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Dr. Arya Sharma discusses the recent approval of Vivus’ Qsymia, highlights the need for weight-maintenance drugs, and explains how societal views of obesity need to change

by Joseph Shivers, Vincent Wu, Alasdair Wilkins, Adam Brown, and Kelly Close

As Chair of Obesity Research and Management at the University of Alberta in Edmonton, Dr. Arya Sharma oversees a program of over 30 healthcare practitioners treating several thousand patients per year – including hundreds that he sees personally. He has also led development of the Edmonton Obesity Staging System (EOSS), a rubric for classifying obese patients based on the severity of weight-related complications rather than BMI or body weight. Dr. Sharma is also an outspoken advocate both for better obesity treatments and for better societal ‘treatment’ of individuals with obesity. He was in the spotlight most recently at the FDA’s Advisory Committee meeting on Qsymia, where he spoke compellingly about the absence of good anti-obesity drugs today and the enormous related costs. And then of course there’s a blog that he updates daily (!) with his take on new research and other obesity-related news – Dr. Sharma’s Obesity Notes.

Dr. Sharma provided valuable perspective on the recent approval of Vivus’ Qsymia (for more information, see this month’s new now next), highlighting that it has the most convincing weight loss data for any obesity drug to date. He also emphasized the under-recognized benefits of simply maintaining one’s current weight, a significant achievement given our weight-loss culture and the expectations of patients. Dr. Sharma also discussed the prospects of using mobile apps for weight loss and maintenance, described why obesity is not merely an issue of personal responsibility, and highlighted the importance of long-term treatment of obesity.

Qsymia’s Approval

Joseph Shivers: Thank you so much for agreeing to speak with us, Dr. Sharma. What factors do you believe contributed to the approval of Qsymia?

Dr. Arya Sharma: A couple special circumstances surrounded Qsymia’s situation. First, because it’s a combination of two drugs that are already generic and are probably already being used off-label by physicians, there was a certain urgency in approving Qsymia that may not exist for other drugs. When drugs are being used off-label, you then have virtually no control over who’s prescribing it or who’s using it. Even more importantly, you would never have a long-term efficacy or safety study because nobody would conduct it.

In terms of weight loss, the data for Qsymia is probably the most convincing we’ve seen from any obesity drug so far. The issues of hypertension, which you’ve seen in previous drugs, clearly do not exist for this drug. There is a very clear blood-pressure-lowering effect. As to the small increase in heart rate – nobody really knows what that means, and most cardiologists would tell you that it’s probably not very relevant, given that the drug has all these other positive effects.

Both circumstances – the fact that you have a very effective drug, and you have a drug that is the best composite of two drugs that are freely available as generics – make Qsymia’s situation special.

Joseph: How do you think the approval of Qsymia (see this month’s new now next) will change the way obese people are treated?

Dr. Sharma: Based on the experience of previous obesity drugs, there’s usually a rush for new drugs, depending on how they’re launched. Usually they launch with quite a bit of fanfare; even if the company is not generating the fanfare, the media is. Often lots of people will try the drug during the first year or so. Given the way it’s going to be dispensed, it will be a prescription, they’ll take it for a couple of weeks, and then some will realize that it’s not working for them or it’s not what they expected or they experience side effects or whatever, and then they’ll stop using it. On the other hand, with the program that will be in place for Qnexa, even obtaining a first prescription may not be that easy, and this will certainly further limit uptake.

Repeat prescriptions of obesity drugs have always been rather limited because most people look at obesity drugs as drugs that you take to help you lose weight. But you have to actually keep taking them to keep the weight off. Most people will think, “You know what, I’ll just get the drug, and once I start losing weight I’ll get more active and do what it takes to keep the weight off.” That’s where everybody kids themselves, because that’s not how these drugs work. That’s not how obesity treatments work in general.

Vincent Wu: At some point, people are going to plateau in terms of how much weight they lose. Given that most people will be paying out of pocket for this drug, what would make it compelling for patients to continue using Qsymia?

Dr. Sharma: Knowing that if they went off the drug the weight would come back. A lot of people become disappointed – whether this is a drug or having bariatric surgery or going on a diet – when they stop losing weight three to six months in. It’s not that the diet has stopped working, it’s that you’ve reached a new state of energy balance. What I can always tell people is that if you went back, and you stopped keeping your food diaries or you stopped your exercise plan or you stopped doing whatever it is you’re doing right now – which in this case would include being on new medication – if you stopped any of this, all that weight that you lost is going to come back. If you lost ten pounds, well, you’re getting those ten pounds back. If you lost twenty pounds, well those twenty pounds are coming back.

