1. Why Surgical Treatment of Diabetes May Not be a Good Option McGill First Canadian Summit on Surgery for Type 2 Diabetes Montréal, Québec May 7, 2010 David C.W. Lau, MD, PhD, FRCPC Professor of Medicine and Biochemistry Julia McFarlane Diabetes Research Centre University of Calgary Email: dcwlau@ucalgary.ca

2. Disclosures Research funding: CIHR, AHFMR, Alberta Cancer Board, AstraZeneca, BMS, Dainippon, GSK, Eli Lilly, Pfizer and sanofi-aventis Consultant or advisory board member: Abbott, Allergan, AstraZeneca, Bayer, Boehringer- Ingelheim, GSK, Eli Lilly, Merck, Novartis, Novo Nordisk, Pfizer, Roche, sanofi-aventis, Sepracor Speaker bureau: CDA, HSFC, AstraZeneca, Abbott, Bayer, Boehringer- Ingelheim, Eli Lilly, GSK, Merck, Novo Nordisk, Pfizer sanofi-aventis and Sepracor

3. Questions How effective is bariatric surgery in treating diabetes? Are all procedures equally effective? What is the durability of diabetes remission? Is bariatric surgery safe? What are the short- and long-term complications? Is bariatric surgery cost effective?

4. 6 - 9 yr follow-up MacDonald et al J Gastrointest Surg 1997;1:213-220 Bariatric Surgery Decreases Type 2 Diabetes 100% 80% 60% 40% 20% 0% 87.0% 8.6% Controls Gastric bypass % Type 2 Diabetes

5. Bariatric Surgery: Improvement in Weight, Glucose, CVD Risk Factors & Energy Intake Sjöström, L et al. N Engl J Med 2004;351:2683-2693

6. Dixon, JB et al. JAMA 2008;299:316-323 Lap Adjustable Gastric Banding for Diabetes First randomized controlled trial comparing surgically induced weight loss with conventional therapy N=60; 28 men, 32 women Mean age ~47 years Recently diagnosed Type 2 Diabetes (< 2 years) Wt 106 kg, WC 115 cm BMI 37.1 kg/m 2 A1C ~7.7%, FPG 8.7 mM

7. Bariatric Surgery: Weight Loss and Diabetes Remission Surgery (N=30)Control (N=30) Remission in % (N)73% (22/30)13% (4/30) Achieving A1C < 6.2% in %80% (N=24)20% (N=6) Medication use (N)428 Weight loss (mean±SD) in %20±9.41.4±4.9 Excess wt loss (mean±SD) %62.54.3 Change in BMI (kg/m 2 )- 7.4- 1.5 Dixon, JB et al. JAMA 2008;299:316-323

8. Weight Loss and Diabetes at 2 Years Dixon, JB et al. JAMA 2008;299:316-323 Remission occurred > 6 months post- surgery 10% body weight loss generally required for diabetes remission, which was achieved in 22 of surgical patients 4/26 patients who lost > 10% body weight failed to achieved remission

9. Weight Loss and Diabetes Remission TotalLAGBGastropG BypassBPD/DS % EBWL55.946.255.559.763.6 % “Cure”78.156.779.780.395.1 % < 2 yrs80.355.081.481.694.0 % ≥ 2 yrs74.658.377.570.995.9 Buchwald H et al. Am J Med 2009;122:248-256 Systematic Analysis of 621 studies, N=135,246 Mean age 40.2 years; BMI 47.9 kg/m 2 ; 80% women

10. How effective is bariatric surgery in treating diabetes? Yes, it is effective with a remission rate is about 84% but no long-term data No data on subjects with longer duration of diabetes Results likely vary with less experienced surgical teams No long term data on efficacy of surgery Not a cure for diabetes

11. Hormonal Mechanisms of Weight loss Weight dependent effects on glucose homeostasis Multiple hypotheses (foregut, hindgut, ghrelin etc.) on weight independent anti-diabetic effects of RYGB but detailed mechanisms remain unknown Gut hormones (GLP-1, ghrelin, PYY and oxyntomodulin) likely play an important role Increased but usually appropriate GLP-1 response with Roux-en-Y gastric bypass (RYGB) surgery Insulin hypersecretion and insulin resistance are normalized following malabsorptive bariatric surgery

12. Hormonal Changes Associated with Bariatric Surgical Procedures Frühbeck G et al. N Engl J Med 2004;350:308-309

13. What are the short- and long-term complications?

14. Complications Operative risks, morbidity and mortality Post-op and short-term mortality  0.1-0.33% for LAGB  0.5% for gastric bypass surgery Long-term  Nutrient and vitamin deficiencies  Malabsorption  Obstruction  Dumping syndrome  Hypoglycemia

15. Nesidioblastosis and Hypoglycemia 5 women and 1 man (median age 47 years; range, 39 to 54) with postprandial symptoms of neuroglycopenia developed 1- 2 years post-surgery Postprandial hyperinsulinemic hypoglycemia and nesidioblastosis were confirmed in 4 patients and islet cell tumors in 2 patients; all underwent partial pancreatectomy Increased levels of a β-cell trophic polypeptide, such as glucagon-like peptide 1, may contribute to the hypertrophy of pancreatic beta cells in these 6 patients Service GJ, et al N Engl J Med 2005;353:249-254

16. Bariatric Surgery for Diabetes Advantages Effective and sustained long-term weight loss > 10% More patients achieve glycemic and metabolic goal targets Reduction in anti-diabetic medications No hypoglycemia May be cost-effective Disadvantages Surgical complications (short- and long-term) Remission not achieved in all patients who achieved > 10% wt loss Long surgical wait list Requires long-term follow- up Long-term efficacy and safety data not available

17. Questions How effective is bariatric surgery in treating diabetes? Are all procedures equally effective? What is the durability of diabetes remission? What are the short- and long-term complications? Is bariatric surgery safe? Access to surgery is a big barrier with long wait times Is bariatric surgery cost effective?

18. Patient Selection, Benefits and Complications of Bariatric Surgery Frachetti KL, et al. Curr Opin Endocrinol Diabetes Obes. 2009;16:119-124 Obesity Surgery Obesity Diabetes Co-Morbidities Operative Risks Benefits: - Weight loss - Metabolic improvements - Mortality benefit Complications: - Nutrient deficiency - Dumping syndrome - Hypoglycemia

19. Is bariatric surgery for the treatment of type 2 diabetes an option? Not quite ready for prime time Needs more research and clinical trial data

20. Thank you Questions?