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Is There a Role for Surgery in the Treatment of Diabetes
 

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 Is There a Role for Surgery in the Treatment of Diabetes Presentation Transcript

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