Endoluminal Duodenal-Jejunal Endoluminal Duodenal-Jejunal Sleeve, Fat Reduction... And the Sleeve, Fat Reduction... And the

FutureFuture

Francesco Rubino, MDFrancesco Rubino, MD

Chief, Section of Gastrointestinal Metabolic SurgeryChief, Section of Gastrointestinal Metabolic SurgeryDirector; Diabetes Surgery CenterDirector; Diabetes Surgery Center

Weill Cornell Medical College- New York Presbyterian HospitalWeill Cornell Medical College- New York Presbyterian HospitalNew York, NY USANew York, NY USA

First Canadian Summit on Metabolic Surgery for T2DMMontreal, May 6-7, 2010

METHODS METHODS Intraluminal Duodenal SleeveIntraluminal Duodenal SleeveIntraluminal Duodenal SleeveIntraluminal Duodenal Sleeve

Controls: Fenestrated Duodenal Sleeve Controls: Fenestrated Duodenal Sleeve

Fig 1 b

Goto-Kakizaki Rat (GK)Goto-Kakizaki Rat (GK)

1.1.Complete tube Complete tube (n=12)(n=12)

2.2.Fenestrated Tube Fenestrated Tube (n=12)(n=12)

3.3.No tube (Sham) No tube (Sham) (n=6)(n=6)

2 & 3 pair-fed to 12 & 3 pair-fed to 1

OGTT OGTT

AUC: P< 0.01AUC: P< 0.01AUC: P< 0.01AUC: P< 0.01

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GK Rats: GIP-Response to GlucoseGK Rats: GIP-Response to Glucose

Wistar Rats: GIP-Response to GlucoseWistar Rats: GIP-Response to Glucose

ELS Improves IP Glucose Tolerance (Kaplan et al)

Endoluminal Sleeve - EndoBarrier™

Food bypasses the duodenum and proximal jejunum

CONFIDENTIAL

Week 1 Data Summary

EndoBarrierEndoBarrier ShamSham pp value value

Weight change (kg)*Weight change (kg)* -4.66-4.66 -5.38-5.38 NSNS

Fasting plasma glucose Fasting plasma glucose – change (mg/dl)– change (mg/dl) - 52 - 52 44 44 +17 +17 78 78 p p = 0.17= 0.17

Mixed meal tolerance Mixed meal tolerance (AUC)(AUC) -18.6%-18.6% +10.1%+10.1% p p = 0.05= 0.05

7-point glucose profile – 7-point glucose profile – aggregate change aggregate change

(mg/dl)(mg/dl)-58 -58 55 55 +1.1 +1.1 46 46 p p < 0.05< 0.05

**Food intake held identical Food intake held identical

EndoBarrierEndoBarrier™ Diabetes Trial (Chile)™ Diabetes Trial (Chile)

EndoBarrier™ Improves HbA1c

-2.9

-1.3

-0.76-0.8

-3.5

-3.0

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

% C

hang

e H

bA1c

EndoBarrier

Sham

N=9 N=3N=4 N=8

*Week 30 p=0.004

Week 12Week 12 Week 30Week 30

EndoBarrierEndoBarrier™ Diabetes Trial (Chile)™ Diabetes Trial (Chile)

Endoluminal Sleeve: Mechanisms

• Isolation of Duodenal Mucosa from Nutrients Contact

• Bile isolated from nutrients

• No expedited delivery of nutrients to the distal gut

Endoluminal Sleeve: Clinical Applications

• Primary Therapy of Diabetes ?– Long-term ?– BMI> 35 ?– BMI < 35 ?

• Diagnostic value ?

• Pre-surgical Test to select candidates for gastric bypass surgery

• Integrated Interventional-Drug approach• “Adjuvant Therapy”

EndoBarrier Weight Loss Results At 6 Months

EndoBarrier Glucose Improvement at 6 Months

Surgery, Adiposity and DiabetesSurgery, Adiposity and Diabetes

Liposuction does not improve diabetes

Surgical resection of greater omentum does not resolve diabetes

S. Klein et al. (ADA 2009)

Metabolic Surgery… the future

• Multidisciplinary approach and guidelines/standards of care development

Annals of Surgery; March 2010

DSS Reccommendations areEndorsed by:

ASMBSIFSO

The Obesity Society (TOS)Int. Ass Study of Obesity

(IASO)Diabetes UK

• Bariatric surgery should be considered for adults with BMI > 35 kg/m2 and type 2 diabetes, especially if the diabetes is difficult to control with lifestyle and pharmacologic therapy. (B)

• Surgery should be considered in Surgery should be considered in pts with BMI > 35 and pts with BMI > 35 and inadequately controlled inadequately controlled diabetesdiabetes.

