Monday, January 26, 2015

Endocrine Society Clinical Practice Guidelines For The Pharmacological Treatment of Obesity

sharma-obesity-medications6Last week, the US Endocrine Society released a rather comprehensive set of evidence-based clinical practice guidelines for the pharmacological management of obesity, published in the Journal of Clinical Endocrinology and Metabolism.

The recommendations in the 21-page document follow the rather rigorous Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) group (from 0 to 4 stars) and goes beyond just evaluating the evidence in favour of pharmacological treatment of obesity itself but also for the pharmacological treatment of overweight and obese individuals presenting other medical conditions.

Here are the (in my opinion) most important recommendations from this document:

1) While diet, exercise and behavioural interventions are recommended in all patients with obesity,

“Drugs may amplify adherence to behavior change and may improve physical functioning such that increased physical activity is easier in those who cannot exercise initially. Patients who have a history of being unable to successfully lose and maintain weight and who meet label indications are candidates for weight loss medications.(****)”

2) “If a patient’s response to a weight loss medication is deemed effective (weight loss > 5% of body weight at 3 mo) and safe, we recommend that the medication be continued. If deemed ineffective (weight loss < 5% at 3 mo) or if there are safety or tolerability issues at any time, we recommend that the medication be discontinued and alternative medications or referral for alternative treatment approaches be considered. (****)”

3) “If medication for chronic obesity management is prescribed as adjunctive therapy to comprehensive life- style intervention, we suggest initiating therapy with dose escalation based on efficacy and tolerability to the recommended dose and not exceeding the upper approved dose boundaries. (**)”

The guidelines also make specific recommendations for the pharmacological treatment of overweight and obese individuals presenting with a wide range of other medical issues, including 2 diabetes mellitus (T2DM), cardiovascular disease, psychiatric illness, epilepsy, rheumatoid arthritis, COPD, HIV/AIDS and allergies.

For example:

“In patients with T2DM who are overweight or obese, we suggest the use of antidiabetic medications that have additional actions to promote weight loss (such as glucagon-like peptide-1 [GLP-1] analogs or sodium-glu- cose-linked transporter-2 [SGLT-2] inhibitors), in addi- tion to the first-line agent for T2DM and obesity, metformin. (***)”

The guidelines also discuss the pros and cons of the anti-obesity medications currently available in the US (phentermine, orlistat, phentermine/topiramate, lorcaserin, buproprion/naltrexone, and liraglutide), which we can only hope will soon also become available to patients outside the US.

The entire document is available here.

@DrSharma
Edmonton, AB

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Friday, January 23, 2015

GLP-1 Analogue Liraglutide For Obesity Gets Positive Vote In Europe

novo_nordiskJust one month after the GLP-1 analogue liraglutide 3 mg received approval for obesity treatment by the US-FDA, liraglutide 3 mg, yesterday, also got a positive nod from the Committee for Medicinal Products for Human Use (CHMP) under the European Medicines Agency (EMA).

Here is how the Novo Nordisk press release describes the mode of action and indication for liraglutide 3 mg:

Saxenda®, the intended brand name of liraglutide 3 mg, is a once-daily glucagon-like peptide-1 (GLP-1) analogue, with 97% homology to naturally occurring human GLP-1, a hormone involved in appetite regulation. The CHMP positive opinion recommends that Saxenda® will be indicated as an adjunct to a reduced-calorie diet and increased physical activity for weight management in adult patients with an initial Body Mass Index (BMI) of >=30 kg/m2 (obese), or >= 27 kg/m² to < 30 kg/m² (overweight) in the presence of at least one weight-related comorbidity such as dysglycaemia (pre-diabetes or type 2 diabetes mellitus), hypertension, dyslipidaemia or obstructive sleep apnoea.”

Regular readers will be aware of the role that the incretin GLP-1 plays in the  regulation of glucose metabolism as well as satiety and appetite.

Data for this approval come from the Phase 3 SCALE trial program involving over 5,000 patients with overweight and obesity, the majority of who also had related comorbidities.

Given that this is an injectable drug that will be available only with a  doctor’s prescription and, as any anti-obesity medication, will need to be used in the long-term, it will be interesting to see how this new approach to obesity treatment will be accepted by doctors and their patients.

