1. Bariatric (Metabolic) Surgery for Life-Long Weight Control and Mortality Risk Reduction First Canadian Summit on Surgery for T2DM May 6, 2010 Montreal, Canada Ted Adams, Ph.D., MPH University of Utah School of Medicine, Salt Lake City, Utah

2. Editorial, NEJM 2007;357:818 George A. Bray, M.D. “The Missing Link – Lose Weight, Live Longer” Editorial, NEJM 2007;357:818 George A. Bray, M.D. “The Missing Link – Lose Weight, Live Longer”

3. Editorial, NEJM 2007;357:818 George A. Bray, M.D. “The Missing Link – Lose Weight, Live Longer??” Editorial, NEJM 2007;357:818 George A. Bray, M.D. “The Missing Link – Lose Weight, Live Longer??”

4. Does Weight Loss = Improved Mortatity? vObservational studies reporting mortality of obese subjects who have lost weight without bariatric surgery are inconclusive, with studies reporting no change, increased, or reduced mortality. Solomon CG & Dluhy. NEJM 2004;351:2751 Hu FB, et al. NEJM 2004;351:2694 Yaari S & Goldbourt U. Am J Epidemiol 1998;148:546 Gregg EW, et al. Ann Intern Med 2003;138:383

5. “The Missing Link – Have Bariatric Surgery, Lose Weight (?), Live Longer” “The Missing Link – Have Bariatric Surgery, Lose Weight (?), Live Longer”

6. “The Missing Link – Have Bariatric Surgery, Lose Weight, Keep Weight Off, Live Longer” “The Missing Link – Have Bariatric Surgery, Lose Weight, Keep Weight Off, Live Longer”

7. Long-term Effect of Gastric Bypass Surgery on Body Weight Pories et al. Ann Surg 1995;222:339. BMI (kg/m 2 ): 50 34 35 35 Weight Loss (% of Excess Weight) Years After Surgery 0 20 40 60 80 100 02468101214

8. Change in BMI Over Time for Patients Followed for >10 Years BMI Figure 3, Christou et al. Ann Surg 2006;244:737.

9. Sjöström, L. NEJM 2004;351:2683-2693. 13% GBP; 19% LAGB & LGB; 68% VBG

10. Maintenance of weight loss after gastric bypass surgery % of Initial Body Weight

11. “The Missing Link – Have Bariatric Surgery, Lose Weight, Keep Weight Off, Improve Health, Live Longer” “The Missing Link – Have Bariatric Surgery, Lose Weight, Keep Weight Off, Improve Health, Live Longer”

12. Improvement in obesity associated diseases with bariatric surgery – McGill Data * * * * * * p<0.001 Christou et al Ann. Surg. 240:416-424, 2004

13. Prevalence, Incidence and Resolution of Diabetes (2 years) GroupPrevalenceIncidenceRemission GBP Surgery 20%0%79% Seeking GBP – No Surgery 22%6%0% Population Controls 23%10%5% Adams, T. et al. Obesity 2009;17:796-802

14. “The Missing Link – Have Bariatric Surgery, Lose Weight, Keep Weight Off, Improve Health, Live Longer” “The Missing Link – Have Bariatric Surgery, Lose Weight, Keep Weight Off, Improve Health, Live Longer”

15. Mortality Following Bariatric Surgery v11 published studies vMethods vary by: surgery type, follow- up time, control group selection, BMI vWhen severely obese control groups are included, all studies report improved mortality for bariatric surgery groups

16. Bariatric Surgery & Reduced Mortality (%) Bariatric Surgery & Reduced Mortality (%) Study Reference% Reduction MacDonald, KG. J Gastrointest Surg 1997;1:213-22088 Flum, DR. J Am Coll Surg 2004;199:543-55133 Christou, NV. Ann Surg 2004;240:416-42489 Sowemino, OA. Surg Obes Relat Dis 2007;3:73-7763 Sjöström, L. NEJM 2007;357:741-75229 Adams. T. NEJM 2007;357:753-76140 Busetto, L. Surg Ob Rel Dis 2007;3:496-50260 Peeters, A. Ann Surg 2007;246:1028-103372

17. Christou, et al. (2004) Christou, et al. (2004) Mean Follow-up 7.1 years (total 18 years) Cases 2.5 y Cases; 2.6 y controls Controls1,035 (81% GBP; 19% VBG), 66% female, 45 y, BMI 50 % Deaths5,746 non-bariatric surgery, 64% female, 47 y, BMI unknown % Death Reduction0.68% cases, 6.2% controls Christou, NV. Ann Surg;2004:416-424.

