Is There a Role for Surgery in the Treatment of Diabetes

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  • Is There a Role for Surgery in the Treatment of Diabetes

    1. 1. Is There a role for Surgery in the treatment of Diabetes? George S. Ferzli, MD, FACS
    2. 2. DISCLOSURE <ul><li>I HAVE NOTHING TO DISCLOSE </li></ul>
    3. 3. Diabetes <ul><li>Considered major public health problem – emerging as a world wide pandemic. In 1995 ~ 135 million people worldwide </li></ul><ul><li>Currently 240 million, expected to rise to close to 380 million by 2025 </li></ul><ul><li>Complications </li></ul><ul><ul><li>Peripheral vascular disease (PVD) accounts for 20-30% </li></ul></ul><ul><ul><li>10% of cerebral vascular accident </li></ul></ul><ul><ul><li>Cardiovascular disease accounts for 50% of total mortality </li></ul></ul><ul><ul><li>1. Venkat et al Diabetes–a common, growing, serious, costly, and potentially preventable public health problem. Diabetes Res </li></ul></ul><ul><ul><li>Clin Pract. 2000; 5 (Suppl2): S77–S784. </li></ul></ul><ul><ul><li>2. H. King et Global burden of diabetes, 1995-2025: prevalence, numerical estimates and projections. Diabetes Care 21 (1998) </li></ul></ul><ul><ul><li>1414-1431. </li></ul></ul><ul><ul><li>3. Annals of Surgery. Volume 251, Number 3, March 2010 </li></ul></ul>
    4. 4. Prevalence of Diabetes <ul><li>From 1980 through 2006, the number of Americans with diabetes tripled (from 5.6 million to 16.8 million). </li></ul><ul><li>~24 million in 2009. </li></ul>
    5. 5. CDC. National Diabetes Fact Sheet, 2007. Source: 2003 –2006 National Health and Nutrition Examination Survey estimates of total prevalence (both diagnosed and undiagnosed) were projected to year 2007.
    6. 6. Obesity and the Metabolic Syndrome <ul><li>1. Syndrome “X” </li></ul><ul><li>2. Insulin Resistance Syndrome </li></ul><ul><li>3. Reaven’s Syndrome </li></ul><ul><li>4. Deadly Quartet </li></ul><ul><li>5. CHAOS </li></ul><ul><li>C oronary Artery Disease </li></ul><ul><li>H ypertension </li></ul><ul><li>A dult Onset Diabetes </li></ul><ul><li>O besity </li></ul><ul><li>S troke </li></ul>
    7. 7. Obesity Associated Conditions Diabetes Hypertension Sleep apnea Congestive heart failure Hyperlipidemia Stroke Coronary artery disease Osteoarthritis Gastroesophageal reflux disease Non-alcoholic fatty liver Psychological disturbances
    8. 8. Derived from Center for Disease Control and Prevention website www.cdc.gov Percent of Obese (BMI ≥ 30) in US Adults
    9. 9. Derived from Center for Disease Control and Prevention website www.cdc.gov Percent of Obese (BMI ≥ 30) in US Adults
    10. 10. County-level Estimates of Obesity among Adults aged ≥ 20 years: United States
    11. 11. <ul><li>National Hospital Discharge Survey Public-use data file and documentation. Multi-year data CD-ROM. National Center for Health Statistics, 1979-1996. </li></ul><ul><li>Nguyen et al. Accelerated growth of bariatric surgery with the introduction of minimally invasive surgery. Arch Surg 2005; 140: 1198-202. </li></ul><ul><li>Griffen et al. The decline and fall of the jejunoileal bypass. Surg Gynecol Obstet 1983; 157: 301-8. </li></ul><ul><li>Shirmer et al. Bariatric Surgery Training: Getting Your Ticket Punched. J Gastrointest Surg 2007;11: 807-12. </li></ul>Popularity of Surgical Management Period or Decades Incidence of Surgery Reason for Change Late 1970’s Early 1980’s 25,000 procedures per year <ul><li>Innovative procedures </li></ul><ul><li>gastroplasty </li></ul><ul><li>loop GBP </li></ul><ul><li>jejuno-ileal bypass </li></ul>Late 1980’s 1990’s 5,000 procedures per year <ul><li>Multifactorial: </li></ul><ul><li>High M&M </li></ul><ul><li>Ineffective long-term </li></ul><ul><li>Perceived failure </li></ul><ul><li>Surgeon experience </li></ul>2000’s 80,000 to 110,000 procedures per year <ul><li>Multifactorial: </li></ul><ul><li>Laparoscopy </li></ul><ul><li>Long-term data </li></ul><ul><li>Centers of Excellence </li></ul>
    12. 12. Current Procedures
    13. 13. <ul><li>Buchwald H, Avidor Y, Braunwald E, Jensen MD, Pories W, Fahrbach K, et al. Bariatric surgery: a systematic review and meta-analysis. JAMA 2004; 292: 1724-37. </li></ul><ul><li>Sjostrom L, Lindros AK, Peltonem M, Torgerson J, Bouchard C, Carlsson B, et al. Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. N Engl J Med 2004; 351: 2683-93. </li></ul>Long-term Weight Control Analysis Studies Type and Size Effect on Weight Effect on Comorbidities Buchwald et al. Meta-analysis n = 22,094 pts Mean excess weight loss: 61% <ul><li>Resolution of: </li></ul><ul><li>Diabetes: 70% </li></ul><ul><li>HTN: 62% </li></ul><ul><li>Sleep apnea: 86% </li></ul>Swedish Obese Subject trial (SOS) Prospective matched cohort n = 4,047 pts <ul><li>At 10 years: </li></ul><ul><li>Med: 1.6% gain </li></ul><ul><li>Surg: 16% loss </li></ul><ul><li>Improved by surgery: </li></ul><ul><li>Diabetes </li></ul><ul><li>Lipid profile </li></ul><ul><li>HTN </li></ul><ul><li>Hyperuricemia </li></ul>
