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Do Genetics Explain Variability in Weight-Loss Response to Liraglutide?

sharma-obesity-dna_molecule9As with any medication (for anything!) not everyone responds the same.

Now a small study by Mojca Jensterle and colleagues from Ljubljana, published in the European Journal of Clinical Pharmacology, reports that genetic variability in the GLP-1 receptor gene may predict the variability to the human GLP-1 analogue liraglutide, now approved for obesity treatment in the US, Canada and Europe.

In their study, Jensterle and colleagues examine the realationship between two common alleles (variants) of the GLP-1 receptor in 57 women with obesity and polycystic ovary syndrome.

All women were treated with liraglutide 1.2 mg QD s.c (well under the 3.0 mg QD dose approved for obesity treatment) for 12 weeks.

Twenty of the participants were classified as strong responders (>5% weight loss), who lost about 7.4 Kg, whereas 37 were considered poor responders losing only 2.2 Kg.

Carriers of at least one rs10305420 allele were about 70% less likely to be a high responder than individuals with two wild-type alleles. Similarly, carriers of at least one rs6923761 allele were about three times as likely to high responders compared to homozygous carriers of the wild type.

Although my previous work in these type of genetic studies have made me highly critical (not to say sceptical) of these types of small studies, the notion that genetic variability in the GLP-1 receptor (the molecular target of liraglutide) may well lead to differences in response is not all that far fetched.

Thus, whether true or not, I have little doubt that indeed much of the variability in pharmacological response to liraglutide (or for that matter any other drug for anything) may well be determined by genetics.

Whether testing people for genetic markers before starting a specific treatment will ever become reality for obesity and whether or not, the genetic variability seen in this study will still be seen when lirglutide is used at the actual dose approved for obesity treatment remains to be seen.

In the meantime, the easiest way to see who responds and who does not is to try it. This why the regulatory approval of liraglutide for obesity comes with a simple stopping rule – if it doesn’t work for you – stop taking it!

Edmonton, Alberta

Disclaimer: I have received consulting and speaking honoraria from Novo Nordisk, the maker of liraglutide.

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Adolescents Undergoing Bariatric Surgery Are Severely Ill

sharma-obesity-bariatric-surgery21The recently released Canadian Practice Guidelines on the prevention and management of overweight and obesity in children and youth released by the Canadian Task Force on Preventive Health Care (CMAJ 2015), rightly recommended that surgery not be routinely offered to children or youth who are overweight or obese.

Nevertheless, there is increasing evidence that some of these kids, especially those with severe obesity, may well require rather drastic treatments that go well beyond the current clinical practice of doing almost nothing.

Just how ill kids can be before they are generally considered potential candidates for bariatric surgery is evident from a study by  Marc Michalsky and colleagues, who just published the baseline characteristics of participants in the Teen Longitudinal Assessment of Bariatric Surgery (Teen-LABS) Study, a prospective cohort study following patients undergoing bariatric surgery at five adolescent weight-loss surgery centers in the United States (JAMA Pediatrics).

While the mean age of participants was 17 with a median body mass index of 50, the prevalence of cardiovascular risk factors was remarkable: fasting hyperinsulinemia (74%), elevated hsCRP (75%), dyslipidemia (50%), elevated blood pressure (49%), impaired fasting glucose levels (26%), and diabetes mellitus (14%).

Not reported in this paper are the many non-cardiovascular problems raging from psychiatric issues to sleep apnea and muskuloskeletal problems, that often dramatically affect the life of these kids.

While surgery certainly appears rather drastic, the fact that these kids are undergoing surgery is merely an indicator of the fact that we don’t have effective medical treatments for this patient population, which would likely require a combination of behavioural interventions and polypharmacy to achieve anything close to the current weight-loss success of bariatric surgery.

That this cannot be the ultimate answer to obesity management (whether for kids or adults), is evident from the rising number of kids and adults presenting with ever-higher BMI’s and related comorbidity – not all of these can or will want surgery.

Thus, while current anti-obesity medications cannot compete with the magnitude of weight-loss generally seen with surgery, medications together with behavioural interventions may well play a role in helping prevent progressive weight gain in earlier stages of the disease.

Unfortunately, I am not aware of any studies that have explored the use of medications in kids to stabilize weight in order to avoid surgery. This would, in my opinion, be a very worthwhile use of such medications.

Edmonton, AB

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All Behavioural Interventions Carry Risks

sharma-obesity-kids-scale1Following the recent release of the Canadian Task Force on Preventive Health Care guidelines for prevention and management of adult obesity in primary care, the Task Force yesterday issued guidelines on the prevention and management of childhood obesity in the Canadian Medical Association Journal (CMAJ).

Key recommendations include:

  • For children and youth of all ages the Task Force recommends growth monitoring at appropriate primary care visits using the World Health Organization Growth Charts for Canada.
  • For children and youth who are overweight or obese, the Task Force recommends that primary health care practitioners offer or refer to formal, structured behavioural interventions aimed at weight loss.
  • For children who are overweight or obese, the Task Force recommends that primary health care practitioners not routinely offer Orlistat or refer to surgical interventions aimed at weight loss.

