1. Metabolic Surgery: Treating Type 2 Diabetes & Cardiovascular Risk in Obese Patients Highlights of Evidence from Recent Studies NAME DATE ©2012 Ethicon Endo-Surgery, Inc. DSL# 12-0485

2. Evidence Summary New RCT evidence supports recent cohort studies & meta- analyses showing bariatric surgery can lead to improvement or resolution of Type 2 Diabetes (T2DM) & other CV co-morbidities – and reduce medication usage Bariatric surgery data shows that surgery may prevent CV events – and has demonstrated safety similar to many other general surgery procedures Major professional medical societies support bariatric surgery – for treatment of T2DM in severely obese patients (BMI>40), and also for obese patients with poorly controlled or uncontrolled diabetes (BMI>35). page 2

3. Implications for Payers Short-term: Bariatric surgery is able to achieve improved glycemic control of Type 2 diabetes in selected obese patients (BMI>35). o Benefits for up to 2 years now shown in RCTs and up to 5 years in matched cohort studies with large groups of patients Long-term: Durability of this effect has yet to be fully characterized & potential benefits have yet to be definitively proven in routine clinical practice. o Exception: Swedish Obesity Subjects study* – 20-year evidence suggests CV benefit & prolonged glycemic control 3 * Source: Sjostrom, L and others. Bariatric Surgery and Long-term Cardiovascular Events. JAMA 2012; 307(1):56-65

4. Implications for Referring Physicians Bariatric surgery is able to achieve better control of Type 2 diabetes with much less medication in selected obese patients (BMI>35). o Focus on those patients who are at highest risk of a CV event: Younger (under 60) Treated less than 10 years Difficulty maintaining glycemic control with pharmacological agents. Having at least one other CV risk factor in addition to T2DM, e.g. elevated insulin, hypertension and/or dyslipidemia. Difficulty maintaining acceptable weight (almost all T2DM patients). o Surgery is a therapeutic intervention, not just for severely obese patients. o Mode of action of bariatric surgery is metabolically analogous to many T2DM medications with positive impact on GLP-1 & insulin sensitivity. 4 Sources: Sjostrom, L and others. Bariatric Surgery and Long-term Cardiovascular Events. JAMA 2012; 307(1):56-65. Berry, J. and others. Lifetime Risks of Cardiovascular Disease. NEJM 2012; 366:321-29.

5. Referring Physicians – Notes for Consideration Metabolic surgery is able to achieve better control of Type 2 diabetes with much less medication in selected obese patients (BMI>35). o Focus on those patients who are at highest risk of a CV event: Younger (under 60) Treated less than 10 years Difficulty maintaining glycemic control with metformin Having at least one other CV risk factor in addition to T2DM, e.g. elevated insulin, hypertension and/or dyslipidemia. Difficulty maintaining acceptable weight (almost all T2DM patients). o Surgery is a therapeutic intervention, not just for severely obese patients. o Mode of action of bariatric surgery is metabolically analogous to many T2DM medications with positive impact on GLP-1 & insulin sensitivity. Background: According to 2012 NEJM study on lifetime risk of CV disease o Among participants 55 years of age, those with an optimal Risk-Factor Profile* had approximately a five times lower risk of death from CV disease through the age of 80 years than those with two or more major risk factors (4.7% vs. 29.6% among men, 6.4% vs. 20.5% among women) o Metabolic surgery addresses all of the risk factors except smoking Risk-Factor Profile: Total cholesterol level, <180mg/deciliter(4.7 mmol /liter); blood pressure, <120 mmHg systolic and 80 mm Hg diastolic; nonsmoking status; and non-diabetic status 5 Sources: Sjostrom, L and others. Bariatric Surgery and Long-term Cardiovascular Events. JAMA 2012; 307(1):56-65. Berry, J. and others. Lifetime Risks of Cardiovascular Disease. NEJM 2012; 366:321-29.