    14. 14. Schauer et al. Effect of laparoscopic Roux-en Y gastric bypass on type 2 diabetes mellitus. Ann Surg. 2003 Oct; 238(4): 467-84 <ul><li>1160 patients underwent LRYGBP 5-year period </li></ul><ul><li>LRYGBP resulted in significant weight loss (60% percent of excess body weight loss) and resolution (83%) of T2DM </li></ul><ul><li>Fasting plasma glucose and HBA1C normalized (83%) or markedly improved (17%) in all patients </li></ul><ul><li>Patients with the shortest duration and mildest form of T2DM had a higher rate of T2DM resolution after surgery </li></ul><ul><ul><li>suggesting that early surgical intervention is warranted to increase the likelihood of rendering patients euglycemic </li></ul></ul>
    15. 15. Biliopancreatic Diversion (BPD) <ul><li>312 BPD, obese patients with type 2 DM were followed for pre and postoperative serum glucose, triglycerides, cholesterol & arterial pressure measurements </li></ul><ul><li>After BPD, fasting serum glucose fell within normal values in 310 patients; remained normal up to 10 years in all but 6 patients </li></ul><ul><li>Evidence of hypertension disappeared in majority of patients </li></ul><ul><li>Glycemic control translates into a reduced mortality for these patients as well as a low frequency of death from cardiovascular events </li></ul><ul><li>TRUE CLINICAL RECOVERY </li></ul>Scopinaro N, Marinari GM, Camerini GB et al. Specific Effects of Biliopancreatic Diversion on the Major Components of Metabolic Syndrome. Diabetes Care . 2005. 28:2406-2411
    16. 16. Biliopancreatic Diversion (BPD) Scopinaro N, Marinari GM, Camerini GB et al. Specific Effects of Biliopancreatic Diversion on the Major Components of Metabolic Syndrome. Diabetes Care . 2005. 28:2406-2411
    17. 17. Rates of Remission of Diabetes in Obese patients Adjustable Gastric Banding Roux-en-Y Gastric Bypass Biliopancreatic Diversion >95% (Immediate) 48% (Slow) 84% (Immediate)
    18. 18. 1995-“Who Would Have Thought It? Pories et al. Annals of Surgery <ul><li>NIDDM is no longer an uncontrollable disease </li></ul><ul><li>The correction on NIDDM occurs within days following gastric bypass, long before significant weight loss has occurred </li></ul><ul><li>Decrease caloric intake and changes in incretin stimulation of the islets by the gut may play a role </li></ul>
    19. 19. Others thought about it !!! <ul><li>1955- Friedman </li></ul><ul><ul><li>3 patients with poorly control DM </li></ul></ul><ul><ul><li>3-4 days after subtotal gastrectomy all 3 pateints showed an improvement in their DM </li></ul></ul><ul><ul><ul><li>Occurred sooner than associated weight loss </li></ul></ul></ul><ul><ul><ul><li>Patients later regained their weight without an associated loss of glucose control or glycosuria </li></ul></ul></ul><ul><li>Mingrone 1977 : Case report </li></ul><ul><ul><li>Young, non obese woman with DM who underwent BPD for chylomicronemia </li></ul></ul><ul><ul><li>Plasma insulin and blood glucose levels normalized within 3 months </li></ul></ul><ul><li>Bittner –1981- subtotal gastrectomy and gastrointestinal reconstructions that excluded duodenal passage (BII and RYGB) </li></ul><ul><ul><li>Lowered plasma glucose and insulin </li></ul></ul><ul><ul><li>Conclusion: Plasma glucose and insulin fall rapidly post-operatively </li></ul></ul><ul><ul><ul><li>antidiabetic medications can be reduced or stopped shortly after gastrointestinal bypass interventions </li></ul></ul></ul><ul><ul><li>Rubino F. Bariatric Surgery:effects on glucose homeostasis. Curr. Opin. Clin. Nutr. Metab. Care 9: 497-507 </li></ul></ul><ul><ul><li>Bittner R. Homeostasis of glucose and gastric resection: the influence of food passage through the duodenum Z Gastroenterology 1981; 19: 698-707. </li></ul></ul><ul><ul><li>Friedman NM et al. The amelioration of diabetes mellitus following subtotal gastrectomy. Surg. Gynecol. Obstetr. 1955; 100:201-204 </li></ul></ul>
    20. 20. <ul><li>“ Gastric bypass and biliopancreatic diversion </li></ul><ul><li>seem to achieve control of diabetes as a primary and </li></ul><ul><li>independent effect, not secondary </li></ul><ul><li>to the treatment of overweight.” </li></ul><ul><li>Potential of Surgery for Curing Type 2 Diabetes Mellitus. Rubino, Francesco, MD; Gagner, </li></ul><ul><li>Michel MD, FACS, FRCSC Annals of Surgery; 236 (5): 554-559, November 2002 </li></ul>2002: Antidiabetic Effect of Bariatric Surgery: Direct or Indirect?
