Cirugía bariátrica-metabólicacomo tratamiento de

la obesidad y enfermedades asociadas:Algunas preguntas abiertas

Josep VidalServicio de Endocrinología y Nutrición

Hospital Clínic Barcelona

American Societyfor Bariatric Surgery

American Societyfor Metabolic

and Bariatric Surgery

From bariatric to metabolic surgery

“Operative manipulation of a normal organ or organ system to achieve a biological result for a potential health gain»

RL Varco, Metabolic Surgery Book 1978

“A set of gastrointestinal operations used with the intent to treat diabetes ("diabetes surgery") and metabolic dysfunctions (which include obesity)”

F Rubino, Ann Surg 2014

“A set of gastrointestinal surgical procedures originally designed to induce weightreduction in morbidly obese patients»

2

The metabolic surgery battleground

Batterham RL and Cummings DE et al. Diab Care 2016

The metabolic surgery battleground

Purnell JQ et al, Diabetes Care 2016

Following RYGB as compared to AGB

higher diabetes remission rates at comparable WL

LABS-2 cohort (677 subjects: 466 RYGB and 140 AGB)

The metabolic surgery battleground

Batterham RL and Cummings DE et al. Diab Care 2016

Surgical manipulation provides a universal effect!

The case of T2D

From the promise of cure to that of an % of subjects with HbA1c<7%

From remission to good metabolic control (HbA1c<7%)…

Schauer et al. N Eng J Med 2001, 2014, 2017

Randomized Clinical TrialSTAMPEDE Trial-Cleveland Clinic: 5 years FU(n=134, Age 48 y, BMI 37 kg/m2, HbA1c preQ 9,2%, DM duration 8,4 y, Insulin Rx 44%)

40%

78%

21%

65%

51%

78%

65%

49%

56%

IMT GBP + IMT SG + IMT

Achievment HbA1c<7%w/ wo medical therapy over time

The case of T2D

From remission to good metabolic control (HbA1c<7%)…

Clinical Trials. gov

RCT Semaglutide (0.5 or 1.0 mg ow) vs Pcb in T2D on basal ins ± metfSUSTAIN 5. 1 year follow up(n=497, Age 59 y, female 44%,BW 92 kg, HbA1c 8,4%)

79%

-3.7

11%-1.45

-1.85

-0.09

-6.4

-1.461%

HbA1c<7%

New therapies vs “diabetes surgery”

Change HbA1c (%) Body weight (kg)

-2

-1,8

-1,6

-1,4

-1,2

-1

-0,8

-0,6

-0,4

-0,2

0

SEMA 0.5 SEMA 1.0 PCB

-7

-6

-5

-4

-3

-2

-1

0

SEMA 0.5 SEMA 1.0 PCB

0

10

20

30

40

50

60

70

80

90

SEMA 0.5 SEMA 1.0 PCB

DSSII Consensus. Diabetes Care 2016

DiabetologistSurgeon In between...

• Don’t dismiss the concept

• Broaden the spectrum when consideringsurgery

• Weight loss is clinically relevant!

The case of T2D: In spite of the >10 RCT!

Broadening the spectrum

T2D

Dislipidemia

HTN

SAHS

NAFLDCancer

A multifactorial approach toobesity related comorbidities

What’s grade A evidence on the effects of Metabolic/Bariatric surgery?

Broadening the spectrum

1 RCT

2 RCT

0 RCT0 RCT

Obstructive Sleep Apnea Hypopnea (OSAH)

Obstructive Sleep Apnea Hypopnea (OSAH)

Obesity as risk factor for OSAH(Cleveland Family Study, n=1149)

Tishler PV et al, JAMA 2003

GráficInteracció IMC edat

Adjusted Odds ratios relating OSAH to potential riskfactors

Interaction between is not as simple as expected(at ages >55, BMI appears to be less important

Interaction between age and BMI(BMI, per unit increase)

Meta-analysisi BS and OSAH(12 studies, n=342 subjects)

Greenburger DL et al, Am J Med 2009

• BS associates a reduction in the apnea hypopnea index (AHI)• Despite BS, AHI is consistent with moderately severe OSA• Thus, BS does not result in the cure of OSA

Obstructive Sleep Apnea Hypopnea (OSAH)

BS and OSAH: RCT conventional therapy vs gastric banding(OSAH dx< 6mo, n=30 per group, baseline BMI 45 kg/m2, males 58%, age 49 y)

Dixon JB et al, JAMA 2012

-27.8 kg-5.1 kg

-14 events-25.5 events

p<0.001

p=0.18

135 kg126 kg

(n=17) (n=20)

Obstructive Sleep Apnea Hypopnea (OSAH)

Dixon JB et al, JAMA 2012

Other Sleep parameters

Obstructive Sleep Apnea Hypopnea (OSAH)

BS and OSAH: RCT conventional therapy vs gastric banding(OSAH dx< 6mo, n=30 per group, baseline BMI 45 kg/m2, males 58%, age 49 y)

