Metabolic Surgery
Stacy Brethauer, MD Staff Surgeon
Endocrinology and Metabolism Institute www.ccf.org/bariatricsurgery
(Diabetes Surgery)
Objectives
• Brief overview of Bariatric Surgery • What is Metabolic Surgery? • What is the evidence to support diabetes surgery?
• What are the current and future clinical applications of metabolic and diabetes surgery?
Within 5 years, will gastrointestinal surgery be
considered an acceptable option for the treatment of Type 2 Diabetes in the nonobese
patient?
Historical Perspective
Vertical Banded Gastroplasty (VBG)
Jejunoileal Bypass (JIB)
Bariatric Procedures Performed Today
Laparoscopic Adjustable Gastric Band
RouxenY Gastric Bypass
Early Postoperative Risks of Laparoscopic
Gastric Bypass
• Conversion to Open < 5% • Bleeding 0 5% • Wound infection 0 5% • Anastomotic Leak 1 4% • DVT 0 1.5% • PE 0 – 1.3%
Risks of Lap Banding
• Bleeding < 1% • Infection < 1% • Perforation < 0.5% • DVT / PE 0.1% • Erosion < 1% • Band Slip / Prolapse 5 – 10% • Port or Tubing problem <5%
Mortality after Lap Banding
• Review of international literature Mortality rate of 0.05%
(Chapman AE, Kiroff G, Game P, et al. Surgery 2004; 135(3):32651.)
Gastric Bypass Postoperative Mortality
• Study of 60,077 Californians undergoing gastric bypass between 1995 and 2004 found 30day mortality of 0.33%
• 54,878 patients from 2001 National Inpatient Sample had 0.4% mortality
Gastric Bypass Postoperative Mortality
• AHRQ Bariatric Surgery Utilization and Outcomes in 1998 and 2004 (Healthcare Cost and Utilization Project Brief # 122)
• Ninefold increase in procedures during six year period
• National inpatient death rated associated with bariatric surgery declined by 78%
• From 0.89% in 1998 to 0.19% in 2004
Bariatric Surgery A Systematic Review and Metaanalysis
• Excess Weight Loss – All Patients: 61.2% (58.1%64.4%) – Gastric Banding 47.5% (40.7%54.2%) – Gastric bypass 61.6% (56.7%66.5%) – Gastroplasty 68.2% (61.5%74.8%) – BPD/DS 70.1% (66.3%73.9%)
• Operative mortality ( 30 days) – Restrictive procedures 0.1% – Gastric bypass 0.5% – BPD/DS 1.1%
–
Buchwald et al. JAMA. 2004;292:17241737
Metabolic Syndrome
Metabolic Syndrome • Abdominal obesity
waist circumference > 102 cm men, >88 cm women
• Fasting blood glucose > 110 mg/dl
• Hypertriglyceridemia > 150 mg/dl
• Low HDLcholesterol (<40 mg/dl men, < 50 mg/dl women)
• Hypertension (> 130/ >85)
54 million Americans!
The expanded Metabolic Syndrome
Type 2 diabetes
NASH
Hypertension
OSA
PCOS
Dyslipidemia
Insulin Resistance
Central Obesity
How Would You Manage This Patient?
