Gema Frühbeck Dept. Endocrinology & NutritionMetabolic Research Laboratory

Pamplona, Spain

Outcomes of bariatric surgery on obesity and its complications

Critical analysis: Need for a paradigm shift

Outline• Types of surgical procedures• Impact of bariatric surgery

• Lessons learnt

• Future perspectives

• Classic effects• Degree of resolution• Temporal pattern

Metabolic surgery

• Human series• Experimental models

• Need for a paradigm shift

Procedures

Restrictive

Malabsorptive

Mixed

GastroplastiesGastric bandingSleeve gastrectomy

Gastric bypassBiliopancreatic div.Duodenal switch

Types of bariatric surgery

Comorbidities. .

Low self-esteem;psychosocial problems

Stroke

Sleep apnoe;hypoventilationHypertension;

coronary heart disease

Steatohepatitis

Gallbladder disease

DyslipidaemiaInfertility

Osteoarthritis

Diabetes mellitus

Atherosclerosis;thromboembolism

Gout

Gastro-oesophagic reflux

Urinary incontinence

Hiatus hernia

Cancer

Life expectancyMortality{

Sjöström, J Intern Med 2013

Percentage weight change in SOS trial

Sjöström, J Intern Med 2013

Cumulative diabetes incidence in SOS trial

Control NO profControl prof

VBGBandingGBP

P<0.001

Sjöström, JAMA 2012

Fatal cardiovascular events Total cardiovascular events

CVD first cause of mortality in both groupsDecreased after bariatric surgery

Cumulative mortality in SOS trial

Effect on cancer incidence in SOS study

Sjöström et al. Lancet Oncol 2009

Decreased cancer incidence following bariatric surgery,but only significant in women

Increased incidence in comparison to the one observed after 2 yearsMaintenance of significant differences after 10 years vs control group

Sjöström et al. N Engl J Med 2004

Follow-up of comorbidity changes in the SOS

CONTROL GROUP BARIATRIC SURGERY

Follow-up of comorbidity changes in the SOS

Sjöström et al. N Engl J Med 2004

CONTROL GROUP BARIATRIC SURGERY

Lack of significant differences in incidence at 2 and 10 yearsbetween control and bariatric surgery groups

Sjöström et al. N Engl J Med 2004

Long-term maintenance of significant differences between control and bariatric surgery groups

CONTROL GROUP BARIATRIC SURGERY

Follow-up of comorbidity changes in the SOS

AGB

RYGB

BPDDS

0 10 20 30 40 50 60 80 90 10070Change/Resolution (%)52.5%

67.5%

75%

83.7%

47.9%

98%

80.8%

93%

77%

Excess weight loss

.T2D resolution T2D improvementAbsolute HbA1c resol.

30-40%Mean weight loss

3.8%

Excess weight loss

T2D resolution T2D improvementAbsolute HbA1c resol.

Mean weight loss 25-35%

2.1-2.9%

Excess weight loss

T2D resolution T2D improvementAbsolute HbA1c resol.

Mean weight loss 15-30%

Excess weight loss

T2D resolution T2D improvementAbsolute HbA1c resol.

Mean weight loss

1.8%

55%

47%75%

20-30%

2.5-2.9%

SG

Effects of type of surgery on body w. & T2D resolution

Frühbeck, Nat Rev Endocrinol 2015

Temporal pattern

Slow, in parallelwith weight loss

Quick, prior tobody weight loss

Quick, prior tobody weight loss

Intermediate,rel. to weight loss

Mechanism beyond body weight loss

Ann Surg 2004Bariatric surgery therapeutic alternative to T2D ttm

Diabetes Surgery SummitConsensus Conference

Recomnendations for the evaluation and use of gastrointestinal surgery to

treatType 2 Diabetes Mellitus

Rubino et al on behalf of DSS Delegates Ann Surg 2010

Frühbeck, Nat Rev Endocrinol 2015

Clinical characteristics of patients relative to surgery

Lancet September 5, 2015

RCT comparison conv. vs RYGB vs BPD treatment over 5 y

Mingrone et al. Lancet 2015

Mingrone et al. Lancet 2015

RCT comparison conv. vs RYGB vs BPD treatment over 5 y

“BRAVE effects”Bile flow alterationReduction of gastric sizeAnatomical rearrangement - altered flow of nutrientsVagal manipulationEnteric hormone modul.

Ashrafian et al. Obesity Rev 2010

Foregut hypothesis Hindgut hypothesisMidgut hypothesis

Mechanisms of action underlying the resolution of type 2 diabetes

Hypothesis

Rubino et al. Annal Surg 2006

T2DM

?