    21. 21. What do we know? DIABETES OBESITY <ul><ul><ul><li>Excess adipose tissue increases </li></ul></ul></ul><ul><ul><ul><li>available triglyceride stores </li></ul></ul></ul><ul><ul><ul><li>Breakdown of TG leads to overabundance </li></ul></ul></ul><ul><ul><ul><li>of circulating fatty acids </li></ul></ul></ul><ul><ul><ul><li>INCREASED FATTY ACIDS </li></ul></ul></ul>INSULIN RESISTANCE INCREASES HEPATIC TRIGLYCERIDE SYNTHESIS & PRODUCTION OF VLDL LOSS OF VASODILATORY EFFECT OF INSULIN PRESERVED SODIUM REABSORPTION HYPERCHOLESTEROLEMIA HYPERTENSION
    22. 22. Rehfeld J, 2004 1967 – Gastric Bypass DISCOVERY OF GASTROINTESTINAL HORMONES
    23. 23. Hormonal Changes after Bariatric Surgery
    24. 24. How Does Bariatric Surgery Effect glucose homeostasis? <ul><li>Intestinal Malabsorption? </li></ul><ul><ul><li>Weight loss reduces insulin resistance </li></ul></ul><ul><ul><li>Glucose malabsorption reduces stress on islet cells </li></ul></ul><ul><ul><li>Fat malabsorption reduces circulating free fatty acids and improves insulin sensitivity </li></ul></ul><ul><li>Hormonal Changes? </li></ul><ul><ul><li>Re-routing of food alters the dynamic of gut-hormone secretion </li></ul></ul><ul><ul><ul><li>Decrease in plasma levels of leptin & insulin </li></ul></ul></ul><ul><ul><ul><li>Increased levels of adiponectin & peptide YY3-36 </li></ul></ul></ul><ul><ul><ul><li>Increased levels of glucagon-like peptide 1 (GLP-1) </li></ul></ul></ul><ul><li>Rearrangement of GI anatomy? </li></ul><ul><ul><ul><li>“ Hindgut hypothesis” </li></ul></ul></ul><ul><ul><ul><li>“ Foregut hypothesis” </li></ul></ul></ul>
    25. 25. Potential Cure for Diabetes Hypothesis Hypoglycemia <ul><ul><ul><li>Rubino et al; Ann. Surg. 2002 </li></ul></ul></ul>
    26. 26. Hypothesis <ul><ul><ul><li>Rubino et al; Ann. Surg. 2002 </li></ul></ul></ul>
    27. 27. GIP and GLP-1 <ul><li>Stimulated by enteral nutrients </li></ul><ul><li>insulin secretion / action </li></ul><ul><li> -cell proliferation </li></ul>… Anti-Incretin <ul><li>Stimulated by enteral nutrients </li></ul><ul><li>insulin secretion / action </li></ul><ul><li> -cell proliferation </li></ul>Anti-incretin
    28. 28. Hypothesis <ul><ul><ul><li>Rubino et al; Ann. Surg. 2002 </li></ul></ul></ul>
    29. 29. Anti-Incretin Insulin resistance Beta cell depletion Hyperglycemia Too Much Dumping Syndrome Nesidioblastosis Hyperinsulinemia Hypoglycemia Not Enough TYPE 2 DIABETES
    30. 30. Hypothesis <ul><ul><ul><li>Rubino et al; Ann. Surg. 2002 </li></ul></ul></ul>
    31. 31. 2004: Rubino et al. Duodenal-Jejunal Exclusion – Foregut Effect of Duodenal-Jejunal Exclusion in a Non-obese Animal Model of Type 2 Diabetes: A New Perspective for an Old Disease. Rubino, Francesco, MD; Marescaux, Jacques MD, FRCS Annals of Surgery; 239 (1): 1-11, January 2004
    32. 32. 2004: Rubino et al. Duodenal-Jejunal Exclusion “ Results of our study support the hypothesis that the bypass of duodenum and jejunum can directly control type 2 diabetes and not secondarily to weight loss or treatment of obesity.” Effect of Duodenal-Jejunal Exclusion in a Non-obese Animal Model of Type 2 Diabetes: A New Perspective for an Old Disease. Rubino, Francesco, MD; Marescaux, Jacques MD, FRCS Annals of Surgery; 239 (1): 1-11, January 2004
    33. 33. Slides taken from: DIABETES IS NO LONGER A HOPELESS DISEASE The Guilty Gut Walter Pories, MD, FACS, Chief, Metabolic Institute East Carolina University Greenville, North Carolina 2006: Rubino et al. Duodenal Exclusion
    34. 34. 2006: Rubino et al. Duodenal exclusion “ This study shows that bypassing a short segment of proximal intestine directly ameliorates type 2 diabetes, independently of effects on food intake, body weight, malabsorption, or nutrient delivery to the hindgut.” The Mechanism of Diabetes Control After Gastrointestinal Bypass Surgery Reveals a Role of the Proximal Small Intestine in the Pathophysiology of Type 2 Diabetes. Rubino, Francesco, MD; Forgione, Antonello, MD; Cummings, David E MD; Vix, Michel MD; Gnuli, Donatella MD; Mingrone, Geltrude MD; Castagneto, Marco, MD (S); Marescaux, Jacques MD, FRCS Annals of Surgery; 244 (5): 741-749, November 2006
    35. 35. <ul><li>Bariatric Surgery clearly has an antidiabetic effect; thought to be secondary to surgically induced weight loss and decreased caloric intake </li></ul><ul><li>But, how do we explain the finding that glycemic control occurs within days, before significant weight loss has been achieved??? </li></ul><ul><ul><li>Direct effect of the surgical bypass of proximal intestines </li></ul></ul><ul><ul><li>Hormonal Regulation of Glucose Metabolism </li></ul></ul><ul><ul><ul><li>Insulin, glucagons-like peptide (GLP-1), glucose-dependent insulinotropic peptide (GIP), glucagon and leptin </li></ul></ul></ul>Pacheco D, et al. The effects of duodenal-jejunal exclusion on hormonal regulation of glucose metabolism in Goto-Kakizaki rats. Am J Surgery; 194 (2007): 221-224 2007: Pacheco et al. Duodenal-Jejunal Exclusion and Glucose Metabolism
