Freed: This is Steve Freed and we’re here at the 2018 AACE meeting. We have a special guest with us who we have talked to before, Dr. Timothy Garvey, and he is very interesting. I’ve got 22 paragraphs about your background but maybe you can give us a 30-second overview of who you are and what you do.
Garvey: I am Tim Garvey, that’s right. I am an endocrinologist. I’m a professor at the University of Alabama at Birmingham, UAB and director of the NIH funded UAB Diabetes Research Center there. I am in academic practice – education and research. My whole career I’ve been interested in insulin resistance and diseases that are characterized by insulin resistance, including diabetes and obesity. And I have enjoyed that tremendously and that’s where I am now.
Freed: Great. Your presentation is called, “Obesity Pharmacotherapy and Alice in Wonderland: Which Cake Will Make You Smaller?”
Freed: I have no clue what that is about so maybe you can explain it?
Garvey: Well, you know the Alice in Wonderland story. So she took a pill, well not a pill, that’s the Jefferson Airplane song. Lewis Carroll (author of Alice in Wonderland) said she ate a cake and she’d get bigger and then another cake and she’d get smaller. So the question in obesity is which weight loss medication do you need to make you smaller? The answer is, there is no one medication that can be recommended above all others across the board. Like [what] we do in diabetes [is], everybody begins with Metformin, but that is not true in obesity. All the medications we have, have different mechanisms of action, different side effects, profiles, different warnings and cautions, different medicine interactions. We really just have to know the pharmacology of these drugs to individualize our therapy for the best outcomes. I wish it was easier but generally as patients come in the door that is really what we have to deal with. So it’s really a matter of learning some pharmacology about these drugs – there’s five that are approved for chronic treatment of obesity by the FDA. It’s not a million drugs so it’s something we can get our arms around. It just requires a little bit of work to get knowledgeable on that.
Freed: If you go back maybe 40 years ago, you’d have diet doctors and you go in and you get speed and it would cause you not to eat as much and maybe clean the house a little bit more effectively. How has it all changed?
Garvey: Well, that’s not an option for long-term therapy, obviously, I mean there are addiction issues and health-related issues there; there’s no long-term safety outcomes for those types of drugs including, for that matter, phentermine and related sympathomimetic means that are approved for short-term treatment of obesity. Usually that’s felt to be three months or less. When those drugs were approved in the 1950s and 1960s, the FDA did not require year-long studies or real rigorous safety-efficacy type studies like they do now. So, we don’t have safety data on phentermine even though it’s the most widely-prescribed drug for obesity at this point, it’s generic. The five that are approved for long-term, chronic therapy are lorcaserin, combination phentermine, topiramate extended release, we have naltrexone extended release, combined with bupropion extended release, liraglutide 3mg which is an injectable, and orlistat.
Freed: So what other changes have you seen in the treatment of obesity as far as maybe the education has changed quite a bit. We know the drugs have changed but where do you see the biggest changes?
Garvey: Well, you know, we’ve made slow progress actually. What we do know more about is the pathophysiology of obesity – the mechanisms that underscore why this is a disease process that involved interactions between satiety hormones that derive from the gastrointestinal tract, how they interact with the satiety center and the hypothalamus, and that’s regulated to create and sustain a higher body weight in people with the disease. Inheriting numbers of susceptibility genes is a part of that, but if you have a lot of susceptibility genes, each conferring a very small relative risk to the disease, but in aggregate, you’re going to have a greater body weight than somebody who doesn’t have those genes at any given environment – there is always an interaction between genes and environment. That is the disease process and the medications that we have act on those satiety centers, and that is why they help patients out – they help them adhere to reduced calorie diet by blunting appetite. That is really the bottom line. And that is all kind of new.
Freed: Nutrition and physical activity are important components of obesity. If you had to put a percentage on it to show the importance, you know, 80 percent nutrition, 20 percent physical activity, to you, what would it be?
Garvey: The bottom line is a reduced calorie diet. If you are not eating less calories, one way or the other, you are not going to lose weight and achieve the therapeutic goals. So, you need a reduced caloric diet. Now, exercise is a caloric expenditure but it’s relatively minor in terms of the grand scheme of things. Exercise is important, though, particularly for weight loss maintenance. It also improves health in general and makes you feel better and improves your morale. Exercise is definitely part of the lifestyle therapy plan as well as behavioral modifications like recording your weight and your activity and your food intake – just the act of self-recording is an important behavior that helps us to sustain part of a successful lifestyle intervention plan. It’s all designed to help patients adhere to a reduced calorie meal plan. In the end, that’s what medications do as well. So, I would say, the nutritional aspect, a meal plan, is the most important component.
