 Good morning. I'm going to speak to this symposium today on the metabolic and cardiovascular risks in obesity. Obesity is classified by the World Health Organization by increments really of five milligrams per meter squared where normal weight is defined as 18.5 to 24.9 from 25 to 30 is really considered overweight and then obesity is classed as any BMI over 30 and sub stratified as class one or mildly obese less than 35, moderately obese 35 to less than 40 and severe obesity greater than 40. There are other potential utilities of methods to assess adiposity that take into account other risk factors that may reasonably increase the prospective ability of us to gauge what cardiac or other risks might be and these methods assess the risk of visceral fat or adiposity around the middle of the body inside the viscera. The waist circumference, the waist to height ratio, the waist to hip ratio, the waist to hyper triglyceride is also another one and these are clinical tools that are being assessed to better delineate the risk of increasing cardiometabolic risk with weight that can be derived clinically easily from simple lab tests and from measurements at any office visit. Radiographic sub studies have shown that CT scans of the belly weighted for fat and MRI with fat localization techniques can much better able to discern the location of fat and a new technique which is called the DEXA scan which is simply the same scan that we use for bone mineral density can also be used to identify total body fat content as well as measurement of visceral fat is also in research techniques. So what about obesity? Well obesity in America as we all know has been increasing over the last 40 years. In fact obesity has doubled in 40 years in America and 70% of US citizens are now considered overweight or obese which is increased from 40% 40 years ago and you can see from 1991 to 2010 the average American has gone from you know blue in this 10 to 20 percent risk of being obese to now considerably we've had reddening of America with most Americans in states with a great propensity of patients over 20 BMI over 25. So we can look at the prevalence of self-reported obesity by the behavioral research study that's compiling data on behavioral risk in the American population and this is data the most recent data from 2020 that looks at obesity rates in states and there are now 16 states with the BMI over 30 in greater than 35% of the population of note four states join this not so admirable designation this year and Texas was among them so you can see that this bright deep deep crimson red is really the south and the Midwest and the states that have the lowest weights are Colorado Hawaii and Massachusetts and the states in the West and also Florida which is actually unique have lower weights and are in better shape if you look at the president the prevalence of diet of obesity among adults in Texas by region you can see that some regions have greater levels of obesity but certainly the prevalence of obesity in the state of Texas is the lowest around Austin and the highest in eastern Texas on the Louisiana line but certainly all of Texas is a really considerably obese and if we look at the percentage of obese high school students from 2019 the scale here is a lower scale so in fact the deepest darkest purple color codes for obesity rates of 15 to 19 percent but you can see that the state the same states that have high levels of adult obesity have high levels of high school students with obesity which is a harbinger of the future for us in the states because these teenagers are going to continue if unabated to become very obese adults which is going to increase the need for medical care in the future if we look at the Burfist data and we break it down by race we can see that non-Hispanic white adults have you know obesity rates this is red or dark red I mean the center of the country seriously high rates certainly the overall percentage of obesity is over 20% in all states in the unit in the union and certainly obesity rates above 30% are very common in all the Midwestern states all the southern states and the rust belt states if you break it down by Hispanic and non-Hispanic blacks you can see a darkening of the crimson red all over the country for Hispanics so you can see that in the red states anything red means the percentage of obesity over 35% in Hispanic adults the only states that don't have this high level are the extreme northeast Montana and Florida if you look at it for non-Hispanic blacks the crimson deep red is present which means obesity rates over 40% in all the states that are in that deep red including California so the metabolic consequences of obesity have been well described they include an increase in insulin resistance metabolic syndrome and type 2 diabetes it also includes hypertension atherogenic dyslipidemia with total elevated cholesterol elevated triglycerides elevated LDL elevated non HDL elevated small dense angry LDL particles with low HDL this is a typical atherogenic pro profile with increasing obesity rates there's an excess in LV volume and cardiac output goes up and this leads to ventricular remodeling with concentric