Since its launch almost a decade ago, the notion that the use of the satiogenic serotonin-norepineprhine-reuptake-inhibitor (SNRI) sibutramine commonly results in an increase in blood pressure, has been a major barrier to its use in high-risk cardiovascular patients, particularly those with high blood pressure.

Nevertheless, over the past years, several lines of evidence have emerged suggesting that while sibutramine may increase blood pressure in a small group of susceptible individuals (particularly in those with normal blood pressure), its overall effect on blood pressure is the opposite, i.e. the vast majority of patients on sibutramine actually experience a fall in blood pressure with treatment. This appears particularly true for patients with moderately elevated blood pressure levels.

So what happens to blood pressure, when sibutramine is used in high-risk patients with poorly controlled blood pressure?

This question was analysed in the 6-week run-in phase of the SCOUT study (an ongoing, double-blind, randomized, placebo-controlled outcome trial in overweight/obese patients at high risk of a cardiovascular event), published in last month’s issue of Diabetes, Obesity & Metabolism.

During the 6-week single-blind lead-in period, 10,742 patients received sibutramine and weight management. Vital sign changes were assessed post hoc by initial blood pressure (mmHg) categorized as normal, high-normal or hypertensive.

To assess the impact of sibutramine on blood pressure and pulse rate, only patients (N = 10,025) who reported no change in the class of antihypertensive medication used and who did not report an increase in antihypertensive medication use were analysed.

At entry, approximately 50% of patients were hypertensive and 26% were high-normal. In hypertensive patients, blood pressure changes decreased by median of -6.5 mmHg systolic and -2.0 mmHg diastolic (P<0.001).

Interestingly, even hypertensive patients with no weight loss or with weight gain had median decreases of -3.5 mmHg systolic and -1.5 mmHg diastolic (p < 0.001).

In contrast, normotensive patients had median increases of 1.5 mmHg systolic and 1.0 mmHg diastolic (p < 0.001), which was attenuated with increasing weight loss in that blood pressure was significantly decreased in normotensive patients, who lost >5% of their initial weight.

Approximately 43% of patients initially categorized as hypertensive had a lower blood pressure category after 6-weeks on sibutramine.

In contrast to the differential effect on blood pressure, pulse rates were uniformly elevated by 1-4 bpm across blood pressure and weight change categories.

Obviously, these results have to be interpreted with caution as there is no control group and there is some potential for regression to the mean. Nevertheless, the results do support the notion that even in high risk patients, the predominant effect of sibutramine administered together with a weight-loss program is a blood pressure decrease - especially in patients with pre-existent hypertension.

It will be of great interest to see what the net effect of sibutramine treatment on cardiovascular outcomes and safety will be, when the final results of SCOUT are revealed on completion of this major obesity outcome study.

AMS
Edmonton, Alberta

Disclaimer: I am on the Executive Steering Committee of the SCOUT study and have received consulting and speaker honoraria as well as research support from Abbott Laboratories, the makers of sibutramine.

In response to yesterday’s post on ADHD and obesity, I was made aware of two recent studies, both relevant to this topic.

In the first, A psycho-genetic study by Caroline Davis and colleagues from York University, Toronto, Ontario, Canada, published in the Journal of Psychiatric Research, the researchers examined whether ADHD symptoms were more pronounced in adults with symptoms of binge eating disorder (BE) than in their non-binging obese counterparts, and whether the links were stronger with inattentive vs impulsive/hyperactive symptoms. They also assessed the role of the dopamine D3 receptor in ADHD symptoms since the DRD3 gene has been associated with impulsivity and drug addiction - both relevant features of ADHD.

In the study that involved 60 cases and 120 controls (60 obese and 60 normal weight), childhood and adults ADHD symptoms were assessed and genotying was performed.

While all of the four ADHD symptom scales were significantly elevated in the BE and obese groups compared to the normal weight group, bearers of three DRD3 genotypes had significantly elevated scores on the hyperactive/impulsive symptom scale.

These results suggest that symptoms of ADHD are more common in obese individuals (irrespective of BED status) and that the D3 receptor may play a role in the manifestation of the hyperactive/impulsive symptoms of ADHD.

In another study, published in this month’s issue of OBESITY by Lance Levy and colleagues from the Nutritional Disorders Clinic, also in Toronto, Ontario, Canada, they describe their success in treating refractory obesity in severely obese adults following the management of newly diagnosed attention deficit hyperactivity disorder.

78 subjects out of 242 consecutively referred severely obese, weight loss refractory individuals were diagnosed as having ADHD, of which 65 received ADHD treatment and 13 remained as controls.

After an average of 466 days of continuous ADHD pharmacotherapy, weight change in treated subjects was -12% of initial weight versus a 3% weight gain in controls.