• in patients with type 2 diabetes and BMI of 30–35kg/m2, there is currently insufficient evidence to generally recommend surgery in patients with BMI35 kg/m2 outside of a research protocol.

• Surgery Surgery may be may be considered as a considered as a non-primarynon-primary alternative in pts with alternative in pts with uncontrolled diabetes and BMI uncontrolled diabetes and BMI 30-30-3535.

Metabolic Surgery… the future

• Solving the BMI issue…

• Controlled clinical trials in these patients should be performed to determine the safety and efficacy of GI metabolic surgery (A) as well as to identify parameters other than BMI as criteria for appropriate patient selection (A).

DSS- BMI

SAME LANGUAGE IN ADA’ STANDARDS OF CARE DOCUMENT

Diabetologia 1996

Metabolic Surgery… the future

• Solving the BMI issue…• Diabetes-specific criteria for surgical indication• Risk-Stratification in diabetes• Improve Standards of Clinical Research

Patient Factors and Outcomes Associated with T2DM Resolution

(N=191)

Improved 33

Resolved 158

P

Age 48.2 47.8 0.724 Gender (% female) 70% 76% 0.615 Preop BMI 51 50 0.270 Postop BMI 37 33 0.002 %EWL 42 62 <0.001 Preop HA1C 8.8 8.1 0.033 Preop FPB 189 183 0.436 Duration of DM 10.7 4.1 <0.001 % insulin users 63% 23% <0.001

Schauer et al. Annals of Surgery Oct 2003

* Any Textbook* Any Textbook

The “Bad Reputation” of Bariatric Surgery

• Randomized controlled trials are strongly encouraged to assess the utility of GI surgery to treat T2DM (A). In patients with BMI <35 kg/m2, determining the appropriate use of GI surgery for the treatment of T2DM is an important research priority (A).

DSS- Research

Worldwide Consortium for Randomized Worldwide Consortium for Randomized Clinical Trials in Diabetes Surgery Clinical Trials in Diabetes Surgery

(WORLDCords)(WORLDCords)

Diabetes Surgery CenterDiabetes Surgery Center

Weill Cornell Medical College-New York Presbyterian HospitalWeill Cornell Medical College-New York Presbyterian Hospital

RYGB (Lap)RYGB (Lap)

vs vs Medical Therapy and Lifestyle Medical Therapy and Lifestyle

ModificationModification

PI: Francesco RubinoPI: Francesco RubinoSteering Committee: H. Lebovitz, J. Buse, A. Steering Committee: H. Lebovitz, J. Buse, A.

Goldfine, J. Roth B. Zinman, B. Wolfe, JP Despres, Goldfine, J. Roth B. Zinman, B. Wolfe, JP Despres, S. Belle S. Belle

Cornell’s Study

Participating Countries

REGIONAL Chapters:• Europe (centers already available in Italy,

Netherlands, Belgium, Spain, England,)• South-Central America (Mexico?, Brasil, Argentina,

Chile, Venezuela,)• North America (Cornell, Tuffs, Univ. of Maryland,

Mount Sinai?)• Asia (Philippines, India, Taiwan, Japan)• Middle East (Quatar, UAE, SA)

Primary Endpoint:Diabetes-Specific Morbidity and Mortality

Primary Endpoint: CV Risk Profile

Primary Endpoint HBA1cSecondary endpoints:

Metabolic Control CV Risk Profile Surrogate measures of diabetes complications

Weill Cornell –NYPStudy (50 pts)

US Multicenter Study200 patients

Worldwide Consortium for RCT500-800 pts

International Consortium for Diabetes Surgery

Metabolic Surgery… the future

• Solving the BMI issue…• Diabetes-specific criteria for surgical indication• Risk-Stratification in diabetes• Improve Standards of Clinical Research• Elucidation of Mechanisms of Action

– Novel Surgical Procedures– Endoluminal Approaches– Novel Targets for Drugs

Re-thinking of Diabetes and Obesity