Dr. Sharma's Obesity Notes

Given my interest in the adipose tissue renin angiotensin and our findings that this system may have metabolic effects, in 2005, my colleague Jens Jordan and I published the results of a small randomised controlled trial comparing the hemodynamic effects of the angiotensin receptor type 1 (AT-1) blocker valsartan to the beta-blocker atenolol in around 70 obese patients with mild to moderate uncomplicated essential hypertension. (Journal of Hypertension, 2005)

Participants were treated with valsartan at a maximal dose of 160 mg/day or with atenolol at a maximal dose of 100 mg/day for 13 weeks. Hydrochlorothiazide at doses of 12.5-25 mg was added in patients with blood pressure > 140/90 mmHg on monotherapy.

As expected, blood pressure levels dropped significantly and similarly with both treatments.

Although we did not see any effects on body weight, lipid levels or hsCRP, insulin resistance, as assessed by homeostasis model assessment for insulin resistance (HOMA-IR) improved with valsartan but not with atenolol.

From this study we concluded that, while both beta-receptor and AT1-receptor blockers, particularly in combination with low-dose diuretics, effectively lower blood pressure in obese hypertensives, treatment with AT1-receptor blockers may have beneficial effects on glucose homeostasis, particularly in obese hypertensives, given their profoundly increased diabetes risk.

Over time, this small study together with evidence from much larger studies has certainly added to the evidence suggesting that blockers of the renin-angiotensin system should be considered first line therapy for hypertension in obese patients.

AMS
Boston, MA

The next few days, I will be attending the 30th Annual Scientific Meeting of The Obesity Society at the San Antonio Convention Centre, just a few steps from the Alamo.

As a Fellow of this organisation and someone, who has sat on well over a handful of TOS committees, attending this conference has become part of an annual rite – one that I certainly enjoy very much.

This year, to coincide with the start of this meeting, the Journal of the American Medical Association (JAMA) dedicates a full issue to obesity.

Articles include a discussion of government’s role in obesity prevention, a number of viewpoint pieces on obesity drugs, a randomised controlled study on the effect of exercise dose on diabetes risk in children, a survey on the possible role of bisphenol A in obesity, a 20 year analysis of the health benefits of bariatric surgery, a randomised controlled trial of surgery versus conservative treatment for obstructive sleep apnea, and a discussion of differences in diabetes risk by adiposity phenotype – in short, a pot-pourri of current topics of interest – no game changers – but certainly a few thoughtful comments, interesting new data and a general indication of the breadth of epidemiological and clinical research in this field.

Certainly an issue of JAMA that all of us working in the field should probably read cover-to-cover (fortunately, most of these articles are available for free download).

Historians may recall that in the end the defenders of the Alamo, despite their heroics, ultimately lost the battle (but not the war). Often, the few researchers and practitioners, who have dedicated most of their careers to better understanding and fighting obesity (and the many misconceptions about it), may feel that they too are fighting against impossible odds.

Just how much progress will be made remains to be seen – the next few days will at least show if we are headed in the right direction.

AMS
San Antonio, TX

Regular readers will be well aware that the goal of obesity treatment is not simply to lose weight.

Rather, the whole point of treating obesity is to improve health and well-being.

Thus, although excess weight is a risk factor and contributor to a wide range of health problems, not everyone who meets BMI criteria for obesity necessarily has (or will develop) these problems. Also, simply losing weight does not necessarily translate into better health.

These facts provide a particular challenge when it comes to assessing the benefits and risks of obesity treatments – a problem of considerable interest to regulators, who have to make decisions about whether or not new obesity treatments provide important health benefits or not.

In an effort to explore the pressing issues and challenges surrounding FDA approval and appropriate use of drugs to treat obesity, The George Washington University School of Public Health and Health Services Department of Health Policy convened the “Obesity Drugs Outcome Measures Dialogue Group,” a group of diverse stakeholders who met to identify the key issues surrounding the evaluation of pharmaceutical interventions for the treatment of obesity. Members of the group included clinicians specializing in adult and pediatric obesity; leaders from patient and consumer groups; public health organizations and industry representatives; and researchers from academia (see list on page two). Officials from the FDA, CDC, and NIH also observed and provided background information to the group to help inform the process (government officials were not asked to endorse or sign on to this final report).

The consensus report of this group has now been released and should be of interest to any one involved in the design and interpretation of obesity interventions.

The report is structured as a series of “Findings” and “Considerations” grouped into six general categories. The following summarises the ‘Considerations’ for each of these categories:

1. Understanding Obesity: Pharmacological interventions under investigation for the clinical treatment of obesity should be approached as obesity treatments rather than weight loss agents.