• Obesity • Hypertension • Dyslipidemia • Type 2 Diabetes
• Nonalcoholic steatohepatitis (NASH)
• Obstructive sleep apnea • Left ventricular hypertrophy
Comorbidity Resolution According to Procedure
86% 92% 80% 78% 95% Resolution of Sleep Apnea
62% 83% 68% 69% 43% Resolution of Hypertension
79% 99% 97% 74% 59% Resolution of Hyperlipidemia
77% 99% 84% 72% 48% Resolution of DM
NR 1.1% 0.5% 0.1% Mortality
61% 70% 62% 68% 47% EWL
Total BPD or DS Gastric Bypass
Gastroplasty Gastric Banding
Buchwald et al. JAMA. 2004;292:17241737
Comorbidity Resolution According to Procedure
86% 92% 80% 78% 95% Resolution of Sleep Apnea
62% 83% 68% 69% 43% Resolution of Hypertension
79% 99% 97% 74% 59% Resolution of Hyperlipidemia
77% 99% 84% 72% 48% Resolution of DM
NR 1.1% 0.5% 0.1% Mortality
61% 70% 62% 68% 47% EWL
Total BPD or DS Gastric Bypass
Gastroplasty Gastric Banding
Buchwald et al. JAMA. 2004;292:17241737
Comorbidity Resolution According to Procedure
86% 92% 80% 78% 95% Resolution of Sleep Apnea
62% 83% 68% 69% 43% Resolution of Hypertension
79% 99% 97% 74% 59% Resolution of Hyperlipidemia
77% 99% 84% 72% 48% Resolution of DM
NR 1.1% 0.5% 0.1% Mortality
61% 70% 62% 68% 47% EWL
Total BPD or DS Gastric Bypass
Gastroplasty Gastric Banding
Buchwald et al. JAMA. 2004;292:17241737
Comorbidity Resolution According to Procedure
86% 92% 80% 78% 95% Resolution of Sleep Apnea
62% 83% 68% 69% 43% Resolution of Hypertension
79% 99% 97% 74% 59% Resolution of Hyperlipidemia
77% 99% 84% 72% 48% Resolution of DM
NR 1.1% 0.5% 0.1% Mortality
61% 70% 62% 68% 47% EWL
Total BPD or DS Gastric Bypass
Gastroplasty Gastric Banding
Buchwald et al. JAMA. 2004;292:17241737
Nonalcoholic fatty liver disease (NAFLD)
14.5 + 9 Time interval to 2 nd biopsy (months)
28% 4: 49% 3: 23% ASA Class 2: 34 (44%) Male sex (%) 47 + 9 Age (in years) 70 Number of patients
Inflammation
0
5 10
15
20 25
30
35 40
45
0 1 2 3 4
1st Bx 2nd Bx
P =<0.001
Score
n
Pre and Postoperative clinical characteristics of patients (=70)
Preoperative Postoperative p value Weight (lbs) 339.1± 72.2 235.5 ± 66.8 <0.001 BMI (kg/m 2 ) 56.0 ± 10.6 38.5 ± 10.3 <0.001
Systolic blood pressure (mm Hg) 134 ± 15 124 ± 14 <0.001 Diastolic blood pressure (mm Hg) 79 ± 9 75 ± 11 0.006 Plasma glucose (mg/dl) 138.5 ± 55.0 98.3 ± 24.6 <0.001 HbA1c (%) 7.69 ± 1.68 5.91 ± 1.11 <0.001 Total cholesterol (mg/dl) 201.4 ± 47.5 173.2 ± 39.3 <0.001 Triglycerides (mg/dl) 170.7 ± 82.8 109.9 ± 51.4 <0.001 HDLC (mg/dl) 44.8 ± 11.5 47 ± 13.1 0.04 LDLC (mg/dl) 121 ± 41.9 108.1 ± 35.0 0.005 AST (IU/l) 30.9 ± 17.9 24.2 ± 11.1 0.003 ALT (IU/l) 37.3 ± 19.0 32.7 ± 19.1 0.06 Albumin (g/dl) 3.87 ± 0.31 3.81 ± 0.36 0.19 Data are presented as mean ± standard deviation and n (%)
Polycystic ovary syndrome
Before and After Bariatric Surgery
Metabolic Surgery • Treatment of metabolic derangements with alterations of the gut anatomy
• Emphasis off weight loss and on the improvement of metabolic conditions resulting from these interventions, particularly the remission of diabetes
Gastrointestinal Metabolic Surgery
Francesco Rubino, MD Director of the Diabetes Surgery Center Chief, Gastrointestinal Metabolic Surgery NewYorkPresbyterian Hospital/Weill Cornell Medical Center
With the section of Gastrointestinal Metabolic Surgery headed by Francesco Rubino, MD, a pioneer in the field of diabetes surgery, NewYorkPresbyterial Hospital/Weill Cornell Medical Center, has become the first academic medical center in U.S. and worldwide to offer a dedicated and highly specialized approach to surgical treatment of type 2 diabetes.