BS and OSAH: RCT conventional therapy vs gastric bandingPost-hoc analysis: Supine OSA vs non-supine OSA

(n=37 per group in whom >20 min of sp and non-sp PSMN were available)

Joosten SA et al, Sleep 2017

P<0.05

Obstructive Sleep Apnea Hypopnea (OSAH)

RCT conventional therapy vs gastric banding(n=66, OSA or Ob hypovent Sd on non-invasive ventilation therapy, age 47 y, BMI 48 kg/m2)

1ary endpoint: Weaning from non-invasive ventilation at 1 and 3 years

Feiger-Guiller B et al, Ob Surg 2015

Obstructive Sleep Apnea Hypopnea (OSAH)

0

10

20

30

40

50

1 year 3 years

INC GB

0

10

20

30

40

50

1 year 3 years

INC GB

0

10

20

30

40

50

%EWL 1y %EWL 3y

INC GB

Excess WL Weaning from NIV Decrease AHI

NS

NS

P=0.002

P=0.014 NS

P=0.015

Pathogenesis of OSA

Jordan AS et al, Lancet 2014

Obstructive Sleep Apnea Hypopnea (OSAH)

Potentially affected by surgery

Arterial Hypertension

Arterial Hypertension

The GATEWAY Randomized Trial(n=100, female 70%, age 44 y, BMI 37 kg/m2, duration of HTN 7 y)

Schiavon CA et al, Circulation 2018

1ary aimReduction of ≥30% of the total number of antihipertensive

medications while maintaining SBP/DBP <140/90 at 12 months

Arterial Hypertension

The GATEWAY Randomized Trial(n=100, female 70%, age 44 y, BMI 37 kg/m2, duration of HTN 7 y)

Schiavon CA et al, Circulation 2018

1ary aimReduction of ≥30% of the total number of antihipertensive

medications while maintaining SBP/DBP <140/90 at 12 months

Primary endpoint

Arterial Hypertension

The GATEWAY Randomized Trial(n=100, female 70%, age 44 y, BMI 37 kg/m2, duration of HTN 7 y)

Schiavon CA et al, Circulation 2018

1ary aimReduction of ≥30% of the total number of antihipertensive

medications while maintaining SBP/DBP <140/90 at 12 months

Antihypertensive medication

Arterial Hypertension

The GATEWAY Randomized Trial(n=100, female 70%, age 44 y, BMI 37 kg/m2, duration of HTN 7 y)

Schiavon CA et al, Circulation 2018

Mechanisms?

Time course WL-1ary outcome

• Hemodinamic changes• WL (decreased intra-abd. Pressure)• Insulin resistance• Inflammation• Gut hormones

Non-alcoholic fatty liver disease

NAFLD and bariatric surgery candidates

90-95% BS candidates

Adapted from Aguilar-Olivos, Metabolism 2016

10-20% BS candidates

10-14% BS candidates

Bariatric surgery associated with:

• Liver enzymes

• Liver esteatosis

• NAFLD activity score (NAS: esteatosis, inflammation, balooning)

• Fibrosis (Kleiner and Metavir scoring systems)

CVD risk(main cause of death)

Non-alcoholic fatty liver disease

Fatty liver disease and bariatric surgery(n=109 MO subjects with NASH prior to BS, 12 m FU)

Lasailly G et al, Gastroenterology 2015

NASH inflammatory activity grade Fibrosis stage

Persistence of NASH associated with higher IR, GGT, and NASH score at baselineand less weight loss

Non-alcoholic fatty liver disease

Fatty liver and bariatric surgery

Chalasani et al, Gastroenterology 2015

American Association for the Study of Liver DiseasesAmerican College of Gastroenterology

Non-alcoholic fatty liver disease

Medical therapies for NAFLD/NASH

Barb D et al, Metabolism 2016

Other: Antifibrotic drugs (elafibranor, simtuzumab), anti-inflammatory agents (cenicriviroc)

If Bariatric/Metabolic Surgery is to be central to NAFLD/NASH treatment, better level evidence should be generated

• Otherwise it risks to fall in the same situat

Weight Loss

Sjostrom L et al, JAMA 2014

The SOS Study: Prospective Non-Randomized Clinical TrialControl: n=2037, Bariatric Surgery: n= 2010 (matched for 18 clinically relevant variables)

Recruitment from September 1987 to January 2001

Long-term weight loss(Mean body weight at baseline 119 kg)

Weight Loss

Relevance of WL in “diabetes surgery”

Purnell JQ et al, Diabetes Care 2016

Following RYGB as compared to AGB

higher diabetes remission rates at comparable WL

LABS-2 cohort (677 subjects: 466 RYGB and 140 AGB)

STAMPEDE Trial-Cleveland Clinic: 3 years FU(n=137, Age 48 y, BMI 36,5 kg/m2, HbA1c preQ 9,3%, DM duration 8,3 y, Insulin Rx 43%)

