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Monday, November 12, 2018

Why Aren't We Taking Anti-Obesity Drugs?



This post was prompted by the following article on Medscape


It is written by Caroline M. Apovian, MD 

I'd encourage you to read this whole thing first, as I'm genuinely interested in that response. Additionally I'm curious as to whether or not your response changes after reading this blog post (or other sources I'm about to link to).






SUMMARY:



In my considered opinion, the designation of obesity as a chronic (incurable) disease was largely, if not entirely, a nod to the pharmaceutical industry.   In short, if the medical faction of the Obesity Industrial Complex could get doctors to prescribe, and insurers to cover the cost of, anti-obesity drugs for indefinite periods of time, the pharmaceutical industry would renew efforts to develop "new" drugs.  Until such time, the turn of the century failures and liabilities created a very hostile environment for the pharmaceutical faction of the OIC.  There just wasn't going to be an impetus to develop drugs unless doctors were going to enthusiastically prescribe them for lengthy periods of time ... only then would the pharmaceutical companies recoup their development costs, etc.*

Therefore, the medical faction of the OIC has done their part in:

  • Getting obesity classified as a chronic, progressive, relapsing, incurable disease that must be medically managed for life, and ...
  • (Perhaps more importantly) Redefining clinical treatment "success" for obesity as somewhere in the neighborhood of 5-10% of baseline body weight.
  • Convincing pharma that there were legions of frustrated doctors who would love to help their obese patients, but for having their hands tied and such a limited pill arsenal to work with.
So the pharmaceutical companies delivered.  Four "new" drugs to add to the arsenal of plain old phentermine and orlistat (the wear-dark-clothes-in-case-you-shit-your-pants drugs Xenical and OTC Alli).  I put "new" in quotes for a reason, because only one, Belviq (locarserin) was developed spicifically for weight loss.  The others are combinations of drugs that had weight loss as a side effect, where specific combos were looked at for weight loss.  The big three here are Contrave (naltrexone and bupropion), Qsymia (phentermine and topiramate), and Saxenda (same active ingredient as diabetes drug Victoza).  
  • The investments of the drug companies were more to convince the FDA that the chronic use was safe and "effective". Thanks to the medical establishment, the hurdle for "effective" had been lowered.  
  • The remaining expense was marketing.  There were aggressive ad campaigns to consumers to get them to "ask their doctor" ... apparently these failed.
  • To their surprise (?), the drug companies STILL had (or rather HAVE) to convince doctors to prescribe their drugs.
This Medscape article is one of many in advance of Obesity Week (put on in part by The Obesity Society of which the author is current President) to get the rank and file in the medical field to lock step in treating obesity as a chronic disease.  It does this in large part by 
  • Essentially blaming the insurance companies for failing to see the benefit of these drugs and shouldering the high costs (especially of two drugs with generic components) to manage this "chronic disease", and
  • Shaming doctors into thinking they are failing their patients by not offering and promoting the long term use of these potentially dangerous drugs in order to "manage" their "disease".
I hope this fails..










I have made no secret here (see Thoughts on Obesity as "Disease" or Choice ~ Part 1: Smoking & Lung Cancer Analogy ) and more frequently on social media, that I do not believe "common" obesity is a disease in and of itself.  It simply fails to meet the standards of any other disease model in medicine.  And yet, it has been decreed for half of a decade now ... and there's likely no going back.  (I find this unfortunate.  When mistakes are made, rectifying them may require eating some crow, but that is better than the alternatives)  

The article begins:  
Obesity is a complex, chronic metabolic disease purported to be caused by a combination of genetic predisposition and the environment.  {italics mine}

Realize that the medical profession has been treating obesity for decades, a "chronic disease" designation was not necessary.  When you view the historical arguments for the 2013 disease designation alongside the timeline of the trials and tribulations of the pharmaceutical industry over the past decade or two, it becomes crystal clear that this is virtually ALL driven by the desire to be able to prescribe anti-obesity medications for long term use ... for life essentially.   It appears as if the pharmaceutical companies worked harder on getting this disease designation, than they have on developing any genuinely new anti-obesity drugs.  To be fair, there's not likely to ever be a magical weight loss pill, so it's not entirely this industry's fault.  In a way, they were sort of willing to shy away from e1
This Medscape commentary seems a little too conveniently timed ... a primer for Obesity Week 2018 that begins on November 11.  Obesity WEEK, because no mere weekend seems sufficient for the premier EXPO of what I like to call the Obesity Industrial Complex.   How odd then, that among her list of credentials, they fail to mention that she currently serves as President of The Obesity Society (TOS) for 2017-18.

Ahh well ... but enough about the author, and on to her question:


Why Aren't We Prescribing Pills for Obesity?


