Surgery for Obesity: Duodeno-Jejunal Bypass for Type 2 Diabetes in Non-Obese – a Cure ? George S. Ferzli, MD, FACS Chairma...
Derived from Center for Disease Control and Prevention website www.cdc.gov Percent of Obese (BMI ≥ 30) in US Adults
Derived from Center for Disease Control and Prevention website www.cdc.gov Percent of Obese (BMI ≥ 30) in US Adults
<ul><li>National Hospital Discharge Survey Public-use data file and documentation. Multi-year data CD-ROM. National Center...
Current Procedures
Metabolic Syndrome <ul><li>Also Known as: </li></ul><ul><li>1. Syndrome “X” </li></ul><ul><li>2. Insulin Resistance Syndro...
Obesity Associated Conditions Diabetes Hypertension Sleep apnea Congestive heart failure Hyperlipidemia Stroke Coronary ar...
Diabetes <ul><li>Considered major public health problem – emerging as a world wide pandemic. In 1995 ~ 135 million people ...
Prevalence of Diabetes <ul><li>From 1980 through 2005, the number of adults aged 18-79 with newly diagnosed diabetes almos...
<ul><li>Buchwald H, Avidor Y, Braunwald E, Jensen MD, Pories W, Fahrbach K, et al. Bariatric surgery: a systematic review ...
Schauer et al. Effect of laparoscopic Roux-en Y gastric bypass on type 2 diabetes mellitus.   Ann Surg. 2003 Oct; 238(4): ...
Biliopancreatic Diversion (BPD) <ul><li>312 BPD, obese patients with type 2 DM were followed for pre and postoperative ser...
Dixon et al. Adjustable Gatric Banding and conventional therapy for type 2 diabetes: a randomized control trial  JAMA 2008...
Dixon et al. Adjustable Gatric Banding and conventional therapy for type 2 diabetes: a randomized control trial  JAMA 2008...
Rates of Remission of Diabetes Adjustable Gastric Banding Roux-en-Y Gastric Bypass Biliopancreatic Diversion >95% (Immedia...
<ul><li>“ Gastric bypass and biliopancreatic diversion  </li></ul><ul><li>seem to achieve control of diabetes as a primary...
1995-“Who Would Have Though It? Pories et al. Annals of Surgery  <ul><li>NIDDM is no longer an uncontrollable disease </li...
Historical Perspective <ul><li>1955- Friedman  </li></ul><ul><ul><li>3  patients with poorly control DM  </li></ul></ul><u...
Rehfeld J, 2004 1967 – Gastric Bypass DISCOVERY OF GASTROINTESTINAL HORMONES
How Does Bariatric Surgery  Effect glucose homeostasis? <ul><li>Intestinal Malabsorption? </li></ul><ul><ul><li>Weight los...
1. Pathophysiology DIABETES OBESITY <ul><ul><ul><li>Excess adipose tissue increases </li></ul></ul></ul><ul><ul><ul><li>av...
2. Hormonal Changes after Bariatric Surgery
GIP and GLP-1 <ul><li>Stimulated by enteral nutrients </li></ul><ul><li>insulin secretion / action </li></ul><ul><li> -ce...
Hypothesis <ul><ul><ul><li>Rubino et al;  Ann. Surg. 2002 </li></ul></ul></ul>
Anti-Incretin Insulin resistance Beta cell depletion Hyperglycemia Too Much Dumping Syndrome Nesidioblastosis Hyperinsulin...
Hypothesis <ul><ul><ul><li>Rubino et al;  Ann. Surg.  2002 </li></ul></ul></ul>
Slides taken from: DIABETES IS NO LONGER A HOPELESS DISEASE The Guilty Gut Walter Pories, MD, FACS,  Chief, Metabolic Inst...
Slides taken from: DIABETES IS NO LONGER A HOPELESS DISEASE The Guilty Gut Walter Pories, MD, FACS,  Chief, Metabolic Inst...
2006: “ This study shows that bypassing a short segment  of proximal intestine directly ameliorates type 2 diabetes,  inde...
<ul><li>Bariatric Surgery clearly has an antidiabetic effect </li></ul><ul><li>Direct effect of the surgical bypass of pro...
Animal Model of DJ Bypass and Glycemic Control <ul><li>Animal Model of non-obese type 2 diabetes; Goto-Kakizaki rats </li>...