6. Body of Evidence High Quality (Level I & II-1,2) Studies on Bariatric Surgery in Diabetic Patients 6 InvestigatorStudy Type # Diabetic PatientsPrimary EndpointStudy Duration STAMPEDE (Schauer)* RCT, single center150 pts, 3 armsHbA1c < 6 with or w/o meds Year 1 of 5-year study MingroneRCT, single center60 pts, 3 armsHbA1c < 6.5 without meds2 years Buchwald*Systematic Review & Meta-Analysis 135,000 pts, 621 studies, 888 arms Effect of bariatric surgery on Type 2 diabetes N/A Klein*Matched Cohort, Claims data1600 pts, 2 arms Economic impact & clinical benefits of bariatric surgery 3 years AHRQ (Segal)*Matched Cohort, Claims data 8400 pts, 2 arms (2100 surgery) Impact of surgery to reduce utilization of CV meds Year 1 of 3-year study Bolen*Matched Cohort, Claims data 14,000 pts, 2 arms (6300 surgery) % Obesity-related co- morbidities between groups 5 years * Supported by a grant from Ethicon Endo-Surgery

7. New Clinical Evidence: STAMPEDE Surgical treatment and medications achieved glycemic control in more patients than medical therapy alone Schauer PR, Kashyap SR, Wolski K, et al. Bariatric Surgery versus Intensive Medical Therapy in Obese Patients with Diabetes. N Engl J Med. 2012 Mar 26. [Epub ahead of print]

8. STAMPEDE Study Design Single site, prospective, randomized controlled trial (Cleveland Clinic), 150 patients Compared the efficacy of three treatments for patients with T2DM and BMI between 27-42 kg/m 2 : 1.Intensive Medical Therapy* 2.Intensive Medical Therapy* + Laparoscopic Sleeve Gastrectomy 3.Intensive Medical Therapy* + Gastric Bypass Primary Endpoint:Proportion of patients with a glycated hemoglobin level of 6.0% or less at 12 months after treatment. page 8 * Intensive medical therapy as defined by American Diabetes Association (ADA) guidelines, including lifestyle counseling, weight management, frequent home glucose monitoring, and the use of newer drug therapies approved by the FDA. Nathan DM, Buse JB, Davidson MB et al. Diabetes Care 2009; 32(1): 193-203 and American Diabetes Association. Diabetes Care 2011; 34(S1):S11-61.

9. STAMPEDE Study Design page 9 * As defined by ADA guidelines, including lifestyle counseling, weight management, frequent home glucose monitoring, and the use of newer drug therapies.

10. STAMPEDE Results: Significantly More Diabetic Patients at Glycemic Control with Bariatric Surgery “In obese patients with uncontrolled type 2 diabetes, 12 months of medical therapy plus bariatric surgery achieved glycemic control in significantly more patients than medical therapy alone.” page 10 Medical Therapy Medical Therapy + Gastric Bypass *p=0.002 Medical Therapy + Sleeve Gastrectomy **p=0.008 * ** Glycemic control: HbA1c < 6.0% with or without diabetes medications, 12 mo after randomization. Figures adapted from study data.

11. STAMPEDE Results: Average levels of HbA1c were also significantly lower after Bariatric Surgery “Mean levels of glycated hemoglobin and fasting plasma glucose were significantly lower in each of the two surgical groups than in the medical therapy group” (p<0.001). page 11

12. STAMPEDE Results: Significant Decreases in Diabetic Medication Usage with Bariatric Surgery The average number of diabetic medications per patient per day tended to increase in the medical therapy group but decreased significantly in each surgical group (p<0.001) : page 12 > 50% of patients in each surgical group used NO diabetes medications at 12 months.

