Metabolic Effects of Surgery. Francesco Rubino, MD. Chief, Section of Gastrointestinal Metabolic Surgery Director, Diabetes Surgery Center

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Metabolic Effects of Surgery

Francesco Rubino, MD

Chief, Section of Gastrointestinal Metabolic Surgery

Director, Diabetes Surgery Center

Weill Cornell Medical

College-New York Presbyterian Hospital

New York, NY

Bariatric Surgery…

Metabolic Surgery

(2)

Bariatric Surgery:

an obsolete, inaccurate definition

From the greek

“Baros” (weight)

Mechanically reduction of energy intake

(restriction and/or malabsorption)

Body weight loss (%EWL) is the primary

outcome of bariatric surgery

Excess body weight (BMI) is the primary

criteria for indication to bariatric surgery

Surgically induced weight loss

determines improvement/resolution

of obesity-related co-morbidities

Metabolic Surgery

Surgical operations aimed to control

metabolic diseases as opposed to BW per se

Mechanisms of action:

Strengthening physiology of

glucose homeostasis (or fixing

underlying pathophysiology of

diabetes/obesity)

%EWL IS NOT the only (nor the primary) outcome of metabolic surgery

(3)

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Conventional Bariatric-Metabolic

Procedures

Adjustable Gastric Banding Roux-en-Y Gastric Bypass Biliopancreatic Diversion

Novel Metabolic Procedures

DJB Ileal Interposition Duodenal-Jejunal Bypass with Sleeve Gastrectomy

(4)

The Heretical Suggestion:

A Surgical Cure For Diabetes ?

Nicolaus Copernicus

(1473-1543)

Rates of “Remission” of Diabetes

Adjustable Gastric Banding Roux-en-Y Gastric Bypass Biliopancreatic Diversion

>95%

48%

84%

Buchwald H. JAMA, 2004

(5)

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« Remission » is at odds with the classic

teaching…

„„Type 2 Diabetes is a Chronic, Progressive and

Irreversible Disease‟‟

* Any Textbook

Is Diabetes only about sugar?

What about all 3 endpoints?

•HTN

•Hypertriglyceridemia

•HA1C

(6)

93% of diabetic patients ARE NOT well controlled for glucose,

cholesterol and blood pressure

37.2% >8% 63%7% 7.8% 25.8% 37.0% 17.0% 12.4% % of patients n = 404 A1C (NHANES), 1999-2000.

Only 7% of adult diabetic patients from NHANES achieved:

A1C <7%

PA <130/80 mm Hg

Total Cholesterol < 200 mg/dL

Saydah SH et al. JAMA. 2004;291:335-342.

0 20 40 60 80 100 >10% >9% >8% 7-8% <7% 37.2% >8% 63%7% 7.8% 25.8% 37.0% 17.0% 12.4%

Gastric Bypass and the 3 Endpoints

(7)

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GBP Band BPD+DS

• Diabetes

84% 38%

98%

• Hyperlipidemia

94% 71%

100%

• Hypercholesterolemia

95%

78% 100%

• Hypertriglyceridemia

94% 77% 100%

• Hypertension

75%

43% 81%

• Sleep apnea

87% 95% 95%

Buchwald H et al, JAMA 2004

Resolution of Comorbid Conditions

Does Tight Glycemic Control Reduce

Cardiovascular Disease or Mortality?

ACCORD

Intensive group: non-fatal MI, hypoglycemia & weight gain

Trial stopped b/o mortality in intensive group (Why?)

ADVANCE

No difference between intensive & conventional treatment in macrovascular disease or mortality (either overall or CV)

VADT

No differences between intensive & conventional treatment in cardiovascular events

Severe hypoglycemia was strong predictor or CVD events & death

(8)

b

b

b

Am J Cardiol 2007;99:222–226

“Bariatric surgery decreases

CHD risk to rates lower than

the age- and gender-adjusted

estimates for the general

population.”