2007-  Results of DJ Bypass on Glycemic Control <ul><li>Group 1 and Group 2 rats remained the same weight during the exper...
Leptin??? <ul><li>Adipocyte-derived hormone </li></ul><ul><li>In mice, leptin acts as a hormonal signal on the afferent li...
Cohen -SAGES 2008
Cohen -SAGES 2008
Cohen -SAGES 2008
<ul><ul><li>Double blind study: 16 patients assigned to LRYGBP and 16 Pts to LSG  </li></ul></ul><ul><ul><li>Patients reev...
<ul><li>“ PYY levels increased similarly after either procedure.  </li></ul><ul><li>The markedly reduced ghrelin levels in...
Vidal et al. Type 2 Diabetes Mellitus and the Metabolic Syndrome Following Sleeve Gastrectomy in Severely Obese Subjects. ...
<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 G...
Non-Obese Patients <ul><li>Slides taken from:  DIABETES IS NO LONGER A HOPELESS DISEASE The Guilty Gut,Walter Pories, MD, ...
<ul><li>First Clinical description of laparoscopic stomach-preserving DJB for treatment of T2DM in non-obese </li></ul><ul...
<ul><li>39 patients underwent laparoscopic ileal interposition into proximal jejunum via sleeve or diverted sleeve gastrec...
DePaula AL. et al. Laparoscopic treatment of type 2 DM for patients with BMI less than 35.  Surg. Endosc. <ul><li>Conclusi...
CLINICAL TRIAL: Duodenal-Jejeunal Bypass for Type 2 Diabetes (DJBD)  <ul><li>SUMMARY: </li></ul><ul><li>Clinical Evaluatio...
Dominican Republic 2007 <ul><li>Prospective controlled clinical trial </li></ul><ul><li>Seeking to recruit total of 50 pat...
Lutheran Medical Center Clinical Trial 2008 <ul><li>Prospective study </li></ul><ul><li>Seeking to recruit total of 50 pat...
Clinical Trial Eligibility Inclusion Criteria <ul><li>Adults age 20-65  </li></ul><ul><li>Clinical diagnosis of type II di...
Clinical Trial Eligibility Exclusion Criteria <ul><li>Diagnosis of type 1 diabetes </li></ul><ul><li>Planned pregnancy wit...
Preoperative work up <ul><li>Detailed informed consent explain to patient. </li></ul><ul><li>Baseline assessment by multid...
Operative Course <ul><li>Laparoscopic Duodenal-Jejunal bypass under GETA  </li></ul><ul><li>Preoperative prophylaxis antib...
Postoperative follow up <ul><li>Follow up with multidisciplinary team </li></ul><ul><ul><li>Surgeon, endocrinologist, prim...
Outcomes/Measures <ul><li>The primary outcome </li></ul><ul><ul><li>Reversion of hyperglycemia to euglycemia (normalizatio...
Clinical Evaluation of the Effect of Duodenal-Jejunal Bypass on Type 2 Diabetes  (June 2007) Results <ul><li>LDJB was perf...
Clinical Evaluation of the Effect of Duodenal -Jejunal  Bypass on Type 2 Diabetes (June 2007) Patient Demographic, June 6,...
Morbidity <ul><li>Initial symptoms included nausea and vomiting </li></ul><ul><ul><li>resolved in all patients by 3 months...
Clinical Evaluation of the Effect of Duodenal-Jejunal Bypass on Type 2 Diabetes  (June 2007) Results <ul><li>HBA1c, Fastin...
Data Results Clinical Evaluation of the Effect of Duodenal-Jejunal  Bypass on Type 2 Diabetes ( June 2007)
Clinical Evaluation of the Effect of Duodenal-Jejunal Bypass on Type 2 Diabetes (June 2007)   Table 2   N Correlation Sig....
!!! <ul><li>One patient required insulin preop, at 6 months she was no longer on insulin and all lab work was normal </li>...
!!! <ul><li>Our Study- 1 year follow-up </li></ul><ul><li>5 patients (71%) T2DM > 10 years (10-19) </li></ul><ul><li>1 pre...
!!! <ul><li>2 patients with c-peptide <1, the HbA1c increased following the procedure </li></ul>
 
