Saturday, March 17, 2012

Qsymia (formerly Qnexa), the Latest Obesity Drug

There are very few obesity drugs currently approved for use in the US-- not because effective drugs don't exist, but because the FDA has judged that the side effects of existing drugs are unacceptable. 

Although ultimately I believe the most satisfying resolution to the obesity epidemic will not come from drugs, drugs offer us a window into the biological processes that underlie obesity and fat loss.  Along those lines, here's a quote from a review paper on obesity drugs that I think is particularly enlightening (1):

Most of the drugs that have entered the market for treating obesity were originally developed to treat psychiatric diseases. During the past decade, understanding of the neural circuits that underlie food intake has increased considerably. Different aspects of ingestive behavior such as meal termination, meal initiation and overconsumption of highly rewarding and palatable foods are modulated by different neuroanatomical structures. Integration of the action of many signaling molecules (e.g. hormones, neurotransmitters and neuropeptides) in these structures results in a response that, ultimately, modulates food intake.
Effective obesity drugs generally act in the brain.  They tend to act on circuits that regulate food intake, typically a combination of 1) reward and/or hedonic circuits*, 2) energy homeostasis circuits**, and 3) satiety circuits.   Recent examples include rimonabant*** and contrave****, which both act on reward and homeostasis circuits in the brain.  The effectiveness of these drugs is another line of evidence supporting the central role of the brain in common obesity.

The FDA is on the verge of re-approving a drug combo called Qsymia [update 7-12: approved], which is effective but had been previously rejected on the basis of negative side effects.  Let's take a look at how this drug works to see if it can offer us any insights into the mechanisms of obesity and fat loss.

Qsymia: How it May Work

Qsymia is a combination of the drugs phentermine and topiramate, both of which have been around for a long time.  If used correctly, the combination causes substantial weight loss in obese people with fairly low rates of negative side effects (2).  Obesity drugs in general don't turn obese people into lean people-- they typically reduce body weight by 5-10 percent, which is equivalent to the more successful long-term diet and lifestyle weight loss interventions.  Orally administered drugs are blunt tools, and the dose must be chosen to balance beneficial effects with negative side effects, so it's not surprising that these aren't miracle cures even though they're probably acting on the right targets.

Phentermine is an amphetamine-like drug that increases the levels of acetylcholine, dopamine and serotonin release in the brain, including in areas important for reward (nucleus accumbens) and the regulation of body fatness (hypothalamus).  Acetylcholine, dopamine and serotonin are three major signals that certain neurons use to communicate with one another (neurotransmitters).  The net effect of phentermine's action in the brain is appetite suppression, reduced food intake and fat loss. 

Until the combination was banned by the FDA in 1997, phentermine and a related drug fenfluramine were prescribed together; abbreviated fen-phen, the combination was an effective fat loss drug.  Interestingly, it's also effective against drug addiction in animal models, emphasizing its effects on reward pathways (3, 4).  Human trials to investigate this went belly up when fen-phen was withdrawn due to cardiac risks.

Topiramate has a structure similar to fructose, but it's chemically modified and behaves differently from fructose biochemically.  It acts on many processes throughout the body, therefore its relevant mechanisms of action are hard to pinpoint and remain poorly understood. In the brain, it acts on several targets that modify communication between neurons.  In rodent models, it suppresses food intake, increases energy expenditure, and affects fatty acid trapping in fat tissue and muscle (5).  In humans, it also reduces body weight (6, 7)

Topiramate was originally used to treat seizures, and later, migraines, bipolar disorder, obesity, binge eating and alcoholism (8, 9, 10).  Topiramate therefore acts prominently in the brain, including presumably on reward circuits.  Again, it's no coincidence that many anti-obesity drugs can also be used to treat addiction (e.g., topiramate, phentermine, rimonabant, naltrexone, bupropion)-- both phenomena involve the stimulation of reward pathways. However, in the case of topiramate in particular, it remains possible that weight loss also involves its actions outside the brain.  It would be interesting to see what happens if topiramate is administered specifically to the brains of obese animals.  This would determine if weight loss depends on the drug's action in the brain or the periphery.  I couldn't find any studies that have investigated this. 

