The Four Links of Obesity: Diabetes, Fatty Liver, Cardiomyopathy and AF The Potential Benefit and Rapid Evolution of Bariatric Surgery

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1 The Fur Links f Obesity: Diabetes, Fatty Liver, Cardimypathy and AF The Ptential Benefit and Rapid Evlutin f Bariatric Surgery Michael E. Farkuh, MD, MSc Peter Munk Chair in Multinatinal Clinical Trials Directr, Heart and Strke Richard Lewar Centre Vice Chair Research and Prfessr Of Medicine University f Trnt

2 Disclsures Research Grant: Amgen

3 The Fur Links f Obesity Obesity is a public health issue, thrugh cmmn pathways, that links: Diabetes Fatty Liver Disease Cardimypathy Atrial Fibrillatin Weight Lss including Bariatric Surgery is the crnerstne f breaking these links and t restring health

4 BMI Fr adults, verweight and besity ranges are determined by using weight and height t calculate a number called the "bdy mass index" (BMI). BMI is used because, fr mst peple, it crrelates with their amunt f bdy fat. See the fllwing table fr an example: Height Weight Range BMI Cnsidered 5' 9" 124 lbs r less Belw 18.5 Underweight 125 lbs t 168 lbs 18.5 t 24.9 Healthy weight 169 lbs t 202 lbs 25.0 t 29.9 Overweight 203 lbs r mre 30 r higher Obese Other methds f estimating bdy fat and bdy fat distributin include measurements f skinfld thickness and waist circumference, calculatin f waistt-hip circumference ratis, and techniques such as ultrasund, cmputed tmgraphy, and magnetic resnance imaging

5 Age-adjusted Prevalence f Obesity and Diagnsed Diabetes Amng US Adults Obesity (BMI 30 kg/m 2 ) N Data <14.0% 14.0% 17.9% 18.0% 21.9% 22.0% 25.9% > 26.0% Diabetes N Data <4.5% 4.5% 5.9% 6.0% 7.4% 7.5% 8.9% >9.0%

6 Natural Histry f Type 2 Diabetes Typical Prgressin f Disease and Treatment Years frm diagnsis Onset Diagnsis Insulin Insulin resistance Insulin secretin Oral mntherapy Oral cmb therapy Diet and exercise Pstprandial glucse Fasting glucse Pre-diabetes Micrvascular cmplicatins Macrvascular cmplicatins Type 2 diabetes Raml-Halsted BA, Edelman SV. Prim Care. 1999;26: Nathan DM. N Engl J Med. 2002;347:

7 Rle f inflammatin in the pathphysilgy f type 2 diabetes and the increased risk f CVD Adapted frm Esser N, et al. Expert Opin Investig Drugs Mar;24(3):

8 Nn Alchlic Fatty Liver Disease (NAFLD): an Epidemilgical and Mlecular Perspective Abnrmalities in fatty acid metablism, alng with adipse tissue, hepatic, and systemic inflammatin are implicated in the develpment f insulin resistance, dyslipidemia, and cardimetablic risk factrs assciated with NAFLD. The prevalence f NAFLD is 80-90% in bese adults. Adapted frm: Bellentani S et al. Dig Dis 2010;28(1):155-61Bekaert M, et al. Obes Rev Jan;17(1):68-80.

9 Ptential targets fr pharmactherapy in type 2 diabetes and related metablic abnrmalities and CVD Adapted frm Esser N, et al. Expert Opin Investig Drugs Mar;24(3):

10 The Elephant in the Rm: 1.8 millin Americans with the Obesity and Heart Failure with Preserved Left Ventricular Functin (HFpEF) Phentype HFpEF is assciated with substantial mrbidity and mrtality HFpEF is characterized by impaired diastlic functin caused by impaired cllagen metablism and increased mycardial fibrsis Obesity is an independent predictr f advanced NYHA class and an independent predictr f a future event f hspitalizatin fr HF r CV death Pathphysilgy: Adipse tissue is metablically active and elabrates inflammatry cytkines; Assciated with Hypertensin Dals D, et al. JACC Jul 12;68(2): Kitzman DW, et al. JACC Jul 12;68(2):200-03

11 Incidence f Atrial Fibrillatin and Relatinship With Cardivascular Events, Heart Failure, and Mrtality: A Cmmunity-Based Study Frm the Netherlands Figure Legend: AF in a Cmmunity-Based Chrt in the Netherlands: Multivariate Determinants f Incident AF Bars represent the hazard rati fr incident atrial fibrillatin (AF) f each individual risk factr in the multivariate mdel. The 95% cnfidence intervals (CIs) are shwn under each bar. BMI = bdy mass index; HT = antihypertensive; MI = mycardial infarctin. Vermnd, RA, et al. JACC. 2015, 66(9):

12 Electrphysilgical, Electranatmical, and Structural Remdeling f the Atria as Cnsequences f Sustained Obesity Mahajan R et al, JACC Jul 7;66(1):1-11