hypertrophy LV and LA dilatation at the late and with LV dysfunction with heart failure both of low EF and preserved EF there's also indications that the metabolic consequences of obesity lead to endothelial dysfunction which leads to atherosclerosis leads to heart failure coronary disease AFib sleep apnea osteoarthritis and cancer so excess adipose tissue causes sleep apnea hypoventilation hypoxia pulmonary arterial hypertension pulmonary venous hypertension and this leads to RV hypertrophy RV enlargement and eventually core pulmonary RV failure if you look at just the circulating blood volume in obese subjects compared to non obese subjects the circulating blood volume is increased the systemic vascular resistance secondarily increases and this leads to increased pressures and increased wall stress in the heart which certainly leads to eccentric LV hypertrophy when adequately compensated leads to only diastolic LV dysfunction but when inadequate it leads to systolic as well as diastolic heart failure it's important to note that for every one point increase in BMI it raises the risk of heart failure by five percent in men and seven percent in women so if we look at death from any cause according to BMI it's well known to be associated with a J shape curve such that when BMI's are below normal or below 18.5 there's this little uptick at the bottom of the J of increased mortality which is thought to be mitigated by physical fitness certainly patients or cohorts with low BMI's may actually be selecting for patients with cokexy and chronic illness so in this important study where 1.46 million patients were followed in a cancer consortium in 19 cohorts with an average 10-year follow-up the subjects were stratified by those that had never stroked and that had never smoked pardon me and for those that were otherwise healthy and in this group certainly this is the blue curve there is a mitigation in that lower end of the J shape curve as well as a mitigation of mortality at the upper ends of the BMI but see here as the BMI increases above 20 all the way to 45 there is a doubling of the hazard ratio or a doubling of the risk of death which may partially be mitigated be influenced by obesity certain in a subjects of this number it gives more confidence that there's really an abnormality related to BMI the optimal BMI in this subject cohort was determined to be between 22.5 and 24.9 so what is it about obesity that gives such heterogeneity because in fact BMI itself is never has never been determined to be an independent cardiovascular risk modulator it's not an independent risk factor in the Framingham heart study or in any pool cohort equations for risk estimation the thought is that the traditional risk factors for heart disease diabetes hypertension and high cholesterol are confounders of obesity another factor that may play into the BMI not being an explainable independent cardiac risk factor is this obesity paradox which has been seen in many cohorts at this point which describes the fact that obese patients with a chronic illness may have better outcomes of an acute exacerbation of that illness compared to the non obese and there are a lot of considerations why this may be true and there's not enough time to divulge into that at this point but another factor that may make BMI not an independent risk is that obesity has many phenotypes and one of the phenotype of obesity is those patients that are obese may actually be very fit and this fitness phenotype may mitigate the risk otherwise that obesity poses more importantly the topography of adipose tissue or where adipose tissue is deposited has most recently been postulated to be a better predictor of cardiometabolic risk in these pooled cohort equations there is a term called the metabolically healthy obese which has been identified in some of these large cohorts and in these cohorts the obesity at BMI of over 30 that's associated with no other metabolic risk so no high blood pressure no low HDL no elevated LDL triglycerides or glucose are considered at baseline to be a relatively unique group but not uncommon so in the in Haines database 51% of overweight individuals in this cohort were considered metabolically healthy whereas 32% of the obese were metabolically healthy and obese so in this group it's thought that there may be less risk but subsequent studies have shown that the metabolically healthy but obese are still at increased risk compared to normal weight metabolically normal individuals in three separate cohorts in those that have been followed for 10-year mortality and for cardiac events there was a 24% increase risk of a negative outcome in those that are metabolically healthy but obese compared to normal weight metabolically normal individuals this is also been shown the metabolically healthy obese are also been shown to have increased risks of heart failure compared to the non obese particularly in those individuals with severe obesity and with long-standing obesity so in fact how long you've been obese may have an effect on your outcome and certainly in cardiovascular disease the metabolically healthy obese have a 60% increase risk in a meta meta analysis