Freed: Can I ask you a personal question?
Freed: What do you do for physical activity?
Garvey: I am a member of the YMCA and I do an elliptical three times a week and do some light resistance exercise with the Nautilus-type machines and listen to Netflix TV series when I am on the elliptical. So that is what I do.
Freed: I’m a firm believer that you have to do it if you tell your patients to do it?
Garvey: (Laughs) Yes, that’s right.
Freed: You’ve been very active in writing the AACE guidelines for obesity. What difference from the TOS/AHA/ACC [The Obesity Society, American Heart Association, American College of Cardiology] guidelines, endocrine guidelines, and the ADA guidelines, OMA guidelines — have you seen? There are so many guidelines and it can make it very confusing for a physician to know which one to follow.
Garvey: Yes. It is confusing and they’re all valuable for certain reasons and I will just briefly go through this. The American Heart Association, American College of Cardiology, and the Obesity Society guidelines were really the first out there. They proposed five questions to address around which there were randomized clinical trials upon which to base their recommendations. The five medications approved for chronic therapy that I mentioned weren’t even approved at that point so they really dealt with a lifestyle and the bariatric surgery issues and came up with recommendations that are pretty reasonable there. But they weren’t really comprehensive in that sense that medications were not part of the overall guidelines. The Endocrine Society have focused on pharmacotherapy and they have reviewed the evidence and basically confirmed the FDA prescribing information is grounded in science. I think their biggest contribution was pointing out iatrogenic obesity. In other words, medications we used for other kinds of comorbidities that really produce more weight gain and make the problem worse and suggest other alternatives for blood pressure medicines or anti-depression type medicines that are associated with less weight gain. So, I think that brought that into the picture very clearly and I think they are very valuable for that reason. The Obesity Medical Association has some guidelines that I think are very good, they are kind of expert opinion, they weren’t subjected a rigorous peer-review process, they are not published in a journal, they’re on their website, but they are very practical and are evidence-based in the final analysis. In fact, they’re kind of similar to the AACE guidelines which I am familiar with because I was a lead author on those. When AACE does the guidelines, they ask all of the questions that are relevant to real-world patient care. Not just questions around which there are randomized clinical trials to address. So what are all the issues that we have to address when a patient walks in the door and we engage them in a long-term therapeutic plan. And then we bring the best level of evidence that there is to address all of those questions and then grade the strength of the recommendations based on the strength of the evidence. But at least we come up with the recommendation based on, again, the totality of the evidence and the best level of evidence there is to help clinicians navigate their way through obesity management. So we had like 123 questions relevant to screening, diagnosis, evaluation, disease staging, therapeutic decision-making, goals of therapy for long-term follow-up, and so I think they are more comprehensive and evidence-based from that perspective. And so, we really kind of look at the goals of therapy to improve the health of the patient, not to get X number of pounds off, but to lose sufficient weight to improve the health of the patient, which we define as the prevention and treatment of weight-related complications. We do this because those are what make the patient sick – it’s the complications that produce the morbidity and mortality of the disease and here I am talking about prediabetes, diabetes, dyslipidemia, hypertension, nonalcoholic fatty liver disease, NASH, those are kind of cardiometabolic related diseases. In addition, what I call the biomechanical complications that are due to kind of carrying around excess body weight over a number of years – obstructive sleep apnea, stress incontinence, osteoarthritis, these are very important complications as well. Those are the things we want to prevent or ameliorate with weight-loss therapy. So, AACE’s kind of strategy for care is really to address the patient from that perspective to improve their health. It’s not a cosmetic in that sense, it’s not to get X number of pounds off, but it’s more of a disease-oriented approach I think.
Freed: Let’s talk about obesity in children. We’re finding more and more of this every day and there are headlines all the time about type 2 diabetes for kids in their teens and kids in grammar school. None of the drugs, I believe, are approved for young children so how do you deal with that?
Garvey: This is such a big problem and there are a lot of pediatric cases that are very sad actually. We have children and adolescents that are very heavy and this really impacts their quality of life. The challenges that adolescents have, they have enough on their plate to begin with. We have patients that even have a hard time kind of moving and walking, and these are just sad cases. We don’t have the tools we need to really be effective in this domain. There is a big clinical need. So we really have to work with lifestyle but first you’ve got the child, then you’ve got the family unit, and then you’ve got the school and the larger environment that the child lives in – you can’t just intervene at any one of those, you’ve got to bring that all together if you’re going to be successful. So that is challenging to a clinician obviously. In our weight loss medicine, we call it at UAB, where we have bariatric surgery, endocrinology, and nutrition sciences, kind of internal medicine obesity medicine specialists in there with dieticians and the clinical psychologists and an exercise trainer and what not, but, we’re bringing in pediatrics to develop more family-based approaches. But it’s largely lifestyle, some physicians use metformin, I’m not sure how successful that is but all of the pharma companies that have developed weight loss medications are mandated by the FDA to do clinical trials in children and adolescents. Some of those are ongoing for some of those medications and some of them haven’t started up yet but that is really what I think is going to be helpful when we do have effective medications to bring in to that treatment of that age group.
