Michael E. Farkouh, MD, MSc

Peter Munk Chair in Multinational Clinical Trials

Director, Heart and Stroke Richard Lewar Centre

Vice Chair Research and Professor Of Medicine

University of Toronto

The Four “Links” of Obesity:

Diabetes, Fatty Liver, Cardiomyopathy and AF

The Potential Benefit and Rapid

Evolution of Bariatric Surgery

o Research Grant: Amgen

Disclosures

Obesity is a public health issue, through common

pathways, that links:

o Diabetes

o Fatty Liver Disease

o Cardiomyopathy

o Atrial Fibrillation

Weight Loss including Bariatric Surgery is the cornerstone

of breaking these links and to restoring health

The Four Links of Obesity

For adults, overweight and obesity ranges are determined by using weight and

height to calculate a number called the "body mass index" (BMI). BMI is used

because, for most people, it correlates with their amount of body fat.

See the following table for an example:

Height Weight Range BMI Considered

5' 9"

124 lbs or less Below 18.5 Underweight

125 lbs to 168 lbs 18.5 to 24.9 Healthy weight

169 lbs to 202 lbs 25.0 to 29.9 Overweight

203 lbs or more 30 or higher Obese

Other methods of estimating body fat and body fat distribution include

measurements of skinfold thickness and waist circumference, calculation of waist-

to-hip circumference ratios, and techniques such as ultrasound, computed

tomography, and magnetic resonance imaging

BMI

Obesity (BMI ≥30 kg/m2)

Diabetes

1994

1994

2000

2000

No Data <14.0% 14.0%–17.9% 18.0%–21.9% 22.0%–25.9% > 26.0%

No Data <4.5% 4.5%–5.9% 6.0%–7.4% 7.5%–8.9% >9.0%

2014

2014

Age-adjusted Prevalence of Obesity

and Diagnosed Diabetes Among US Adults

http://www.cdc.gov/diabetes/data

Insulin secretion

0 5-10

-5 10 15

Pre-diabetes

Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26:771-789Nathan DM. N Engl J Med. 2002;347:1342-1349

Insulin resistance

Postprandial glucose

Fasting glucose

Type 2 diabetes

Years from diagnosis Onset Diagnosis

Oral combo therapy

Insulin

Macrovascular complications

Diet and exercise

Oral monotherapy

Microvascular complications

Natural History of Type 2 Diabetes

Typical Progression of Disease and Treatment

Adapted from Esser N, et al. Expert Opin Investig Drugs. 2015 Mar;24(3):283-307

Role of inflammation in the pathophysiology of

type 2 diabetes and the increased risk of CVD

Non‐Alcoholic Fatty Liver Disease (NAFLD):

an Epidemiological and Molecular Perspective

Abnormalities in fatty acid metabolism, along with adipose tissue, hepatic, and systemic

inflammation are implicated in the development of insulin resistance, dyslipidemia,

and cardiometabolic risk factors associated with NAFLD.

The prevalence of NAFLD

is 80-90% in obese adults.

Adapted from: Bellentani S et al. Dig Dis 2010;28(1):155-61Bekaert M, et al. Obes Rev. 2016 Jan;17(1):68-80.

Adapted from Esser N, et al. Expert Opin Investig Drugs. 2015 Mar;24(3):283-307

Potential targets for pharmacotherapy in type 2 diabetes

and related metabolic abnormalities and CVD

o HFpEF is associated with substantial morbidity and mortality

o HFpEF is characterized by impaired diastolic function caused by impaired collagen metabolism and increased myocardial fibrosis

o Obesity is an independent predictor of advanced NYHA class and an independent predictor of a future event of hospitalizationfor HF or CV death

o Pathophysiology:

• Adipose tissue is metabolically active and elaborates inflammatory

cytokines;

• Associated with Hypertension

Dalos D, et al. JACC. 2016 Jul 12;68(2):189-99

Kitzman DW, et al. JACC. 2016 Jul 12;68(2):200-03

The Elephant in the Room: 1.8 million Americans with the Obesity and Heart Failure with

Preserved Left Ventricular Function (HFpEF) Phenotype

Vermond, RA, et al. JACC. 2015, 66(9):1000–1007

Figure Legend:

AF in a Community-Based Cohort in the Netherlands: Multivariate Determinants of Incident AF

Bars represent the hazard ratio for incident atrial fibrillation (AF) of each individual risk factor in the

multivariate model. The 95% confidence intervals (CIs) are shown under each bar. BMI = body mass

index; HT = antihypertensive; MI = myocardial infarction.

