Retrying To Get Rejected Obesity Drugs FDA Approved

“Obesity experts” met with FDA representatives on March 22 in a seeming attempt to push the passage of three new medications that were recently rejected by the FDA Contrave, QNexa and Lorquess seeking answers for what type of supplemental information would be required to get these drugs FDA approved. 

Here is a brief overview of the three meds in question:

Contrave is a combination of two existing medications (bupropion – an anti-depressant and naltrexone).  64.9 percent of the patients who took Contrave lost at least 5 percent of their body weight after 56 weeks, and 39.4 percent lost at least 10 percent of their body weight in pre-release studies.  Bupropion is a metabolite of diethylpropion (more commonly known as tenuate) and as such carries some weight loss potential.  In fact, there is a dose-dependent weight loss with bupropion ranging  from 5-10% on average.   Presumably, the naltrexone was designed to help with cravings, although it seems as if the results really weren’t much of an improvement.  While this was the closest of the drugs to being passed, it was put on hold pending further cardiac outcomes. Frankly, I can’t see what the big deal is with this drug and why it represents any improvement over bupropion alone.

Qnexa is the most intriguing of the three of these medications as it combines two medications that can have relatively potent weight loss effects. Phentermine is that last remaining FDA approved weight loss drug with potential for dramatic weight loss.  It is a stimulant that revs up metabolism and decreases appetite.  As a stimulant, though, the side effect profile can include increased heart rate, increased blood pressure, anxiety, insomnia and dry mouth.  Some people are willing to tolerate these side effects to get pounds off.  My biggest concern with it, is that a percentage of people who take it quickly regain the weight they lost.  Topiramate is an anti-seizure drug that is also quite effective in treating migraine headaches.  It was found at higher doses to produce fairly significant weight loss.  The side effect profile on this drug, though, is not clean either, including fatigue, memory loss and word-finding difficulties, peripheral nerve issues and in less common, but serious cases, vision problems involving glaucoma.  The potential for side effects, not questions of efficacy blocked this combo pill from coming out on the market. 

Lorquess is the only new compound that was up for review and also got rejected for potential ill-effects (a number of heart-valve problems and even tumors in rat-brains).  It’s mechanism of action is the targeting of appetite controlling serotonin receptors in the brain, similar to Meridia (sibutramine) which was removed from the market recently for concerns over cardiac risks.  The effects of Lorquess would likely not be as dramatic as Qnexa, although the rejection was over safety, not efficacy. 

One of the problems I have always had with obesity drug studies is that they determine efficacy of the drug by percentage of weight loss usually with a cutoff of 5% total body weight loss and sometimes comparing to 10%.  For most obese patients, though, this is a drop in the bucket, particularly if the weight loss is medically induced.  A good suggestion proposed by Dr. Louis Aronne, one of the representatives meeting with the panel and the former president of NAASO/The Obesity Society, is looking at obesity-related disease modification rather than just weight.  If someone could improve their obstructive sleep apnea , diabetes management or cardiovascular risk through weight loss, does it really matter what percentage of body weight is involved?  This is probably a good metric for many drug studies.  It is quick and easy to judge how much a blood pressure is lowered by an agent in days, weeks or months, but blood pressure leads to serious complications – heart attack, stroke, kidney disease, etc.  Long term outcomes are why we modify the modifiable (such as blood pressure, blood sugar or in this case excess weight).  I just don’t think these drugs are potent or new enough to warrant necessarily passing them through.

I will write more soon on my take on weight-loss drugs, but my experience to date is that very few people who need to lose a significant amount of weight get and stay at their healthy target via weight-loss medications.  Proper diet, increased physical activity and an eye towards calorie balance are what is called for in most cases.  The tougher question for physicians is not what medication to prescribe, but how to help people adapt their lifestyle accordingly.