What Does it Mean?

In conjunction with the rest of the obesity literature, it means the brain is a central player in obesity.  The most effective obesity drugs and drug combinations to date have multiple actions in the brain that target circuits that govern body fatness, food intake and food reward.  Targets outside the brain may also be relevant, but to my knowledge this remains to be demonstrated convincingly.

Given the current pace of obesity research, it's likely that we will have access to increasingly effective obesity drugs in the next few decades.  I'm not really against obesity drugs; like most drugs they have their place.  However, it's easy to imagine them being overprescribed and replacing solutions based on diet and lifestyle.  Ultimately, the most satisfying solution to the obesity epidemic would come from society-wide changes in how we live and eat, but I recognize that's a tall order.  Maybe in the future, people who maintain their weight and health through a good diet and lifestyle will be viewed as a backward minority, while the majority will pop anti-obesity pills and continue eating junk food.

* Reward.  The brain contains a "reward" system, whose job it is to gauge the desirability of food (among other things) and reinforce and motivate behaviors that favor the acquisition of desirable food.  For example, if you eat a strong cheese for the first time, maybe it won't taste very good to you.  As it's digested, your reward system gets wind that it's full of calories however, and the next few times you eat it, it tastes better and better until you like the flavor.  This is called an acquired taste, and the reward system is what does the acquiring, motivating you to obtain a food it has deemed safe and desirable.  Eventually, you may go out of your way to purchase the cheese or beer at the grocery store because you like it so much, and maybe you'll consume cheese or beer even if you aren't hungry or thirsty.  This is an example of the reward system reinforcing and motivating behaviors related to foods that it considers desirable.  Processed "junk foods" such as ice cream, fast food, sweetened soda, cookies, cake, candy and deep fried foods are all archetypal hyper-rewarding foods. 

Palatability is a related concept-- it is simply the pleasantness of a food; how much a person enjoys eating it.  Palatability is determined in part by inborn preferences (e.g., a taste for sugar and energy dense foods), and in part by the reward system (acquired tastes).  Palatability is governed by the hedonic system in the brain, which is closely integrated with the reward system.

The reward system is what motivates you to get food and put it to your lips, every time you eat.  When scientists shut it down in mice, they completely cease eating (11).  The hedonic system influences how much you eat once you begin a meal-- highly palatable food generally increases food intake by activating this system (12).  Together, reward and hedonic circuitry in the brain determine in large part how often you eat, what you eat, and how much you eat.

** Homeostasis = stability over time.  The energy homeostasis system regulates the amount of energy that's stored in the body in the form of fat, resisting changes over time.

*** A CB1 cannabinoid receptor antagonist.  It's an effective weight loss drug, but it was not approved by the FDA due to negative side effects.

**** A combination of naltrexone and bupropion.  Naltrexone is an opioid receptor antagonist and bupropion is a norepinephrine-dopamine reuptake inhibitor.  This combination is effective for weight loss but did not secure FDA approval.


marie said...

Thank you for the overview. The use effects of such drugs are sometimes referred to in various presentations and discussions, but not in context like this. Also, the notes at the end effectively act as a glossary for key terms as well - that's incredibly useful, IMHO. Any chance you could make that a standard feature and more or less permanently for 'reward' and 'palatability'?

Unknown said...

It would be nice to have safe and effective drugs for folks who can't otherwise battle obesity--particularly morbid obesity.

I, however, would much rather achieve success on my own. Having dropped over half of my excess weight, I'm currently trying to stabilize a bit. I'm calling it "training for maintenance" as that's where I've failed in the past.

You know, there are many of us who've proven repeatedly able to LOSE fat--we've just failed to maintain the better weights. So that's my goal this time.

Keenan said...

I thought Co2 made you fat

Karan said...

It is a good news that we have a safe weight loss medication. However, I think changing our lifestyle is the best option to have a healthy body weight.

nothing91 said...

There are effective weight loss drugs? Is that the consensus in the research community? How about amongst doctors?