Freed: At what point would you prescribe bariatric surgery for obesity for an adult?
Garvey: Well, there is definitely a place for bariatric surgery. I think if you just follow the guidelines which are being updated right now by AACE and the American Society of Metabolic and Bariatric Surgery, if you have a BMI greater than 40, regardless of the complication burden, that satisfies criteria, or if its 35-40 BMI, with complications, that satisfies the criteria. I find most useful in patients with a BMI greater than 40 who have diabetes and a lot of associated hypertension and dyslipidemia who are on a lot of medicines, the bariatric surgery particularity roux-en Y gastric bypass or a sleeve gastrectomy can be very helpful to those patients. We’re getting hints that, that even promotes longevity in cohort studies. So, I think that, that’s the most valuable use of bariatric surgery in the patients that I deal with.
Freed: Have you heard of anything? There is so much research going on and so many studies going on when it comes to obesity. Have you participated or have you read about something that you have a lot of hope for?
Garvey: Well, yes, I think there is a lot of new drugs being developed around these satiety hormones and their targets in the hypothalamus. Most of these are peptides so they will be injectable unless we can figure out a way to orally take peptides and work is being done there too. But doing combinations of these peptides, any one single medication that acts on one pathway. There’s so much redundancy and so many pathways creating excess calorie intake in patients with this disease that the more pathways you can hit, the more effective you’re going to be. So combinations of these medicines, including combinations of new peptides designed around satiety hormones that we really haven’t developed therapeutics for at this point, I think are really going to be the answer. There’s one glp-1 receptor agonist that we now have for diabetes, semaglutide, which is a once-a-week preparation that is one milligram. The company Novo Nordisk is developing this medication at a higher dose, 2.4 milligrams a week for a weight loss indication. Some of the early phase 2 data are very promising – really kind of bringing weight loss down into the level that we could achieve by lap band surgery. So we are beginning to close the gap between medications and bariatric surgery there. Of course, this medication is not on the market yet but it’s just an example of developing medications that are going to be more effective in the clinic.
Freed: You had mentioned before that obesity is now a disease. But when it comes to coding for physicians it’s still in the primordial stage and they haven’t addressed that yet.
Garvey: Yes, this is a sad situation. The most common code for obesity, E66, says obesity due to excess calorie intake. And you translate that and what it means is that you are fat because you eat too much. If you were an employer and you had a thousand employees and you were negotiating benefit coverage plans for your employees and you had to pay a little more to cover them for obesity medicine and the code was, you’re fat because you eat too much, you’re not going to be too inclined to pay extra money to cover your employees there. It’s not scientifically based, it’s antiquated notions about obesity. Patients aren’t obese because they want to be – they don’t say I’m going to eat food until I have a BMI of 35 and I’ll just stop there. That’s just not how it works. They have a disease process that creates that excess adiposity and how that impacts their health. So, I think we need a more kind of scientifically-based disease-based coding system for the disease. I think AACE is developing a positioning statement right now based on their new diagnostic term for obesity – adiposity based chronic disease. Not going to replace the term obesity, we got that, but obesity means so many different things to different people – it’s heavily stigmatized, its use in social media and is usually negatively used and insulting. So we need a medical term that says what the disease is and why we’re treating it. It’s adiposity based because it involves various degrees of abnormalities in adipose tissue mass, distribution and function. It’s a chronic disease because it offers opportunities for primary, secondary and tertiary treatment and prevention like any other chronic disease. It’s also associated with complications that lead to the morbidity and mortality of disease. So, adiposity based chronic disease says what’s causing the disease and why we need to treat it. So, we’re envisioning building a coding system around this term so you can have uncomplicated disease or you can have adiposity based chronic disease; unfortunately the acronym is ABCD. But you could have ABCD with osteoarthritis, ok, so that’s why we’re engaging the patient in weight loss therapy or with diabetes or with obstructive sleep apnea. It could be due to monogenetic or syndromic cases of obesity. So, I think we’re trying to reform that coding system. Hopefully in the end, we hope to enhance the access to evidence-based therapies for our patients.
Freed: Well, I want to thank you for your time, enjoy the rest of your stay here in Boston and again, thank you, I thought it was very informative.
Garvey: Always fun talking to you guys so thank you.