1. BARIATRIC (METABOLIC) SURGERY FOR LIFE-LONG WEIGHT CONTROL AND REMISSION OF ASSOCIATED CHRONIC DISEASES – A METAANALYSIS OF PUBLISHED CLINICAL PAPERS TO-DATE Henry Buchwald, M.D., Ph.D. University of Minnesota

2. DISCLOSURES Henry Buchwald, MD, PhD Consultant or Research Support Ethicon Endo-Surgery MetaCure W.L. Gore

3. BARIATRIC SURGERY: A REVIEW AND METAANALYSIS Henry Buchwald, MD, PhD, University of Minnesota Yoav Avidor, MD, Ethicon Endo-Surgery, Inc. Eugene Braunwald, MD, Harvard Medical School Michael D. Jensen, MD Mayo Clinic Walter Pories, MD, East Carolina University Kyle Fahbach, PhD, MetaWorks Karen Schoelles, MD, MetaWorks JAMA 2004;292:1724-1737

4. OBJECTIVES Primary – To determine the impact of bariatric surgery on 4 of the major obesity comorbidities: diabetes, hyperlipidemia, hypertension, and obstructive sleep apnea. Secondary – To determine the weight loss and operative mortality in the studies selected for review and metaanalysis.

5. METHODS Broad electronic search of the English- language literature, 1990-2003, using MEDLINE, Currents Contents, and the Cochran Library databases. Manual reference checks. Two levels of screening.

6. METHODS: LEVEL 1 SCREENING Abstract review, exclusion criteria: Publication of abstract only Case reports Letters Comments Reviews Animal or in vitro studies Fewer than 10 patients Follow-up less than 10 days Language other than English No surgical intervention Intragastric balloon therapy (experimental)

7. METHODS: STATISTICAL ANALYSIS A random effects model was used for the metaanalysis (results expressed as means and CIs). Weighted means were used for a non- metaanalytic comparison.

8. RESULTS: DATA RETRIEVAL 2738 citations identified 1772 studies rejected prescreening 961 studies retrieved 253 Studies rejected by screening 708 studies 572 studies for catalog only 136 studies (91 kin) qualifying for metaanalysis

9. RESULTS: STUDIES SELECTED Total: 134 primary studies (2 health care economics studied excluded from 136 for no efficacy or mortality data) (179 study groups, 22,049 patients) 5 randomized controlled trials (9 study groups, 621 patients) 28 nonrandomized controlled trials (48 study groups, 4,613 patients) 101 uncontrolled case series (122 study groups, 16,860 patients)

10. RESULTS: STUDY CHARACTERISTICS 56 studies North America 58 studies Europe 20 studies elsewhere

11. RESULTS: PATIENT CHARACTERISTICS Gender: 19% men 73% women 8% not reported Age:  x 39 (range, 16-64) Baseline BMI:  x 46.85 (range, 32.30-68.80)

12. RESULTS: WEIGHT LOSS Total Population: % EWL: 61.2% (95% CI, 58.1 - 64.4)  BMI: 14.2 kg/m 2 (95% CI, 13.3 - 15.1)  Absolute Weight: 39.7 kg (95% CI, 37.2 – 42.2) All weight loss reductions p < 0.001

13. RESULTS: WEIGHT LOSS Surgical Groups % EWL (95% CI): Gastric Banding47.5% (40.7 – 54.2) Gastric Bypass61.6% (56.7 – 66.5) Gastroplasty68.2% (61.5 – 74.8) Biliopancreatic Diversion/ Duodenal Switch70.1% (66.3 – 73.9) All weight loss reductions p < 0.001

14. RESULTS: OPERATIVE MORTALITY (  30 DAYS) Purely restrictive 0.1% (n=2,297 gastric banding, n=749 gastroplasty) Gastric Bypass 0.5% (n=5,644) Biliopancreatic diversion/duodenal switch1.1% (n=3,030)