Image courtesy of alainu on flickr 

The Obesity Environment: Population Dynamics and Food Quality

My high school European history teacher, Dr. McLintock, introduced me to the works of Thomas Malthus, the 18^th century author of An Essay On The Principle Of Population.  In a nutshell, Malthus proposed that while food supplies increase arithmetically (in small increments – think addition), populations increase geometrically (think multiplication). The result is that at some point we will outgrow our food supply, leading to natural checks on our population via hardships and suffering, as people deal with the shortage of supplies and competition for resources.

While a very compelling view centuries ago, what Malthus did not account for is technology, which post-industrial revolution, has increased geometrically to keep up with our population. You can even argue that, given the fact that our country produces far more calories than need to be consumed and given the extent our obesity epidemic, our ability to feed ourselves has charged ahead of the need to feed a growing population.  For instance our agricultural industry now produces genetically altered, subsidized crops that are easier to manufacture in bulk and more resistant to bugs, disease and spoiling than ever before.  The result is that we have an over-abundance of corn and soy that gets altered and fed into almost all commercially produced foods from junk foods to condiments to our livestock in unnatural ways.  Another example is how we have learned how to raise cows almost twice as fast as when they simply grazed and grass in an open field.

While technology has helped us overcome some of the fears of Malthus, his ultimate concern holds true (even if for another reason).  The second half of his theory was that the discrepancy between our earth’s population and sustenance would ultimately put a cap on population growth through the suffering of man.  While populations continue to grow and the struggle for food in industrialized nations is not what he would have predicted, we are suffering some of the negative consequences of this struggle in obvious ways even as it pertains to the few advances I have illustrated.

1. The production of excess crops (corn comes to mind) has encouraged obesity in more ways than one.  High fructose corn syrup is dumped into countless commercial food products (even those that would not be thought of as sweet such as ketchup and pickles).  Additionally, there is more energy produced in our country than is expended.  In other words, there is more food in our country than is needed – with this excess clearly showing on our bodies.
2. The potential harms of genetically modified crops (even genetically modified fish is on its way) and the pesticides that they can tolerate have yet to be fully illustrated.  At the very least there are associations between pesticide levels in the urine and hormones such as testosterone.
3. The unnatural feeding of our livestock (and inhumane conditions in which they are raised) has necessitated the use of antibiotics and toxic substances that kill microbial infestation that would otherwise not be the case (cow’s that are grass fed are less susceptible to E. coli as the bacteria cannot thrive in a basic environment. Grain fed cattle’s stomachs have an acidic environment like humans, and therefore E. coli proliferates. So when we eat beef and dairy we are consuming antibiotics.
4. In order to make more of the meats we want and quicker, our livestock is pumped with hormones leading to a myriad of known (and unknown) health complications.  This might be the case in anything from meat, to cheese, butter, milk and anything else with dairy.
5. The emphasis on creating large amounts of food (calories) quickly has created a situation where the focus of technology, profit motive and our own genetic susceptibilities perpetuate a system where calorie dense, nutrient-poor and health deteriorating foods have flooded our supermarkets and homes.

What to do?

1. Avoid obviously genetically modified foods (like GMO soy products) until we know for sure what the long term consequences are.

2. If you can afford it, stick to organic meats and poultry

3. Buy local.  Small local farms are far less likely to engage in the practices that might harm your health.  If we don’t buy local, the small farmer will completely disappear in the future.

4. Avoid food with high fructose corn syrup or gratuitous corn or sugar added to the ingredient list.  If you are going to buy pre-packaged foods or snacks, make sure the ingredient list is short.

5. Eat fruits and vegetables instead of processed grains and fats.

Tune in to my next entry for a brief overview of the food industry and how it is contributing to our obesity epidemic.

Image courtesy of Miller Info Commons on Flickr

New Year’s Resolutions: A Chance For a Revolution

It is now the second Monday in January, and for most, the dreaded first week back of work has passed;  time to get down to the business of fulfilling those New Year’s resolutions.  More than one third of New Year’s resolutions will be entirely ignored or dropped almost immediately with most of them ultimately going unfulfilled after several attempts.   Perhaps trying a systematic approach this year will yield better results.