    36. 36. <ul><li>Animal Model of non-obese type 2 diabetes; Goto-Kakizaki rats </li></ul><ul><li>Twelve (12-14 wk old) rats randomly underwent </li></ul><ul><li>gastrojejeunal bypass or no intervention </li></ul><ul><li>* All fed with same type of diet </li></ul><ul><li>* All fed with same amount of diet </li></ul><ul><li>* Pre-op, post-op 1 wk & 1 month </li></ul><ul><li>weight assessment & fasting glycemia </li></ul><ul><li>* Oral Glucose Tolerance Test performed at each </li></ul><ul><li>time point </li></ul><ul><li>* Hormone levels were measured after 20 minutes of oral </li></ul><ul><li>overload </li></ul>2007: Pacheco et al. Duodenal-Jejunal Exclusion Pacheco D, et al. The effects of duodenal-jejunal exclusion on hormonal regulation of glucose metabolism in Goto-Kakizaki rats. Am J Surgery; 194 (2007):221-224
    37. 37. 2007:Pacheco et al. Duodenal-Jejunal Exclusion <ul><li>Group 1 and Group 2 rats remained the same weight during the experiment </li></ul><ul><li>OGTT improved in DJ bypass group </li></ul><ul><li>Glucose levels were better at 1 week & 1 month after DJ bypass in all times of OGTT (basal, 10 min, 120 min) </li></ul><ul><li>Post-oral glucose load levels of glucagon, insulin, GLP-1 and GIP remained unchanged in both groups </li></ul><ul><li>In DJ bypass group there is a significant decrease in leptin levels noted </li></ul>Pacheco D, et al. The effects of duodenal-jejunal exclusion on hormonal regulation of glucose metabolism in Goto-Kakizaki rats. Am J Surgery; 194 (2007): 221-224
    38. 38. Leptin??? <ul><li>Adipocyte-derived hormone </li></ul><ul><li>In mice, leptin acts as a hormonal signal on the afferent limb of a negative feedback loop between the adipose tissue and hypothalmic centers </li></ul><ul><li>Physiological increase in plasma leptin has been shown to significantly inhibit glucose-stimulated insulin secretion in vivo and to determine insulin resistance </li></ul>Pacheco D, et al. The effects of duodenal-jejunal exclusion on hormonal regulation of glucose metabolism in Goto-Kakizaki rats. Am J Surgery; 194 (2007): 221-224
    39. 39. <ul><ul><li>Double blind study: 16 patients assigned to LRYGBP and 16 Pts to LSG </li></ul></ul><ul><ul><li>Patients reevaluated on the 1st, 3rd, 6th, and 12th mos </li></ul></ul><ul><ul><li>Results: </li></ul></ul><ul><ul><ul><li>No change in ghrelin levels after LRYGB Significant decrease in ghrelin after LSG ( P < 0.0001) </li></ul></ul></ul><ul><ul><ul><li>Fasting PYY levels increased after either surgical procedure ( P <= 0.001) </li></ul></ul></ul><ul><ul><ul><li>Appetite decreased in both groups but to a greater extend after LSG </li></ul></ul></ul>2008: Karamanakos et al. RYGB vs SLEEVE Karamanakos et al , Weight loss, appetite suppression, and changes in fasting and postprandial ghrelin and peptide-YY levels after Roux-en-Y gastric bypass and sleeve gastrectomy: a prospective, double blind study. Ann Surg . 2008 Mar; 247(3): 401-7 .
    40. 40. <ul><li>“ PYY levels increased similarly after either procedure. </li></ul><ul><li>The markedly reduced ghrelin levels in addition to increased </li></ul><ul><li>PYY levels after LSG, are associated with greater appetite </li></ul><ul><li>suppression and excess weight loss compared with LRYGBP” </li></ul>2008: Karamanakos et al. RYGB vs SLEEVE Karamanakos et al , Weight loss, appetite suppression, and changes in fasting and postprandial ghrelin and peptide-YY levels after Roux-en-Y gastric bypass and sleeve gastrectomy: a prospective, double blind study. Ann Surg . 2008 Mar; 247(3): 401-7.
    41. 41. 2008: Vidal et al. RYGB vs SLEEVE <ul><li>12 mos prospective study 9 severely obese T2DM patients LSG (SG; n = 39) or LRYGB (GBP; n = 52) </li></ul><ul><li>Matched for DM duration, type of DM treatment, and glycemic control </li></ul><ul><li>Results </li></ul><ul><ul><li>T2DM resolved 84.6% SG and (84.6%) GBP (p = 0.618) </li></ul></ul><ul><ul><li>Weight loss was not associated with T2DM resolution after SG or GBP </li></ul></ul><ul><ul><li>Shorter DM duration and DM treatment and glycemic control associated with both groups </li></ul></ul>Vidal et al , Type 2 Diabetes Mellitus and the Metabolic Syndrome Following Sleeve Gastrectomy in Severely Obese Subjects.. Obes. Surg. June 2008
    42. 42. <ul><li>SG is as effective as GBP in inducing remission </li></ul><ul><li>of T2DM and the MS. </li></ul><ul><li>SG and GBP represent a successful an integrated strategy for the management of the different cardiovascular risk components of the MS in subjects with T2DM </li></ul>2008: Vidal et al. RYGB vs SLEEVE Vidal et al, Type 2 Diabetes Mellitus and the Metabolic Syndrome Following Sleeve Gastrectomy in Severely Obese Subjects. Obes. Surg. 2008
    43. 43. <ul><li>Goal: </li></ul><ul><ul><li>Compare the effects of LRYGB to the effects of LSG on glycemcic control in morbidly obese </li></ul></ul><ul><li>13 pts randomized to LRYGB and 14 pts to LSG </li></ul><ul><li>Results: </li></ul><ul><ul><li>Markedly increased postprandial plasma insulin and GLP-1 level </li></ul></ul><ul><ul><li>LRYGB- early and augmented insulin responses within 1week </li></ul></ul><ul><ul><li>No significant difference in insulin and GLP-1 levels between two group after 3months . </li></ul></ul>Aug. 2009: Peterli
    44. 44. <ul><li>Conclusion </li></ul><ul><ul><li>Both procedures markedly improved glucose homeostasis </li></ul></ul><ul><ul><li>Lack of support for proximal small intestine mediating improvement in glucose homeostasis </li></ul></ul>2009: Peterli et al. RYGB vs SLEEVE Peterli et al. Improvement in glucose metabolism after bariatric surgery: comparison of laparoscopic Roux-en-Y gastric bypass and laparoscopic sleeve gastrectomy: a prospective randomized trial Ann Surg. 2009 Aug;250(2):234-41.