Schauer et al. N Eng J Med 2014

Time course of HbA1c

• In the whole population: Change in BMI was the only predictor for 1ary aim [OR 1.41 (95%CI 1.22-1.64)]

• In the surgical groups: Change in BMI and T2D duration <8 years

The case of T2DRelevance of WL in “diabetes surgery”

Joosten SA et al, Sleep 2017

• Weight loss was the sole predictor of changes in total AHI

• Stronger association between changes in non-supineOSA and WL as compared to supine OSA and WL

• Suggestion for a threshold effect (little effect beyond10% WL)

• Althoug OSA was resolved only in 3% of the cohort, non-supine OSA was resolved in 22%

Relevance of WL for OSAH after BS

BS and OSAH: RCT conventional therapy vs gastric bandingPost-hoc analysis: Supine OSA vs non-supine OSA

(n=37 per group in whom >20 min of sp and non-sp PSMN were available)

0

10

20

30

40

50

60

70

80

90

100

0 4 8 12 16 20 24 36 48 60

Time after surgery (months)

Exce

ss W

eigh

t Lo

ss (

%)

(658)[658]

(658)[643]

(658)[622]

(658)[622]

(658)[539]

(658)[586]

(649)[596]

(640)[514]

(413)[382]

464

451

451389 427

438 438262

102129

132

137127143

146

148

3125 28 23

2226 23 18

Hospital Clinic, University of BarcelonaN=658 subjects with at least 24 mo follow up. GBP (70%) y SG (30%)

Good-WL72.3%

1ary poor-WL 4.7%

2ary poor-WL 23.0%

WL trajectories following GBP or SG

Vidal J et al, Ob Surg 2015

Weight Loss following BS

Vidal J et al. Unpublished data

0

10

20

30

40

50

2 y 5 y 8 y 10 y

Ind

ivid

ual

s (p

erce

nt)

“Poor” WL(<20% WL relative to baseline)

Ind

ivid

ual

s (p

erce

nt)

“Poor” WL(<50% EWL relative to baseline)

0

10

20

30

40

50

2 y 5 y 8 y 10 y

Case Series – Hospital Clínic, Cohort of patients operated in 2005-2006

N=292 1ary BS procedures [GBP (78%), SG (22%)]. Age 45 y, BMI 48 kg/m2, female 72%

Data at 10 y FU available in 200/272 subjects (74%) - 20 subjects died throughout FU

The importance of time elapsed after surgery

Weight Loss following BS

• What are the determinants of WL variability

• What’s the goal of WL of bariatric surgery?

Weight Loss following BS

Potentially affected by surgery

Determinants of variable weight loss

Biological factors

• Genetic factors • Conflicting results• Combination of up to 7 variants accounting for 11% EBMIL

• Gut hormones • No evidence for causality in humans

• Bile acids • No evidence for causality in humans

• Gut microbiota • No evidence for causality in humans

• Adipose tissue • Association between ECM fibrosis pre-Q and WL @ 12 m after BS

Cumulative food intake over the course of the test (kcal)

0

100

200

300

400

500

600

700

800

900

Saline Octreotide

Good-WL 2ary Poor-WL

393

579 519

P<0.001

758

P<0.001

P=0.014

P=0.036

Causation: cumulative FI of a SMLM over 60’ with or without blockade of GI hormonal secretion with

octreotide @ 72 mo after GBP

De Hollanda A et al. J Clin Endocrinol Metab 2015

Gut hormones and weight loss

Efficacy of the FXR activator obethicolic acid in humans(RCT: n= 283, age 52 y, BMI 35 kg/m2, 53% T2DM)

Weight loss Glucose metabolism

Neuschwander-Tetri BA et al. Lancet 2015

FXR activation and WL in humans

Arq Bras Cir Dig 2015

Based on Total WL at 6 mo after surgery:Controlled obesity : >20 %Partially controlled obesity: 10-20%Uncontrolled obesity: <10%

Although other factors should be considered in the definition of Obesity Control

(patient satisfaction, improvement of comorbidities, any WL prior tosurgery)

Weight regain:Recidivism: 50% of WL regained in the long term, or 20% WL-R if comorbidities relapseControlled recidivism: WL-R 20-50%Expected weight gain: WL-R <20%

Yet utilized, all the proposed cut offs are arbitrary and not based on clinicaloutcomes

Definition of succesful WL

• But no specific recommendation on how tocategorize success/failure.

• Difficult to standardize research in this area.

Brethauer SA et al. SOARD 2015

Definition of succesful WL

SummaryThe mainstream view of metabolic surgery…

Obesity is an heterogeneous disorder

One size does not fill all

(set for variability)

BS targets a limited set of the contributors to obesity

Limited response expected(set for failure)

SummaryStill a lot research is needed in this field!

• Better understanding of how to address such heterogeneity

• Better understanding of how to incorporate BS as part of a multicomponent thrapeuticapproach

Gracias por su atención