Tuesday, January 27, 2015

Canadian Clinical Practice Guidelines For Obesity: We Need More Than Diet and Exercise

sharma-obesity-doctor-kidYesterday, saw the release of new Clinical Practice Guidelines from the Canadian Task Force on Preventive Health Care to help prevent and manage obesity in adult patients in primary care.

Similarly to the Endocrine Society’s Guidelines for the pharmacological treatment of obesity (see yesterday’s post), the authors use a GRADE system to rank and rate their recommendations.

Key recommendations are summarized as follows:

  • Body mass index should be calculated at primary health care visits to help prevent and manage obesity.
  • For normal weight adults, primary care practitioners should not offer formal structured programs to prevent weight gain.
  • For overweight and obese adults health care practitioners should offer structured programs to change behaviour to help with weight loss, especially to those at high risk of diabetes.
  • Medications should not routinely be offered to help people lose weight.

Virtually all of these recommendations are supported by evidence that is rated between moderate to very low, which essentially leaves wide room for practitioners to either do nothing or whatever they feel is appropriate for a given patient.

The guidelines do not discuss the role of bariatric surgery (arguably the most effective treatment for severe obesity) and make no recommendations for when this should be discussed with patients.

The rather subdued recommendations for the use of medications is understandable, given that the only prescription medication available for obesity in Canada is orlistat (why the authors chose to also discuss metformin, which is not indicated for obesity treatment, is anyone’s guess).

Overall, the reader could easily come away from these guidelines with a sense that obesity management in primary care is rather hopeless, given that behavioural interventions are modestly effective at best (which is probably why the authors recommend that these not be routinely offered to patients at risk of weight gain).

Indeed, it is hard to see how primary care practitioners can get more enthusiastic about obesity management given this rather limited range of treatment options currently available to Canadians.

If there is anything to take away from these guidelines, it is probably the simple fact that we desperately need more effective treatments for Canadians living with obesity.

@DrSharma
Edmonton, AB

The whole document is available here

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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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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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Thursday, January 8, 2015

Hope For Hypothalamic Obesity And Beyond?

craniopharyngoma

Craniopharyngoma

Hypothalamic obesity, is a rare but serious condition that occurs in about 50% of individuals who have suffered injury to their hypothalamus (e.g. because of a craniopharyngoma or trauma).

Severe weight gain in these patients may not be all that surprising given that the hypothalamus plays a key role in the regulation of hunger, satiety and other aspects of energy balance.

Now, Zafgen, a US biopharmaceutical company, announces surprising early results of treating such patients with beloranib, an inhibitor of methionine aminopeptidase 2 (MetAP2), an enzyme that modulates the activity of key cellular processes that control metabolism. 

According to Zafgen, their small proof-of-principle trial (ZAF-221), conducted in 14 obese patients (nine women and five men) who were confirmed by magnetic resonance imaging (MRI) to have had hypothalamic injury, the results look most promising.

Here is the description of their findings taken from their press release:

“ZAF-221 was a randomized, double-blind, placebo controlled study of twice-weekly subcutaneous injections of 1.8 mg beloranib or placebo in patients with HIAO to evaluate weight reduction and safety over four weeks, followed by an optional four week open-label extension. Beloranib treatment resulted in mean weight loss of 3.4 kg and 6.2 kg in patients with HIAO after four and eight weeks of treatment with beloranib, respectively, in contrast to 0.3 kg mean weight loss in patients treated with placebo for four weeks (p = 0.01). Improvements in cardiovascular disease risk factors of lipids and inflammation (measured by C-reactive protein) were also observed. Beloranib 1.8 mg was well tolerated in this population, with no serious or severe adverse events reported. Safety measures such as laboratory, electrocardiogram, and vital sign measurements revealed no signals of concern, and all subjects randomized to beloranib completed the trial.”

What I find most surprising about these findings, is that this drug appears to work in people where key centres for appetite regulation are no longer intact. This points to the existence of a non-hypothalamic mode of action for this drug – an action that is powerful enough to work independently of the centres in the brain known to play a key role in energy regulation.

The company is also pursuing beloranib for individuals with Prader-Willi Syndrome, another hypothalamic form of obesity as well as patients with severe obesity.

Needless to say, this finding may well also hold promise for other forms of obesity, reason enough to closely watch the further development of this compound.

@DrSharma
Edmonton, AB

Disclaimer: I have served as a paid consultant to Zafgen.

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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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