of 22 studies when compared to those that have normal weight and are otherwise metabolically normal fat distribution it turns out is an important risk modifier and the phenotype of the greatest risk would be those with visceral adiposity versus subcutaneous adiposity and the severity of how obese people patients are has an impact as well so in this study I mean in this cartoon you can see two individuals a 67 year old male with the BMI of 25 and visceral fat of 2.6 liters per meter squared and kind of low skeletal muscle mass look at the legs of the guy on the left he's kind of a skinny obese in fact his skeletal muscle mass is low and he has a lot of visceral adiposity compared to the gentleman to the right who's a 53 year old man with the BMI of 30 but a visceral fat of only 0.9 these two individuals have pretty disparate risks although the guy on the right has the BMI just barely in the obese range whereas the guy on the left has a lot of visceral obesity but overall his BMI is only 25 so in fact the heterogeneity of where we put adipose tissue can be subcutaneous which has been deemed to have less metabolic risk in fact the subcutaneous fat may actually be unique in its healthy mechanism because it acts as a buffer for free fatty acids which are collected when we have excess food intake and it can be easily shuttled into the subcutaneous tissue and access easily for times of increased physical demand and low caloric consumption visceral fat is really kind of a nasty fat in that it's dysmetabolic it contributes the most to the dysmetabolic state of insulin resistance it contributes to athrogenetic athrogenic um um lipid profile and an inflammatory milieu all of these things contribute to increase cardiovascular risk and potentially adverse major cardiac events a third kind of adiposity is ectopic adiposity which includes most commonly by definition distribution of fat into tissues that don't normally store fat the most common place where we see an abnormality of fat deposition is in liver concentration of fat which has been demarcated as an excess risk factor for heart disease and with liver failure which is non-alcoholic steatohepatitis ectopic fat distribution has been shown to be distributed in the heart and around the heart in the pericardium as well as in skeletal muscle tissue severe adiposity is associated with a bmi over 40 and in a bmi over 35 with one additional risk from obesity the factors that are associated with visceral adiposity include increasing biomarkers of hypertension insulin resistance inflammation high triglycerides remember that and high triglycerides are associated with small dense lipoproteins which increase their atherogenic profile these biomarkers increase the risk for atherosclerosis the deposition of calcium in the coronary arteries and such increase the coronary calcium score and lead to the deposition of plaque within the aorta certainly um visceral adiposity by definition is liver fatty disease and lifestyle behaviors including sedentary behavior poor nutrition high caloric intake and sweetened sugary beverages alcohol intake as well as smoking have been associated with the deposition of fat in the visceral location increasing age sex distributions and race certainly plays a role and we're going to get to that in a little bit certainly genetics play a role in where you put your fat a key and central illustration to visceral fat and cardiac risk is demonstrated in this slide that shows a guy with genetic susceptibility who's got energy in more than energy out and he has two choices to put fat he can put the fat into subcutaneous adipose tissue or in visceral adipose tissue all on the right of the screen which leads to fat infiltration of this visceral organs which leads to fatty liver fatty heart atherosclerosis as opposed to the guy who puts his fat in these subcutaneous tissue which is metabolically more inert and doesn't increase the risk of heart disease ectopic adipose tissue certainly is seen in NASH and unknown metabolic and genetic factors certainly are driving this ectopic fat deposition into these ectopic tissues severe adiposity associated with a bmi over 40 or a bmi over 35 with one additional risk modulator women are more likely than men to have severe adiposity and as our slides show African Americans are at greater risk than Hispanic who are at greater risk than white people but certainly no one in our country is immune from severe adiposity which is growing much more common over time the highest risk of cardiovascular disease is associated with severe adiposity certainly most importantly heart failure in fact 9.2 of the u.s population in 2020 was characterized as severely obese but almost 20 of patients that have heart failure have severe obesity so how do we measure adiposity well the bmi is the easiest and most standardized measurement it's in all the databases every patient's medical record it's just the weight in kilograms divided by the square root of the height in centimeters certainly addition of waist circumference is a better indicator of as an index of total body fat it also is an indicator of increased mortality risk in all bmi categories and is