This is the wrong question, or rather the answer to this question is the answer to the question in the title of this post:

Why Aren't We Taking Anti-Obesity Drugs?


When one-third of Americans are obese, and we're easily the most medicated nation on the planet, why, then, are we not clamoring for these weight loss pills?   The article laments that fewer than 2% of obese patients are offered a prescription and fewer than 1% of obese patients actually fill a prescription.  

Answer:  

Every weight loss drug must be used in conjunction with lifestyle change.


NOTE:  The above are screen-capture compilations made from the "front page" of the manufacturer websites.  My purpose is to highlight that each of these drugs is marketed as an adjunct to a reduced calorie plan, sometimes specifically requiring reduced fat intake, and often an increased activity component.  Orlistat is largely marketed OTC so I used the Alli.

This is issue number one.  Even orlistat, which reduces the absorption of dietary fat (thus allowing for some "free calories"), requires adherence to a reduced calorie and reduced fat diet in order to see results.  Indeed it may be the worst of the bunch because if you take the drug and eat a fatty meal, you're in for a world of GI hurt and potential embarrassment.

Still, if these drugs deliver on their promises, one can expect to lose more weight and/or at a faster rate.  So here's where the relatively anemic weight loss seen in the various studies on these drugs comes in.

I'm unsure why Avopian is so seemingly enthusiastic about these drugs in her Medscape article.  After all, she references two journal articles bearing her name when making this statement:
In 1- and 2-year randomized, placebo-controlled trials, use of these agents resulted in weight loss of approximately 5%-10% of original weight.[3,4] 
The references listed below include links to the full texts:
3. Current pharmacotherapy for obesity.  Srivastava, G., & Apovian, C. M. (2017) Nature Reviews Endocrinology, 14(1):12–24. 
4.  Pharmacological Management of Obesity: An Endocrine Society Clinical Practice Guideline.  Caroline M. Apovian, Louis J. Aronne, Daniel H. Bessesen, Marie E. McDonnell, M. Hassan Murad, Uberto Pagotto, Donna H. Ryan, and Christopher D. Still (2015).  The Journal of Clinical Endocrinology & Metabolism, 100(2):342–362.
So Apovian is not simply parroting industry "talking points", she's looked in depth at the totality of the clinical evidence regarding both the efficacy and safety of these drugs.    The below is annotated with brand names (from Reference 3):


The above, put into context, provides the second answer to the question.  Also scan down the column of the percentage of participants who lose over 5% of their baseline weight.  


Why Aren't We Taking Anti-Obesity Drugs?    

Answers:

The best case above showed additional weight loss vs. placebo of 0.3 lbs per week ... That's pathetic.


The average "response rate" (for >5% loss) is somewhere under two-thirds. and this is often for completers ... that's just not good enough.
So people are generally stupid ... sorry.  And many obese people can be desperate to lose weight.  Yet still, the promise here goes something like this:  "Well, over a year this drug MIGHT be able to help you adhere to that diet and exercise program, and ... well ... sorry ... you're not likely to lose a practically significant amount of weight vs. if you just commit to that diet and exercise program on your own.

More Answers:


WHATEVER the clinical significance of 5-10% body weight loss is, these figures from clinical trials translate to somewhere in the range of 10 to 30 lbs lost in one year. ... That's pathetic.*
This averages out to < 1 lb per month to 2.5 lbs per month.  Don't even bother with per week numbers!  That's pathetic.
A 220 lb person who loses 11 lbs weighs 209 lbs.  This is the 5% benchmark for "success" ... all this to become somewhat less obese???

* To clarify: I'm not poo pooing any weight loss, but these amounts over that length of time are not impressive.  Most would probably rather do something more extreme for a shorter time to knock off that amount of weight, and I'd venture to guess that many obese people have lost 5-10% of their body weight more than once in their lifetime, it's the keeping it off that proves to be more elusive for most.

These studies are conducted in mostly women (around three-fourths = 75%) with baseline average weight of 100 kg = 220 lbs.  While different people can have widely varying changes in body comp and measurements/clothing sizes at different weights, the bottom line is that for almost every obese person, a 5% weight loss puts them at "somewhat smaller, still obese".   The more obese to begin with translates to more weight lost, but even less meaningful end result.  For example a 300 lb person losing 5% weighs 285 lbs, and 10% weighs 270 lbs.    At higher weights like this, depending on how one carries their weight, those losses may not even be noticeable.



Still One More Answer:


From the article itself ...