18. Sjöström et al. SOS (2007) Sjöström et al. SOS (2007) Mean Follow-up 10.9 years Cases 2,010 (13% GBP; 68% VB; 19% GB), 67% female, 47 y, BMI 41 Controls2,037 no bariatric surgery, 67% female, 47 y, BMI 41 % Deaths5% cases, 6% controls % Death ReductionUnadjusted, 24% Adjusted, 29% Sjöström, L. NEJM 2007;357:741-752.

19. Adams et al. (2007) Adams et al. (2007) Mean Follow-up 7.1 years (total 18 years) Cases 7,925 (100% GBP), 84% female, 39.5 y, BMI 45.3 Controls7,925 no bariatric surgery, 84% female, 39.3 y, BMI 46.7 % Deaths2.7% cases, 4.1% controls % Death ReductionUnadjusted, 34% Adjusted, 40% Adams, et al. NEJM 2007;357:753-761.

20. Results: % Difference (based on mortality HR) Matched Groups Results: % Difference (based on mortality HR) Matched Groups Cause of DeathGBP Patients vs DL Applicants Total Mortality 40% decrease (p<0.001) All CVD 49% decrease (p<0.001) CAD 59% decrease (p=0.006) Heart Failure 41% decrease (p=0. 54) All Strokes 57% decrease (p=0.14) Diabetes 92% decrease (p=0.005) All Cancers 60% decrease (p<0.001) All Diseases 52% decrease (p<0.001) Adams, et al. NEJM 2007;357:753-761.

21. Results: % Difference (based on mortality HR) Matched Groups (cont.) Results: % Difference (based on mortality HR) Matched Groups (cont.) Cause of DeathGBP Patients vs. DL Applicants Accident unrelated to drugs 22% increase (p=0.56) Poisoning of undetermined intent 82% increase (p=0.36) Suicides 103% increase (p=0.22) All non-disease causes 58% increase (p=0.04) Adams, et al. NEJM 2007;357:753-761.

22. Christou, N. et al. Ann Surg 2006;244:734-740 v272 post-gastric bypass patients followed (4.7 to 14.9 years) = 7 deaths  (1) suicide at 4.8 years  (1) suicide at 5.7 years  (1) liver failure at 6.6 years  (1) Unknown cause at 8 years  (1) Pulmonary embolus at 8.8 years  (1) Cardiac failure at 8.8 years  (1) Cardiovascular accident at 13 years

23. Results: First Year Deaths by Matched Groups GBP Patients42 deaths (0.53% mortality for first year) DL Applicants41 deaths (0.52% mortality for first year) Adams, et al. NEJM 2007;357:753-761.

24. An Unexpected Finding! Sjöström, L. NEJM 2007;357:741-752 Adams et al. NEJM 2007;357:753 vThe SOS study on mortality revealed a strong effect from cancer (control group, 47 deaths; surgery group, 29 deaths) vThe Utah study on mortality reported a 60% reduction in cancer deaths following bariatric surgery when compared to severely obese controls

25. Well Known Finding Increased BMI  Increased CA Risk

26. Association Between BMI and Cancer Risk World Cancer Research Fund (WCRF) vBody fatness associated with increased cancer risk for:  Oesphageal adenocarcinoma  Pancreas  Colorectum  Postmenopausal breast  Endometrium  Kidney  And probable association for gallbladder WCRF. Food, Nutrition, Physical Activity, and Prevention of Cancer: A Global Perspective, 2 nd ed. Washington, D.C.: American Institute for Cancer Research, 2007.

27. Association Between BMI and Cancer Risk Renehah, et al. Lancet 2008;371:569 Association Between BMI and Cancer Risk Renehah, et al. Lancet 2008;371:569 221 data sets analyzed 282,137 incident cases 5 kg/m 2 increase in BMI associated with the following cancers: Renehah, et al. Lancet 2008;371:569

28. Association Between BMI and Cancer Risk Association Between BMI and Cancer Risk Male Cancers Relative Risk (p value) Female Cancers Relative Risk (p value) Oesophageal adenocarcinoma 1.52 (<0.0001)Endometrial1.59 (0.0001) Thyroid1.33 (=0.02)Gallbladder1.59 (0.0001) Colon1.24 (<0.0001) Oesophageal adenocarcinoma 1.51 (=0.04) Renal1.24 (<0.0001)Renal1.34 (0.0001) Renehah, et al. Lancet 2008;371:569