Although liraglutide 3 mg may not work for or be tolerated by everyone, I am confident that this much-needed addition to the obesity treatment tool-box will provide a new treatment option to some patients – especially those with obesity related health problems.

@DrSharma
Edmonton, AB

Disclaimer: I have received honoraria for consulting and speaking from Novo Nordisk

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Friday, January 16, 2015

The Physiological Benefits Of Laughter

theater_masksAs regular readers are well aware, over the past year, I have been exploring the use of stand-up comedy in communicating about the science of obesity to anyone who cares to listen.

While preparing for this new venture included working with professional comedians, taking improv classes, and, yes, impromptu appearances at local “open-stages”, I have also delved into the (sometimes rather serious) literature on the science of comedy and laughter.

Indeed, as one may suspect, there is indeed a rather large and growing body of scientific literature on humor, comedy and laughter – including its physiological and psychological effects, its therapeutic use (in everything from depression and chronic pain to cancer and obesity), and as a communication tool for health professionals.

Anyone interested in this topic, may wish to refer to a recent article by Dexter Louie and colleagues from the University of California, Harvard Medical School and the Joslin Diabetes Centre on laughter as a tool for lifestyle medicine that recently appeared in the American Journal of Lifestyle Medicine (btw – a term that I really don’t like).

The article begins with a brief discussion of the three preeminent theories (out of over 100 competing ideas) of why we laugh, which are summarized as follows (the examples are mine):

1. Release theory, which argues that laughter is the physical manifestation of repressed desires and motivations (which explains potty jokes).

2. Superiority theory, which posits that laughter is a means of increasing one’s self-esteem at the expense of others (which is probably why most people laugh at fat jokes).

3. Incongruity theory, which states that humor is created by a sense of incongruity between two or more objects within a joke (e.g. an obesity doctor making jokes about obesity doctors).

The article then goes on to briefly review the physiological effects of laughter, whereby it makes a clear distinction between spontaneous and and self-induced laughter:

“The former refers to “genuine” or unforced laughter, often in response to a stimulus, whereas the latter describes laughter that is simulated de novo. Spontaneous laughter is often associated with positive mood, whereas simulated laughter is primarily physical and is not necessarily associated with positive emotions or feelings. Neuroimaging suggests that different neural pathways are used in these 2 forms of laughter.”

The researchers review a range of studies documenting the positive effects of spontaneous laughter on stress hormones, endorphins, immune response, pain tolerance, anxiety as well as studies showing that the cardiovascular response to a good laugh are virtually identical to those elicited by a bout of physical exercise (exercise physiologists take note!).

Despite these promising findings, the authors are also quick to point out that,

“There is great potential for future research in laughter. Randomized controlled large-scale trials are needed to further elucidate the physiologic effects of laughter.”

In the second part of the article, the authors discuss whether or not physicians should use humor as a tool to induce therapeutic laughter?

“Of course, health is a serious and often grave matter, and humor delivered at inappropriate times can be devastating, insensitive, and crass……Within the bounds of appropriateness, however, both humor and laughter can be beneficial. For one, laughter shared between the provider and patient conveys a measure of trust and light-heartedness. Furthermore, humor can improve communication, as a joke can signal a transition in the conversation from the serious to more benign topics.”

The authors even have suggestions on how to address the issue of laughter in clinical practice:

“Providers can ask, “What has made you laugh recently?” or “How often do you laugh?” Inquiring about laughter opens the door to light heartedness and also could lead to counseling on laughter and sharing the latest research with the patient. More important, it allows the provider to determine what the patient finds funny, thereby allowing the provider to tailor recommendations to better fit the patient’s needs and preferences. This also contains the potential to deepen the therapeutic relationship between patient and provider. Put together with a more structured approach, the health care provider could consider prescribing laughter to patients.”

And here is what a laughter prescription could look like (directly borrowed from exercise prescriptions):

(F) Frequency: once a week
(I) Intensity: belly laughing
(T) Time: 30 minutes

(T) Type: your favorite sit-com

While much remains to be studied in terms of the therapeutic use of laughter (e.g. spontaneous vs. self-induced, individual vs. group laughter, dose-response relationships, laughter yoga, etc.), as the authors point out, there is an increasing body of evidence pointing to potential benefits for health and well-being.