13. STAMPEDE Increased Weight Loss Bariatric surgery also resulted in significantly greater weight loss than intensive medical therapy: page 13 Medical Therapy Medical Therapy + Gastric Bypass Medical Therapy + Sleeve Gastrectomy Mean % Weight Loss 5.2% 27.5%* p<0.001 24.7%* p<0.001 Mean % Excess Weight Lost13% 88%* p<0.001 81%* p<0.001 Table adapted from study data

14. STAMPEDE Results: Bariatric Surgery is Safe No deaths in the study 4 surgery patients required re-operation to address adverse events: Cholelithiasis (gallstones) Self-limited bleeding Nausea & vomiting Gastric leak No episodes of serious hypoglycemia page 14 EES strongly recommends that bariatric surgery be performed in a Center of Excellence

15. STAMPEDE Study Limitations Single-center study (Cleveland Clinic) Unable to be conducted as a blinded study Patients were outside of NIH limits for surgically-eligible patients (includes patients with BMI between 27 and 34) Includes only one-year data Durability remains to be assessed with ongoing evaluations over five years page 15

16. New Clinical Evidence: Mingrone Bariatric surgery resulted in better glucose control than did medical therapy Mingrone, G, et. al. Bariatric Surgery versus Conventional Medical Therapy for Type 2 Diabetes, N Engl J Med 2012, March 26, [Epub ahead of print]

17. Mingrone Study Design page 17

18. Mingrone Study Glycated Hemoglobin Levels during 2 Years of Follow-up 18

19. Clinical Evidence Bariatric Surgery and Diabetes Management Matched Cohort Studies / Administrative Claims Data

20. Buchwald: Systematic Review & Meta-Analysis (2009) T2DM resolved or improved in 87% of patients following bariatric surgery 20 Buchwald H, Estok R, Farbach K, et al. Weight and Type 2 Diabetes after Bariatric Surgery: Systematic Review and Meta-analysis. Am J Med. 2009;122(3):248-256. Figure adapted from source data. Data included includes 621 studies with 888 treatment arms & 135,246 patients; 103 treatment arms with 3188 patients reported on resolution of diabetes. Systematic review & meta-analysis reviewing 621 studies including 135,246 patients Overall, T2DM 87% resolved or improved (78% resolved) for patients after bariatric surgery 81% 87% 85% 99% Total

21. Klein: 3-Year Matched Cohort Analysis (2011) 46% fewer T2DM-related claims for patients with bariatric surgery 21 Source: Klein S, Ghosh A, Cremieux PY, Eapen S, McGavock TJ. Economic impact of the clinical benefits of bariatric surgery in diabetes patients with BMI ≥35 kg/m2. Obesity. 2011;19:581-587. 3-year matched cohort analysis comparing claims from 1,616 privately insured patients (808 per cohort) At 6 months, 28% of surgery patients reported a diabetes claim vs. 74% of control patients (p<0.001) The trend in diabetes claims was sustained to 3 years.

22. Bolen: 5-Year Matched Cohort Analysis (2012) Lower proportion – and likelihood - having T2DM at 5yr with bariatric surgery 22 Source: Bolen, Shari and others. Clinical Outcomes after Bariatric Surgery: A Five-Year Matched Cohort Analysis in Seven US States. Obesity Surgery (2012) 22: 749-763, Figure adapted from source data. Non-concurrent, matched cohort study following 22,693 persons who underwent bariatric surgery using logistic regression between groups for up to 5 years. 5-year matched cohort analysis comparing 22,693 obese patients with versus without bariatric surgery from seven BCBS plans The proportion of patients with T2DM at 5 years was 18% lower with bariatric surgery (15% vs. 33%) Bariatric surgery patients had a 31% lower likelihood (odds ratio) of having T2DM at 5 years

23. Clinical Evidence Bariatric Surgery and Medication Usage Matched Cohort Studies/Administrative Claims Data

24. Segal: AHRQ 1-Year Cohort Study (2010) 76% decline in diabetes medication use at 12 months post-surgery (p≤0.0001) 24 Source: Segal JB, Clark JM, Shore AD, et al. Prompt reduction in use of medications for comorbid conditions after bariatric surgery. Effective Healthcare Research Report No. 28. Rockville, MD: Agency for Healthcare Research and Quality; 2010. (Fig 1, page 14) 3-year cohort study using BCBS data from 7 plans, covering 6,235 patients (34% of whom had T2DM) 55% decrease in the mean number of diabetes medications within three months Patients without surgery had an increase in mean number of diabetes medications during the same period ■ nonsurgical group ◊ surgical group