29. Possible Reasons Why Obesity Increases Cancer Risk 1. Chronic inflammation  adipocyte release of inflammatory promoters Tumor nucrosis factor-alpha interleukin-6 (TNF-IN-6) C-reactive protein Leptin – shown to increase in inflammatory states Calle, et al. Obesity and Cancer. Oxford University Press, Oxford, pp. 196. Renehan, et al. Arch Physiol Biochem 2008;114(1):71. WCRF. Food, Nutrition, Physical Activity, and Prevention of Cancer: A Global Perspective, 2 nd ed. Washington, D.C.: American Institute for Cancer Research, 2007.

30. Possible Reasons Why Obesity Increases Cancer Risk (cont.) 2. Increased release of sex-steroid hormones Estrogens Androgens Progesterone Adipocyte  primary point for synthesis of estrogen for men and postmenopausal women Increased body fat  increase in insulin-like growth factor 1 (IGF-1)  rise in estradiol in men and women and potential increase in testosterone in women Calle, et al. Obesity and Cancer. Oxford University Press, Oxford, pp. 196. Renehan, et al. Arch Physiol Biochem 2008;114(1):71. WCRF. Food, Nutrition, Physical Activity, and Prevention of Cancer: A Global Perspective, 2 nd ed. Washington, D.C.: American Institute for Cancer Research, 2007.

31. Possible Reasons Why Obesity Increases Cancer Risk (cont.) 3. Insulin related mechanisms Increased body fatness (in particular, abdominal or central obesity)  increased insulin resistance Subsequent increased insulin production by the pancreas Hyperinsulinemia in the face of insulin resistance increases risk of colon and endometrial cancer with potential increased risk of pancreatic and kidney cancer Calle, et al. Obesity and Cancer. Oxford University Press, Oxford, pp. 196. Renehan, et al. Arch Physiol Biochem 2008;114(1):71. WCRF. Food, Nutrition, Physical Activity, and Prevention of Cancer: A Global Perspective, 2 nd ed. Washington, D.C.: American Institute for Cancer Research, 2007.

32. Important Question??? Increased BMI  Increased CA Risk but does Decreasing BMI  Decrease CA Risk??

33. To Date – Four Cancer & Bariatric Surgery Studies v 1 Prospective  Sjöström, L. et al. Lancet Oncol 2009;10:653-62 v 3 Retrospective  Christou, N. et al. Surg Obes Relat Dis 2008;4:691-95  McCawley, G. et al.J Am Coll Surg 2009;208:1093-98  Adams, T. et al. Obesity 2009;17:796-802

34. Sjöström, L. et al. Lancet Oncol 2009;10:653-62 vUnique  First prospective, controlled intervention study  Weight loss follow-up  compare weight loss to cancer incidence  Medical and lifestyle history followed over time v2010 bariatric surgery patients; 2037 well-matched controls v1 st time cancers: 117 surgery group;169 control group (HR 0.67, p=0.0009) v1 st CAs in women: 79 surgery group; 130 control group (HR 0.58, p=0.0001) vNo effect in men: 38 surgery group; 39 control group (HR 0.97, p=0.90)

35. Sjöström, L. et al. Lancet Oncol 2009;10:653-62 vSimilar results after CAs in the first 3 years of study excluded vSagittal trunk diameter  strong multiple CA predictor vBody weight, BMI and reduced energy intake were not CA incidence predictors

36. The Canadian Bariatric Cohort Study vRestrospecitve, observational 2-cohort v1035 post-bariatric surgery patients; 5746 severely obese controls (ICD-9 codes) without surgery vCA diagnosis within 6 months prior to study onset excluded vPhysician/hospital visits for all CA-related diagnosis vFollow-up for a maximum of 5 years vCancer-related visits: 2% (21 visits) surgery group; 8.5% (487 visits) control group (RR 0.22, p=0.0001) Christou, N. et al. Surg Obes Relat Dis 2008;4:691-95

37. Five-Year Incidence of Overall Cancer Risk Diagnosis: Cohort BariatricControlsRelative Risk P-value N%N%Estimate95% CI Any Cancer 212.0%4878.5%0.220.140.350.001 The Canadian Bariatric Cohort Study 78% Reduction in Overall Cancer Risk