So your motivation for staying on the drug is to keep off whatever weight you’ve lost. You can actually think of this as an investment – once you’ve been taking the drug for three months, you’ve lost X amount of weight, but you’ve also invested whatever amount of dollars. When you stop the drug, all of that weight comes back and you’re back to square one – you’ve essentially wasted all that money. This also happens with any diet program. One of the first things is to have a conversation with a patient and say, “This is long-term treatment. This is treatment for a condition that is not going to be cured by this medication. If the medication works, you’re going to be on it for a long time.”

Vincent: So it’s not just about weight loss now, but maintaining weight loss over the long term.

Dr. Sharma: It’s not a diet pill and it’s not a weight loss pill – it’s a treatment for obesity. That’s an important distinction. Diets sound like they’re something you do for a little while: people go on a seven-day diet, a six-week diet, or a twelve-week diet. Well, that doesn’t work, and taking this treatment for just three months doesn’t work either. Because you’re going to have to continue treating it – that’s why it’s a chronic condition.

Changing Mainstream Attitudes Toward Obesity

Joseph: One of the big themes in your own work, and in particular in your presentation at the Qsymia Advisory Committee in February, is that obesity is a chronic medical condition like high blood pressure or high cholesterol, even though it’s not often seen this way. What do you think will be required to change cultural and medical attitudes toward obesity?

Dr. Sharma: I think a lot of it comes from the public understanding of obesity. As an aside, I’m the Scientific Director and founder of the Canadian Obesity Network, which, interestingly, is the largest professional national obesity non-governmental organization in the world. One of the primary strategic objectives of the Canadian Obesity Network is to address weight bias and discrimination. The reason we’ve put weight bias and discrimination as our primary goal is because most decisions made around obesity – whether it’s management, access to care, public health measures, drug reimbursement, physicians or health professionals wanting to treat obesity, and perhaps even drug approvals – are held back by weight bias and discrimination.

Nobody likes fat people, and everybody thinks it’s their fault. Most people don’t understand the science and the biology behind obesity. They think this is really a matter of personal responsibility, and if you would eat better and get your butt off that couch, then you would be fine. As long as the public and government and everybody believes that to be true, you are not going to have the same kind of level playing field that you’ll have for hypertension or depression or any of those other conditions.

That’s going to have to change. It’s not a question of having better data. Organizations like the Canadian Obesity Network, or in the US, the Obesity Action Coalition or The Obesity Society, have to step up and educate the public and the decision-makers. Obesity is not merely an issue of self-responsibility, there’s actually a very complex biology here. Even if you were highly motivated to lose weight, your chances of keeping it off are actually pretty slim. Those are the messages that actually need to get out to decision-makers.

Joseph: The prospect of long-term weight loss in the population as a whole seems very challenging based on most interventions for which we have long-term data. Assuming that we turn this around in the next 50 years, what do the turning points have to be? Will it be better therapy? Some really refined and effective surgery? Impacting childhood obesity?

Dr. Sharma: If I had to bet, I’d bet on drugs and not on surgery. I think surgery is a phase. It’s being done now; it’ll be around for probably another decade or so, maybe longer, until we get new drugs.

I think that there are two things that may need to change in drug development, or even in the thinking about pharmacological treatment of obesity. The first is starting to differentiate obese people into subsets of obese people. So a drug that doesn’t have to be for whoever has obesity, but rather for a subset of patients with obesity because they have a certain eating disorder or there’s a certain pathway in their brains that is promoting overeating or they have a certain lack of satiety. That is a group of patients for whom a given drug really works. They are the ones who should be getting it. The drug may not work for everybody else. You would start splitting down this whole indication into other groups.

That may or may not happen. In hypertension, it never happened. We have 100 drugs for hypertension and people have always said, “Let’s break it down and let’s decide who’s the best patient for a diuretic and who’s the best patient for a beta blocker and who’s the best patient for an ACE inhibitor.” That actually never worked. In the end, even today, hypertension practice is pretty much trial and error, with fixed combinations becoming more and more accepted. So, I’m not holding my breath that that will happen with obesity. I think if you find drugs that are overall effective and well tolerated in most people or at least half the people you treat with them, it probably doesn’t matter.