25. Segal: AHRQ 1-Year Cohort Study (2010) Significant declines in cardiovascular medication use at 12 months post-surgery 25 Use of medication for hypertension & hyperlipidemia declined 51% and 59%, respectively, at 12 months post-surgery (p<0.0001) Patients without surgery had an increase in medications for hypertension and hyperlipidemia Source: Segal JB, Clark JM, Shore AD, et al. Prompt reduction in use of medications for comorbid conditions after bariatric surgery. Effective Healthcare Research Report No. 28. Rockville, MD: Agency for Healthcare Research and Quality; 2010. (Fig 1, page 14)

26. Klein: 3-Year Matched Cohort Analysis (2011) 56% fewer diabetes prescriptions were filled for bariatric surgery patients 26 Source: Klein S, Ghosh A, Cremieux PY, Eapen S, McGavock TJ. Economic impact of the clinical benefits of bariatric surgery in diabetes patients with BMI ≥35 kg/m2. Obesity. 2011;19:581-587. Figure adapted from study data. 3-year matched cohort analysis covering 1,616 obese patients with diabetes (808 per cohort) Six months post-surgery, only 34% of surgery patients had filled a prescription for diabetes medication in the previous three months, compared to 90% of control patients (p<0.001) This difference is sustained to the end of the study period (three years)

27. Klein: 3-Year Matched Cohort Analysis (2011) Significantly lower supply costs in diabetes medication for surgery patients 27 Source: Klein S, Ghosh A, Cremieux PY, Eapen S, McGavock TJ. Economic impact of the clinical benefits of bariatric surgery in diabetes patients with BMI ≥35 kg/m2. Obesity. 2011;19:581-587. Figure adapted from study data. Total diabetes medication costs decreased significantly among surgery patients relative to controls. 3 months after bariatric surgery, the average total cost of diabetes medications and supplies for surgery patients was $33, compared to $123 for control patients (p<0.001) Total monthly prescription drug costs for surgery patients were 72% lower at two years. P < 0.001

28. Prior Clinical Evidence Bariatric Surgery Safety & Durability Matched Cohort Studies/Administrative Claims Data

29. CMS: Inpatient Discharge Data (2010) Morbidity & mortality rates of gastric bypass are similar to other common procedures 29 Source: Direct Research, LLC, Center for Medicare and Medicaid Services, FY 2010 MedPAR, Medicare Fee-for-Service Inpatient Discharges with Selected Procedures

30. Bariatric Surgery Prevents CV Events (2012) “High insulin may be a better selection criteria for bariatric surgery than high BMI, as far as CV events are concerned” 30 Sjostrom, L et. al., Bariatric Surgery and Long-term Cardiovascular Events. JAMA 2012; 307(1):56-65; illustration from page 63.

31. Surgery has shown long-term weight loss Weight loss of selected bariatric procedures to 20 years page 31 Sjostrom, L et. al., Bariatric Surgery and Long-term Cardiovascular Events. JAMA 2012; 307(1):56-65. Figure adapted from illustration page 59.

32. Bariatric Surgery - Medical Society Support

33. A growing consensus favors bariatric surgery page 33 “Bariatric surgery should be considered for adults with BMI ≥ 35 kg/m 2 and type 2 diabetes, especially if the diabetes is difficult to control with lifestyle and pharmacologic therapy.” – American Diabetes Association (2009) “When indicated, surgical intervention leads to significant improvements in decreasing excess weight and co- morbidities that can be maintained over time.” – American Heart Association (2011) “Bariatric surgery is an appropriate treatment for people with type 2 diabetes and obesity not achieving recommended treatment targets with medical therapies” – International Diabetes Federation (2011) “The beneficial effect of surgery on reversal of existing DM and prevention of its development has been confirmed in a number of studies” – American Association of Clinical Endocrinologists (2011) Sources: American Diabetes Association. Standards of medical care in diabetes – 2009. Diabetes Care 2009; 32(S1):S13-S61, Poirier P, Cornier M-A, Mazzone T et al. Bariatric surgery and cardiovascular risk factors: A scientific statement from the American Heart Association. Circulation 2011; 123:00-00. International Diabetes Federation. Bariatric surgical and procedural interventions in the treatment of obese patients with type 2 diabetes. 2011. Handelsman Y, Mechanick JI, Blone L et al. American Association of Clinical Endocrinologists medical guidelines for clinical practice for developing a diabetes mellitus comprehensive plan. Endocr Prac 2011; 17(Suppl 2).