The lack of enthusiasm for the prevention of childhood obesity is perhaps understandable as the authors note that,

“The quality of evidence for obesity prevention in primary care settings is weak, with interventions showing only modest benefits to BMI in studies of mixed-weight populations, with no evidence of long-term effectiveness.”

leading the Task Force to the following statement,

“We recommend that primary care practitioners not routinely offer structured interventions aimed at preventing overweight and obesity in healthy-weight children and youth aged 17 years and younger. (Weak recommendation; very low-quality evidence)”

Be that as it may, the Task Force does recommend structured behavioural interventions for kids who already carry excess weight based on the finding that,

“Behavioural interventions have shown short-term effectiveness in reducing BMI in overweight or obese children and youth, and are the preferred option, because the benefit-to-harm ratio appears more favourable than for pharmacologic interventions.”

What caught my eye however, was the statement in the accompanying press release which says that,

“Unlike pharmacological treatments that can have adverse effects, such as gastrointestinal problems, behavioural interventions carry no identifiable risks.” (emphasis mine) 

While I would certainly not argue for the routine use of orlistat (the only currently available prescription drug for obesity in Canada) in children (or anyone else), I do take exception to the notion that behavioural interventions carry no identifiable risks – they very much do.

As readers may be well aware, a large proportion of the adverse effects of medications is attributable to the wrong use of these medications – problems often occur when they are taken for the wrong indication, at the wrong dose (too high or too low), the wrong frequency (too often or too seldom), and/or when patients are not regularly monitored. In a perfect world,  many medications that often lead to problems would be far less problematic than they are in the real world.

Interestingly, the same applies to behavioural interventions.

Take for example diets – simply asking a patient to “eat less” can potentially lead to all kinds of health problems from patients drastically reducing protein, vitamin and mineral intake as a result of going on the next “fad” or “do-it-yourself” diet. Without ensuring that the patient actually follows a prudent diet and does not “overdo” it, which may well require ongoing monitoring, there is very real potential of patients harming themselves. There is also the real danger of promoting an eating disorder or having patients face the negative psychological consequences of yet another “failed” weight-loss diet. Exactly how many patients are harmed by well-meant dietary recommendations is unknown, as I am not aware of any studies that have actually looked at this.

The same can be said for exercise – simply asking a patient to “move more” can result in injury (both short and long-term) and coronary events (in high-risk patients).  Again, ongoing guidance and monitoring can do much to reduce this potential harm.

In short when patient apply behavioural recommendations at the wrong dose (too much or too less), wrong frequency (too often or too seldom), and/or are not regularly monitored, there is indeed potential for harm – I would imagine that this potential for harm is of particular concern in kids.

This is not to say that we should not use behavioural interventions – we should – but we must always consider the potential for harm, which is never zero.

I’d certainly be interested in hearing from anyone who has seen harm resulting from a behavioural intervention.

Edmonton, AB

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Weight Gain With Methadone Treatment For Opioid Addiction

scaleWeight gain is not an uncommon phenomenon with addiction treatment. This has been reported both in smokers and in those with alcohol addiction.

Now a study by Jennifer Fenn and colleagues from the University of Vermont report significant weight gain with methadone treatment for opioid addiction in a paper published in the Journal of Substance Abuse Treatment.

The retrospective chart review included 96 patients enrolled in an outpatient methadone clinic for ≥ 6 months.

Overall mean BMIs increased by about 3 units (from 27.2 to 30.1), which corresponds roughly to an 18 lb or 10% increase in body weight.

Interestingly, the weight gain was predominantly seen in women, who gained about 28 lbs or 17.5% body weight compared to men, who only increased their weight by about 12 lbs or 6.4%.

As the study did not have access to food records, one can only speculate as to the causes. While better nutrition may well play a role, one could also speculate that there may be some addiction transfer from opioids to calorie-dense foods.

Whatever the cause, clinicians should probably be aware of this potential impact of methadone treatment on body weight, as prevention of excess weight gain may be easier than treating obesity once it is established.

Edmonton, AB

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MetAP2 Inhibitor Beloranib Produces Weight Loss in “Simple” Obesity

sharma-obesity-insulin-injectionReaders may recall a previous post on the remarkable efficacy of beloranib, a methionine aminopeptidase 2 (MetAP2 ) inhibitor, in patients with hypothalamic obesity.

Now, a paper by Dennis Kim and colleagues present the results of a phase II study in individuals with “simple” obesity, published in Diabetes, Obesity and Metabolism.

The study included 147 participants with moderate obesity, who were randomised to 0.6, 1.2, and 2.4 mg beloranib or placebo for 12 weeks, with no specific diet or exercise recommendations.

At 12 weeks, participants had on average lost between 5.5 and 10.9 Kg in a dose-dependent fashion.

This reduction in body weight was associated with relevant improvements in waist circumference, lipids and blood pressure.

Adverse effects included dose-dependent increase in sleep latency and mild to moderate gastrointestinal symptoms.

Beloranib is an investigational weight loss therapy with a novel mechanism of action. This study assessed the efficacy, safety, and tolerability of beloranib treatment for obesity.

This is certainly a most remarkable degree of weight loss seen at 12 weeks and it will be interesting to see the results of the longer-term studies that are currently underway.

Edmonton, AB

Disclaimer: I have received consulting honararia from Zafgen, the maker of belanorib.

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