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