(9)

9

SOS Stuy: Overall Mortality

Effect on Long-term Mortality Compared to

Non-Operated Controls

Study Procedure F/U Mortality Reduction MacDonald,1997 RYGB 9 yrs 88% Flum, 2004 RYGB 4.4yrs 33% Christou, 2004 RYGB 5 yrs 89% Sowemimo, 2007 RYGB 4.4 yrs 50% O’brien, 2006 LAGB 12 yrs 73%

Adams, 2007 RYGB 8.4 yrs 40% Sjostrom, 2007 VBG/other 14 yrs 31%

(10)

- 92%

reduction in diabetes-specific

mortality risk after gastric bypass

surgery

Adams et al, New Engl.J. Medic. Aug 2007

1%

Of all patients with BMI > 40 Kg/m2 have

access to bariatric surgery in U.S.

(11)

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Diabetes Surgery:

Cultural Barriers

Professional biases /interests

Limited awareness of benefits/risk of metabolic

surgery/bariatric surgery

Misperceptions / Preconceptions

Radical departure from conventional treatment and

thinking (Healthy Skepticism)

Diabetes Surgery:

Cultural Barriers

Professional biases /interests

Limited awareness of benefits/risk of metabolic

surgery/bariatric surgery

Misperceptions / Preconceptions

Radical departure from conventional treatment and

thinking (Healthy Skepticism)

(12)

Bariatric surgery is dangerous/drastic measure (?)

Misperceptions / Preconceptions

AHRQ Data: Bariatric Surgery Utilization

and Outcomes in 1998 and 2004

1998

2004

% change

Number

13,386

121,055

804%

Inpatient

death

0.89%

0.19%

-79%

(13)

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Mortality Rates Following Common

Operations in U.S. Hospitals

Aortic Aneur

CABG Craniot Esophag Resect Hip Replac Panc Ped. Heart Surger y Number of Hospitals performing operation 2485 1036 1600 1717 3445 1302 458 National Average Mortality rate( %) 3.9 3.5 10.7 9.1 0.3 8.3 5.4 Average Hospital caseloads Median 30 491 12 5 24 8 4 ]

Dimick JB, Welch HG, Birkmeyer JD. Surgical mortality as an indicator of hospital quality. JAMA 2004,292, 847-851

SRC: Bariatric Surgery Mortality

0.3%

(55,567 patients)

(14)

Morbidity of Bariatric Surgery

Agency for Healthcare Research and Quality (AHRQ)

Medical Care May 2009

Overall Complication Rate is 15% (all types of complications)

Hernias, Leaks, Respiratory Failure and pneumonia fell

btw 29 and 50%

• 21% decline from 2002 to 2006 (from 24% to 15%)

• Post-surgical infection rate dropped by 58%

Ulcers, Hemorrhage, deep-vein thrombosis, PE, MI unchanged

But their risk ranges between 2.4 and 0.1%

Increased use of Laparoscopy, increased surgeon experience

and use of restrictive procedures

(15)

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(16)

Haffner, et al. N Engl J Med 1998; 339: 229-234 3.5% 18.8% 0 5 10 15 20 25 30 35 40 45 No DM, No MI No DM, MI p < 0.001 20.2% 45.0% DM, No MI DM, MI p < 0.001 Incidence of

(17)

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Mechanisms of Diabetes Control

by Metabolic Surgery

Misperceptions / Preconceptions

“Bariatric surgery enforces life-style changes

and mechanically reduce nutrient absorption

and/or intake of nutrients”

(18)

The Old Dogma…

1. Restriction

(19)

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Rehfeld J, 2004

1967 – Gastric Bypass

(20)

Misperceptions / Preconceptions

Common belief that weight loss itself improves diabetes

is not “scientifically” correct

Is diabetes control dependent on the intervention that

causes weight loss or weight loss per se?

Intervention:Decreased caloric intake and intensive physical activity (NOT WEIGHT LOSS!!)

(21)

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January 2004

Diabetes Resolution is a Direct Effect of Surgery, not Unique of Obese Individuals

P<0.001

(22)

Troy S,

et al

Cell Metab 8:177, 2008

1. DJB

2. Banding >

3. Sham >

Significantly better glucose tolerance in DJB mice

Pair-fed with DJB animals

BMI

• BMI-%fat relationship varies with age,

gender and race/ethnicity…BMI is not an

equivalent measure of fatness across

groups

• BMI does not accurately reflect the risk of

patients with established diabetes

• BMI does not predict successful outcome

of surgery

(23)

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Dixon et al Jama, January 2008

BMI 30-40 (total: 60 pts- 13 pts <35)