15. RESULTS: OUTCOMES – DIABETES Total Population With Diabetes: Resolution76.8% (70.7-82.9) Resolution or Improvement86.0% (78.4-93.7) Reduction FBG13.33 mg/dL (10.81-15.86) All values p < 0.01

16. RESULTS: OUTCOMES – DIABETES Surgical Groups % Resolution: Gastric Banding47.9% (29.1-66.7) Gastroplasty71.6% (55.1-88.2) Gastric Bypass83.7% (77.3-90.1) Biliopancreatic Diversion/ Duodenal Switch98.9% (96.8-100) All values p < 0.01

17. RESULTS: OUTCOMES – HYPERLIPIDEMIA Patients Improved With Hyperlipidemia: Total Population79.3% (68.2-90.5) Gastric Banding58.9% (28.2-89.6) Gastroplasty73.6% (60.8-86.3) Gastric Bypass96.9% (93.6-100.0) Biliopancreatic Diversion/ Duodenal Switch99.1% (97.6-100.0) All values p < 0.01

18. RESULTS: OUTCOMES – HYPERLIPIDEMIA Total Population With Hyperlipidemia: Total CholLDL-CholHDL-CholTriglycerides Change-33.20 mg/dL-29.34 mg/dL2.70 mg/dL79.65 mg/dL CI23.17-43.6317.76-40.930-5.7964.60-95.58 p value<0.01< 0.01 < 0.1<0.01

19. RESULTS: OUTCOMES - HYPERTENSION Total Population With Hypertension: Resolution61.7% (55.6-67.8) Resolution or Improvement78.5% (70.8-86.1) All values p<0.01

20. RESULTS: OUTCOMES – OBSTRUCTIVE SLEEP APNEA Total Populations With Obstructive Sleep Apnea: Resolution 85.7% (79.2-92.2) Resolution or Improvement83.6% (71.8-95.4) Apneas or Hypopneas-33.85/hr (17.47-50.23) All values p<0.01

21. SUMMARY Review and metaanalysis of 136 studies involving 22,094 patients. Results:  x % EWL61.2%  x Operative (  30 days) Mortality0.1-1.1% Resolution of Diabetes76.8% Resolution of Hyperlipidemia79.3% Resolution of Hypertension61.7% Resolution of Obstructive Sleep Apnea85.7%

22. CONCLUSION A substantial majority of morbidly obese patients with diabetes, hyperlipidemia, hypertension, and/or obstructive sleep apnea have total resolution or marked improvement of their comorbid conditions after bariatric surgery.

23. EFFECTS OF BARIATRIC SURGERY ON TYPE 2 DIABETES: A SYSTEMATIC REVIEW AND METAANALYSIS Henry Buchwald, MD, PhD, 1 Rhonda Estok, RN, BSN, 2 Kyle Fahrbach, PhD, 2 Deirdre Banel, BS, 2 Michael D. Jensen, MD, 3 Walter Pories, MD, 4 John Bantle, MD, 1 Isabella Sledge, MD, MPH 2 1 University of Minnesota, Minneapolis, MN; 2 United BioSource Corporation, Medford, MA; 3 Mayo Clinic College of Medicine, Rochester, MN; 4 East Carolina University School of Medicine, Greenville, NC Am J Med 2009;122:248-256

24. DIABETES METAANALYSIS GOAL: To determine the impact of bariatric surgery procedures on type 2 diabetes mellitus in association with the weight reduction achieved.

25. DIABETES METAANALYSIS METHODS: 1.Screening of all papers published in English, from January 1, 1990 to April 30, 2006, identified through electronic searches in MEDLINE, Current Contents,  and the Cochran Library, supplemented by manual reference checks. 2.All accepted studies were assigned a level of evidence (Centre for Evidence-Based Medicine, Oxford, UK), and randomized controlled trials were rated for quality by the Jadad scoring method.

26. DIABETES METAANALYSIS METHODS: 3.Restricted, maximum likelihood, random-effects metaanalyses (REM) were performed and heterogeneity was assessed using Cochran’s Q statistic. 4.Diabetes outcomes assessed for <2 years and  2 years.

