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.