Incidence of Atrial Fibrillation and Relationship With

Cardiovascular Events, Heart Failure, and Mortality:

A Community-Based Study From the Netherlands

Mahajan R et al, JACC. 2015 Jul 7;66(1):1-11

Electrophysiological, Electroanatomical, and Structural

Remodeling of the Atria as Consequences of Sustained Obesity

Obesity requires long-term treatment

Weight loss of 0.5-9 kg associated with:

o 53% reduction in cancer deaths

o 44% reduction in diabetes associated mortality

o 20% reduction in total mortality

Survival increased 3-4 months for every kg of weight loss

Modest, sustainable weight loss can be achieved

Gregg EW et al. Ann Intern Med. 2003

Approaches to Obesity Control

Restrictive Gastric Banding Restrictive Gastric Sleeve

Combined Roux-en-Y Gastric Bypass

Bariatric Operative Approaches

60-80 cc new stomach pouch

Stomach thatIs removed

200-500ml

200 cm

50 cm

Bypassed portion of stomach

Long roux-limb

Common limbColon

Duodenum

Pouch

Combined Biliopancreaticdiversion

Courtesy of David Lau, Univ. of Calgary

Schauer PR et al. N Engl J Med 2014;370:2002-2013

Bariatric Surgery/ Diabetes Outcomes: STAMPEDE: 3-Year Results

Study# of

SubjectsType of Surgery Primary Outcome

Follow-up

(mos)

Kral 2004 104 BPD Severe fibrosis decreased in 27 41 ± 25

Keshishian 2005 78 BPD 60% improvement in steatosis 6–36

Mattar 2005 70 RYGB Improvement of 83% in grade of liver disease 15 ± 9

Mottin 2005 90 RYGB 82% had improvement or resolution of steatosis 12

Stratopoulos 2005

51 VBG Steatosis improved in 84.3% 18 ± 9.6

Dixon 2006 60 AGBReduced high-grade steatosis from 77% to

20%29.5 ± 16

Mathurin 2009 381 BIB, RYGB, AGB Decreased steatosis from 37.4% to 16% 50 ± 7.8

Weiner 2010 116RYGB, AGB, and

BPDComplete regression of NAFLD in 83% 18.6 ± 8.3

Karcz 2011 236 LSG Transaminase levels reduced >50% 12

Moretto 2012 78 RYGB Decreased fibrosis from 45% to 31% Unavailable

Cazzo 2015 63 RYGB Resolution rate of advanced fibrosis of 55% 12

Summary of Cohort Studies Examining the Effect of Bariatric Surgery

on NAFLD (Clanton J et al., Surgical Clinics of North America 2016)

Excess weight loss (EWL) 54%

Baseline% Resolution

Improvement

Corrected effect

estimates (95% CI)

Hypertension 44.4% 62.5% 0.36 (0.31 to 0.42)

Diabetes mellitus 24.0% 73.2% 0.26 (0.21 to 0.31)

Hyperlipidemia 43.6% 65.2% 0.34 (0.28 to 0.40)

Baseline Follow-up

Blood Pressure (mm Hg)

Systolic 140.2 129.6

Diastolic 87.6 80.2

Lipid profile (mg/dl)

Total cholesterol 213.6 184.5

LDL 115.5 90.5

N of subjects contributing 19,021

Amanda RV, et al. Heart. 2012 Dec;98(24):1763-77

Bariatric Surgery and CV outcomes: Systematic review of 18 studies with mean follow-up of 58 months

Sjöström L , et al. JAMA. 2012;307(1):56-65

Figure Legend:

The combined end point of myocardial infarction and stroke, whichever came first, with fatal

cardiovascular events and total (fatal and nonfatal) cardiovascular events are shown

The incidence rates per 1000 person-years for fatal cardiovascular events were 0.9 the surgery

group and 1.7 in the control group; and for total cardiovascular events, 6.9 and 8.3, respectively

Bariatric Surgery and Long-term Cardiovascular Events

Abed, HS, et al. JAMA. 2013;310(19):2050-2060.

Figure Legend:

Changes in Atrial Fibrillation Symptom Scale (AFSS) Scores Over Study

A, Between-group level of significance: P = .41 at time 0, P = .12 at 3 months, P < .001 at 6, 9, 12,

and 15 months

B, Between-group level of significance: P = .49 at time 0, P = .17 at 3 months, P < .001 at 6, 9, 12,

and 15 months

Effect of Weight Reduction and Cardiometabolic Risk Factor Management on Symptom Burden and Severity in Patients With

Atrial Fibrillation: A Randomized Clinical Trial

1415 consecutive patients symptomatic paroxysmal or persistent

(>1 week) AF

825 had BMI ≥ 27kg/m2

o risk factor management and participation in a tailored

exercise program

o 355 were included in this analysis

o Weight loss was categorized

Group 1 (≥10%)

Group 2 (3% to 9%)

Group 3 (<3%)

Pathak RK et al. JACC. 2015; 65(20):2159–2169

Long-term Effect of Goal-Directed Weight Management

in an Atrial Fibrillation Cohort: LEGACY Study

Time (Days) 0 365 730 1095 1460 1825 0 365 730 1095 1460 1825

10% WL 135 101 72 42 31 13 135 130 114 86 67 36

3-9% WL 103 62 36 22 13 7 103 93 83 57 35 22

3% WL or Gain 117 66 44 22 11 9 117 105 85 53 32 22

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Pathak RK et al. JACC. 2015; 65(20):2159–2169

LEGACY TRIAL

o We can impact on all 4 links to Obesity

o We should press for CV outcomes trials

o The duration of diabetes may play a role: consideration

of “earlier” surgery instead of the current “salvage”

approach

o Lowering the BMI threshold from 35 to 30 would have

the potential for high public health impact

o Work in multidisciplinary teams not in silos

Future Considerations for Bariatric Surgery