SAGES 2008 <ul><li>35 patients T2DM for 2-10 years l underwent LDJB </li></ul><ul><li>April-Nov 07 </li></ul><ul><li>15 wo...
Complications <ul><li>1 death  </li></ul><ul><li>2 intestinal obstruction </li></ul><ul><li>1 pos-operative pancreatitis <...
Results <ul><li>HbA1c decreasing from 8.9 to 6.1. </li></ul><ul><li>72.3% of patients had control of their hypertension: r...
Interim Conclusions <ul><li>Very promising initial experience.  </li></ul><ul><li>The vast majority of insulin users do no...
Interim Conclusions <ul><li>What are the correct inclusion/exclusion criteria? Should we cut off at 8, 9, 10 years? </li><...
Interim Conclusions <ul><li>Don ’t  rush to withdraw medication.  </li></ul><ul><li>We add an incretin effect, but METFORM...
Interim Conclusions <ul><li>What are the appropriate limb lengths? 50/75/80? </li></ul><ul><li>Is it necessary to bypass t...
The Surgeon and the Diabetologists
 
Acknowledgements <ul><li>Kell Juliard </li></ul><ul><li>Martin Bluth, MD, PhD </li></ul><ul><li>Giancarlo Cires, MD </li><...
Upcoming SlideShare
Loading in …5
×

Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?

3,785 views

Published on

Published in: Health & Medicine

Surgery for Obesity Duodeno-Jejunal Bypass forType 2 Diabetes in Non-Obese - A Cure?