Bariatric surgery offers a 25%-33% total weight loss with maintenance of most of that weight loss long-term.
One absolutely cannot ignore the very real transformation that many who have WLS (especially Roux-en-Y gastric bypass) achieve, and though the remission rate is considerable, so too are the long term maintenance rates of truly significant weight loss. Yes, it IS a lifestyle change too, but for a variety of reasons, it's "easier".  Note the quotes there, as I do not wish to imply it is easy, nor do I wish to imply it is without downsides.  But really this post is about the drugs, so let's get back to those.  In summary, a "best case scenario" for drugs doesn't even come close to the "worst case scenario" for WLS.  Also, as the article states, some taking the drugs even gain weight, whereas virtually all WLS lose significant weight (at least initially).

Obesity is NOT Like Hypertension


As the Medscape article progresses, Apovian reaches into the "chronic disease"-analogy-bin to try to make a case for these anti-obesity drugs.  If one looks at cardiovascular disease risk data, hypertension is a key risk for heart attacks and the most prominent factor for stroke.  There are several different classes of anti-hypertensives -- all of which work directly on some mechanism that predictably regulated blood pressure.  The major hurdle with these drugs comes more from patients taking them regularly as prescribed.  Some require a lot of tweaking and/or monitoring to stabilize BP, but for the most part, these drugs are highly effective in NORMALIZING blood pressure while the patient continues their usual lifestyle.  Indeed I'd say that antihypertensives are a classic example of American's love affair with pills vs. lifestyle change.

Of course there are patients who don't respond to one or another class of drugs, and/or who require some lifestyle changes to optimize their effect, but pretty much any person who takes one of these drugs will see their blood pressure drop.  The more targeted the mechanism of action, the more predictable the effect.  But it happens.  This is simply not the case for these anti-obesity drugs.

Indeed, calling them "anti-obesity" and deeming them "effective" at 5-10% weight loss is borderline criminal.  An average height (5'4") American woman weighing 200 lbs (some 20 lbs less than the average baseline weight in studies)  has a BMI of 34.3, and losing 10% body weight ends up at 180 lbs with a BMI of 30.9 -- this is still obese by medical metrics (and some 35 lbs north of "normal weight' by the BMI standard that IS used).  The more obese at baseline, the worse it gets, and if we are starting at 300 lbs/BMI 51.5 and ending at 270 lbs/BMI 46.3, how can you pass this off as even a clinical success?   (You can even ignore BMI and the reality changes very little)

You put a person, at any weight, on drugs to reduce blood pressure, and chances are good you normalize that blood pressure.  Drugs simply do not deliver normal weight in all but a few isolated cases, and even then, not without major lifestyle changes.

Rather than address this point, Avopian looks to other reasons why these drugs haven't caught on.  These being:
  1. While more insurers are covering them, there's still a lack of insurance coverage for these rather pricey medications.
  2. Until more recently, doctors could only prescribe these drugs for 3-6 months and while exact stats are unclear, there's reason to believe that regain rates are at least similar to those who lose weight by diet (and/or exercise) alone.
Ahhh ... but there's a solution!  From the Medscape article


Chronic Therapy for a Chronic Condition

The discussion of pharmacotherapy interventions includes the statement that "data were lacking about the maintenance of improvement after discontinuation of pharmacotherapy." But you would not expect maintenance of improvement after discontinuing pharmacotherapy for hypertension or type 2 diabetes, which are considered diseases. Likewise, you should not expect sustained weight loss after discontinuing medication that readjusts the body-weight set point by improving satiety.


The endgame here is to clear the way for doctors to prescribe these medications for indefinite periods of time, perhaps even for life.   This is what is behind the chronic disease designation.  But even the "long" clinical trials provide no evidence that these drugs would continue to be as (in)effective as they are over several years.  Safety?  We really have no data there either.  


So We Have Yet Another Answer:

Nobody wants to take any of these drugs, with their potential side effects, for years on end.


Clearly the insurance companies are not convinced that covering these drugs in the interim, let alone in perpetuity, will result in a net savings.  This is, after all, why ANY insurer -- private or taxpayer funded -- would cover a medication.  More importantly, this is why any individual should consider the not just the cost of such medications when deciding whether to take them.

Yes, with 5-10% weight loss, many obese see improvements in their cardiometabolic health markers.  But there is little to no evidence that these improvements -- often measured immediately following a period of caloric deficit or after a few weeks of maintenance -- persist once that still-obese person maintains that slightly lower state of excess weight for a year or even several months.  When even done, most clinical study followups deliver less than encouraging news.   




Since Obesity Week is in full swing now ... I'm going to post this up, and hopefully follow up with specific post, at least, on how Qsymia, the most effective drug, factors in here.













http://carbsanity.blogspot.com/2018/05/thoughts-on-obesity-as-disease-or.html

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