Dr. Sharma's Obesity Notes

In the first post on several articles on obesity and mental illness published in the January issue of the Canadian Journal of Psychiatry, I would like discuss the paper by Constadina Panagiotopoulos and colleagues form the University of British Columbia, that looks at the prevalence of metabolic syndrome (MetS) and its components in children and youth treated with second-generation antipsychotics (SGA).

The study sample consisted of 117 SGA-treated and 217 SGA-naive children prospectively recruited from the Psychiatry Emergency Unit at British Columbia Children’s Hospital.

MetS was present in 19% of SGA-treated kids (including 2 cases of newly discovered type 2 diabetes) compared to less than 1% of SGA-naive kids showing an almost 30-fold increased risk of MetS in the former.

Among all of the various predictors studies, being treated with SGA and being male were the two major predictors.

Furthermore, the authors note that measurement of waist circumference as a measure of abdominal adiposity was more sensitive (92.9%) than BMI (68.8%) in detecting MetS, while fasting glucose of 5.6 mmol/L or more and HDL-C of 1.03mmol/L or less were most specific (94.1%).

It is perhaps also of interest that overall prevalence of overweight and obesity, although higher in the SGA treated kids, was almost twice as high in the general paediatric populations reported in British Columbia. This suggests that having a mental health condition alone already puts these kids at increased risk for obesity, a risk that is further drastically compounded by the use of SGA.

The authors conclude that standardized metabolic testing may be indicated in children treated with SGA and efforts to mitigate this risk should be started early in treatment.

While these ’side-effects’ are concerning and it may well be that increased risk of MetS may put these kids at long-term risk for cardiovascular problems, there are often poor alternatives for these children, who require such medications.

On the other hand, as I will discuss in tomorrow’s post, there is considerable ‘off-label’ use of antipsychotic and other psychiatric medications in kids, a practice that may require careful scrutiny given these findings.

AMS
Edmonton, Alberta

Regular readers are well aware that losing weight is never a ‘cure’ for obesity - in fact, we know that any weight loss (by whatever means - perhaps with the exception of surgery) leads to hormonal changes that will facilitate weight regain. This is why conventional (diet and exercise) weight-loss strategies sooner or later tend to result in relapse or weight regain.

Just how pervasive and multi-faceted these long-term hormonal responses to weight loss are, is demonstrated by Priya Sumithran and colleagues from the University of Melbourne, in a paper published in the New England Journal of Medicine.

In order to examine whether or not changes in the circulating levels of several hormones involved in the homeostatic regulation of body weight persist over time, the researchers studied 50 overweight or obese individuals, who participated in a 10-week very-low-calorie-diet weight-loss program.

The 36 subjects, who completed the intervention lost about 14% of initial weight and were still well below initial weight (about 8%) 62 weeks after the start of the study.

This weight loss was associated with significant reductions in levels of leptin, peptide YY, cholecystokinin, insulin, and amylin, whereas levels of ghrelin, gastric inhibitory polypeptide, and pancreatic polypeptide increased - most of these changes were still clearly evident at 62 weeks.

In addition, subjective levels of hunger increased and remained significantly elevated at 62 weeks.

Thus, the authors note that:

“One year after initial weight reduction, levels of the circulating mediators of appetite that encourage weight regain after diet-induced weight loss do not revert to the levels recorded before weight loss.”

Given these profound and persistent hormonal changes that affect hunger, appetite, and metabolism, it should come as no surprise that maintaining weight loss is so difficult. It certainly seems like the homeostatic system is happy to wait for the weight to come back - even if this takes several months or even years.

As I have noted before, the challenge in obesity treatment is never how to lose weight - it is all about how to keep it off. This is why, I am never too enthusiastic about new diets or medications that promise to help lose weight - unless these diets or medications also counteract or effectively block the counter-regulatory responses seen in this study, chances are that they will be ineffective in the long term.

Or, as the authors put it:

“..successful management of obesity will require the development of safe, effective, long-term treatments to counteract these compensatory mechanisms and reduce appetite. Given the number of alterations in appetite-regulating mechanisms that have been described so far, a combination of medications will probably be required.”

We do not really need new treatments for weight loss - we do, however, need treatments for weight-loss maintenance or for keeping patients in ‘remission’.

