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