This study not only confirms that ADHD is a highly prevalent condition in severely obese patients, but that the treatment of ADHD is associated with significant long-term weight loss in individuals with a lengthy history of weight loss failure.

Levy suggests, as I did in earlier postings on this topic, that ADHD should be considered as a primary cause of weight loss failure in obese patients.

As he points out, this finding may also be important for patients seeking obesity surgery, as surgical patients with unmanaged ADHD may display poor compliance with diet and supplement requirements.

AMS
Edmonton, Alberta

p.s. Caroline Davis will be presenting at the upcoming 1st National Obesity Summit, Kananaskis, Alberta, May 7-10, hosted by the Canadian Obesity Network

No question - Canada, as many other Western countries is experiencing an unprescedented epidemic of childhood overweight and obesity. Many of these children will need obesity treatment - they are beyond the stage where “prevention” is likely to help.

So do obesity interventions for kids actually work?

This was the topic of a Cochrane review by Oude Luttikhuis and colleagues from the University of Groningen published earlier this year.

The authors analysed all randomised controlled trials (RCTs) of lifestyle (i.e. dietary, physical activity and/or behavioural therapy), drug and surgical interventions for treating obesity in children (mean age under 18 years) with or without the support of family members, with a minimum of six months follow up (three months for actual drug therapy).

The final analysis included 64 RCTs (5230 participants). The studies included varied greatly in intervention design, outcome measurements and methodological quality (the surgical studies were considered to be of too poor quality to include in the analysis).

The authors conclude that although there is not enough data to to recommend one treatment program versus another, there is little doubt that combined behavioural lifestyle interventions are superior to standard care or self-help in producing clinically meaningful reduction in overweight in children and adolescents. In obese adolescents, consideration should also be given to the use of either orlistat or sibutramine, as an adjunct to lifestyle interventions.

As they point out, there is a continuing need for high quality research that considers psychosocial determinants for behaviour change, strategies to improve clinician-family interaction, and cost-effective programs for primary and community care.

It appears to me that obesity management in kids is no different than treatment in adults in that it requires multidisciplinary intervention and ongoing monitoring to assure that lost weight is not regained.

Unfortunately, we are far from having the infrastructure, the resources, or the medical expertise to provide adequate obesity interventions to the over 500,000 Canadian kids (and their parents?), who urgently require obesity treatments.

AMS
Edmonton, Alberta

Yesterday, EnteroMedics announced European approval of their VBLOC system (Maestro) for obesity. As blogged previously, the system reduces food intake by blocking vagal signals from the stomach and gut to the brain. The system is implanted laparoscopically and uses high-frequency, low-energy electrical impulses to intermittently block vagal activity.

On their website, the company reports results of their pivotal study, which showed show excess weight loss, or EWL, of 37.6% in 9 patients at 18 months of VBLOC Therapy and 28.1% in 17 patients at 12 months of therapy. To date, no deaths or unanticipated adverse device events have been reported.

It will be interesting to see how this new treatment for obesity is embraced in Europe and whether or not it will find its niche in obesity management.

AMS
Edmonton, Alberta

The hypothalamus, located deep inside the brain, is a critical centre for the integration and regulation of hunger and satiety signals in humans and animals. A team of New Zealand and US researchers has now reported that transferring a gene to this part of the brain can significantly reduce body weight both in genetically and dietary-induced obese mice.

The paper by Lei Cao, published in yesterday’s issue of Nature Medicine, describes the hypothalamic injection of an adenoviral vector containing brain-derived neurotrophic factor (BDNF) coupled to a physiological responsive regulatory element. This gene transfer resulted in a 20% weight loss within 3 weeks of injection with subsequent weight maintenance over 11 months (several decades in human years).

The researchers also demonstrated that they can “rescue” these mice from the treatment, thereby theoretically increasing the safety of this approach. This may not be a bad idea, because in some experiments where the BDNF gene transfer was not coupled with a regulatory element, the animals showed bizarre behavioural changes with catastrophic weight loss.

Clearly the researchers are pleased with their results and in their paper go as far as stating that this treatment for severe obesity may become available for human treatment in the foreseeable future. Indeed, Matthew During, the senior author on the paper is co-owner of Neurologix, a biotechnological company that is currently conducting a Phase 2 neurosurgical gene treatment study in patients with severe Parkinson’s disease. This demonstrates that first human neurosurgical experiments with BDNF gene transfer may not be too far away.

While these new findings clearly point to the importance of central neuroregulation in energy homeostasis and show that this can be modified to reduce severe obesity, I find it difficult to foresee widespread use of neurosurgical treatment for a disorder as common as obesity. After all, even if this treatment was limited only to people with severe obesity, we’d still be looking at millions of people worldwide.

In the near future, I’d rather place my bets on gastrointestinal than on stereotactic neurosurgery.

AMS
Edmonton, Alberta