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Qsymia (formerly Qnexa), the Latest Obesity Drug

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					  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 do

				
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