Nigel Kinbrum said...

Bupropion looks very promising as an anti-depressant (Wellbutrin) with appetite-suppressing properties but in the UK, it's licensed for use only as anti-smoking therapy (Zyban).

Bah, humbug!

Jenny said...

The commonly cited statistic that effective diets only result in 5-10% weight losses ignores the fact that the percent is an average derived from a group where large numbers of people don't stick to their diets and other people lose a lot more weight.

I wish there would be subanalyses published with all diet studies of those who adhere to the diet and graphs showing the trajectory of individuals so we could see the individual curves of say 50-100 dieters. As it is the numbers are very misleading.

Also, while you're looking at the role of the brain--which I'm loving--I'm curious what your take is on why SSRIs and the atypical antipsychotics pack weight on people. I know the data shows they increase IR and that the atypical antipsychotics create diabetics in people who would otherwise not be diabetic, but I'd love to understand what the actual mechanism is. Especially since there is evidence these drugs may not, as claimed, raise serotonin levels in the brain over time.

Unknown said...

Buproprion and topamax both have a long track record of causing weight loss and are FDA approved for other indications. Not everyone can tolerate one or the other but I've had a patient lose 120 pounds and avoid gastric bypass on topiramate (topamax). This person had already seen a dietician and was working out daily with little success.

Rakesh C. Patel, M.D. said...

I have seen patients lose large amounts of weight with Topamax as well (over 100 lbs). Interesting how patients describe how it makes things taste bad (particularly carbonated drinks), food reward?

Unfortunately it carries a multitude of side effects, including numbness in the extremities and cognitive issues, giving it it's nickname "Stupamax"

Sue said...

Bupropion looks very promising as an anti-depressant (Wellbutrin) with appetite-suppressing properties but in the UK, it's licensed for use only as anti-smoking therapy (Zyban).

Zyban lists anorexia is a side-effect.

Unknown said...
This comment has been removed by a blog administrator.
rps said...

What do you think of the naloxone/Wellbutrin combo weight loss drug that was nuked by the FDA a few years ago? It seems like a better option than Qnexa to me, because it has no amphetamines and no stupor-inducing epilepsy drugs, but the FDA wanted them to do massive studies proving that it doesn't have fen-phen like cardiac effects, even though it worked through completely different mechanisms

Nigel Kinbrum said...

Sue said...
""Bupropion looks very promising as an anti-depressant (Wellbutrin) with appetite-suppressing properties but in the UK, it's licensed for use only as anti-smoking therapy (Zyban)."

Zyban lists anorexia is a side-effect."
Exactly. If I wanted to get bupropion (I don't), I'd have to lie about being a long-term smoker.

I'll just stick with a paleo-ish diet instead.

Galina L. said...

I was prescribed an anty-seizure medication which is also works for a bipolar disorder by my neurologist in Russia in order to prevent migraines. Later I started to use a ketogenic diet instead which completely recreated the effect of my mind-altering medicine minus side-effects.
Yes, mind-altering drugs influence eating behavior but it doesn't look like "it means the brain is a central player in obesity" because diet may influence brain as powerfully as the drugs itself. It looks like there is no central-player in obesity, but a pathological self-feeding loop without an hierarchic structure. Drugs could be means to brake that loop from the brain side, I was lucky to have enough of discipline and common sence to use a diet approach.

Stephan Guyenet said...

Hi Marie,

My goal is to make that standard, but I'm hoping to make it more concise.

Hi nothing91,

Yes, effective in the sense that they produce clinically meaningful weight loss. None of the currently available drugs turn obese people into lean people.

Hi Jenny,

Good point.

Hi Emily,

Wow! 120 pounds is pretty amazing.

Hi Dr. Patel,

Thanks for your perspective, that's interesting.

Hi rps,

Yes, that's contrave. It's effective for weight loss, but the FDA wasn't convinced enough that it's safe. From what I've heard it was quite close to being approved.

Hi Galina,

I don't understand why your experience would challenge the idea that the brain is a central player in obesity.

Galina L. said...