But I think the other piece that really matters is whether or not we can come up with a way to license drugs to help with weight-loss maintenance. The mechanisms that help you lose weight may not be the same mechanisms that help you keep weight off. Take leptin, for example. Leptin is not a great drug for losing weight, but it may be the perfect drug to keep weight off. But there’s no regulatory pathway. If I wanted to license leptin for weight management, I would have to go to the FDA and show that it helps people lose weight, which it doesn’t, and so I’d never be able to license it. I need a regulatory pathway that’s going to allow me to specifically get regulators to approve a drug that is efficacious for helping people maintain weight loss, even if it does not promote weight loss in itself. So, the idea is you go lose weight and come back to the doctor’s office, and then he’ll put you on these drugs so that your weight doesn’t come back. That is a regulatory pathway that doesn’t exist right now.

Weight Loss and Weight-Loss Maintenance

Joseph: It seems like the standard of care for weight-loss, excluding drugs and devices in some patients, is intense diet and exercise as a starting point. What do you think about this approach?

Dr. Sharma: It’s simply not going to work. All that diet and exercise talk is like what we used to do for cholesterol and for diabetes. I’m not saying it’s not important, and there’s no question that if I get somebody to diet and exercise, they’ll lose weight. But it works for obesity in the same way that the DASH [Dietary Approaches to Stop Hypertension] diet works for hypertension. I can put people on the DASH diet and show that their blood pressure gets better. But if I were to take 100 people off the street, put them all on the DASH diet, and hope that everybody’s blood pressure’s going to be fine, it won’t be. Only five guys would actually stick to the diet, and they’d be fine, but the other 95 would not be fine. Obesity is pretty much the same; I don’t see any difference at all.

Kelly Close: Presumably, weight-loss maintenance also goes back to improving the public’s understanding of obesity and addressing weight bias and discrimination.

Dr. Sharma: Absolutely. We are bombarded with anecdotal instances of how easy it is to lose vast amounts of weight – not just the ‘weight-loss industry’ – think of TV reality shows, popular magazines, and fad diets. We celebrate people for losing weight, but we seldom check to see if they are still keeping it off. I am always asked by patients, “How much weight can I lose and how fast can I lose it?” I tell them that that’s the wrong question – the only weight loss that matters is the weight you can keep off – this is why we introduced the term ‘best weight’ – the lowest weight you can realistically maintain. Your ‘best weight’ depends on your individual circumstances, and everyone’s ‘best weight’ will be different. The public but also health professionals and policy makers need to understand that when you pay for ‘weight loss’ you get ‘weight loss’ – when you pay for ‘maintenance of weight loss’ you get ‘maintenance of weight loss’. As a health professional I’d rather see my patients or payers paying for the latter than the former.

Additionally, we often frame weight regain as ‘failure,’ when it is really the only natural expected consequence of stopping the treatment for a chronic condition. Even worse, the failure is often framed in the context of the treatment. So if you take a drug, lose weight, stop the drug, and regain the weight, we attribute the failure to the drug and not to ‘stopping’ the drug. No drug or treatment works when you don’t take it – when you have an obesity treatment that works, the question is not to find more effective weight loss drugs but to find a more effective way of ensuring that people continue taking it. The same, incidentally, applies to treatments for hypertension or diabetes. For many conditions, we don’t need more drugs (unlike for obesity) – we simply need to figure out how to get patients to continue taking the meds that are already out there – that’s where I’d be putting most of my research money.

Joseph: You’ve talked about many different causes for initial weight gain. Would you say that those are truly all different, or might they all be manifestations of an underlying disorder that shows up in different ways but ultimately motivates overeating?

Dr. Sharma: No, I think that you’ve got two things. One is a genetic predisposition, where people who have the same stressors and same behaviors, will have a different rate of weight gain. But even when you take people who are just overeating, you will find lots of different reasons why people will overeat: time management, using food as a coping strategy, lack of knowledge about how many calories they’re consuming, peer pressure, customs, beliefs, culture, not enough money, food insecurity, etc. Those are the social drivers of obesity, some of which you can approach with drugs. But for a lot of these, the underlying problem is not an obesity problem. So, if you take somebody who is self-medicating their depression with food, after getting treatment and better control of their depression, they’ll get better control of food intake. Simply slapping on a drug that, say, increases their metabolism or reduces their appetite, without addressing their mood problem, isn’t a medically sensible thing to do.

There’s one caveat here, which I think is important. This is fundamental, but I find that a lot of people don’t get this: if mood is the factor that is causing weight gain, treatment is not necessarily going to give weight loss. Let me give you a typical example. If I diagnose binge-eating disorder in someone and that person stops binging, I don’t necessarily expect to see weight loss. What I expect to see is that this person will stop gaining weight. What you’re actually removing is the driver of weight gain, which means that weight gain stops. It does not mean that when you stop weight gain you end up with weight loss.

