4 new drugs for long term treatment of chronic obesity.

If there is an epidemic of obesity why are you not treating it?  LINK above


As a Diplomat of the American Board of Obesity Medicine and a Fellow and Diplomat in the National Lipid Association  I think you should consider putting your obese patients on one of the following diet pills for the chronic disease of obesity on a long term basis:

1- Lorcaserin (BELVIQ)

2- Phentermine/Topiramate (QSYMIA)

3- Liraglutide (SAXENDA)

4- Naltrexone/Bupropion (CONTRAVE)



My personal experience with Victoza, Invokana and Qsymia link

Update 12-13-15 Post ABOM exam:

 

Let me give some ideas as to how to choose which drug, which should be done in concert with your physician. 



Diet meds usually indicated if BMI >26 + comorbidity or > 30.

First step.
If fast glucose >99 go on Metformin. 

Second step. 
If diabetic already on maximum dose metformin add Victoza as this Liraglutamide will be paid for .  

Third step
If on Insulin try switching over to Invokana.  Careful monitoring of glucose during transition and suggest switching to Atkins or LCHF.

Now for the Diet medicines themselves. 

First choice?
LOCASERIN (Belviq)
Why?
May be  safest drug.
Young women are less of a concern than with Qsymia. 
Caution with depressed patients.
There is a concern for serotonin syndrome but to my knowledge this drug does not increase serotonin levels. 
Downside: Only 50% have good response. 

Solution: After two or three months add Phentermine one half tab 37.5 mg a day if no cardiac or anxiety contraindications. This is generic drug now. This addition is off label for long term despite the combination in Qsymia having the indication for long term.

Second choice?
PHENTERMINE/TOPIRAMATE (Qsymia)
Main concern: REMS caution for pregnancy testing.
Good point: Can give to depressed patients.
Side-effects: high dose can cause cognition problems
dysgeusia especially with diet soda. 
Potentiates alcohol.
Metabolic acidosis, decrease potassium, increase Creatinine. 
 Consider getting chemistry level after first month of treatment.

Third Choice?
NALTREXONE/BUPROPION/CONTRAVE
Best news: Non-scheduled drug
Bad news: Label legacy
These 2 drugs have been around for some long that many side effects have shown up on the PDR over the years. 
BLACK BOX WARNING: Depression and Neuro-psych disorders
Do not give to people on narcotic pain medicine. 
Careful in people prone to seizures.  
Thus in young folks who might binge on alcohol this might not be the first choice. 
Not for bulemia or anorexia nervosa 
Don't take with Levadopa or Amantadine
UPDATE: Still some concerns about increase HTN?

Four Choice?
LIRAGLUTAMIDE (Saxenda)
Expensive and an injection.
If diabetic can get lower dose paid for as Victoza. 
BLACK BOX WARNING: Thyroid C cell tumors
Side effects: vomiting, pancreatitis, abdominal pain
Good news: Non-scheduled drug 

Frank Greenway Recent of Obesity Medicine link

"Following gastric bypass surgery, levels of ghrelin are extremely low,39 while GLP-1 and PYY are elevated,46 which should attenuate appetite."

"However, recent studies in rodents have indicated that weight loss following sleeve gastrectomy is not mediated by changes in ghrelin or GLP-1, or through the melanocortin (MC)-4 receptor in the hypothalamus.47, 48, 49 Instead, as shown by a knockout mouse study, the mechanism of weight loss in sleeve gastrectomy appears to involve the nuclear bile acid receptor, farnesoid X receptor.50

Note that the observation that gut hormones such as ghrelin and GLP-1 are not involved in the mechanism of weight loss with sleeve gastrectomy does not mean that they are not important mediators of body weight."

Choosing which weight lost surgery is best for a patient is not based on random controlled head to head trials.  Lap band by experience has lost favor. 

The surgeons are allowed this freedom to discover the best course for the obese patients. 

Likewise, ABOM specialists will treat "off label" the multiple pathways that cause weight regain with multiple drugs. 

 

 






  




  

View from panoramic room on 15th floor.

Exciting times for weight loss as science of obesity advances

Exciting times in weight loss as science of obesity advances





The above link explains the sea change from diet and exercise to drugs and surgery as the ultimate answer to the obesity epidemic for now. 

Text states different facts about reduction in RMR or REE after weight loss? UPDATE JULY 14, 2015

I wrote Dr. Frank Greenway about the incongruence of the Handbook of Obesity and he updated me with more recent studies. `

"Conclusions: Despite relative preservation of FFM, exercise did not prevent dramatic slowing of resting metabolism out of proportion to weight loss. This metabolic adaptation may persist during weight maintenance and predispose to weight regain unless high levels of physical activity or caloric restriction are maintained. (J Clin Endocrinol Metab 97: 2489 –2496, 2012)"

"In conclusion, we found that an intensive lifestyle intervention consisting of daily vigorous exercise plus self-selected dietary restriction resulted in massive weight loss of similar magnitude to a matched group of subjects following gastric bypass surgery. Both groups showed significant improvements in cardio-metabolic profile and a resolution of Class III obesity. Unlike RYGB patients who lost a substantial amount of FFM, Biggest Loser Contest participants partially pre- served FFM despite rapid weight loss. However, FFM preservation did not attenuate the reduction of metabolic rate and both groups demonstrated a significant metabolic adaptation to weight loss that was correlated with the energy deficit and changes in leptin."
Obesity | VOLUME 22 | NUMBER 12 | DECEMBER 2014  p2567 Metabolic Adaptation with Massive Weight Loss Knuth et al.