  1. 1. Surgery for Obesity: Duodeno-Jejunal Bypass for Type 2 Diabetes in Non-Obese – a Cure ? George S. Ferzli, MD, FACS Chairman of Surgery, Lutheran Medical Center Professor of Surgery, SUNY HSC Brooklyn, New York, USA
  2. 2. Derived from Center for Disease Control and Prevention website www.cdc.gov Percent of Obese (BMI ≥ 30) in US Adults
  3. 3. Derived from Center for Disease Control and Prevention website www.cdc.gov Percent of Obese (BMI ≥ 30) in US Adults
  4. 4. <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>
  5. 5. Current Procedures
  6. 6. Metabolic Syndrome <ul><li>Also Known as: </li></ul><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. 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. Diabetes <ul><li>Considered major public health problem – emerging as a world wide pandemic. In 1995 ~ 135 million people worldwide </li></ul><ul><li>Expected to rise to close to 300 million by 2025 </li></ul><ul><li>CDC (2008) cases of diabetes have increased to 15% in just the past two years </li></ul><ul><li>2002-Annual direct health care cost was estimated to be $132 billion in US </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>Retinopathy, ESRD </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. CDC website @ www.CDC.com </li></ul></ul>
  9. 9. Prevalence of Diabetes <ul><li>From 1980 through 2005, the number of adults aged 18-79 with newly diagnosed diabetes almost tripled from 493,000 in 1980 to 1.4 million in 2005 in the United States </li></ul><ul><li>Annual number (in thousands) of new cases of diagnosed diabetes among adults aged 18-79 years, United States, 1980–2005 </li></ul>
  10. 10. <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>
  11. 11. 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>
  12. 12. 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
  13. 13. Dixon et al. Adjustable Gatric Banding and conventional therapy for type 2 diabetes: a randomized control trial JAMA 2008 <ul><ul><li>Un-blinded randomized control trial </li></ul></ul><ul><ul><li>60 obese patients (BMI >30 & <40) with T2DM </li></ul></ul><ul><ul><li>Interventions : </li></ul></ul><ul><ul><li>- Conventional diabetes control with lifestyle modification vs. LAGB </li></ul></ul><ul><ul><li>Results: </li></ul></ul><ul><ul><ul><li>-55 (92%) completed with 2 year follow-up </li></ul></ul></ul><ul><ul><ul><li>-Remission of diabetes was achieved in 73% in surgical group and 13% in the conventional-therapy group </li></ul></ul></ul>
  14. 14. Dixon et al. Adjustable Gatric Banding and conventional therapy for type 2 diabetes: a randomized control trial JAMA 2008 <ul><ul><li>CONCLUSIONS: </li></ul></ul><ul><ul><ul><li>Participants randomized to surgical therapy were more likely to achieve remission of type 2 diabetes through greater weight loss. </li></ul></ul></ul><ul><ul><ul><li>These results need to be confirmed in a larger, more diverse population and have long-term efficacy assessed. </li></ul></ul></ul>
  15. 15. Rates of Remission of Diabetes Adjustable Gastric Banding Roux-en-Y Gastric Bypass Biliopancreatic Diversion >95% (Immediate) 48% (Slow) 84% (Immediate)
  16. 16. <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?
  17. 17. 1995-“Who Would Have Though 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>
  18. 18. Historical Perspective <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 (B2 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>
  19. 19. Rehfeld J, 2004 1967 – Gastric Bypass DISCOVERY OF GASTROINTESTINAL HORMONES
  20. 20. 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>Increased levels of glucagon-like peptide 1 (GLP-1) </li></ul></ul></ul><ul><ul><ul><li>Decrease in plasma levels of leptin & Grhelin </li></ul></ul></ul><ul><ul><ul><li>Increased levels of adiponectin & peptide YY3-36 </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>
  21. 21. 1. Pathophysiology 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. 2. Hormonal Changes after Bariatric Surgery
  23. 23. 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>3. Anti-Incretin Theory <ul><li>Stimulated by enteral nutrients </li></ul><ul><li>insulin secretion / action </li></ul><ul><li> -cell proliferation </li></ul>Anti-incretin
  24. 24. Hypothesis <ul><ul><ul><li>Rubino et al; Ann. Surg. 2002 </li></ul></ul></ul>
  25. 25. Anti-Incretin Insulin resistance Beta cell depletion Hyperglycemia Too Much Dumping Syndrome Nesidioblastosis Hyperinsulinemia Hypoglycemia Not Enough TYPE 2 DIABETES
  26. 26. Hypothesis <ul><ul><ul><li>Rubino et al; Ann. Surg. 2002 </li></ul></ul></ul>
  27. 27. 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:
  28. 28. 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:
  29. 29. 2006: “ 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
  30. 30. <ul><li>Bariatric Surgery clearly has an antidiabetic effect </li></ul><ul><li>Direct effect of the surgical bypass of proximal intestines </li></ul><ul><li>Hormonal Regulation of Glucose Metabolism </li></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 Bypass & Glucose Metabolism
  31. 31. Animal Model of DJ Bypass and Glycemic Control <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>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
  32. 32. 2007- Results of DJ Bypass on Glycemic Control <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
  33. 33. 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
  34. 34. Cohen -SAGES 2008
  35. 35. Cohen -SAGES 2008
  36. 36. Cohen -SAGES 2008
  37. 37. <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 LRYGBP 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>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. Karamanakos et al Ann Surg . 2008 Mar; 247(3): 401-7.
  38. 38. <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><ul><li>March 2008: Weight loss, appetite suppression, and changes in fasting and postprandial ghrelin and peptide-YY levels after </li></ul><ul><li>Roux-en-Y gastric bypass and sleeve gastrectomy: a prospective, double blind study. Karamanakos et al Ann Surg. 2008 Mar; </li></ul><ul><li>247(3): 401-7. </li></ul>March 2008:
  39. 39. Vidal et al. Type 2 Diabetes Mellitus and the Metabolic Syndrome Following Sleeve Gastrectomy in Severely Obese Subjects. Obes. Surg. June 2008 <ul><li>12 mos prospective study 9 severely obese T2DM patients LSG (SG; n = 39) or LRYGP (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>Shorter DM duration and DM treatment and glycemic control associated with both groups </li></ul></ul>