RCT LAGB+conv/behav. Rx vs conv/behav rx

alone

Complete remission (Hb6<0): 73 vs 13% @2 yr

Weight loss: 20.7 vs 1.7%%

(24)

Patient number by procedure DJB RYGB BPD GB SG BPD without SG 157 44 14 11 10 1

Total= 237 patients

(25)

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0 1 2 3 4 5 6 7 8 9 10 DJB RYGB BPD GB SG HA1c (%) Procedure Type

HA1c comparison before

and after surgery

HA1c Pre-op HA1c post-op: 3 months HA1c post-op: 1 year

Authors: Menchaca, Frenzen, Lee, Shah, Resa, Patolia, Castagneto,

Berry, Muffazal, Ramos-Neto

(26)

BMI > 35

Evidence for Weight-Independent

Mechanisms of Surgical Control of

(27)

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0

100

200

300

400

500

0

4

8

12 16 20 24 28

Days After Surgery

Blood

Glucose

(mg/dl)

Rapid Improvement of Diabetes After RYGB

90 units insulin Adapted from Pories W, 1980

0

100

200

300

400

500

0

4

8

12 16 20 24 28

Days After Surgery

Blood

Glucose

(mg/dl)

Rapid Improvement of Diabetes After RYGB

90 units insulin 0 insulin 0 0 4 8 4 8 8 16 Adapted from Pories W, 1980

(28)

Just Starvation

& Weight Loss?

OGTT GK rats 0 100 200 300 400 500 600 0 50 100 150 200 Time (min) G lu c o s e l e v e ls ( m g /d l) GK DJB GK Sham

Pair-feeding

(29)

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Mechanisms of Diabetes Control

after GI Surgery:

Weight Loss ?

Effects on Glucose Homeostasis of

Equivalent Weight Loss

from RYGB

vs

.

Diet

Type 2 diabetes patients

matched for BMI, age, degree of diabetes

Studied at

9.7 kg

Studied at

9.2 kg

RYGB Diet Laferrère et al JCEM 93:2479, 2008

(30)

Before RYGB Before Diet After Diet

After RYGB

Gluc

os

e

(m

g/

dL)

OGTT

More Improved Glucose Tolerance After RYGB

Than After Equivalent Dietary Weight Loss

Sleeve Gastrectomy vs. Gastric Bypass

~A Randomized Trial for T2DM Treatment

Indication

Established T2DM patients

Moderate obesityBMI 27-35

30-60 Y/O

HbA1C>8%

Sleeve Gastrectomy Sleeved Gastric Bypass (Minigastric Bypass) Courtesy of Dr Lee

(31)

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After 6 months , there was no difference in weight

loss between the two groups

Results –

Weight loss

BMI

Weight loss

Sleeve

Gastric

Endpoint

Gastrectomy

Bypass

• % A1c <7.0

46.7%

93.3%

• LDL

23

16

mg/dL

• Triglycerides

107

130

mg/dL

• % at Rx Goals

14%

60%

– A1c < 7% – LDL < 130 – TG < 150 Lee WJ et al, 2008

(32)

Service et al. NEJM353:249 (2005)

Control

Post-RYGB

Hyperinsulinemia Hypoglycemia After Gastric Bypass:

Too much of a good thing for islets?

Korner J, et al JCEM90:359, 2005

Increase in Postprandial GLP-1 and PYY After RYGB

Korner J, et al SOARD3:597, 2007 Meal

PYY

Meal

GLP-1

(33)

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Diabetes Care 2008 online

Evidence for weight-independent

mechanisms

Kinetics of diabetes

resolution

Glucose homeostasis

studies at equivalent weight

loss after RYGB

vs

. other

(34)

…There is increasing evidence that intestinal

bypass procedures may have glycemic effects

that are independent of, and additive to, their

effects on weight”

.

(35)

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Gastric

Band

Sleeve

Gastrex RYGB DJB BPD

Inter-position luminal Sleeve Gastric Restriction

±

Gastrectomy

Altered gastric function

?

Gastric exclusion

Duodenal exclusion

Enhanced distal nutrient delivery

Malabsorption

Partial vagotomy

±

?

Courtesy of

Lee Kaplan

Gastric Band Sleeve Gastrex RYGB DJB BPD Ileal Inter-position Endo-luminal Sleeve Gastric Restriction

±

Gastrectomy

Altered gastric function

?