certainly an indicator of increased visceral adiposity which as we described is a greater risk to the health of our society the waist to hip the waist to height are also measurements that are easily obtained to estimate visceral fat the interesting factor is that high triglycerides when combined with the waist circumference may be a better indicator of visceral adiposity and many research projects are looking at this so stay tuned to future research that's going to come out looking at whether or not elevated triglycerides with an elevated waistline has an added benefit in all bmi categories certainly CT scans our research tools that have radiation exposure MRIs are also unique and used for research they're a little bit more time-consuming both of these techniques are more expensive the DEXA is kind of a unique opportunity to do quick kind of cheapish studies to look at how much fat is in the body and whether or not it's viscerally concentrated so here's a slide that looks at these potential uses for screening tests but importantly many of these tests are related to the ethnic propensity of a population to have visceral adiposity so you can see that in southeast asians and in japanese visceral adiposity is more prevalent at lower waistline circumferences so there's a lower threshold for calling somebody abnormal in japanese chinese and in southeast asians compared to patients of european descent this Edmonton obesity staging system is been developed and may be helpful to associate obesity with other metabolic and functional limitations related to obesity and you can use this for categorization of your clinic patients into better treatment groups the benefits of obesity are important because really we've identified a subgroup of americans and citizens all over the world that are at excess risk for metabolic and cardiometabolic risk but what can we do and how does treatment of obesity affect their outcome so it turns out that the three slides to the right demonstrate the results of the diabetes prevention program which is a uk-based intensive interventional lifestyle that was done in patients who had pre-diabetes which encouraged a seven percent or greater weight loss with 150 minutes of weekly exercise and in this study the top slide shows on the right that there was a 58 percent versus 31 percent reduction in the onset of type 2 diabetes with the intensive lifestyle modification compared to metformin which was intermediate to placebo the benefits of this program persisted for a long term which says that lifestyle intervention should be the hallmark of what we strive for unfortunately the risks of keeping the lifestyle intervention going at 15 years diminished and so there was attenuation of the effect over time although there was a reduction in cardiovascular risk factors you can see that on the side two slides of note the look ahead or action for health and diabetes trial looked at 5100 individuals with type 2 diabetes in a bmi over 25 they were randomized to intensive lifestyle versus regular diabetes education unfortunately there is no benefit to major adverse cardiac events which may be because a rigorous intervention isn't enough to make the risk decline so the treatment of obesity really is centered dramatically with lifestyle modification i would submit to you that lifestyle modification needs to precede the development of obesity because if we encourage our citizens to live a healthy active lifestyle with a concentration of plant-based diet with low-ish red meats and careful attention to you know lean white meats chicken and fish then we might improve our society by preventing obesity which is probably a better way to do it but once people have become obese certainly diet and exercise are the fundamentals of treatment for obesity related complications certainly the Mediterranean diet has been shown in patients at risk for cardiac events to decrease cardiac events even without weight loss among those that have diabetes in a study exercise itself has been shown to decrease visceral fat much greater than it reduces bmi and that this weight waste loss is more important than weight loss in the trajectory of treatment in the obese certainly exercise without weight loss significantly improves insulin sensitivity improves cardiac risk factors and biological risk factors better actually than pharmacologic interventions cardio metabolic fitness is the goal and the goal should be encouraged at every possible way we can in American society and in all visits to healthcare professionals weight loss itself is always the good goal but i really try to emphasize the things that you can control which includes your diet and your exercise routine because in many patients weight loss is very difficult and the lack of weight loss leads to um um decreased ability to participate in a diet and exercise program because people get so sad that they they didn't lose weight quickly the reduction in weight is also associated obviously with the reduction in visceral fat an increase in lean muscle mass a decrease in cardio metabolic risk and a decrease in ectopic fat deposition but most importantly 50 of people that lose weight have a remission