2. Characterizing the Population: More sophisticated criteria should be employed to characterize individuals at different levels of health, feeling, and functioning impairment, to determine appropriate patient-centered benefits and risks analysis.

3. The Need for Additional Treatments for Obesity: When the FDA determines that the benefits of taking a particular drug outweigh its risks in treating obesity, that drug should be available for clinical use in patients where such use is safe and medically appropriate. Although obesity drugs may not be safe or suitable options for all individuals wishing to use them, it is important that safe and effective drugs be made available as treatment options for individuals with obesity that require an alternative or additional weight loss intervention to diet, exercise, or surgery.

4. Limiting or Mitigating the Risk of Medically Inappropriate or Unsafe Use of Obesity Drugs: Given the concern over medically inappropriate or unsafe use of obesity drugs by those for whom the risks outweigh the benefits, the FDA could potentially employ a mechanism, such as Risk Evaluation and Mitigation Strategies (REMS) or an alternative, that will allow drug approval, distribution, and use solely for those for whom the drug is indicated.

5. Limitations in the Current FDA Approval Process, and Altering the Risk-Benefit Framework for Evaluation of Obesity Drugs: Individuals with obesity are not all alike; in evaluating the benefits and risks of obesity-related treatments, patients at different points on the obesity spectrum should be viewed separately. Higher risk of adverse effects of drugs may be acceptable for individuals with more severe obesity and comorbidities. The FDA could consider evaluating the risks and benefits of obesity drugs across several different patient profiles and could tailor approval decisions, combined with risk mitigation strategies described above, to allow access to the drug for those patients with obesity for whom the benefits of the drug outweigh its risks. To effectively address patient perspectives in making obesity drug approval decisions, tools to measure QoL or PROs that are acceptable to the FDA for regulatory measures need to be developed and utilized in the immediate future. The FDA should consider patient improvements in feeling and function associated with weight loss as part of the risk-benefit calculus in its evaluation of drugs for the treatment of obesity where data are provided demonstrating benefit in a drug-specific clinical trial. The FDA should update its Guidance to Industry to include improvements in feeling and functioning domains, for which validated means of measuring such improvements exist, as appropriate and optional secondary endpoints.

6. Special Considerations regarding Pediatric Patients with Obesity: Unique ethical and practical issues come into play when studying any drug in children. However, when these issues can be resolved appropriately, children and adolescents should be included in clinical trials for obesity drugs once safety concerns have been addressed. Pediatric patients with severe obesity could be considered candidates for drug therapy after the failure of more conservative therapies. The government and/or research community should prioritize development of a registry of children and adolescents who have been treated with obesity drugs for an extended period of time to assess long-term outcomes and side effects.

The document also lists measures to determine long-term, intermediate, and immediate outcomes of obesity treatment that should be considered in obesity treatment trials.

Not only, do I wholeheartedly agree with the overall recommendations of this document, but I was also delighted to see a direct mention and discussion of the Edmonton Obesity Staging System (EOSS) as a possible approach to better characterising obese individuals. In fact, the appendix of this document includes a copy of our EOSS staging tool.

While it is hard to determine the ultimate impact of these recommendations, it is indeed reassuring to see many of the issues raised in these postings reflected in this document.

The full report is available for download here.

AMS
Edmonton, Alberta

Last week, the US Food and Drug Administration (FDA) approved Arena’s lorcaserin (to be marketed in the US as Belviq), for the treatment of obesity.

Although widely touted as a new ‘diet’ or ‘weight loss’ pill – lorcaserin in neither. As all prescription medications, lorcaserin is to be used as indicated – in this case, its indication is for the treatment of obesity.

Anyone thinking they could simply go on this ‘diet’ pill to quickly (and effortlessly) lose a few pounds, should probably keep their hands off it.

Although the FDA has evidently deemed it not just effective but also rather safe (and it so happens, that I was on the Safety Monitoring Board for one of the early trials of this compound), adverse events undetected in clinical trials or with long-term use can never be completely ruled out – not for obesity drugs, nor for any other new compounds that enter the market for ANY indication.

Thus, as with the any drug, it is essential to weigh the potential benefits against any potential risks of treatment .

Obviously, even at low levels of risk (which will likely never be zero), the potential benefit is what determines the ‘value’ of a drug.

Thus, while losing a few pounds for someone who has obesity related health problems (Stage 2 or Stage 3 obesity), lorcaserin is likely to offer clinically relevant benefit, in an otherwise healthy overweight or obese person (Stage 0 or even Stage 1 obesity), benefit may modest to non-existant.

Remember, only when the risk of not treating exceeds the risk of treating, should we treat. This should apply as much to lorcaserin as it does to any other treatments.