What is the Evidence to Support the Concept of Diabetes Surgery?
Rates of Remission of Diabetes
Adjustable Gastric Banding
RouxenY Gastric Bypass
Biliopancreatic Diversion
>95% (Immediate)
48% (Slow)
84% (Immediate)
DISCOVERY OF GASTROINTESTINAL HORMONES DISCOVERY OF GASTROINTESTINAL HORMONES
Rehfeld Rehfeld J, 2004 J, 2004
1. Enhanced secretion of 1. Enhanced secretion of something good something good for for glucose homeostasis ? glucose homeostasis ?
2. Reduced production of 2. Reduced production of something bad something bad for glucose for glucose homeostasis ? homeostasis ?
Mechanisms of Diabetes Resolution after Gastrointestinal Bypass
Surgery
or or
Mechanisms of diabetes control after RYGB Mechanisms of diabetes control after RYGB
Nutrients reach the distal ileum Nutrients reach the distal ileum within 5 min of the ingestion of within 5 min of the ingestion of food and this stimulates the food and this stimulates the secretion of GLP secretion of GLP 1 by L 1 by L cells cells located in this area located in this area
Mason E. Obes Surg 2005 15, 459 Mason E. Obes Surg 2005 15, 459 461 461
Distal Distal bowel hypothesis bowel hypothesis
Mechanisms of Surgical Treatment of T2D Mechanisms of Surgical Treatment of T2D
The exclusion of the duodenal The exclusion of the duodenal nutrient passage may offset an nutrient passage may offset an abnormality of gastrointestinal abnormality of gastrointestinal physiology responsible for physiology responsible for insulin resistance and type 2 insulin resistance and type 2 diabetes diabetes
Proximal Proximal bowel hypothesis bowel hypothesis
Is there an increase in anorectic peptides if the distal gut is given greater exposure to nutrients?
Strader et al. Am J Physiol Endocrinol Metab 2005
Strader et al. Am J Physiol Endocrinol Metab 2005
• IT rats had less food intake
• IT rats lost more weight
Strader et al. Am J Physiol Endocrinol Metab 2005
• IT rats had 3x higher GLP1 levels than controls
• No difference in GTT • IT rats were more insulinsensitive than sham
Strader et al. Am J Physiol Endocrinol Metab 2005
IT rats had increased PYY levels
Strader et al. Am J Physiol Endocrinol Metab 2005
• Suggests that procedures that promote gastrointestinal endocrine function (GLP1, PYY) can reduce energy intake
Biliopancreatic diversion in rats is associated with intestinal hypertrophy and with increased GLP1, GLP
2 and PYY levels. Borg CM, le Roux CW, Ghatei MA, Bloom SR, Patel AG.
Obes Surg. 2007 Sep;17(9):11938.
• Increased PYY, GLP1, GLP2, small bowel mucosal mitotic activity in BPD rats compared to shams.
Gut hormones as mediators of appetite and weight loss after RouxenY gastric bypass.
le Roux CW, Welbourn R, Werling M, et al. Ann Surg. 2007 Nov;246(5):7805.
– Correlated peptide YY (PYY) and glucagonlike peptide 1 (GLP1) changes within the first week after gastric bypass with changes in appetite • Postprandial PYY and GLP1 profiles start rising as early as 2 days after gastric bypass (P < 0.05).
• Changes in appetite are evident within days after gastric bypass surgery (P < 0.05), and unlike other operations, the reduced appetite continues.
Mechanisms of recovery from type 2 diabetes after malabsorptive bariatric surgery. Guidone C, Manco M, ValeraMora E, et al. Diabetes. 2006 Jul;55(7):202531. Links
– 10 diabetic morbidly obese subjects before and shortly after biliopancreatic diversion (BPD) • Insulin sensitivity, insulin secretion, and circulating levels of intestinal incretins and adipocytokines were studied
• Diabetes disappeared 1 week after BPD, while insulin sensitivity at 1 week and 4 weeks was fully normalized.