Unfortunately, the regulators still do not appear to have a pathway for approving drugs that will help with the latter.

AMS
Edmonton, Alberta

Hat tip to Bill Colmers for pointing me to this article.

Sumithran P, Prendergast LA, Delbridge E, Purcell K, Shulkes A, Kriketos A, & Proietto J (2011). Long-term persistence of hormonal adaptations to weight loss. The New England journal of medicine, 365 (17), 1597-604 PMID: 22029981

Yesterday, I discussed how part of the improvements in type 2 diabetes patients after gastric bypass surgery may be due to increased postprandial release of GLP-1.

However, it is becoming increasingly apparent that GLP-1 also exerts central effects on hunger and satiety, and perhaps even affects the desire for certain foods.

Therefore, not surprisingly, GLP-1 analogues, while already available for treating diabetes, are currently being investigated for the treatment of obesity.

This topic was recently reviewed by Torekov and colleagues from the University of Denmark, in a paper published in Obesity Reviews.

As the authors note, GLP-1 receptors are expressed in many regions of the brain and in particular in the arcuate nucleus and other hypothalamic regions involved in the regulation of food intake. Animal studies have confirmed that GLP-1’s has central effects on hunger and satiety that are independent of its peripheral effects on glucose metabolism.

However, whether peripherally injected GLP-1 actually makes it into the human brain, as suggested by some animal studies, is still a matter of debate. It is also possible that some of the effects of GLP-1 agonists on food intake may be mediated by interaction with sensory afferent neurones of the vagus nerves in the gastrointestinal tract.

The notion that GLP-1 analogues may affect feeding even when they do not enter the brain is supported by studies showing that large molecular size GLP-1 receptor agonists (albumin-conjugated GLP-1 receptor agonists), that cannot cross the blood-brain barrier can inhibit feeding in both humans and mice.

Thus, it appears that GLP-1 analogues may affect feeding behaviour both through central and peripheral effects.

As a side note, it may be of interest that while the ‘hunger hormone’ ghrelin appears to counteract (or rather override) the effects of GLP-1 on satiety, the commonly used anti-diabetic drug metformin appears to increase expression of GLP-1 receptors and enhance GLP-1 secretion and sensitivity in both rodents and humans.

Currently, the long-acting GLP-1 analogues exenatide and liraglutide are being investigated as potential anti-obesity drugs, with early indications that this may indeed be worthwhile.

Thus, for example, as noted by the authors, in one study with liraglutide, obese subjects in the quartile of greatest weight loss had a mean weight loss of 18 kg with 3.0 mg of liraglutide compared with only 9 kg on placebo.

Overall, the authors conclude that:

“The recognition that several gastrointestinal hormones, released in response to nutritional stimuli are important regulators of appetite (PYY, oxyntomodulin, GLP-1 and decreased secretion of ghrelin), offers a strategy for the development of more effective ant-iobesity agents….treatment of obesity could involved a combination of hormones, e.g. GLP-1, PYY, and/or oxyntomodulin to produce a superior appetite suppressing hormone profile that may result in a weight loss far exceeding that seen in single-agent trials. Using several hormones in low doses and incorporating lifestyle interventions might maximize the clinical effect while minimizing the side effects.”

Clearly, many patients would find daily injections of hormones preferable to undergoing bariatric surgery, even if these injections would need to be continued in the long-term to keep the weight off.

Wether or not such injections would in the end also prove cost-effective will remain to be seen.

AMS
London, UK

Disclosure: I am a consultant to Novo-Nordisk and involved in studies with liraglutide.

Torekov SS, Madsbad S, & Holst JJ (2011). Obesity - an indication for GLP-1 treatment? Obesity pathophysiology and GLP-1 treatment potential. Obesity reviews : an official journal of the International Association for the Study of Obesity, 12 (8), 593-601 PMID: 21401851

Yesterday, at the 47th EASD meeting, I spent most of my time in sessions dealing with the improvement of insulin.

While there was a lot of fascinating basic and clinical science and, certainly, newer insulin analogues appear less obesogenic than their older cousins, this entire line of treatment at least for type 2 diabetes, by definition, cannot be considered anything other than palliative (even if diabetologists would argue that insulin treatment helps prevent many of the complications of diabetes).

