Arya M. Sharma, MD

Following yesterday’s post on the issue of weight gain and metabolic syndrome seen in kids treated with second-generation antipsychotics (SGAs), today, I look at another paper by Silvia Alessi-Severini and colleagues from the University of Manitoba published in the same issue of the Canadian Journal of Psychiatry.

This paper examines the use of antipsychotics in children and adolescents (aged 18 years or younger) based on data collected from the administrative health databases of Manitoba Health and the Statistics Canada census between the fiscal years of 1999 and 2008.

Over these 10 years, prevalence of antipsychotic use increased with the introduction of the SGAs from 1.9 per 1000 in 1999 to 7.4 per 1000 in 2008.

The male-to-female antipsychotic usage ratio increased from 1.9 to 2.7 as the male youth population represented the fastest-growing subgroup of antipsychotic users in the entire population of Manitoba.

Notably, the paper finds that total number of prescriptions also increased significantly despite the lack of approved indications in this population.

More than 70% of antipsychotic prescriptions to children and adolescents were written by general practitioners with the most common diagnoses being attention-deficit hyperactivity disorder and conduct disorders. In fact, the use of antipsychotics in combination with methylphenidate (ritalin) increased from 13% to 43%.

Thus, it appears that there is extensive off-label use of SGAs in kids and youth in Manitoba (and likely in other provinces), a finding that is of concern not least because of the significant (30-fold increased) risk of weight gain and metabolic syndrome associated with the use of these compounds.

So, while there is no doubt that these drugs may provide important clinical benefits in kids who do need them, it is hard to imagine that this degree of off-lable prescription is indeed warranted.

Again, I would love to hear from my readers regarding experience with these medications in children and youth.

AMS
Ottawa, Ontario

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