    45. 45. 2009: Kasama et al. DJB with SLEEVE <ul><li>Laparoscopic sleeve gastrectomy with Duodenojejunal bypass (SG/DJB) </li></ul><ul><li>Goal: </li></ul><ul><ul><li>Procedure without exclusion –allow better surveillance for gastric ca in high prevalence area (Asia) </li></ul></ul><ul><ul><li>Restrictive and malabsorptive procedure </li></ul></ul><ul><li>21 pts with mean BMI 41.0 kg/m2 </li></ul><ul><li>High risks of gastric cancer-H. pylori positive </li></ul>Kasama et al Laparoscopic Sleeve Gastrectomy with Duodenojejunal Bypass:. Obesity Surgery sept. 2009
    46. 46. 2009: Kasama et al. RYGB with SLEEVE <ul><li>Effective weight loss </li></ul><ul><ul><li>Reduction of ghrelin </li></ul></ul><ul><li>Resolution of Co-morbidities </li></ul><ul><ul><li>Similar outcome compare with RYGB </li></ul></ul><ul><li>T2DM resolution </li></ul><ul><ul><li>Adding the proximal intestinal exclusion compare to SG </li></ul></ul><ul><li>Avoid dumping phenomenon </li></ul><ul><ul><li>Preserve intergrity of latarjet nerve and pylorus </li></ul></ul>Kasama et al. Laparoscopic Sleeve Gastrectomy with Duodenojejunal Bypass:. Obesity Surgery sept. 2009
    47. 47. 2009: Kasama et al. DJB with SLEEVE <ul><li>LSG/DJB is feasible, safe, and effective procedure for treatment of morbidly obese patients with risk of gastric cancer </li></ul><ul><li>Effective in weight loss, resolution of co-morbid conditions and T2DM </li></ul><ul><li>Kasama et al Laparoscopic Sleeve Gastrectomy with Duodenojejunal Bypass:. Obesity Surgery sept. 2009 </li></ul>
    48. 48. Feb 2010: Schouten <ul><li>Objective: </li></ul><ul><ul><li>To determine the safety and efficacy of EndoBarrier Gastrointestinal Liner </li></ul></ul><ul><ul><ul><li>Duodenal-jejunal bypass sleeve </li></ul></ul></ul><ul><li>Designed to achieve weight loss in morbidly obese patients. </li></ul><ul><li>First European experience </li></ul><ul><ul><li>41 patients included </li></ul></ul><ul><ul><li>30 underwent sleeve implantation. </li></ul></ul><ul><ul><li>11 - diet control group. </li></ul></ul><ul><ul><li>All followed the same low-calorie diet during the study period. </li></ul></ul>
    49. 49. 2010: Schouten et al. Role of EndoBarrier <ul><li>26 devices were successfully implanted </li></ul><ul><ul><li>Mean procedure time -35 min (range: 12–102 min) </li></ul></ul><ul><ul><li>No procedure related adverse events. </li></ul></ul><ul><ul><li>Mean excess weight loss after 3 months </li></ul></ul><ul><ul><li>19.0% device vs 6.9% for control ( P < 0.002) </li></ul></ul><ul><li>Type 2 diabetes mellitus </li></ul><ul><ul><li>8 pts with baseline Type 2 diabetes mellitus </li></ul></ul><ul><ul><li>Improvement in 7 patients during the study period </li></ul></ul>Schouten et al. A multicenter, randomized efficacy study of the EndoBarrier Gastrointestinal Liner for presurgical weight loss prior to bariatric surgery. Ann Surg. 2010 Feb;251(2):236-43.
    50. 50. 2010: Schouten et al. Role of EndoBarrier Schouten et al. A multicenter, randomized efficacy study of the EndoBarrier Gastrointestinal Liner for presurgical weight loss prior to bariatric surgery. Ann Surg. 2010 Feb;251(2):236-43.
    51. 51. 2010: Schouten et al. Role of EndoBarrier <ul><li>The EndoBarrier Gastrointestinal Liner </li></ul><ul><ul><li>Feasible and safe noninvasive device </li></ul></ul><ul><ul><li>Excellent short-term weight loss results. </li></ul></ul><ul><li>Type 2 DM </li></ul><ul><ul><li>Significant positive effect </li></ul></ul><ul><ul><li>Long-term randomized and sham studies necessary </li></ul></ul>Schouten et al. A multicenter, randomized efficacy study of the EndoBarrier Gastrointestinal Liner for presurgical weight loss prior to bariatric surgery. Ann Surg. 2010 Feb;251(2):236-43.