Or, as the authors put it,

“With no downsides, side-effects, or risks, perhaps it is time to consider laughter seriously.”

@DrSharma
Edmonton, AB

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Tuesday, January 13, 2015

Leptin Mediates Obesity Hypertension – End Of Story!

sharma-obesity-obese_miceSome times you think that a scientific question has long been adequately answered when someone comes along and puts any remaining doubts to rest.

This happened last week, when Stephanie Simonds and an international group of researchers, in a paper published in Cell, present a rather elegant and sophisticated range of studies clearly demonstrating that the adipocyte-derived hormone leptin is a key mediator of hypertension in diet-induced (and probably other types of) obesity.

The reason I thought that this question had already long been put to rest was due to a series of rather convincing animal and human studies published in the early 2000s (some of which I was directly involved in) that nicely demonstrated a) that obesity in hypertension is largely mediated by an increase in (renal) sympathetic activity; b) that leptin stimulates sympathetic activity and sodium retention; c) in dogs and humans leptin concentrations are closely correlated with sympathetic nerve activity and blood pressure. We’ve also known that obese mice lacking leptin or its receptor do not develop hypertension despite considerable weight gain.

If anyone should have any remaining questions, these are now answered in the paper by Simonds and colleagues which uses an array of experiments involving animals deficient in leptin or leptin receptors, humans with loss-of-function mutations in leptin and the LepR and show that leptin’s effects on blood pressure are mediated by neuronal circuits in the dorsomedial hypothalamus (DMH), an effect that is prevented or reversed by blocking leptin with a specific antibody, antagonist, or inhibition of the activity of LepR-expressing neurons in the DMH. 

All of this is interesting and highlights the fact that adipose tissue is far more than a simple storage organ for fat but rather a tissue that plays an active role in the regulation of a wide range of bodily functions.

Leptin alone, just one of the many hormones secreted by fat cells (often collectively referred to as adipokines), has been shown to play an important role in appetite and energy regulation, immune function and bone development.

As for bringing us a step closer to obesity treatments, the study suggests that it may not be easily possible to harness leptin as a treatment for weight loss, as one expected side effect would be an increase in blood pressure and heart rate – effects that have limited the clinical tolerability of other “sympathomimetic” drugs.

@DrSharma
Edmonton, AB

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Friday, December 5, 2014

Hypothalamic Inflammation In Human Obesity

sharma-obesity-astrogliosisRegular readers may recall the exciting body of work from animal models of obesity showing that hypothalamic inflammation involving microscarring (gliosis) may play an important role in appetite and energy regulation in obesity.

Now, a study by Josep Puig and colleagues from the University of Girona, Spain, published in the Journal of Clinical Endocrinology and Metabolism, provides evidence for a similar process in humans.

The researchers used an MRI technique called diffusion tensor imaging (DTI) to measure hypothalamic damage in 24 consecutive middle-aged obese subjects (average BMI 43) and 20 healthy volunteers (average BMI 24).

Not only did the obese participants show greater signs of hypothalamic inflammation but these changes were also strongly associated with higher BMI, fat mass, inflammatory markers, carotid-intima media thickness, and hepatic steatosis and lower scores on cognitive tests.

While these studies do not prove cause and effect, these findings are consistent with findings in animal models and point to the role of pro-inflammatory pathways in the areas of the brain known to be intimately linked to appetite and energy regulation.

Understanding what exactly triggers this inflammatory response (in animal models, one fact appears to be a high-fat diet) and how this process could be inhibited, may open new avenues for obesity prevention and treatment.

@DrSharma
Madrid, Spain

ResearchBlogging.orgPuig J, Blasco G, Daunis-I-Estadella J, Molina X, Xifra G, Ricart W, Pedraza S, Fernández-Aranda F, & Fernández-Real JM (2014). Hypothalamic damage is associated with inflammatory markers and worse cognitive performance in obese subjects. The Journal of clinical endocrinology and metabolism PMID: 25423565

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In The News

Diabetics in most need of bariatric surgery, university study finds

Oct. 18, 2013 – Ottawa Citizen: "Encouraging more men to consider bariatric surgery is also important, since it's the best treatment and can stop diabetic patients from needing insulin, said Dr. Arya Sharma, chair in obesity research and management at the University of Alberta." Read article

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