The Four “Links” of Obesity: Diabetes, Fatty Liver...
Transcript of The Four “Links” of Obesity: Diabetes, Fatty Liver...
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