For patients, who do have obesity related health problems, lorcaserin is the first new drug in over a decade that offers a chance – it is no magic bullet and not everyone will respond – but many will stand to benefit.

For those, who do not respond to lorcaserin or do not tolerate it, this FDA decision gives cause for hope that other obesity drugs awaiting approval will soon be added to the pharmacopeia.

After all, for treating high blood pressure we have over 100 compounds – for obesity we may soon have two!

AMS
Calgary, Alberta

The 3rd and final day of the Hot Topics Conference on Obesity and Mental Health focussed on the potential obesogenic side effects of medications commonly used to manage mental health disorders.

As pointed out by Rohan Ganguli (Toronto), persons with schizophrenia, bipolar disorder, and other psychotic illnesses, have rates of obesity 2-3 times that of the general population. They also have 2-3 times the rates of diabetes, heart disease, and premature mortality, when compared to the general population. The increased prevalence of these chronic conditions are due to multiple factors, but it has become clear that certain antipsychotics, particularly some of the newer antipsychotics, mood stabilizers, and antidepressants, contribute to the increased risk of obesity. His presentation provided a succinct overview of the evidence from controlled clinical trials regarding the risk of weight gain for different psychotropic medications. He also proposed prescribing strategies, which would minimize the exposure to these risks. This presentation was nicely complemented by Tony Cohn’s (Toronto) talk on the importance of metabolic monitoring for adults prescribed antipsychotic medications

This problem, unfortunately, is also relevant in the treatment of mental health disorders in kids. In her presentation on the Canadian Guidelines on Monitoring and Management of Metabolic Side Effects of Second Generation Antipsychotic Medications in Children, Tamara Pringsheim (Calgary) discussed the considerable evidence that second generation antipsychotic medications are associated with metabolic side effects in children, including weight gain, increased waist circumference and body mass index, as well as elevations in cholesterol, triglycerides, glucose and insulin levels. These metabolic complications can have long-term adverse effects on cardiovascular health. With the more widespread use of antipsychotic medications in children, there is a need for formal guidelines on how to monitor children for adverse effects of these medications.

The Canadian Alliance for monitoring Safety and Effectiveness of Antipsychotic medications in Children (CAmESA) guidelines seek to provide health care providers with evidence based recommendations on what, when and how to monitor children started on an antipsychotic medication for metabolic and extrapyramidal side effects. Companion guidelines have also been created which provide evidence based recommendations on the management of metabolic and extrapyramidal side effects if they are detected over the course of monitoring drug safety in kids.

The considerable problem of obesity and mental health in the Aboriginal population was discussed by Piotr Wilk from London, Ontario.

The issue of first doing no harm, especially in public messaging about obesity, was addressed by Gail McVey (Toronto). She noted that in our quest to prevent childhood obesity it is imperative that we avoid the costly mistake of triggering the competing public health issues of disordered eating, weight-related bullying and associated depression, anxiety and social exclusion. Professionals need to capitalize on opportunities for greater integration by agreeing to adopt a common set of child and youth health indicators and to settle on an integrated approach to prevention across the broad spectrum of weight-related problems. nowhere is this common vision more important than in the messaging delivered to children and youth about healthy weights.

Similarly, as pointed out by Annick Buchholz (Ottawa), dialogue between researchers and clinicians from the fields of eating disorders and obesity can take advantage of evidenced-based frameworks and key treatment approaches from the field of eating disorders and discuss its applications to working with individuals and families struggling with weight management issues. Treatment approaches such as externalizing the problem, promoting positive body image, de-emphasizing weight as a goal in treatment, understanding ambivalence, and working closely with families in treatment are all important approaches to this problem.

On a slightly different note, Peter Selby (Toronto) discussed the potential learning from tobacco prevention. Given that behaviours are determined by the net effects of the current and embodied opportunities and constraints in global, macro, mezzo, and micro environments interacting with biological and psychological abilities of the individual, disorders of consumption such as smoking and excess eating share common pathways and are modifiable through policy and clinical interventions. High reach interventions focussing on policy and legislation are likely to have a bigger impact on health than only a high risk approach to obesity. However, mitigation of unintended consequences of such measures must also be considered in order to prevent disparity in the disease burden.

Thus, after 3 days of intense presentations and discussions, I believe that the participants left with a much better appreciation and understanding of the links and commonalities between obesity and mental health.

I, for one, certainly felt very pleased to see many of the concerns and approaches discussed by the participants at this conference, nicely reflected in the 5As of Obesity Management.

Presentations from this conference are available for download here.

AMS
Edmonton, Alberta