1. Take a thorough look at the resolution.  Does it make sense?  Does it fit into the larger scheme of what you are trying to accomplish.  Given the amount of effort required for more involved behavior changes, makes sure that there is a purpose behind what you are doing.  There is no sense in wasting your time on a theoretical goal that won’t accomplish anything.  If you do believe in what you are doing, that is the first step in accomplishing it.
2. Make a plan if you have not already done so.  It is one thing to say you are going to lose weight or start to exercise or eat a certain way, but think about how much more complicated it is to add another dimension to your life that has previously been lacking even if you knew it was good for you.  This requires time, space and discipline, but also a realistic review of the logistics of the plan. Put pen to paper if need be.
3. No matter what the resolution or plan, resolve to create more space.  Packing more into your day might add more stress and ultimately doom you to failure. Space can come in many forms.  Take time in between tasks.  Get to bed on time so that you can wake up more early.  Try to avoid adding complicated or unnecessary tasks and avoid or minimize exposure to toxic relationships.  With the proper space, the world around slows down and allows more time to accomplish what you feel is important.
4. Try to get support around your resolution, but do not depend completely on it. Engage in activities, discourse, and relationships with people who are like-minded or at least support your new efforts.  The corollary to that is try to avoid people that will drag you down.  If you are used to hanging out with the same happy hour crowd every Thursday night which leads to excessive beer drinking and late night eating, you can imagine what will happen if you keep going to happy hour.  That said relying exclusively on external support can also set you up for failure.  Just because your buddy doesn’t go with you to the gym as promised on New Year’s eve doesn’t mean you still can’t go.
5. Finally, be mindful.  You will notice that virtually every one of my blogs includes this phrase but ultimately these tips are really only a starting point.  In the end, the work that is put in day-to-day will yield your results.  It helps to be thoughtful in preparation but also mindful of your surroundings, your feelings and your impulses.

Making a realistic plan, creating a healthy environment with more space and being mindful will all help aid the discipline you are looking for.  If all goes well, you might find that other good habits come from the fulfilling the one that was pledged, making it a New Year’s Revolution.

Join me and ultramarathoner, fitness enthusiast and insipirational speaker, Sarah Staley on a twitter #wellnesschat this Thursday, January 13 at 8:00 EST.

Image courtesy of vagabond_in_the_sky on flickr.com

The Obesity Environment: Evolution, Genetics and Metabolism

One of the common questions asked by my patients is why me?  Why is It that my friends or my sister or my husband can eat whatever they want and don’t have to starve themselves and go to the gym to maintain their weight?  There are often two answers to that question.  First I explain that if their friends and family are overeating and under-exercising, it will ultimately catch up to them.  Yes there are those few who live seemingly indulgent lifestyles, yet remain slender.  However, living with a positive calorie balance almost always catches up to people (some early in life and others as they reach middle-age).

The second part that I explain to them is that they are likely evolutionarily advanced.  While that might sound backward we likely have stopped evolving (or at least not as quickly) as technology has been developed faster than our ability to adapt naturally.  Just as some people are more apt to run long distances (those packed with slow-twitch muscle fibers) than sprint or lift heavy weights (those with a predominance of fast-twitch muscle fibers), the same holds true for metabolism.  As a culture, we think of big eating slim people as advantaged.  That probably was not so in the distant past when food sources were unreliable.  At that time those people who could store their energy for longer (who knew when the next heard of buffalo would pass by) likely had a competitive advantage over those who burned quickly and needed frequent refills to keep going.  In the modern era, where we have readily available food supplies (including foods higher in fat and sugar than in the state of nature) the ability to metabolize slowly has become a liability as it predisposes people to the diseases of excess nutrition: diabetes, heart disease, strokes, obesity and metabolic syndrome.