  40. 40. <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><ul><li>Type 2 Diabetes Mellitus and the Metabolic Syndrome Following Sleeve Gastrectomy in Severely Obese </li></ul><ul><li>Subjects. Obes. Surg. 2008, Vidal et al </li></ul>June 2008
  41. 41. Non-Obese Patients <ul><li>Slides taken from: DIABETES IS NO LONGER A HOPELESS DISEASE The Guilty Gut,Walter Pories, MD, FACS </li></ul>
  42. 42. <ul><li>First Clinical description of laparoscopic stomach-preserving DJB for treatment of T2DM in non-obese </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>
  43. 43. <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><li>Mean post-op follow up was 7 months </li></ul></ul><ul><ul><li>Mean operative time was 185 minutes </li></ul></ul><ul><ul><li>87% of patients discontinued preop oral hypoglycemics, insulin or both </li></ul></ul><ul><ul><li>Hemoglobin A1c decreased from 8.8% to 6.3% </li></ul></ul><ul><li>All but one patient experienced normalization of cholesterol </li></ul>DePaula AL. et al. Laparoscopic treatment of type 2 DM for patients with BMI less than 35. Surg. Endosc.
  44. 44. DePaula AL. et al. Laparoscopic treatment of type 2 DM for patients with BMI less than 35. Surg. Endosc. <ul><li>Conclusion: </li></ul><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>
  45. 45. 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 Advanced 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>
  46. 46. 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>
  47. 47. 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>
  48. 48. 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>
  49. 49. 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 gastroperesis </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 (those that involve the stomach and proximal bowel). </li></ul>
  50. 50. Preoperative work up <ul><li>Detailed informed consent explain to patient. </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>
  51. 51. Operative Course <ul><li>Laparoscopic Duodenal-Jejunal bypass under GETA </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/Intra-operative 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>
  52. 52. 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>
  53. 53. 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>- lipid profiles, and C-peptide </li></ul></ul>
  54. 54. Clinical Evaluation of the Effect of Duodenal-Jejunal Bypass on Type 2 Diabetes (June 2007) Results <ul><li>LDJB was performed successfully in 7 patients </li></ul><ul><li>Mean age of 43.3 range (33-52) </li></ul><ul><li>Limb was 75cm/75cm </li></ul><ul><li>Operative time average 98 min </li></ul><ul><li>Length of stay 3 days </li></ul>
  55. 55. Clinical Evaluation of the Effect of Duodenal -Jejunal Bypass on Type 2 Diabetes (June 2007) Patient Demographic, June 6, 2007
  56. 56. Morbidity <ul><li>Initial symptoms included nausea and vomiting </li></ul><ul><ul><li>resolved in all patients by 3 months post-operatively </li></ul></ul><ul><li>One patient developed a liver abscess </li></ul><ul><ul><li>required drainage unrelated to the procedure </li></ul></ul><ul><li>No deaths </li></ul>
  57. 57. Clinical Evaluation of the Effect of Duodenal-Jejunal Bypass on Type 2 Diabetes (June 2007) Results <ul><li>HBA1c, Fasting Blood Glucose (FBG), Triglycerides (TG), Cholesterol (Chol) and C-peptide (Cpep) were measured at pre-op and 1 year </li></ul><ul><li>The mean HBA1c at pre-op and 1 year was 9.371 and 8.500 respectively </li></ul><ul><li>FBG at pre-op and 1 year were 208 and 154 respectively for the seven patients (p=0.057) </li></ul><ul><li>Lipid profiles improved with lower total cholesterol levels and triglycerides 1 year </li></ul>
  58. 58. Data Results Clinical Evaluation of the Effect of Duodenal-Jejunal Bypass on Type 2 Diabetes ( June 2007)
  59. 59. Clinical Evaluation of the Effect of Duodenal-Jejunal Bypass on Type 2 Diabetes (June 2007) Table 2   N Correlation Sig. HBA1c Pre-op & HBA1c 1yr 7 -0.040 0.933 FBG Pre-op & FBG 1YR 7 0.74 0.057 Chol preop & Chol 1yr 7 0.632 0.128 TG pre-op & TG 1yr 7 -0.245 0.596 Cpep pre-op & Cpep 3 months 7 0.546 0.205
  60. 60. !!! <ul><li>One patient required insulin preop, at 6 months she was no longer on insulin and all lab work was normal </li></ul><ul><li>She became pregnant at 6 months following surgery </li></ul><ul><li>Her diabetes returned and her insulin requirement is at the pre-op level </li></ul><ul><li>It is unclear whether she had resolution of her T2DM or had developed gestational diabetes requiring insulin for her pregnancy at the 1-year follow-up </li></ul>
  61. 61. !!! <ul><li>Our Study- 1 year follow-up </li></ul><ul><li>5 patients (71%) T2DM > 10 years (10-19) </li></ul><ul><li>1 pre oral/insulin-free from medication at 1 yr </li></ul><ul><li>2 required less dosages </li></ul><ul><li>The remaining two diabetic patients with a clinical diagnosis greater than ten years still require their insulin and oral hypoglycemics. </li></ul><ul><li>All 5 patients –no symptoms and improved state of health </li></ul>
  62. 62. !!! <ul><li>2 patients with c-peptide <1, the HbA1c increased following the procedure </li></ul>
  63. 64. SAGES 2008 <ul><li>35 patients T2DM for 2-10 years l 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>
  64. 65. Complications <ul><li>1 death </li></ul><ul><li>2 intestinal obstruction </li></ul><ul><li>1 pos-operative pancreatitis </li></ul><ul><li>2 intracavitary bleeding </li></ul>
  65. 66. Results <ul><li>HbA1c decreasing from 8.9 to 6.1. </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>
  66. 67. 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>
  67. 68. 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>
  68. 69. 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>
  69. 70. Interim Conclusions <ul><li>What are the appropriate limb lengths? 50/75/80? </li></ul><ul><li>Is it necessary to bypass the entire duodenum? </li></ul><ul><ul><li>If yes, how can we assess that? </li></ul></ul><ul><ul><li>Does it make any difference? </li></ul></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, mainly in those with BMI>32? </li></ul><ul><ul><li>Or is a LRYGB more adequate? </li></ul></ul>
  70. 71. The Surgeon and the Diabetologists
  71. 73. 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>

×