Gastric exclusion

Duodenal exclusion

Enhanced distal nutrient delivery

Malabsorption

Partial vagotomy

±

?

Courtesy of

Lee Kaplan

(36)

Mechanisms of diabetes control after RYGB

Nutrients reach the distal ileum within 5 min of the ingestion of food and this stimulates the secretion of GLP-1 by L-cells located in this area

Mason E. Obes Surg 2005 15, 459-461

« Distal mechanism »

Mechanisms of Surgical Treatment of T2D

The exclusion of the duodenal

nutrient passage may offset an

abnormality of gastrointestinal

physiology responsible for

insulin resistance and type 2

diabetes

(37)

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November 2006

Gastro-jejunal Anastomosis

Early Ileal Stimulation

(38)

OGTT GK rats

0 100 200 300 400 500 600 0 50 100 150 200 Time (min) G lu c o s e l e v e ls ( m g /d l) GK DJB GK Sham GK GJ

Oral Glucose Tolerance

Annals of Surgery Nov 2006

Duodenal Exclusion

(39)

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OGTT after Doudenal

Exlcusion

44000 49000 54000 59000 64000 69000

Duodenal Pass. Duod. Exclus

OGTT AUC

Duodenal Pass. Duod. Exclus

P<0.05

Annals of Surgery Nov 2006

Restoration of Duodenal

Passage

AUC OGTT X 2

(40)

Exclusion of the proximal small bowel from the flow of

nutrients is the

primary

mediator of diabetes resolution

after DJB

Annals of Surgery Nov 2006

(41)

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Diabetes

Surgery

Summit

Rome

2007

Reccommendations Endorsed

by:

ASMBS

IFSO

TOS

IASO

(42)

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

• Although small trials have shown glycemic benefit of bariatric surgery in patients with type 2 diabetes and BMI of 30–35kg/m2, there is currently insufficient evidence to generallyrecommend surgery in patients with BMI35 kg/m2 outside of a research protocol. (E)

• The long-term benefits, cost effectiveness, and risks of bariatric surgery in individuals with type 2 diabetes should be studied in well-designed randomized controlled trials with optimal medical and lifestyle therapy as the comparator. (E)

• 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

pts with BMI > 35 and

(43)

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• in patients with type 2 diabetes and BMI of 30–35kg/m2, there is currently insufficient evidence to

generallyrecommend surgery in patients with BMI35 kg/m2 outside of a research protocol.

Surgery may be considered as a

non-primaryalternative in pts with uncontrolled diabetes and BMI 30-35.

42 yo female

Type 2 diabetes diagnosed 5 years ago

Multiple drugs and insulin with NO benefit

HbA1c >8

Hyperlipidemia

Hypertension

BMI: 33.9

42 yo female

Joint Pain

BMI 37

(44)
(45)

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The Heretical Suggestion:

Is Diabetes an Intestinal Disease?

Nicolaus Copernicus

(46)

Surgical Control of Diabetes

1. Enhancing a positive mechanism

that improves glucose homeostasis

2. Fixing alterations of glucose

homeostasis

Distal Mechanism

GLP1

(47)

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DJB in

non-diabetic

rats

(48)

DJB in

non-diabetic

rats

P=0.02

Annals of Surgery Nov 2006

(49)

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Gastrectomy and Glucose

Tolerance

RCT: Duodenal exclusion vs Preservation of

Duodenal Passage

« If duodenal passage is eliminated

a pathologic glucose tolerance develops »

Schwarz et al; World J Surg. 1996:

(50)

Mechanisms of Diabetes

Resolution

Gastrointestinal bypass surgery

(duodenal exclusion) improves glucose

homeostasis ONLY in subjects with

impaired glucose tolerance but not in

normal individuals

Thaler & Cummings Nature452:941, 2008 Relating to:

Wang PY et al. Nature452:1012, 2008

(51)
(52)
(53)

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Anti-Incretin

(54)

Anti-Incretin

Dumping Syndrome

Nesidioblastosis

Hyperinsulinemia

Hypoglycemia

Not Enough

(55)

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diet Overeating

Food preservatives Bugs?

“It is not about living

with

diabetes; it is

about living

without

it”.

1

st

World Congress on Interventional Therapies for

Type 2 Diabetes

(56)

Fall 2010

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