Indeed, if we consider obesity as one of the main ‘modifiable’ risk factors for type 2 diabetes (some would prefer the term ‘root cause’), then treating diabetes without also treating obesity, is hardly a solution.

Unfortunately, our ability to treat obesity ranges from the notoriously limited “Eat-Less-Move-More” (ELMM) approaches to the rather drastic surgical treatments, with little in terms of conservative medical treatment in between.

This, as I have often discussed in the past, is in part due to the rather ultra-conservative approach that regulators have taken towards approving obesity drugs - a situation that has considerably stifled enthusiasm of pharmaceutical companies to forge ahead with the necessary investments in this area.

It is therefore perhaps occasion for guarded optimism to note that in a report accompanying the 2012 US appropriations bill for agriculture, rural development and FDA, the US Senate Committee on Appropriations has now directed the FDA to provide a report by March 30, 2012, regarding steps the agency will take to support the development of new treatments for obesity.

The committee was apparently “concerned with the absence of novel medicines to treat obesity” and called the lack of obesity drugs “a significant unmet medical need,” noting that obesity is “a disease linked to cancer, high blood pressure, heart disease, diabetes, and stroke” and is the second leading cause of preventable deaths in the US.

The committee’s directive for FDA to look at risk mitigation recognizes that safety issues have been a major stumbling block for developers of weight-loss drugs.

Such steps, the report says, include the use of Risk Evaluation and Mitigation Strategies and other post-market authorities “to mitigate risk and ensure rigorous post-market scrutiny while increasing access to novel medications.”

On a side note, the FY12 bill, as part of the Transforming Food Safety and Nutrition Initiative, states that

“the FDA will also begin an $8.8 million program to improve nutrition labeling on restaurant menus and vending machines so that consumers can adopt healthier diets….the investments in this initiative will empower consumers to make better nutritional choices and will motivate food producers to develop healthier foods.”

While I am not sure, what influence the infusion of a paltry $9 Million into food labelling and similar (’educational’) approaches will have, I do believe that the strongly worded ‘warning’ to the FDA regarding taking a more ’supportive’ attitude towards finding ways to hasten the development and launch of new anti-obesity drugs, may prove promising.

I know for one that despite a rather large number of molecules in early pipelines (and a few that are further along) as well as the substantial number of druggable targets, many large pharmaceutical companies appear to have taken a rather unenthusiastic ‘wait-and-see’ attitude towards developing competitive anti-obesity portfolios.

At least from what I see here at the EASD, there appears far greater enthusiasm for playing it safe, even if only with another ‘me-too’ launch in the already ‘overloaded’ anti-diabetes market.

The FDA will now need to report back in six-months - I (as many others) will be watching closely to see what they come up with.

From my perspective, risk mitigation strategies must include development programs and approval pathways that target ‘complicated obesity’ (Edmonton Obesity Stages 1-4) rather than simply weight loss, and take the rather heterogenous nature and etiological heterogeneity of obesity into account (there is absolutely no reason why any obesity drug should work for all - rendering average weight loss or even response rates meaningless).

It is perhaps time for companies and researchers to begin ‘pigeon holing’ obesity drug development into categories that better reflect risk and aetiology in a manner that would essentially make BMI-based definitions and approaches obsolete.

AMS
Lisbon, Portugal

Regular readers will be aware that we currently have virtually no effective drugs for the treatment of obesity (which, interestingly, leaves the field wide open for the snake oil pedlars, who, in addition, enjoy an apparently ‘free-for-all’ unregulated scam-artist utopia).

That said, one can only wonder why, despite billion dollar investments, the pharma industry has not been able to bring a single new anti-obesity drug to market in North America since 1999. Is perhaps the regulatory bar simply too high?

This issue is the subject of a discussion paper by Morgan Downey (author of the Downey Obesity Report), Christopher Still (Geisinger Obesity Institute) and myself, published in the latest issue of Current Opinions in Endocrinology, Diabetes & Obesity.

As we point out, since July 2010, the FDA’s Endocrine and Metabolic Advisory Committee has reviewed three new drug applications and one previously approved drug for the treatment of obesity - all three new drug applications were declined while the one existing drug (sibutramine) was ‘voluntarily’ pulled from the market despite a split vote by the Advisory Committee.