34. A growing consensus favors bariatric surgery “The Endocrine Society recommends that practitioners consider several factors in recommending surgery for their obese patients with type 2 diabetes, including patient’s BMI and age, the number of years of diabetes and the assessment of the (patient’s) ability to comply with the long-term lifestyle changes that are required to maximize success of surgery and minimize complications.” “… remission of diabetes, even if temporary, will still lead to a reduction in the progression to secondary complications of diabetes (such as retinopathy, neuropathy and nephropathy), which would be an important outcome of … surgery.” – The Endocrine Society (March 2012) page 34 Source: The Endocrine Society, Evaluating the Benefits of Treating Type 2 Diabetes with Bariatric Surgery, March 30, 2012.

35. Conclusions & Recommended Next Steps

36. Conclusions 36 The evidence shows how bariatric surgery : Helps Type 2 diabetic patients achieve glycemic control more effectively than intensive medical therapy within 1 year (STAMPEDE & Mingrone) Resolves or improves Type 2 diabetes and other obesity-related CV comorbidities for up to 5 years (STAMPEDE, Buchwald, Klein and Bolen) Reduces medication use for Type 2 diabetes and other CV comorbidities for up to 3 years (STAMPEDE, AHRQ/Segal and Klein) Results in morbidity & mortality rates that are similar to well-established general surgery procedures such as gallbladder surgery and hysterectomy (CMS) Reduces the risk of cardiovascular death (myocardial infarction or stroke) compared to customary intervention (Sjostrom) Achieved consensus as an acceptable treatment option for obese patients with T2DM by professional medical societies including the ADA, AHA, IDF, AACE & the Endocrine Society.

37. Next Steps – Encourage referring physicians & PCPs … Recommend bariatric surgery to selected obese patients (BMI>35) with Type 2 diabetes to achieve better control of their diabetes with much less medication: o Focus on those patients who are at highest risk of a CV event: Younger (under 60) Treated less than 10 years Difficulty maintaining glycemic control with metformin Having at least one other CV risk factor in addition to T2DM, e.g. elevated insulin, hypertension and/or dyslipemia. Difficulty maintaining acceptable weight (almost all T2DM patients). o Rethink surgery as a therapeutic intervention, not just for severely obese patients. Mode of action of bariatric surgery is metabolically analogous to many T2DM medications with positive impact on GLP-1 & insulin sensitivity. page 37 * Sources: Sjostrom, L and others. Bariatric Surgery and Long-term Cardiovascular Events. JAMA 2012; 307(1):56-65. and Berry, J. and others. Lifetime Risks of Cardiovascular Disease. NEJM 2012; 366:321-29.

38. Discussion…. “What are your thoughts?”

39. Backup Slides – STAMPEDE study

40. STAMPEDE Trial Results: Bariatric Surgery vs Intensive Medical Therapy in Obese Patients with Diabetes – Schauer et al March 2012 publication in NEJM DSL 12-0384 ©2012 Ethicon Endo-Surgery, Inc. All rights reserved.

41. Population page 41 Baseline Intensive Medical Therapy Lap Roux-en Y Gastric Bypass Lap Sleeve Gastrectomy N total (% female)50 (62)50 (58)50 (78) Mean Duration T2DM, in years8.98.28.5 Insulin use, N(%)22 (44) Mean BMI, kg/m² (%, BMI<35) [BMI, kg/m² range] 36.8 (38) [31.8 - 42.3] 37.0 (28) [30.6 - 43.0] 36.2 (36) [28.0 - 43.0] Mean HbA1c¹, %8.99.39.5 Mean FPG², mg/dl155193164 (1)Normal:HbA1c, < 6% (2)Normal FPG, 82 to 110 mg/dl Population consisted of predominately female, moderately obese patients with long standing and uncontrolled T2DM 44% required the use of insulin No statistically significant differences existed between the three groups with regard to baseline characteristics