    52. 52. The Nonobese Patient
    53. 53. <ul><li>39 patients underwent laparoscopic ileal interposition into proximal jejunum via sleeve or diverted sleeve gastrectomy </li></ul><ul><ul><li>BMI < 35 </li></ul></ul><ul><ul><li>All had type II DM for at least 3 years </li></ul></ul><ul><ul><ul><li>Mean operative time was 185 minutes </li></ul></ul></ul><ul><ul><ul><li>Mean post-op follow up was 7 months </li></ul></ul></ul><ul><li>87% of patients discontinued preop oral hypoglycemics, insulin or both </li></ul><ul><li>Hemoglobin A1c decreased from 8.8% to 6.3% </li></ul><ul><li>All but one patient experienced normalization of cholesterol </li></ul>2006: DePaula et al. BMI < 35 DePaula et al. Laparoscopic treatment of type 2 DM for patients with BMI less than 35. Surg. Endoscopy 2006
    54. 54. 2006: DePaula et al. BMI < 35 DePaula et al. Laparoscopic treatment of type 2 DM for patients with BMI less than 35. Surg. Endoscopy 2006
    55. 55. 2006: DePaula et al. BMI < 35 DePaula et al. Laparoscopic treatment of type 2 DM for patients with BMI less than 35. Surg. Endoscopy 2006
    56. 56. 2006: DePaula et al. BMI < 35 DePaula et al. Laparoscopic treatment of type 2 DM for patients with BMI less than 35. Surg. Endoscopy 2006
    57. 57. 2006: DePaula et al. BMI < 35 DePaula et al. Laparoscopic treatment of type 2 DM for patients with BMI less than 35. Surg. Endoscopy 2006 <ul><ul><li>Laparoscopic ileal interposition via either a sleeve gastrectomy or diverted sleeve gastrectomy seems to be a promising procedure for the control of T2DM and the metabolic syndrome </li></ul></ul>
    58. 58. 2006: Early results in Non-Obese Patients <ul><li>Slides taken from: DIABETES IS NO LONGER A HOPELESS DISEASE The Guilty Gut,Walter Pories, MD, FACS </li></ul>
    59. 59. <ul><li>First Clinical description of laparoscopic stomach-preserving DJB for treatment of T2DM </li></ul><ul><li>2 patients with >12 mos f/u (13/15 mos) </li></ul><ul><li>By 5 th week of surgery, both patients were euglycemic and free of all antidiabetic medications </li></ul><ul><li>Conclusion: </li></ul><ul><ul><li>LDJB is a feasible and safe </li></ul></ul><ul><ul><li>could represent valuable therapeutic option </li></ul></ul>2007: Cohen
    60. 60. CLINICAL TRIAL: Duodenal-Jejeunal Bypass for Type 2 Diabetes (DJBD) <ul><li>SUMMARY: </li></ul><ul><li>Clinical Evaluation of the Effect of Duodenal-Jejunal Bypass on Type 2 Diabetes </li></ul><ul><li>FACILITY: </li></ul><ul><li>Center for Advance Medicine </li></ul><ul><li>Santo Domingo, Dominican Republic </li></ul><ul><li>STUDY OFFICIALS/INVESTIGATORS: </li></ul><ul><li>George Ferzli, MD, FACS - Study Principal Investigator, </li></ul><ul><li>SUNY Downstate, Brooklyn, New York, USA </li></ul><ul><li>Abel Gonzalez, MD - Center for Advanced Medicine, </li></ul><ul><li>Santo Domingo, Dominican Republic </li></ul><ul><li>Martin Bluth, MD, PhD - Director of Research, Assistant Professor, </li></ul><ul><li>Departments of Surgery and Pathology, Brooklyn, NY, USA </li></ul>
    61. 61. Dominican Republic 2007 <ul><li>Prospective controlled clinical trial </li></ul><ul><li>Seeking to recruit total of 50 patients </li></ul><ul><li>www.clinicaltrials.gov </li></ul><ul><li>Unique Protocol ID: AS07006 </li></ul><ul><li>Clinicaltrials.gov ID: NCT00487526 . </li></ul>
    62. 62. Lutheran Medical Center Clinical Trial 2008 <ul><li>Prospective study </li></ul><ul><li>Seeking to recruit total of 50 patients </li></ul><ul><li>www.clinicaltrials.gov </li></ul><ul><li>ID: NCT00694278, LMC 95 </li></ul>
    63. 64. Clinical Trial Eligibility Inclusion Criteria <ul><li>Adults age 20-65 </li></ul><ul><li>Clinical diagnosis of type II diabetes: </li></ul><ul><ul><li>a) A normal or high C-peptide level (to exclude type 1 diabetes) (>.9ng/ml) </li></ul></ul><ul><ul><li>b) A random plasma glucose of 200mg/dl or more with typical symptoms of diabetes </li></ul></ul><ul><ul><li>c)A fasting plasma glucose of 126mg/dl or more on more than one occasion </li></ul></ul><ul><li>BMI 22-34 KG/m2, </li></ul><ul><li>Patients on oral hypoglycemic medications or insulin to control T2DM Inadequate control of diabetes as defined as HbA1c>7.5 </li></ul><ul><li>No contraindications for surgery or general anesthesia </li></ul><ul><li>Ability to understand and describe the mechanism of action and risks and benefits of the operation </li></ul>