• Fasting insulin secretion rate and total insulin output dramatically decreased, while a significant improvement in betacell glucose sensitivity was observed.
• Both fasting and glucosestimulated gastrointestinal polypeptide decreased, while glucagonlike peptide 1 significantly increased.
• 13 BMImatched controls • 10 Lap Band patients 2 yrs postop • 13 RYGB patients 2 yrs postop • All subjects nondiabetic • 474 ml Optifast with blood draw at 30, 60, 90, 120, 180 minutes
January 2004 January 2004
Goto Goto Kakizaki Rat (GK) Kakizaki Rat (GK)
Animal model of type 2 Animal model of type 2 diabetes diabetes – – The most The most widely used widely used lean model in type 2 lean model in type 2 diabetes research diabetes research ( (Nature Genet 1996 Nature Genet 1996) )
• • Non Non obese obese • • Normolipidemic Normolipidemic • • Hyperinsulinism Hyperinsulinism • • Insulin resistance Insulin resistance
Duodenal Duodenal Jejunal Bypass (DJB) Jejunal Bypass (DJB)
P=0.001 P=0.001
OGTT (DJB RATS)
0
50
100
150
200
250
300
350
400
450
Baseline 10 min 30 min 60 min 120 min 180 min
mg/dl
Preop 1 week p.o.
42% reduction of AUC (P<0.001)
Results Results
OGTT
0 50 100 150 200 250 300 350 400 450
Baseline 10 min 30 min 60 min 120 min 180 min
Diet
Bypass
Sham
P<0.001
Results Results
DJB in nondiabetic rats OGTT Wistar rats
60 70 80 90 100 110 120 130
0 20 40 60 80 100 120 140 160 180
T ime (min)
W Sham
Annals of Surgery Nov 2006 Annals of Surgery Nov 2006
DJB in nondiabetic rats OGTT Wistar rats
60
80
100
120
140
160
0 20 40 60 80 100 120 140 160 180
T ime (min)
W DJB W Sham
P=0.02 P=0.02
Annals of Surgery Nov 2006 Annals of Surgery Nov 2006
Is GI Bypass Surgery Is GI Bypass Surgery Fixing What is Broken ? Fixing What is Broken ?
November 2006 November 2006
Gastro Gastro jejunal Anastomosis jejunal Anastomosis
Early Ileal Stimulation Early Ileal Stimulation
Annals of Surgery Nov 2006 Annals of Surgery Nov 2006
(GJA) (GJA) DJB DJB
Sham +
PF to DJB
Annals of Surgery Nov 2006 Annals of Surgery Nov 2006
OGTT GK rats
0
100
200
300
400
500
600
0 50 100 150 200
Time (min)
Gluco
se le
vels (m
g/dl)
GK Sham
Oral Glucose Tolerance
Annals of Surgery Nov 2006 Annals of Surgery Nov 2006
OGTT GK rats
0
100
200
300
400
500
600
0 50 100 150 200
Time (min)
Gluco
se le
vels (m
g/dl)
GK DJB
GK Sham
Oral Glucose Tolerance
Annals of Surgery Nov 2006 Annals of Surgery Nov 2006
OGTT GK rats
0
100
200
300
400
500
600
0 50 100 150 200
Time (min)
Gluco
se le
vels (m
g/dl)
GK DJB
GK Sham
GK GJ
Oral Glucose Tolerance
Annals of Surgery Nov 2006 Annals of Surgery Nov 2006
Duodenal Exclusion
Annals of Surgery Nov 2006 Annals of Surgery Nov 2006
OGTT after Duodenal Exclusion
44000
49000
54000
59000
64000
69000
Duodenal Pass. Duod. Exclus
OGTT AUC
Duodenal Pass. Duod. Exclus
P<0.05
Annals of Surgery Nov 2006 Annals of Surgery Nov 2006
Restoration of Duodenal Passage
AUC OGTT X 2 AUC OGTT X 2 Annals of Surgery Nov 2006 Annals of Surgery Nov 2006