My experience demonstrates how much diet affects brain. Ketogenic diet also decreases appetite and food cravings, which is directly related to the obesity treatment. Of course, it is easier and more socially convenient to put somebody on pill than on a diet.

Jane said...

'Given the current pace of obesity research, it's likely that we will have access to increasingly effective obesity drugs in the next few decades.'

Dunno about this. If obesity is caused by damage to the brain, or to the liver or pancreas or whatever, an obesity drug that works must repair the damage. What drug can do that? But again, what scientist can admit this problem, being dependent on the drug companies for funding? I have a lot of friends in this predicament. The research must be done, and I watch my friends losing their waistlines to micronutrient deficiencies because they have to keep the drug companies happy.

CarbSane said...

Although ultimately I believe the most satisfying resolution to the obesity epidemic will not come from drugs, drugs offer us a window into the biological processes that underlie obesity and fat loss.

For all the negative connotations for the pharmaceutical industry, I don't think we'd know a tenth of what we do about human metabolism and such were it not for the industry.

I also detect a stigma amongst low carbers against diabetes meds for example, just LC is the answer for all. Many of these folks will supplement with large doses of a laundry list of often expensive things with little way of really knowing for sure if they are working. Sure, some of the meds out there have unacceptable side effects, but at least those meds have been tested and one is aware of the potential side effects to watch out for, as well as the specific mode of action and appropriate dose*. This can tell a person a lot about themselves -- IOW if they respond to med A but not to med B this can be valuable information where diagnosis based on glycemic parameters often cannot pinpoint the underlying pathology.

*This is a huge one because we don't know what toxic levels of certain supplements are. I jumped foolishly on the more is better VitD bandwagon a while back with rather unpleasant results. Now my dose (varied 5000-10000 IU/day) was not out of the ordinary and even low for what I see some taking, but apparently I'm not deficient and it was not appropriate for me.

CarbSane said...

BTW, Stephan, I love the new "lighter" look here on your blog! MUCH easier on the eyes :)

Galina L. said...

@ Evelyn,

I am sure I fit very well to a profile of LCarber who believes into ketosis miracles, I really can see it. However, I believe at that particular instance I could be excused from being a keto-maniac because the described effects of the drag remind effects of ketosis so much. "Obesity drugs in general don't turn obese people into lean people-- they typically reduce body weight by 5-10 percent, which is equivalent to the more successful long-term diet and lifestyle weight loss interventions."- sounds like a standard experience of a LC dieter when people loose 20 - 25lb and stack on a long plateau. All that, plus the description of the medication "Topiramate was originally used to treat seizures, and later, migraines, bipolar disorder, obesity, binge eating and alcoholism " was quite close to the description of the anti-seizure drug I was taken but later replaced it with a ketogenic diet.Too many correlations for me to restrain myself from jumping up and pointing on it.

My opinion is that a diet option should be tried first before exercising a medication option. Judging from what is going on right now, it is not going to happen.I see a lot of people around who take pills instead of lifestyle changes which have a bigger potential to mess-up their body systems. If some drug mostly causes a 10% weight loss and reduces appetite, then it is pretty much what a LC diet does for many. Not a miracle, but not a pill with side-effects. I am sure there are plenty of scientist working hard right now trying to recreate the effect of exercise in pharmacological form.
I am sure, it would be cruel to deny a medication that may cause a weight loss to a person already scheduled for a horrible bariatric surgery and unable to restrain his/her diet on his own, so I am not 100 % against a weight-loss drug, just I don't believe it would be used appropriately in the majority of cases. Stephen realistically thinks the same "the majority will pop anti-obesity pills and continue eating junk food."

CarbSane said...

@Galina: Except in critical circumstances, I agree. I think most doctors do as well. This notion that docs are dispensing pills left and right as the first order of intervention for everything is simply not true. I think we'd (the collective community as it were) do better to improve on educating MD's and patients on the wider possibilities for dietary intervention. I'm all on board that for obese/IR a LC diet is a good and perhaps preferable option. But for the long haul I'm not sure it's beneficial for nearly as many as think it is. And the cult atmosphere makes it very difficult for those doing it to try something different and receive any sort of support at all.