42. 1-year Outcomes, Impact on T2DM Control page 42 GroupsIMTLRYGBLSG N (%)41 50 49 Euglycemia¹5(12.2)21(42.0)18(36.7) Complete Remission²0(0)21(42.0)13(26.5) Partial or Complete Remission²0(0)34(68.0)22(44.9) No Diabetes Medications0(0)38(77.6)25(51.0) (1) HbA1c < 6.0, i.e., "normal” with or without medications (2) Diabetes Care. 2009 Nov;32(11):2133-5 "Complete Remission" : HbA1c <6.0, “normal” without medications "Partial Remission": HbA1c <7.0, “in control” without medications Bariatric surgery was associated with significantly more subjects in control of their T2DM; many without the use of diabetes medications. Gastric bypass produced the most dramatic results, with 68% of subjects in control without medications; sleeve gastrectomy, with 45% in control without medications. 42% of gastric bypass subjects achieved complete remission; 26.5% of sleeve gastrectomy subjects.

43. page 43 Bariatric surgery was associated with rapid, dramatic improvement in lab parameters of glycemic control ; a 3 percentage point drop in HbA1c with a concurrent reduction in medications and no severe episodes of hypoglycemia The medical group also significantly improved with intensive care. A.Normal:HbA1c, < 6% B.Normal FPG, 82 to 110 mg/dl 1-year Outcomes Impact on T2DM Control

44. 1-year Outcomes Impact on Diabetes Medication Use and Body Weight page 44 Bariatric surgery was associated with rapid, dramatic improvement in glycemic control; with a concurrent reduction in medications Bariatric surgery resulted in significant weight loss

45. 1-year Outcomes Subjects Receiving 0 to 3 or more Diabetes Meds page 45 Bariatric surgery was associated with dramatically reduced need for diabetes medications 78% of gastric bypass patients were without diabetes medications; as were 51% of sleeve gastrectomy patients.

46. 1-year Outcomes Subjects Receiving Insulin page 46 Bariatric surgery was associated with a dramatically reduced need for insulin. Only 4% of gastric bypass patients and 8% of sleeve gastrectomy patients whereas 38% of the medical group required insulin.

47. 1-year Outcomes Subjects Receiving 1 or more Drugs for Hypertension or Dyslipidemia page 47 Bariatric surgery was associated with reduced need for cardiovascular medications, while blood pressure and lipids remained in control Bariatric surgery resulted in the reduction of cardiovascular risk factors for participants well below that for intensive medical management Bariatric surgery, according to the IDF 2011 definition, substantially improved the metabolic state of patients [Diabet Med. 2011 Jun;28(6):628-42]

48. Surgical Risk As with any surgical procedure, bariatric surgery may present risks and complications. Serious complications can occur. Death can occur during or soon after any surgery, even when every precaution has been taken. Patients should consult their physician to discuss these risks and their surgical options. Bariatric surgery may not be right for patients with certain conditions. Individual patient results may vary and are not indicative of all potential outcomes. page 48

49. 1-Year Outcomes Conclusions In obese patients with long standing and uncontrolled T2DM, bariatric surgery: –was associated with rapidly and dramatically improved glycemic control, and concurrently, substantially reduced need for diabetes, lipid-lowering and hypertension medications 68% of gastric bypass patients and 45% of sleeve gastrectomy patients achieved glycemic control without diabetes medications; 42% of gastric bypass patients and 26.5% of sleeve gastrectomy patients achieved euglycemia without diabetes medications; insulin use dropped from 44% of patients pre-surgery to 4% of those undergoing gastric bypass, 8% of those undergoing sleeve gastrectomy, and to 35% of those receiving intensive medical management alone. –was associated with substantially improved metabolic state, reducing the cardiovascular risk profile of the patients well below that of those receiving intensive medical management alone –resulted in significant weight loss –achieved these benefits without serious hypoglycemic events –only 4 patients required a return to the OR for re-operation page 49