To illustrate this I like to use an analogy I once heard from Dr. David Katz at Yale.  He compared  a human in the modern era to a polar bear in the desert.  With its thick white coat of fur (to keep it warm and hidden in the snow) and its layer of fat and non-porous black skin (to absorb heat and trap it inside) it is the perfect evolutionary design…that is for an arctic environment.  Imagine that same animal trapped in the desert (where releasing of excess heat is at a premium).  Its ability to absorb and retain heat now is a potentially lethal liability, and its white fur hides it from no one .

Evidence is actually mounting to suggest that hormones play a role in this.  A relatively new concept, known as fullness resistance syndrome suggest that many obese people have an insensitivity to satiety hormones (that ordinarily would make you full) much in the same way that diabetic patients have an insensitivity to the action of insulin. Sure, there is some information gained by those who have always struggled with their weight.  Someone might have relatively sluggish thyroid function or polycystic ovarian syndrome that has previously been undiagnosed.  And sticking to a lower-glycemic diet with increased exercise is a must for those who have always struggled with their weight.  For the most part, weight gain and the diseases that come with it are phenomena  of people who once were adept and surviving and are now more susceptible to the western diet and lifestyle.  The part that people don’t want to hear, this evolutionary advantage often means you just have to work harder today.

Image courtesy of luxnatura on flickr.

Obesity In America: Our Broken Medical System

As a nation, the U.S. spends more money on healthcare than any other country  (over $5700 per capita annually and over 15% of the GDP) crushing all other developed nations– and yet we rank 37^th in the world according to the most recent World Health Organization report.  What is the cause for this?  Is the environment in which we live so toxic that we need to spend our way back to health, or is the system simply too broken?

Sure, if you have a serious medical illness, or one that involves obscure or esoteric treatment, you’ll want to look no further than a major American university hospital for cutting edge treatment and research.  Most of the disease burden in America, though, deals with preventive issues that we as a nation have a difficult time with.  No problem in our healthcare system is better illustrated than the disconnect between primary care medicine and the management of overweight and obesity.  I touched on this issue in a previous entry.  Here are some of the following reasons the system is rigged against success:

1. the incentive in our medical world, just like it is in all sectors of our economy is to turn a profit, where you can argue that healthcare and profit don’t mix
2. too many hands in the pot – not enough money to go around for health insurance companies to be turning profits (10% margin)
3. drugs are too expensive (sometimes randomly so if you compare drugs of similar efficacy).
4. incentives lie in procedures and new drugs, not in maintaining the overall health of patients
5. not enough emphasis on primary care medicine (#4 means that is where the money is, so most of the best and brightest will go towards procedure-oriented medicine)
6. Law suits – not just defensive medicine, but precious time taken away fluffing up notes to prevent against law suit even though 75% of documentation has little to do with genuine patient care

What does this mean for you?

It means that your primary care physician cannot, for logistical and financial reasons, help assume responsibility for doing something about your conditions that are so effected by lifestyle an environment and are not solved by a simply test.  It means that there is no funding on the way that is going to change this any time soon.  This problem is here to stay and I fear that in spite of some of the good that will come from health care reform (expanded coverage for the sick and uninsured) ultimately the insurance companies, societal litigiousness and financial incentives are drawing physicians into mega-practices that lower the level of care as it pertains to obese, lifestyle issues and chronic disease prevention.

What can you do about it?

All things being equal, try to opt for insurance plans with out-of-network benefits giving you freedom to see doctors you think are better.  Opt to see people that will spend time with you and have a reputation for doing so.  Don’t simply accept “you must lose weight” from your doctor, but don’t blame them either.  Realize that managing overweight and obesity is a crucial part of primary care medicine but just isn’t built into the system. Ultimately you are responsible.  If you need to see a specialist or someone you can help, speak to your doctor about it or seek it out yourself.  Take steps to initiate the process on your own changing eating and exercise habits and a safe way.

Image courtesy of rosmary on Flickr