4-15 Video on REE after bariatric surgery

In above video:
Dr. Dympna Gallagher shows that REE (resting energy expenditure) reduces more in weight loss than  can be explained.

To my confusion, as I study for the Obesity Boards in Dec 2015 I found this passage in the Handbook of Obesity edited by George A. Bray and Claude Bouchard Vol 2 Fourth edition on p. 442 in a chapter authored byDavid Heber and Frank L Greenway:

"Weight loss is always accompanied by a reduction in resting energy expenditure, but this decrease is proportional to the loss of lean body mass, and therefore, there is no evidence of adaptive decreases in resting metabolic rate due to surgery that could explain weight regain."

To further confound me I found this passage on p 147 in the same book in a chapter written by Steve Anton, John Froeyt, and Michael G. Perri:

"Recent findings suggest that the hormonal changes that encourage food intake following diet-induced weight loss persist and do not revert to baseline levels even after 1 year following the initial weight reduction.  Moreover, after a period of dieting,  resting metabolic rate decreases beyond the level expected from the loss of body mass alone.  see POUNDS LOST study.

References: 
de Jonge L, Bray GA, Smith, Ryan, De Souza  Effect of diet composition  and weight loss on resting energy expenditure in the POUNDS LOST STUDY Obesity 2012 (12):2384-9

My favorite video explaining why the reduced obese regain weight is this from Weight of the Nation HBO: 
Columbia University

Myth #3 from NEJM article Feb 2013

4 points about rapid weight loss



POINT ONE:

"Hefty, rapid weight is linked with poorer long-term outcomes than gradual weight loss"

"The above myth arose in reaction to adverse effects of very low calorie less than 800 calorie per day.

"Within weight-loss trials, more rapid and

greater initial weight loss has been associated

with lower body weight at the end of long-term

follow-up.

9,10

A meta-analysis of randomized,

controlled trials that compared rapid weight loss

(achieved with very-low-energy diets) with slower

weight loss (achieved with low-energy diets —

i.e., 800 to 1200 kcal per day) at the end of short-

term follow-up

(≥1 year) showed that, despite the association of

very-low-energy diets with significantly greater

weight loss at the end of short-term follow-up

(16.1% of body weight lost, vs. 9.7% with low-

energy diets), there was no significant difference

between the very-low-energy diets and low-energy

diets with respect to weight loss at the end of

long-term follow-up.

10

Although it is not clear

why some obese persons have a greater initial

weight loss than others do, a recommendation

to lose weight more slowly might interfere with

the ultimate success of weight-loss efforts."

 
http://www.nejm.org/doi/full/10.1056/NEJMsa1208051 link


 
POINT TWO:

Look Ahead data shows those who lost more wt maintained more wt loss link
from
Obesity (Silver Spring). 2015 Jul;23(7):1353-6. doi: 10.1002/oby.21112.



POINT THREE:


The usual concern about losing weight rapidly is that a great deal of muscle is lost as well as fat as this article below shows.

"The healthiest way to lose one to two pounds per week is to eat about 1,500 calories per day if you're female, or about 2,000 calories per day if you're male.

This will help ensure adequate nutrition while still allowing you to easily burn more calories than you eat each day, which is how you lose weight.

Even with a sensible eating plan, however, you may lose muscle mass without working out."

The rest of the article is at Nina Kate's article 


POINT FOUR

 2013 High Protein diet during wt loss may decrease fat free mass loss link to article

"In summary, we determined that consuming dietary protein at levels exceeding the RDA may protect fat-free mass during short-term weight loss."

 

 

The Three Treatments of Obestiy

Again from Handbook of Obesity Edited by Bray and Brouchard Vol. 2 p 397-398 written by Lars Sjostrom:

Conclusions

“As illustrated by the conventionally treated obese control group of SOS, nonpharmacological obesity treatment at primary health-care centers is not, on average, associated with any weight loss in the short or long term.”

“Treatment with currently available antiobesity drugs typically results in 7-10% weight reduction over 2-4 years as compared to 4% to 6% in placebo/lifestyle groups.”

“Reports from SOS trial have demonstrated that sustained positive effects on risk factors over 10 years require persistent weight loss in the range of 10% to 30%.”

“Obese patients with prediabetes and T2D deserve extra attention.
 It is more difficult to achieve conventional or pharmacologically induced weight loss in diabetic obese patients.
Moreover, even when weight loss is achieved almost all patients relapse within a few years. Treatment with sulphonylureas or insulin causes weight gain.
 Thus, obesity not only causes diabetes but is also a complication of diabetes treatment with some medications.
This vicious spiral must be broken for a successful management of T2D.”