in their um expected rates of diabetes pharmacologic agents are listed here but i'm going to concentrate on an important study this summer which looked at semi-glutide treatment in people with obesity but without diabetes so semi-glutide is a glp1 agonist which is important treatment in diabetes that has been shown to reduce cardiovascular events notably heart failure and in patients treated with up to one milligram weekly subcutaneously in those that have diabetes in this study however they took 1961 non-diabetic obese patients with a bmi over 30 or a bmi over 27 with one additional risk factor and they were treated with a scaled up approach placebo double-blinded two-to-one um randomization schema to semi-glutide versus placebo and you can see in the top schematic that as the dose is escalating and it escalates every four weeks from 0.25 to 0.5 to 1 to 2 to 2.4 it takes a while to get to the peak dose but weight loss starts occurring by two weeks into the treatment trial with the lowest dose of semi-glutide which says that this has a pretty profound effect on weight loss the glp1 agonists have been known to decrease appetite decrease gastric emptying and to reduce glucose over time certainly the thought is that in this study that the weight loss may be contributing to the effect of the treatment certainly we see in this treatment trial that a third of patients lost over 20 of their body weight which is by far the largest intervention pharmacologically for weight loss that's ever been seen which is the reason i highlight the study today 55 percent of the population lost greater than 15 percent and 75 percent of the population lost greater than 10 percent so certainly in this study which beat the diabetes prevention program considerably because that was just a seven and a half percent total body weight loss 75 percent of these patients achieved over 10 percent weight loss which is staggering so you would expect that in this population if they were at increased risk for diabetes that they would have a significant impact on that in the future the reduction in waste circumference in this trial was 13 and a half centimeters versus four which certainly argues that there was a significant reduction in visceral adipose tissue this trial went to 68 weeks and you can see that the curve split early and that there was continuing benefit really out to 60 50 late 50s 60 weeks where there was a plateau of the effect when we looked at semi-glutide in non-alcoholic steatohepatitis 300 and Nash patients were randomized with fibrosis and a bmi over 25 with or without diabetes 2.1 0.2 0.4 versus placebo and in this group steatohepatitis rates were dramatically reduced although fibrosis was not significantly altered in the entire group although in the group that got the 0.4 semi-glutide there was a reduction in fibrosis but the the trial was not powered to look at this treatment effect at that low rate bariatric surgery as by means probably the best weight loss producing remedy for severe obesity candidates for bariatric surgery include the severe obese with the bmi over 40 or those with the bmi over 35 with additional risk including Nash with fibrosis after they failed a six-month lifestyle modification the bariatric surgery options now include really two surgical procedures the gastric ruin wide bypass which is being performed in about 20 to 25 percent of cases and the sleeve gastrectomy which has turned out to be really efficacious procedure originally it was intended as just the first phase of the gastric bypass in the super obese in whom weight loss was hopefully going to be activated and a secondary surgery for the full bypass was planned for later but with sleeve gastrectomy at 75 percent of the procedures today the sleeve gastrectomy is overtaken all forms of gastric surgery options the gastric banding is a less prevalent because it doesn't have enduring results and is now performed in less than five percent of cases of note gastric bypassed or sleeve gastrectomy is associated with significant sustained weight loss at least 60 percent 66 percent of the body mass and certainly even greater for gastric full bypass at 70 to 80 percent visceral adiposity is decreased 40 to 50 percent as well as subcutaneous adipose tissue decreasing by 10 percent so primarily the weight loss from gastric surgery is visceral adiposity which is really what you want to get rid of because it's the nasty fat diabetes remission rates for the bypass and the gastrectomy is about 66 percent by banding early on it may be 29 percent but that is attenuated over time the benefits of gastric surgery increase decrease the risk of heart failure decrease risk of Nash and liver failure in the end obesity affects every aspect of a person's lives from health to relationships to how you feel about yourself to orthopedic injuries to the increased risk of cancer and suddenly every opportunity that we can to reinforce a healthy lifestyle and plant-based diet should be followed in order to improve the health in our lives thank you for participating in this conference today your attendance is so so helpful to helping sustain this symposium over the over the years thanks again