Conclusion
Exclusion of the proximal small bowel from the flow of Exclusion of the proximal small bowel from the flow of nutrients is the nutrients is the primary primary mediator of diabetes resolution mediator of diabetes resolution after DJB after DJB
Annals of Surgery Nov 2006 Annals of Surgery Nov 2006
Hypothesis Hypothesis
Altered gut signaling in response to duodenal passage of nutrients may impair glucose homeostasis in diabetic subjects
METHODS METHODS Intraluminal Duodenal Sleeve Intraluminal Duodenal Sleeve
Controls: Fenestrated Duodenal Sleeve Controls: Fenestrated Duodenal Sleeve
Complete Sleeve Complete Sleeve
Fenestrated Sleeve Fenestrated Sleeve
OGTT: Complete Tube OGTT: Complete Tube
P< 0.01 P< 0.01
OGTT OGTT
AUC: P< 0.01 AUC: P< 0.01
Prestudy
0
100
200
300
400
500
600
BASE 10 min 30 min 60 min 90 min 120 min 180 min
Prestudy
Postop complete intraluminal tube
0
100
200
300
400
500
600
BASE 10 min 30 min 60 min 90 min 120 min 180 min
Prestudy Post sleeve
9th day pop with lac.
0
100
200
300
400
500
600
BASE 10 min 30 min 60 min 90 min 120 min 180 min
Prestudy
Post op 2 day post lac
0
100
200
300
400
500
600
BASE 10 min 30 min 60 min 90 min 120 min 180 min
Prestudy 9th pop tube 2nd post lac 9th post lac
Conclusions Conclusions
These findings in rats support the These findings in rats support the hypothesis that a dysfunction of the hypothesis that a dysfunction of the duodenum may contribute to the duodenum may contribute to the pathophysiology pathophysiology of type 2 diabetes of type 2 diabetes
UNITED NATIONS RESOLUTION UNITED NATIONS RESOLUTION
“240 million people worldwide are living with diabetes; 380 million by 2025”
“It kills one person every 10 seconds”
Obesity and Diabetes Prevalence
India Urban
Italy India (total)
Greece Kuwait
Saudi Arabia USA Bahrain
Australia
England
Hungary
Peru
Germany Finland
Turkey
Korea
Japan
China Laos
Netherlands
France
Switzerland
0
2
4
6
8
10
12
14
0 5 10 15 20 25 30 35 40
Obesity Rate (%)
Diabetes Rate (%
)
Diabetes Surgery Diabetes Surgery
Is BMI an adequate criteria to define indication to surgical Is BMI an adequate criteria to define indication to surgical treatment of diabetes ? treatment of diabetes ?
DiabetesSpecific Interventions ?
TYPE 2 DIABETES
Surgical Therapy ?
Surgery is more effective than medical therapy in treating diabetes
Key point
1995;222:339350 Y;vol:pp
Pories WJ, Swanson MS, MacDonald KG, et al Authors
Who would have thought it? An operation proves to be the most effective therapy for adult onset diabetes mellitus
Title
Journal
Diabetes Therapy: Surgery?
83% of type 2 diabetic subjects euglycaemic
851 bariatric surgery patients
852 matched controls
10 year followup
Significant reduction in incidence of diabetes in surgery group (7% v. 24%, p< 0.001) at 10 years
7,925 Gastric Bypass Patients 7,925 controls matched for age, sex, BMI Mean followup 7.1 years
Primary outcome was death from any cause
Adams et al.