    64. 65. Clinical Trial Eligibility Exclusion Criteria <ul><li>Diagnosis of type 1 diabetes </li></ul><ul><li>Planned pregnancy within 2 years of entry into the study </li></ul><ul><li>Previous gastric or esophageal surgery, immunosuppressive drugs including corticosteroids, coagulopathy, anemia, any contraindication to laparoscopic gastric bypass or medical hypoglycemic therapy </li></ul><ul><li>Severe concurrent illness likely to limit life (e.g. cancer) or requiring extensive disorder (e.g. pancreatic insufficiency, Celiac sprue, or Crohn’s disease) </li></ul><ul><li>Pre-existing major complications of diabetes, significant proteinuria (>250mg/dl), severe proliferate retinopathy, severe neuropathy or clinical diagnosis of gastropathy </li></ul><ul><li>MI in the previous year </li></ul><ul><li>Unable to comply with study requirements, follow-up or give verbal consent </li></ul><ul><li>Liver cirrhosis </li></ul><ul><li>Previous abdominal surgery </li></ul>
    65. 66. Preoperative work up <ul><li>Detailed informed consent explain to patient and </li></ul><ul><li>Baseline assessment by multidisciplinary surgical team </li></ul><ul><ul><li>Surgeon, primary physician, endocrinologist, cardiologist, gastroenterologist, psychiatrist, nutritionist </li></ul></ul><ul><li>Routine work-up and blood work </li></ul><ul><ul><li>(CBC, electrolytes, serum creatinine, fasting glucose, HbA 1c , fasting lipid profile (HDL and LDL cholesterol, triglycerides), free fatty acids, leptin, insulin like growth factor 1 (ILGF-1), Glucagon, Glucagon-like peptide 1 (GLP-1), CCK, FFA, Cholesterol, Ghrelin, C-peptide and Gastro-inhibitory peptide (GIP) levels. ) </li></ul></ul><ul><li>Studies </li></ul><ul><ul><li>Electrocardiogram (ECG), chest radiograph, and Esophagogastroduodenoscopy (EGD), PFT’S (if indicated) </li></ul></ul>
    66. 67. Operative Course <ul><li>Laparoscopic Duodenal-Jejunal bypass under general anesthesia </li></ul><ul><li>Preoperative prophylaxis antibiotic (Ancef or Clinda in PCN allergy) </li></ul><ul><li>Sequential compression devices for deep venous thrombosis (DVT) prophylaxis in addition to LMWH (5,000units SQ). </li></ul><ul><li>Operative/Intraoperative data </li></ul><ul><ul><li>OR time, EBL, complications, unusual findings </li></ul></ul><ul><li>NPO until upper gastrointestinal (UGI) on POD#1 </li></ul><ul><li>Clear fluids are begun following the UGI study, and continue for 5-7 days </li></ul><ul><li>Patient follow up with nutritionist for dietary guidelines </li></ul>
    67. 68. Postoperative follow up <ul><li>Follow up with multidisciplinary team </li></ul><ul><ul><li>Surgeon, endocrinologist, primary care physician and nutritionist at 2 weeks, 4 weeks, 3 months, and from then on at intervals of 3 months or more often if necessary, for 2 years </li></ul></ul><ul><li>Blood drawn for fasting glucose and fasting insulin on days 2 and 7 and at 2 weeks and 4 weeks and 3 months after initiation of treatment </li></ul><ul><li>Nutritionist follow up – continue to puree diet </li></ul><ul><li>Attend support group </li></ul>
    68. 69. Outcomes/Measures <ul><li>The primary outcome </li></ul><ul><ul><li>Reversion of hyperglycemia to euglycemia (normalization of HbA 1c to <7%) </li></ul></ul><ul><li>Secondary outcomes </li></ul><ul><ul><li>Hypogycemic agents, Clinical symptoms and lipid profile. </li></ul></ul>
    69. 70. Results <ul><li>Overall, no complications were observed that in any way stemmed from the procedure. </li></ul><ul><li>One patient developed a liver abscess six months later </li></ul><ul><ul><li>required drainage. </li></ul></ul><ul><li>All patients consistently felt relief from their preoperative symptoms. </li></ul>
    70. 71. 2009: Ferzli et al
    71. 72. 2009: Ferzli et al
    72. 73. 2009: Ferzli et al. Results at 12 months <ul><li>A ll subjects consistently felt relief from fatigue, pain and/or numbness in the extremities, polyuria, and polydypsia. </li></ul><ul><li>Clinical resolution was obtained for one patient, and the preoperative diabetic medication requirements decreased for most of the other patients. </li></ul><ul><li>The subjects demonstrated an overall improved HbA1c (from 9.4% to 8.5%) and fasting blood glucose level (from 209 to 154 mg/dl). </li></ul>
    73. 74. 2009: Ferzli et al. Conclusions <ul><li>Clinical improvement was obvious in all of our seven patients </li></ul><ul><li>LDJB may not be effective at inducing remission of T2DM and the MS in certain patients undergoing this operation. </li></ul><ul><li>Larger patient studies should be conducted </li></ul><ul><li>Longer follow-up is required for better evaluation. </li></ul>
    74. 76. SAGES 2008 <ul><li>35 patients T2DM for 2-10 years, underwent LDJB </li></ul><ul><li>April-Nov 07 </li></ul><ul><li>15 women, 20 men </li></ul><ul><li>Comorbidities </li></ul><ul><ul><li>75% with HTN </li></ul></ul><ul><ul><li>58% Hypercholesteremia </li></ul></ul><ul><ul><li>62.5% Hypertriglyceremia </li></ul></ul><ul><li>Mean OR time = 46 minutes (33-78 min) </li></ul><ul><li>Hospital stay 30 hrs –81 days </li></ul><ul><li>PPI for 90 days </li></ul><ul><li>Patients kept on metformin/glimeperide (metformin withdrawn when HBA1c <6) </li></ul>Cohen, Duodenojejunal bypass for the treatment of T2DM in patients with BMI from 22 to 34. (Nevis).