That’s a very important distinction, because a lot of people think that if they stop doing what is causing their weight gain, they should somehow start losing weight. In fact, a lot of people are really disappointed. Then they say, “Well, you know what, I used to drink soda or I used to eat out a lot, and my weight was going up. Now that I’ve changed my diet and my life style, why is my weight not going down?” It’s not going down because you’ve only removed what was causing the weight gain. The success of that is that you’ve stopped gaining weight. But that doesn’t mean that you’re now going to lose weight. That is your second step. We don’t normally think of this as a two-step process. And then of course there’s the third step – keeping the weight off!

Joseph: That certainly isn’t something that we hear talked about very much. It seems like stopping weight gain is much easier. How would you ballpark your own clinic’s success rate in that regard?

Dr. Sharma: We would be hitting 80%, if not more, on stopping the weight gain. In every single case where a patient continues to gain weight, we know there’s a problem that we’ve not yet identified and have not yet addressed.

Joseph: Do you think it is possible to stop weight gain across the whole population?

Dr. Sharma: Absolutely. Preventing weight gain generally does not require a lot of resources. I think prevention of weight gain does not even require 20% of the resources you would require if you were trying to get people to lose weight and keep it off. Losing weight and keeping it off is extremely expensive; prevention of further weight gain is cheap.

If the 70 million obese people in the US could all stop gaining weight – and the other 200 million who don’t have obesity but might be overweight – could stop gaining weight, 10 years from now we would have a huge population impact without anybody losing any weight. I think that is very achievable with not a lot of resources. It may not be what the patient wants, because patients all want to lose weight. I don’t know how many people will actually pay to simply not gain weight. I don’t see that there’s a big market there. From a medical perspective, if I were a family doctor, I’d say, “I see you once a year, and every time I see you, you’re up two pounds. That’s got to stop. Instead of seeing you once a year, I’m going to start seeing you once every three months. Here’s all the things that I think could do that could stop weight gain and that’s what we’re going to be focused on.” I think that’s very doable.

Joseph: It seems that this could also increase the demand for contact outside regular doctors’ visits. We’ve heard a lot of enthusiasm for mobile-health interventions: various iPhone apps and web-based programs that help you track what foods you’re eating, etc. What do you think about these sorts of interventions?

Dr. Sharma: The people who’ve been using an iPhone app – not just for a while, but who will continue using an iPhone app – are doing it right. Can you get the entire population using an iPhone app? No, in part because that starts with having an iPhone.

We have all of these different approaches. For one guy, it’s just showing up at the doctor’s office. For another guy, it’s: “I’ve got a scale at home that I get on every day and I automatically send my body weight straight to my doctor’s office.” Another guy says, “Well, I go Tweet my body weight to the doctor’s office, it goes on to my Facebook profile, or it gets Tweeted to my buddies.” The next guy says, “My thing is that at the end of every week, I read my food diary.” And the other guy says, “Well, you know what? I’ve started Weight Watchers. I go there once a week, and I sit there and I get weighed.” I don’t actually care. Whatever works for you.

We all live in a mobile world and there is a huge potential not just for spreading information, but for providing immediate feedback on what is going on. So an app that tells me how much I have eaten, reminds me to get up and walk around a few steps every hour or so (and actually measures if I do), tracks my medications and perhaps sends this info straight to my doctor or pharmacist – there are lots of possibilities there. The question is more whether enough people will use such services in the long term – in the short-term, I have no doubt that such interventions work – but like all interventions, they only work when people stick with them. That’s not different from taking a drug. I tell my patients, stopping your food journal it is like stopping your medication.

The principle is that you’re never done. The idea you’re going to do something for a while and then stop doing it is not going to work. The bottom line is that obesity is a chronic condition that requires lifelong management. So don’t do anything that you can’t afford to do, or that is so time-intensive that you’re just going to run out of time to do it, or so onerous that you’re just not going to stick with it. But if you’re going to stick with it, then do it.

Joseph: How about dividing it into phases? For example, one could have a really aggressive weight-loss phase, followed by more subdued weight maintenance, for patients who are overweight and obese.

Dr. Sharma: Here’s what I always say: Don’t do things to lose weight that you cannot do forever.

Joseph: Dr. Sharma, thank you for taking the time to talk to us today on so many fronts.

Dr. Sharma: You’re very welcome.

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