27. DIABETES METAANALYSIS RESULTS: Data Set 621studies (136 in 2004) 888treatment arms (179 in 2004) 135,246patients (22,094 in 2004)

28. DIABETES METAANALYSIS RESULTS: Study Characteristics Study Location Europe44.4% North America43.2% Australia/New Zealand3.5% South America3.1% Asia1.5% Others4.5%

29. DIABETES METAANALYSIS RESULTS: Patient Characteristics – Total Mean Age40.2 years Mean BMI47.9 kg/m 2 GenderMale19.9% Female79.6% Type 2 Diabetes22.3%

30. DIABETES METAANALYSIS RESULTS: Weight Reduction Metaanalysis % EBWL Overall TotalGastric BandingGastroplastyGastric BypassBPD/DS 55.9 46.2 55.5 59.5 63.6

31. DIABETES METAANALYSIS RESULTS: Diabetes Outcomes Metaanalysis Overall Total Gastric BandingGastroplasty Gastric BypassBPD/DS % Resolved78.156.779.780.395.1 % Resolved or Improved 86.680.687.284.599.0 % Improved37.438.138.546.314.0 % Unchanged14.318.112.021.21.9 % Worsened1.13.8–0.3– Insulin (pml/L)-97.4-68.6-102.9-114.6-135.4 HbA1c (%)-1.3-0.5-1.6-2.0– Glucose (mmol/L)-1.4-0.6-0.7-1.8-2.8

32. DIABETES METAANALYSIS RESULTS: Diabetes Outcomes Metaanalysis < 2 Years Total Gastric BandingGastroplasty Gastric BypassBPD/DS % Resolved80.355.081.481.694.0 % Resolved or Improved 86.082.389.084.0100.0 % Improved48.751.645.850.632.1 % Unchanged12.07.822.820.60.0 % Worsened0.40.37–0.3– Insulin (pml/L)-86.7-63.0-88.3-116.7-98.8 HbA1c (%)-1.3-0.5-1.6-2.0– Glucose (mmol/L)-1.2-0.5-0.6-1.8-1.7

33. DIABETES METAANALYSIS RESULTS: Diabetes Outcomes Metaanalysis  2 Years Total Gastric BandingGastroplasty Gastric BypassBPD/DS % Resolved74.658.377.570.995.9 % Resolved or Improved 87.278.784.485.398.9 % Improved19.414.733.027.65.0 % Unchanged16.124.710.122.42.0 % Worsened2.85.9––– Insulin (pml/L)-188.0-76.9-152.9–-97.8 HbA1c (%)-1.4-0.8––– Glucose (mmol/L)-2.0-1.14-1.5-4.3

34. DIABETES METAANALYSIS RESULTS: Diabetes Outcomes Metaanalysis Diabetic Patients Only Overall Total Gastric Banding Gastric BypassBPD/DS % Resolved79.362.780.599.4 % Resolved or Improved 98.995.7100.0– % Improved23.630.120.4– % Unchanged1.54.30.00.7 Insulin (pml/L)-98.0-99.6-40.2-125.0 HbA1c (%)-2.1-1.4-2.2– Glucose (mmol/L)-4.4-2.5-3.9-5.4

35. DIABETES METAANALYSIS RESULTS: Diabetes Outcomes Metaanalysis Patients Resolved Associated With Weight Reduction Achieved and Procedure Performed Total Gastric BandingGastroplasty Gastric BypassBPD/DS % EBWL55.946.255.559.763.6 % Resolved Overall 78.156.779.780.395.1 % Resolved <2 yrs80.355.081.481.694.0 % Resolved  2 yrs 74.658.377.570.995.9

36. DIABETES METAANALYSIS STRENGTHS OF THE STUDY 1.The data set is global, comprehensive, and as inclusive as possible, limited only by a predetermined time span. 2.The selection criteria are independent of outcomes and, therefore, to a large extent, eliminate selection bias. 3.The derived metabolic data are weighted by the number of study patients, as well as by the variability among studies.