Foregut hypothesis

Mechanisms of action underlying the resolution of type 2 diabetes

Gastric Inhibitory

Peptide(GIP)

“Anti-incretin” factor

Foregut hypothesis

Increasedtransit

Mechanisms of action underlying the resolution of type 2 diabetes

Non obesediabetic

rat

DiabetesResolution

Reappearance of diabetes

Effects of intraluminal devices

EndobarrierEndobarrierperforated

Midgut hypothesis

“Hepato-portal sensing”

Mechanisms of action underlying the resolution of type 2 diabetes

Midgut hypothesis

Increased expression of the bile acid transporter BSEP via activation of the

coactivator SRC-2, & subsequent increase in biliar secretion

AMPK stimulates absorption of lipids

Intestinal gluconeogenesisIncreased activity & protein levels of neoglucogenic enzymes (G6Pasa &

PEPCK) elevated in EA

Increased production intestinal glucose

Mechanisms of action underlying the resolution of type 2 diabetes

Hindgut hypothesis

GLP-1 PYY

Mechanisms of action underlying the resolution of type 2 diabetes

GLP-1 Gastric Bypass >> Gastric Banding

Le Roux. Ann Surg 2006

Rodieux. Obesity 2008

GBPG banding

LeanObese

GBP

G banding

GBP

G banding

GBPG banding

Wilson-Perez et al. Diabetes 2013

GLP-1

Hindgut hypothesis

Mechanisms of action underlying the resolution of type 2 diabetes

Ileal transposition Ahima & Carr, Gastroenterology 2010

Cummings et al, Gastroenterology 2010

• produced in intestinal L cells• secr. in resp. to calorie intake• inhib. GI motility & secr. pancr/int. • produces satiety & dism. intake• low PYY production in obese indiv.

PYY

* anatomical

* hormonal

* neural

* secretory * absorptive

* microbiological

Underlying mechanisms of action

Fasting, caloric restriction

Bile acidsmetabolism

Gastrointestinalhormones

Other signalshepatoportal Changes in

microbiota

Weight loss

Inflammation

Adiposity

Vagalstimulacion

Intestinalgluconeogenesis

Insulinresistance

Frühbeck (in preparation)

Integrated Medical/SurgicalDiabetes Care Algorithm

DSS-II Consensus

• Perspectives

Evolución comparativa entre IMC y porcentaje de grasa corporal

BMI (kg/m2) % Body fat

Comparison of changes in BMI and body fat following RYGB in the CUN

More profound changes in BMI than in body fatIncrease in adiposity after 2 years of performing the gastric bypass

METABOLICSurgery

BARIATRICSurgery

BMI 30-35 kg/m2 BMI > 35-40 kg/m2BMI 35 kg/m2

Frühbeck, Nat Rev Endocrinol 2015

Eligibility criteria separation based on BMI

BMI 30-35 kg/m2 BMI > 35-40 kg/m2BMI 35 kg/m2

Dysfunctional adiposity

METABOLICSurgery

BARIATRICSurgery

Frühbeck, Nat Rev Endocrinol 2015

Eligibility criteria separation based on BMI blurred by adiposity

Bariatric surgery eligibility according to body fat

HbA1c

Gómez-Ambrosi et al. Obes Surg 2015

Lean

BMI<35 H

F

BMI35-40

com

BMI>400

50

100

150

200

250

300

350m

g/dL

Lean

BMI<35 H

F

BMI35-40

com

BMI>400

50

100

150

200

250

300

350

mg/

dL

**** ***

†

*** ******

Triglycerides Triglycerides

CRP CRP

Lean

BMI<35 H

F

BMI35-40

com

BMI>40

-0.5

0.0

0.5

1.0

1.5

2.0

Lean

BMI<35 H

F

BMI35-40

com

BMI>40-0.5

0.0

0.5

1.0

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2.0*********

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Bariatric surgery eligibility according to body fat

Frühbeck et al. Diabetes 2014

Habegger et al. Diabetes 2014

Response to GLP1 receptor agonistpredicts glycemic control after RYGB

Calculation of DiaRem score for prediction of T2D remission

Still et al. Lancet Diabetes Endocrinol 2014

CUN – Compl. Hosp. Nav.

Javier SalvadorCamilo SilvaPatricia IbañezNeus VilaMª Ang. MargallSonia Romero

Metabolic Research Laboratory Javier Gómez AmbrosiAmaia RodríguezVictoria CatalánLeire Méndez

Sara BecerrilBeatriz RamírezAndoni LanchaSilvia Ezquerro

AcknowledgmentsMultidisciplinary Obesity Team

Víctor ValentíFernando Rotellar

Rafael MoncadaJavier A.

CienfuegosMª Jesús Gil

Ana ZugastiEstrella Petrina

Amelia Marí

Changes in bile acid & cholesterol physiology in ileal interposition

Kohli R et al. Am J Physiol Gastrointest Liver Physiol 2010

GLOBAL WEIGHT

LOSS

HORMONAL CHANGES

FAT MASS

DECREASE

Weight loss-dependent

Weight loss-independent Adiposity-dependent

Respiratory functionObstructive sleep apneaGastroesophageal reflux

Psycho-social alterationsHealth-related quality of life

Osteoarthritis and joint problems

Type 2 diabetesDyslipidemia

Non-alcoholic fatty liver diseaseCardiovascular diseasesLow-grade inflammation

HypertensionCancer