38. The Canadian Bariatric Cohort Study (p=0.001) 83% 68% (p=0.063)

39. Adams, T. et al. Obesity 2009;17:796-802 vRetrospective, 2-cohort vCompared incidence, case-fatality, and mortality of total and stage-specific cancer vSurgical Group: From 9949 GBP patients all non-Utah residents excluded leaving 6709 patients (surgery 1984 through 2002) vComparative Group: 9609 severely obese (Utah driver’s license applicants – 1984 through 2002) v In previous study, comparative group matched to represent the gender, age, and body mass index (BMI) distribution of the surgical patients

40. Methods vSubjects linked to Utah Cancer Registry for years 1984 through 2007 (24 year follow-up; mean of 12.5 years) vType of cancer (CA), stage of CA, date of diagnosis, vital status, and death date (SEER standards used) vSEER standards: 0 = in situ; 1 = localized; 2-5 = regional; 7 = distant; and unstaged vPrevalent CA (1.9% surgery group; 2.0% comparative group) was excluded Adams, T. et al. Obesity 2009;17:796-802

41. Incidence (Rates/1,000 PY) Cancer SiteSurgery Group Comparative Group Hazard Ratio (P) All cancers3.14.30.76 (0.0006) All cancers, male 3.73.81.02 (0.91) All cancers, female 3.04.40.73 (0.0004) Obesity-related1.32.30.62 (0.0001) Non obesity- related 1.92.00.91 (0.37) Adams, T. et al. Obesity 2009;17:796-802

42. HR for Incident Cancer – Surgery versus Comparative Cancer StageHazard RatioP Value 0 (In Situ)0.860.44 1 (Local)0.860.17 2-5 (Regional)0.610.009 7 (Distant)0.610.03 Unstaged0.400.07 Adams, T. et al. Obesity 2009;17:796-802

43. Mean Time to Diagnosis by Cancer Stage, years Cancer StageSurgery Group Comparative Group 0 (In Situ)9.29.10 1 (Local)8.49.0 2-5 (Regional)9.38.9 7 (Distant)9.59.0 Unstaged6.28.9 Adams, T. et al. Obesity 2009;17:796-802

44. Mortality (Rates/1,000 PY) Cancer SiteSurgery Group Comparative Group Hazard Ratio (P) All cancers (males & females) 0.500.94 0.54 (0.001) All cancers, male 0.12 0.21 0.70 (0.35) All cancers, female0.380.73 0.38 (0.0003) Obesity-related 0.24 0.48 0.54 (0.02) Non obesity-related0.250.460.53 (0.02) Adams, T. et al. Obesity 2009;17:796-802

45. Opportunity for Discovery! (Similar to diabetes remission following bariatric surgery) vWhat are the causes for reduced cancer incidence?  Weight loss (or not)  Change in central adiposity  Reduced energy intake  Other mechanisms?? vHow rapid are the effects that influence cancer incidence reduction – what is the timeline? vDoes cancer incidence vary in relation to bariatric surgical procedures (i.e., GBP vs. banding)? vDoes bariatric surgery influence cancer remission (if yes, does this vary by surgery type)?

46. Opportunity for Discovery (cont.) vDo protective cancer effects (physiological mechanisms) following bariatric surgery vary based upon gender? vDo protective cancer effects (physiological mechanisms) following bariatric surgery vary based upon cancer type? vIf larger data sets representing male bariatric surgery data were available, would reduced cancer incidence appear? vCan robust animal models of obesity and cancer risk be explored and combined with human bariatric surgical outcomes?

47. Final Perspective – Thought #1 It would appear that recent national guidelines recommending weight loss to reduce future cancer risk are supported by results from these bariatric surgery cancer-related studies.

48. Final Perspective – Thought #2 “… to put this risk reduction (HR 0.58) into perspective, it might be helpful to compare it with statin treatment, where the HR for reduction in incidence of fatal plus non-fatal myocardial infarction (vs placebo) has been in the order of 0.80.” Sjöström, L. Lancet Oncol 2009;10:653-62

49. Final Perspective – Thought #3 “As the obesity epidemic shows few signs of abating, incidences of obesity-related cancers may rise; however, the establishment that the development of these cancers is reversible brings about an encouraging new paradigm in cancer prevention.” Andrew G. Renehan Lancet Oncology 2009;10:640

50. “The Missing Link – Have Bariatric Surgery, Lose Weight, Keep Weight Off, Improve Health, Live Longer” “The Missing Link – Have Bariatric Surgery, Lose Weight, Keep Weight Off, Improve Health, Live Longer”