In this paper we examine in detail the Advisory Committee’s consideration of the risk–benefit equation of the four drugs, especially in light of its decision on sibutramine and the results of the SCOUT study.

Currently, the FDA’s criteria for effectiveness for anti-obesity drugs has two alternatives: The first is a mean efficacy defined as medication-associated weight reduction of 5%. The alternative criteria is a categorical efficacy endpoint defined as a significantly greater proportion (at least 35%) of those individuals receiving the medication, compared with controls, maintaining a 5% weight loss from their initial weight. Demonstrating the resolution of any obesity associated comorbidities is not a requirement (although, it perhaps should be - see below).

These effectiveness criteria are certainly not the rate limiting step - at least one of these effectiveness criteria was met by all of the existing or newer medications.

The problem appears to lie rather in the FDA’s apparent ‘zero-tolerance’ for adverse effects, clearly holding anti-obesity drugs to far higher standards than any other prescription medications currently on the market.

Curiously enough, while the components in two of the combination medications (Qnexa and Contrave), have been around for decades and are widely used for depression or smoking cessation (bupropion), seizures or migraines (topiramate), narcotic and alcohol dependency (naltrexone), or short-term weight loss (phentermine), these drugs were deemed too ‘dangerous’ for the treatment of obesity.

Unless, the Advisory Committee (which notably lacked any members with clinical expertise in obesity management), does indeed believe that obesity in itself is not a condition worthy of pharmacological treatment, one can only speculate whether the FDA and its advisors believe that both health professionals and obese patients are largely incompetent when it comes to ascertaining risk/benefit rations for themselves or in following prescription information.

Thus, as we point out:

“…panelists expressed doubts as to the reliability of physicians to prescribe an antiobesity drug appropriately, the reliability of patients to take the drug as prescribed, the limited value of the label information, the limited value of primary care providers to work with patients on complex problems like obesity, the lack of predictability that a REMS program, or a program of limited distribution would be successful and whether insurance companies would reimburse for the drug.”

This, attitude unfortunately reeks of bias and discrimination against both health professionals who treat obesity, as well as people who have this problem.

After all, for every other indications, the FDA appears perfectly happy with approvals that include all kind of warnings and caveats - apparently these ‘warnings’ work fine for other indications like high blood pressure, diabetes, or heart failure - it is only when used for obesity treatment that suddenly all these regulatory measures are ineffective.

“One can ask, therefore, whether this skepticism extends to other areas of medical practice or are these concerns sui generis to obesity. If so, are they based on evidence or assumptions about the behavior of patients with obesity and the doctors who treat them?”

On the other hand, it may simply be that the FDA

“…currently does not view obesity as a serious disease and so any risk is too great.”

If this is indeed the case, our recent publication of the Edmonton Obesity Staging System may provide a ready solutions - as our studies show, while for some individuals carrying a few (or even substantially more) extra pounds may have little or no health risk, for others obesity related health problems pose very severe risks, shortening 20 year survival by 10 years!

So while ‘no-risk’ is acceptable for using drugs to treat obesity in ‘healthy’ overweight or obese individuals, considerable risk (as long as it is less than the natural risk of this condition) may well be acceptable for patients with higher Stage obesity.

In addition, as pointed out before, much needs to be done to prospectively define specific target populations based on an etiological framework rather than simply on the presence of excess body fat.

Will the FDA and other regulators change their views on this?

I don’t know. What I do know is that until that happens, few pharma companies will dedicate the necessary resources or invest in the large and extensive trials needed to bring new anti-obesity drugs to market.

In the meantime the beneficiaries of this lack of insight will be the snake oil pedlars on the one hand and bariatric surgeons on the other. The clear losers will be the millions of people struggling with obesity and its consequences.

AMS
Calgary, Alberta

Disclaimer: I have received speaking and consulting honoraria from makers of anti-obesity drugs.

Downey M, Still C, & Sharma AM (2011). Is there a path for approval of an antiobesity drug: what did the Sibutramine Cardiovascular Outcomes Trial find? Current opinion in endocrinology, diabetes, and obesity, 18 (5), 321-7 PMID: 21878755