13 Appraches t Obesity Cntrl Obesity requires lng-term treatment Weight lss f kg assciated with: 53% reductin in cancer deaths 44% reductin in diabetes assciated mrtality 20% reductin in ttal mrtality Survival increased 3-4 mnths fr every kg f weight lss Mdest, sustainable weight lss can be achieved Gregg EW et al. Ann Intern Med. 2003

14 Bariatric Operative Appraches Restrictive Gastric Banding Restrictive Gastric Sleeve cc new stmach puch Stmach that Is remved Cmbined Rux-en-Y Gastric Bypass Cmbined Bilipancreatic diversin Puch ml Dudenum Bypassed prtin f stmach Lng rux-limb 200 cm 50 cm Cln Cmmn limb Curtesy f David Lau, Univ. f Calgary

15 Bariatric Surgery/ Diabetes Outcmes: STAMPEDE: 3-Year Results Schauer PR et al. N Engl J Med 2014;370:

16 Summary f Chrt Studies Examining the Effect f Bariatric Surgery n NAFLD (Clantn J et al., Surgical Clinics f Nrth America 2016) Study # f Subjects Type f Surgery Primary Outcme Fllw-up (ms) Kral BPD Severe fibrsis decreased in ± 25 Keshishian BPD 60% imprvement in steatsis 6 36 Mattar RYGB Imprvement f 83% in grade f liver disease 15 ± 9 Mttin RYGB 82% had imprvement r reslutin f steatsis 12 Stratpuls 2005 Dixn AGB 51 VBG Steatsis imprved in 84.3% 18 ± 9.6 Reduced high-grade steatsis frm 77% t 20% 29.5 ± 16 Mathurin BIB, RYGB, AGB Decreased steatsis frm 37.4% t 16% 50 ± 7.8 Weiner RYGB, AGB, and BPD Cmplete regressin f NAFLD in 83% 18.6 ± 8.3 Karcz LSG Transaminase levels reduced >50% 12 Mrett RYGB Decreased fibrsis frm 45% t 31% Unavailable Cazz RYGB Reslutin rate f advanced fibrsis f 55% 12

17 Bariatric Surgery and CV utcmes: Systematic review f 18 studies with mean fllw-up f 58 mnths Excess weight lss (EWL) 54% N f subjects cntributing 19,021 Baseline % Reslutin Imprvement Crrected effect estimates (95% CI) Hypertensin 44.4% 62.5% 0.36 (0.31 t 0.42) Diabetes mellitus 24.0% 73.2% 0.26 (0.21 t 0.31) Hyperlipidemia 43.6% 65.2% 0.34 (0.28 t 0.40) Baseline Fllw-up Bld Pressure (mm Hg) Systlic Diastlic Lipid prfile (mg/dl) Ttal chlesterl LDL Amanda RV, et al. Heart Dec;98(24):

18 Bariatric Surgery and Lng-term Cardivascular Events Figure Legend: The cmbined end pint f mycardial infarctin and strke, whichever came first, with fatal cardivascular events and ttal (fatal and nnfatal) cardivascular events are shwn The incidence rates per 1000 persn-years fr fatal cardivascular events were 0.9 the surgery grup and 1.7 in the cntrl grup; and fr ttal cardivascular events, 6.9 and 8.3, respectively Sjöström L, et al. JAMA. 2012;307(1):56-65

19 Effect f Weight Reductin and Cardimetablic Risk Factr Management n Symptm Burden and Severity in Patients With Atrial Fibrillatin: A Randmized Clinical Trial Figure Legend: Changes in Atrial Fibrillatin Symptm Scale (AFSS) Scres Over Study A, Between-grup level f significance: P =.41 at time 0, P =.12 at 3 mnths, P <.001 at 6, 9, 12, and 15 mnths B, Between-grup level f significance: P =.49 at time 0, P =.17 at 3 mnths, P <.001 at 6, 9, 12, and 15 mnths Abed, HS, et al. JAMA. 2013;310(19):

20 Lng-term Effect f Gal-Directed Weight Management in an Atrial Fibrillatin Chrt: LEGACY Study 1415 cnsecutive patients symptmatic parxysmal r persistent (>1 week) AF 825 had BMI 27kg/m 2 risk factr management and participatin in a tailred exercise prgram 355 were included in this analysis Weight lss was categrized Grup 1 ( 10%) Grup 2 (3% t 9%) Grup 3 (<3%) Pathak RK et al. JACC. 2015; 65(20):

21 Ablatin free drug free AF freedm Ttal AF freedm LEGACY TRIAL Time (Days) % WL % WL % WL r Gain Pathak RK et al. JACC. 2015; 65(20):

22 Future Cnsideratins fr Bariatric Surgery We can impact n all 4 links t Obesity We shuld press fr CV utcmes trials The duratin f diabetes may play a rle: cnsideratin f earlier surgery instead f the current salvage apprach Lwering the BMI threshld frm 35 t 30 wuld have the ptential fr high public health impact Wrk in multidisciplinary teams nt in sils

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