    75. 77. Complications <ul><li>1 death </li></ul><ul><li>2 intestinal obstruction </li></ul><ul><li>1 post-operative pancreatitis </li></ul><ul><li>2 intracavitary bleeding </li></ul>Cohen, Duodenojejunal bypass for the treatment of T2DM in patients with BMI from 22 to 34. (Nevis).
    76. 78. Results <ul><li>HbA1c decreasing from 8.9 to 6.1 and 72.3% </li></ul><ul><li>72.3% of patients had control of their hypertension: reduced sympathetic outflow? </li></ul><ul><li>13/35 patients reported food intolerance: 8/13 required admission (no women) </li></ul><ul><li>Oral Ginger and sildenafil are very helpful </li></ul><ul><li>75% complained of post-prandial sleepiness </li></ul><ul><ul><li>These side effects may be attributed to gastroparesis and the postulated diminished sympathetic outflow, a result of central leptin suppression and duodenal bypass </li></ul></ul>Cohen, Duodenojejunal bypass for the treatment of T2DM in patients with BMI from 22 to 34. (Nevis)
    77. 79. Geloneze et al. Surgery for Nonobese Type 2 Diabetic Patients: An Interventional Study with Duodenal-Jejunal Exclusion Obesity Surgery:2009 <ul><li>24 weeks prospective trial </li></ul><ul><li>Open (GJB) vs. control group on standard medical care </li></ul><ul><li>T2DM <15yrs, BMI (25-29.9kg/m2) </li></ul>DePaula AL. et al. Laparoscopic treatment of type 2 DM for patients with BMI less than 35. Surg. Endosc.
    78. 80. 2009: Geloneze et al . <ul><li>Results: </li></ul><ul><ul><li>Fasting FG </li></ul></ul><ul><ul><ul><li>14% vs. 7% on CG </li></ul></ul></ul><ul><ul><li>A1C </li></ul></ul><ul><ul><ul><li>8.78->7.84 (p<0.01) </li></ul></ul></ul><ul><ul><li>Daily Insulin requirement </li></ul></ul><ul><ul><ul><li>93% vs. 29% (p<0.01) </li></ul></ul></ul>Geloneze et al. Surgery for Nonobese Type 2 Diabetic Patients: An Interventional Study with Duodenal-Jejunal Exclusion Obesity Surgery:2009
    79. 81. 2009: Geloneze et al Geloneze et al. Surgery for Nonobese Type 2 Diabetic Patients: An Interventional Study with Duodenal-Jejunal Exclusion Obesity Surgery:2009 <ul><ul><li>Duodenal-Jejunal bypass (DJB) </li></ul></ul><ul><ul><ul><li>Effective treatment for nonobese T2DM subjects superior to standard care in achieving better glycemic control. </li></ul></ul></ul>
    80. 82. Interim Conclusions <ul><li>Very promising initial experience. </li></ul><ul><li>The vast majority of insulin users do not use it anymore very early in the post-op. </li></ul><ul><li>In most of those patients with overweight or grade 1 obesity, weight loss is not a major player regarding the control of T2DM, as some had no weight modification or regained weight and there was no recurrence. </li></ul><ul><li>In patients with higher BMIs, but still under 35 (32-35), it seems that major weight loss is needed to achieve control of T2DM. </li></ul>
    81. 83. Interim Conclusions <ul><li>What are the correct inclusion/exclusion criteria? Should we cut off at 8, 9, 10 years? </li></ul><ul><li>Time of T2DM history does not seem important, but C peptide below 1 YES!!! </li></ul>
    82. 84. Interim Conclusions <ul><li>What are the appropriate limb lengths? 50/80? </li></ul><ul><li>Do we need complex operations in this subset of patients? </li></ul><ul><ul><li>Are the mortality/ complication rates reasonable? </li></ul></ul><ul><li>Will an added sleeve gastrectomy in selected patients be needed to avoid gastroparesis ? </li></ul>
    83. 85. The Diabetes Surgery Summit Consensus Conference Rubino et al. Annals of Surgery. Vol 251, Number3,300-405, March 2010 45% of type 2 patients with diabetes world-wide demonstrate a BMI less than 30 ADA : “ Bariatric Surgery should be considered for adults with BMI > 35Kg/m2 And type 2 diabetes ,especially if the diabetes is difficult to control with lifestyle And pharmacologic therapy
    84. 86. The Surgeon and the Diabetologists
    85. 87. Acknowledgements <ul><li>Kell Juliard </li></ul><ul><li>Martin Bluth, MD, PhD </li></ul><ul><li>Giancarlo Cires, MD </li></ul><ul><li>Rosemarie E Hardin, MD </li></ul><ul><li>Joel Ricci, MD </li></ul>
    86. 88. What The Future Holds? <ul><li>Zhou et al. In vivo reprogramming of adult pancreatic cells to B-cells. Nature. October 2008 </li></ul><ul><li>Transcription factors Ngn3, Pdx1 and Mafa reprograms differentiated pancreatic cells in adult mice into cells that closely resemble Beta cells… </li></ul><ul><li>Department of Stem Cell and Regenerative Biology, Howard Hughes Medical Institute, Harvard University. </li></ul>
    87. 89. Interim Conclusions <ul><li>Don ’t rush to withdraw medication. </li></ul><ul><li>We add an incretin effect, but METFORMIN helps to decrease hepatic defective glucose production. </li></ul><ul><li>What is the antidiabetes mechanism? </li></ul><ul><li>Cold pressor test before and after duodenal exclusion to assess sympathetic response ? </li></ul>

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