“Surgery is the only treatment of obesity resulting, on average, in more than 15% documented weight loss over 10 years.”

My comment in purple:
Orlistat was used in Look Ahead trial link

Graph showing weight loss over 10 years in Look Ahead link


The mantra taught at NY Presbyterian/Columbia College of Physicians course on Obesity in April 2015 was that providers should be satisfied with 5-8% weight loss reduction as it tends to improve risk factors. 

Now that I have read the above text I wonder at the false hope that is presented. 

The good news is that Qsymia (phentermine/topiramate ER) maintained a weight loss of 10.7% from baseline after two years in the SEQUEL study.

Weight loss with diet and medicine not yet shown to improved mortality? Bariatric surgery has.

I am studying the Handbook of Obesity for my Obesity Boards in Dec 2015.  It is edited by Bray and Bouchard.

In Vol. 2 Fourth edition p385-386 are the following excerpts:

“However with the the exception for the Swedish Obese Subjects (SOS) trial, controlled interventional studies demonstrating that weight loss is in fact reducing mortality have been lacking”

“To date most observational epidemiological studies have indicated that overall and cardiovascular mortality is increased after weight loss even in subjects who were overweight or obese at baseline.”

“...the observed weight loss might be the consequence of conditions that lead to death rather than the cause of death.”

“Lifestyle interventions to protect against diabetes have not prevented cardiovascular events after 10-20 years of follow up.”

References:

24-Yaari. Voluntary Wt. loss. Am J Epidemiol 1998: 148: 546-555

25- Wannamethee. Older men who lose weight. Am J Epidemiol 2000; 151:667-75

26- Li G. Long term-effect of life-style interventions. Lancet 2008;371: 1783-9

27- Uusitupa. Morbidity in Finnish Diabetes Prevention Study. PLoS One 2009; 4e5656

28- Nissen SE. Rimonabant in STRADIVARIUS TRIAL. JAMA 2008; 299 1547-60

NLA has individualized guidelines for statin therapy.

High dose statin should be last step in combo therapy link



My comment:

Many patients have been lost to statins because of failure to avoid side effects at high doses.  

My opinion is to use lowest dose first as there is a variability of response (as noted above).  

Individualize therapy with goal of compliance being equally important to goal of LDLp < 750 to 1,000. 

Adding low dose(1,000 mg)  Slo-niacin or Endur-acin is very inexpensive and has additive effect of lowering LDLp better than higher dose of statin. If we are to treat earlier and for longer periods we need to use lowest effective dose at lowest price with least side effects.  

REE is lower than expected after weight loss from surgery

Dr. Gallagher shows surprising result in REE after surgery link to 1 min 17 sec video





Dr. Dympna Gallagher shows that REE reduces more in weight loss than  can be explained.

Fat Free Mass(FFM) of 60 to 50 should just move REE down same(red) line but it moves to lower lines(Green & Blue).  "Which is something that is well noted in EE studies,  that when people loss weight the REE decreases to a greater extent than can be explained by the decrease in FFM. "


"Resting Energy Expenditure (REE) is largely mediated by your body composition."

Graph in photo below shows REE as a function of FFM (fat free mass) before surgery (red line), one year later (green line) two years later (blue line)

Sponge Syndrome discussed at Obesity Board Review 2015

Sponge Syndrome link


Dr. Gallagher answers question about large number of fat cells 
 link to 1 min 43 sec video above



I asked Dr. Dympna Gallagher about the number of fat cells before and after gastric bypass not being changed by 32% weight loss.  Those million of cells are always there ready to take on lipids at a low calorie level.

Do Statins cause cancer by lowering LDLc?

2012 Meta-analysis  link


Need to look at overall mortality- Statins good for this link to original letter and rebuttal



I respect Uffe Ravnskov and his recent letter about colon-cancer contained an impressive list of random controlled trials.

I include in this blog the authors rebuttal to Ravnskov but I felt I could look up the specific trials and find out what the total mortality was. Cancer cachexia will have low LDLc. Suicides also occur. This is why it is important to look at total mortality. 4S trial and HPS did this.

4S trial results
"The Scandinavian Simvastatin Survival Study (4S trial) randomized 4444 patients with acute coronary syndromes to simvastatin versus placebo. All-cause mortality, fatal coronary events and coronary revascularization procedures were reduced in the simvastatin group. This was regardless of the baseline HDL or LDL cholesterol levels."

HPS on wiki
"The number needed to treat in the study was 57 patients to postpone one death and 19 to prevent one cardiovascular "event" (in those taking the drug simvastatin for 5 years). There was no mortality benefit in women. Cancer risk was suggestively lower in the treatment group. No worsening of lung disease was found, an initial concern with statin drugs, and simvastatin did not decrease osteoporosis."

Statins have been given to millions of people since 1987. To my knowledge there is no association of a surge of cancer?

Ravnskov states the lower the LDLc the more the chance of cancer. In JUPITER, LDLc were as low as 35 to 55 but no increased mortality.