Galina L. said...

@ Sure, cult atmosphere may prevent a critical approach, and we are different and have different reactions on the same treatment. We are not in a high school any longer, adult people suppose to ignore irrelevant noise, however unpleasant it may be.
About doctors dispersing pills... I have a nice and thinking GP, however, his first reaction on a complain is to give a prescription. Well, he suppose to do something. Like giving a water pill for swollen ankles. He told me many women my age had it for so far unknown reason. When I started to come often with different complains between 45 and 46 years old into his office, he just gave me a prescription for each complain, and a nurse from my insurance company started to call regularly (because I went to doctor too often) making sure I did exercises often and eat a healthy diet which I did. Honestly, I can't blame him, it is not an official data yet that you can became IR but your blood work could be still in a normal range, your ankles would be swollen, you will be tired and hungry all the time, catching every flue around, gaining weight fast. A pre-menopause is easy to blame or at least use as an explanation. When I visited him again in 6 month (I needed a blood work for thyroid) and my health was markedly improved from LC diet, weight lost, no more swollen legs, he asked me what I did. Then he said that some of his patients reported similar results on Atkins, South Beach, other LC diets but he couldn't recommend it personally because it was officially considered to be too far from the standard of care. The guy has a job and regulations. It is me who can do whatever.

My biggest problem with the anty-obesity pill is that it supposed to be taken for a long time in order to manage something which is difficult to manage with pills but easy with a diet. It is the same as I would get myself a cute cat as a pet while being severely allergic to cats , but plan to take some Claritine or even oral cortisone (because Claritine or Benadrill would not be enough) until that cat lives with me. A very wrong plan. said...

I've provided clinical support to hundreds of patients in hospital weight loss programs, private doctors offices, and my own private practice. The methods ranged from Medifast to PhenFen to "balanced" diets to LC/ketosis over the course of 20 years. This includes all the PhenFen years. I certainly would not describe this drug combination, or the separate parts of the combination that were being used back then, as effective - the weight loss was low, the side effects high. I am currently, however, seeing decent results when people use metformin. I don't, however, believe this drug fits into a central hypothesis of obesity. It seems to help people who's insulin resistance is high (per HOMA-IR and other labs) get going on weight loss.

HoneyRazwell said...

This is a nice article.

Stephan is right. The brain IS strongly involved in obesity and body weight regulation. Its involvement CENTRAL.

I wished the clueless Internet gurus who blog would realize this. This has been my own point for YEARS.

Real, genuine scientists are hoping to make great progress in the next decade understanding the neural circuitry that controls our body weights and fat mass. Also, feeding behavior itself is extremely complex and many thing go into it. No one thing alone will guarantee that you will eat.

A deeper understanding of obesity almost certainly won't be found in some flip flopping charlatan Internet gurus' latest fat loss books or from bloggers critcizing high carb or low carb and their silly mindless "waht cheese is the moon made of " type debate........

If the public knew more about SCIENCE, and how it works, they would stop buying ALL of these these various Internet gurus' fat loss books.

All drugs have side effects. Adiponectin *MIGHT* pan out.

Drugs in the future might directly target fat cell regulation etc.

The first generation will have the most risk. They will be the "experimental rats", so to speak.

But these will be reserved for those severely obese most likely. Michael Jordan gaining a few pounds from his playing days is NOT at all the same situation as a severely obese 800 pounds. THAT man can not do much about his condition. Jordan could ( if he was not on meds etc or diseased)

The people MOST stigmatized in society are the people LEAST able to do anything about it. The 600 to 800 pounders and more.,

Nigel Kinbrum said...
This comment has been removed by the author.
Nigel Kinbrum said... said...
"I am currently, however, seeing decent results when people use metformin. I don't, however, believe this drug fits into a central hypothesis of obesity. It seems to help people who's insulin resistance is high (per HOMA-IR and other labs) get going on weight loss."
Lowering IR helps people to lose weight by reducing the fluctuations in blood glucose they get after eating high-GL carbs.