gastrectomy and Glucose Tolerance RCT: Duodenal exclusion vs Preservation of Duodenal Passage «If duodenal passage is eliminated a pathologic glucose tolerance develops» Schwarz et al; World J Surg. 1996: Surgery, Gynecology & Obstetrics; February

50 Mechanisms of Diabetes Resolution Gastrointestinal bypass surgery (duodenal exclusion) improves glucose homeostasis ONLY in subjects with impaired glucose tolerance but not in normal individuals Relating to: Wang PY et al. Nature 452:1012, 2008 Thaler & Cummings Nature 452:941,

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53 Anti-Incretin Not Enough 53

54 Anti-Incretin Not Enough Dumping Syndrome Nesidioblastosis Hyperinsulinemia Hypoglycemia 54

55 Overeating Food preservatives Bugs? diet It is not about living with diabetes; it is about living without it. 1 st World Congress on Interventional Therapies for Type 2 Diabetes NYC Sept 15-16,

56 2 nd WORLD CONGRESS Fall