37. DIABETES METAANALYSIS WEAKNESSES OF THE STUDY 1.It is impossible to extrapolate the effects on outcomes of missing – unreported – data from good and from bad series. 2.There is limited reporting of longer-term diabetes data.

38. DIABETES METAANALYSIS SUMMARY 1.Bariatric surgery causes resolution of type 2 diabetes: 78.1% in entire metaanalysis 79.3% in diabetic patients only cohort. 2.Bariatric surgery causes resolution or improvement of type 2 diabetes: 86.6% in entire metaanalysis 98.9% in diabetic patients only cohort

39. DIABETES METAANALYSIS SUMMARY 3.The resolution and resolution or improvement of type 2 diabetes is associated with the degree of weight reduction achieved and, thereby, the bariatric procedure performed: Adjustable gastric banding < gastroplasty < gastric bypass < BPD/DS in entire metaanalysis Adjustable gastric banding < gastric bypass < BPD/DS in diabetic patients only cohort 4.Weight and diabetes parameters showed little difference at <2 years and  2 years; thus, these effects appear to be lasting.

40. DIABETES METAANALYSIS SUMMARY 5.Insulin, HgA1c, and fasting glucose values declined substantially after bariatric surgery, giving laboratory metabolic substantiation to the clinical findings.

41. DIABETES METAANALYSIS CONCLUSION Bariatric surgery is effective therapy for type 2 diabetes.

42. BARIATRIC SURGERY WORLDWIDE 2008 Henry Buchwald, MD, PhD Professor of Surgery and Biomedical Engineering University of Minnesota Minneapolis, MN, USA Obes Surg 2009; 19:1605-1611

43. RESULTS: QUESTION #1 Country

44. RESULTS: QUESTION #2 Country

45. RESULTS: QUESTION #3 Bariatric surgery procedures worldwide Lap.=laparoscopic VBG=vertical banded gastroplasty RYGB=Roux-en-Y gastric bypass LL=long-limb

46. RESULTS 2008

47. RESULTS TRENDS: 2003 to 2008

48. RESULTS TRENDS: 2003 TO 2008

49. REGIONAL TREND EUROPE Number (%)Operations% Change 20032008 Total33,77166,769+97.7% RYGB3,744 (11.1%)26,023 (39.0%)+595.1% AGB21,496 (63.7%)28,843 (43.2%)+34.2% BPD/DS2,061 (6.1%)3,270 (4.9%)+58.7% SG0 (0%)4,677 (7.0%)

50. TRENDS: 2003 TO 2008 EUROPE

51. REGIONAL TREND USA/CANADA Number (%)Operations% Change 20032008 Total103,000220,000+113.6% RYGB87,550 (85.0%)112,200 (51.0%)+28.2% AGB9,270 (9.0%)96,800 (44.0%)+944.2% BPD/DS4,635 (4.5%)2,200 (1.0%)-52.5% SG0 (0%)8,800 (4.0%)

52. TRENDS: 2003 TO 2008 USA/CANADA

53. CONCLUSION Bariatric surgery worldwide has grown markedly in the past 10 years (1998 to 2008) Operations/year%  199840,000 266% 2003146,301761% 135% 2008344,221

54. METABOLIC SURGERY IS THE FUTURE OF SURGERY Surgery has evolved from incisional to extirpative to reparative and reconstructive and now to metabolic. We are in the forefront of that evolution.

55. Hypothetical Female Patient With Full-Blown Metabolic Syndrome Medical Therapy (Life-time diet, drugs, behavior modification) Outcomes Obesity – extremely poor Type 2 diabetes – palliative at best Dyslipidemia – palliative at best Hypertension – palliative at best Nonalcoholic steatohepatitis – extremely poor Polycystic Ovary Syndrome – extremely poor Metabolic/Bariatric Surgery Therapy (one operation, one time) Outcomes Obesity Type 2 diabetes DyslipidemiaExcellent Hypertension Nonalcoholic Steatohepatitis Polycystic Ovary Syndrome