• 40% reduction in allcause mortality • 56% reduction in cardiovascular mortality • 56% reduction in cancer mortality • 90% reduction in diabetesrelated mortality
Recent Developments:
Standard procedures in lower BMI patients
New procedures in obese and nonobese diabetic patients
Omentectomy
Primary endpoints PreOP 3 Month p value HOMA 2.28 1.86 Men 2.4 1.6 0.08 Women 2.13 2.22 0.74
HbA1c 7.6 7.1 Men 8.4 6.7 0.22 Women 6.9 7.5 0.32
Secondary Endpoints PreOP 3 Month p value TG 243 191 Men 234 158 0.03 Women 253 223 0.19
Chol 210 182 Men 214 169 0.016 Women 205 195 0.39
HDL 43 40 Men 40.4 38.6 0.4 Women 46.2 40.8 0.07
LDL 121 110 Men 136 109 0.17 Women 108 109 0.92
•Vanderbilt University • n=10 omentectomy • 5 men • 5 women
Richards et.al. unpublished
Treatment of Mild to Moderate Obesity with Laparoscopic Adjustable
Gastric Banding or an Intensive Medical Program A Randomized Trial
Paul E. O’Brien, MD; John B. Dixon, et al. Ann Int Med. 2006;144:625633
• BMI 3035 • VLCD, Pharmocotherapy, lifestyle modification vs.
Lap Band • 2 year followup • 87% vs. 22% EWL • 24% vs. 3% resolution of metabolic syndrome
Adjustable Gastric Banding and Conventional Therapy for Type 2 Diabetes
A Randomized Controlled Trial John B. Dixon, MBBS, PhD, Paul E. O’Brien, MD, et al. JAMA.
2008; 299(3)
BMI 30 – 40 kg/m 2
N = 60 (BMI = 37, HbA1c = 7.8)
Best Medical Therapy vs. Best Medical Therapy plus Lap Band
2 year followup
62.5% vs. 4.3% EWL
73% vs. 13% remission of diabetes
Laparoscopic RouxenY gastric bypass for BMI 35 kg/m2: a tailored approach
Ricardo Cohen, M.D.*, Jose S. Pinheiro, M.D., Jose L. Correa, M.D.,Carlos A. Schiavon, M.D.
Surgery for Obesity and Related Diseases 2 (2006) 401–404
• 37 patients • Diabetics on two oral meds • 81% EWL at two years • All patients had normalization of FBG off meds
• “First in Man” Duodenal Jejunal Bypass
4
9
8
7
6
5
0 1 2 3 4 5 6 7 8 9
HbA
1c (%
)
Time Post Surgery (month)
2 6
3 0
2 9
2 8
2 7
0 1 2 3 4 5 6 7 8 9
BMI (kg/m2)
Time Post Surgery (month) R Cohen et.al SOARD, 2007
DuodenoJejunal Bypass (DJB)
Ileal Interposition
• Ileal Transposition +/ Sleeve Gastrectomy – Physiologic Basis: = Increase of GLP1 and distal gut peptides
– Highlights • 3 GI anastomosis • Scant worldwide experience
DuodenalJejunal Bypass Sleeve
• 12 patients • 60 cm DJBS placed endoscopically • 23% excess weight loss at 12 weeks • All 4 diabetic patients had normal fasting glucose levels off medication during DJBS therapy
Philip Schauer, MD Bariatric & Metabolic Institute
Sangeeta Kashyap, MD Endocrinology
Stacy Brethauer, MD – Bariatric & Metabolic Institute
Deepak Bhatt, MD – Cardiology, C5
STAMPEDE
Surgical Therapy AndMedications Potentially Eradicate Diabetes Efficiently
STAMPEDE Study Summary
• Patient population – T2DM (HbA1c > 7.5%) / BMI 30 – 40 kg/m 2
• Objective – assess effects on glycemic control – Advanced medical therapy alone – Combined bariatric surgery / medical therapy
• Primary endpoint – Biochemical resolution of DM @ 12 mo HbA1c < 6%
• Sample size – 150 pts randomized to 1 of 3 arms
• Followup 5 years
Conclusions • Gastrointestinal bypass procedures can improve diabetes by mechanisms beyond changes in food intake and body weight
• Anatomic modification of various regions of the GI tract likely contribute to the amelioration of T2DM through distinct physiological mechanisms.
• Gastric bypass and Adjustable Gastric Banding provide effective, durable therapy for all the components of the metabolic syndrome (through different mechanisms)
• Surgical therapy for Type 2 diabetes is highly effective in patients with severe and mild obesity
Thank You