Lorcaserin for Obesity
Serotonin plays an important role in the regulation of ingestive behaviour. Lorcaserin (APD356), a potent, selective 5-HT(2C) agonist is currently under development by ARENA pharmaceuticals for the treatment of obesity. In this month’s issue of OBESITY, Steven Smith and colleagues from the Pennington Biomedical Research Centre, Baton Rouge, LA (where I happen to be visiting today), report on the safety and efficacy of lorcaserin for weight reduction in obese patients. The randomized, double-blind, placebo-controlled, parallel-arm study enrolled 469 men and women between ages 18 and 65 and with BMI 30-45 . Patients received placebo, lorcaserin 10 mg q.d., lorcaserin 15 mg q.d., or lorcaserin 10 mg b.i.d. for 12 weeks, and were counseled to maintain their usual diet and activity. Safety analyses included echocardiograms at Screening and day 85/study exit. Lorcaserin was associated with progressive weight loss of 1.8 kg, 2.6 kg, and 3.6 kg at 10 mg q.d., 15 mg q.d., and 10 mg b.i.d., respectively, compared to placebo weight loss of 0.3 kg (P < 0.001 for each group). The proportions of completers achieving >5% of initial body weight were 12.8, 19.5, 31.2, and 2.3% in the 10 mg q.d., 15 mg q.d., 10 mg b.i.d., and placebo groups, respectively. The most frequent adverse events were transient headache, nausea, and dizziness. Echocardiograms showed no apparent drug-related effects on heart valves or pulmonary artery pressure. This short-term study shows that lorcaserin was well tolerated and efficacious for weight reduction. Obviously, 12 weeks is too short to determine the full efficacy or safety of this compound. Nevertheless, the results appear promising and it will be interesting to see how longer-term studies that combine locaserin with behaviour modification turn out. AMS Baton Rouge, LA Disclaimer: I have served on the locaserin echocardiography data safety monitoring board for ARENA and have received honoraria in this capacity.
Bypassing Breast Cancer?
The strong link between obesity and many forms of cancer is well documented. Not surprisingly, previous studies on obesity surgery have shown dramatic reductions (up to 60%) in overall cancer mortality. These data are supported by yet another study, this time from Nicolas Christou and colleagues from McGill University in Montreal. Apart from being a renowned Canadian bariatric surgeon, Christou is also the Past-President of the Canadian Association of Bariatric Physicians and Surgeons. In this study, published in in the latest issue of Surgery for Obesity and Related Diseases, Christou and colleagues conducted an observational 2-cohort study consisting of a treatment cohort of 1035 patients who had undergone bariatric surgery from 1986 to 2002 and a control group consisting of 5746 age- and gender-matched morbidly obese patients identified from an administrative database. The cohorts were followed up for a maximum of 5 years. While the patients who underwent bariatric surgery (mostly gastric bypass) experienced a weight loss of around 31%, their rate of any cancer diagnosis was only 23% of that in the control group (77% risk reduction!). The biggest risk reductions were seen for breast (83%) and colorectal (68%) cancers. Thus, while bariatric surgery has long been documented to remarkably improve a host of obesity-related disorders including type 2 diabetes, dyslipidemia, heart disease, sleep apnea, osteoarthritis and pain, the reduction in cancer morbidity and mortality has perhaps been less well recognized. I wonder just how much the “Run for the Cure” has contributed to research on obesity and bariatric surgery to date? AMS Edmonton, Alberta
Airline Seats Revisited
BEST HEALTH BLOG FINALIST: The second round of voting is on – please vote AGAIN for your favourite health blog by clicking here Last week I blogged about the recent Supreme Court ruling mandating that airlines accommodate oversized passengers. This ruling was picked up by international media, especially in the US, where in light of their own obesity epidemic, this ruling attracted substantial attention. In fact, I was interviewed by MSNBC for my take on this, especially with regard to the question how airlines should determine who would qualify for an extra seat and who would not. My simple solution, as reported by MSNBC was as follows: “You can’t bring it down to a BMI. People’s body shapes are different.” Instead, the chair of obesity research at the University of Alberta suggests a solution inspired by the baggage sizers already in place at many airports. Instead, Sharma would like airlines to place an airplane seat in the terminal — “somewhere that offers travelers a bit of privacy.” Then, if it’s not obvious that a traveler won’t fit in one seat, they can sit in the sample seat. “If they don’t fit in the seat, then they’re too big and they’ll need to have that extra seat. At no cost. It’s not rocket science.” Obviously, other “experts” had other suggestions including bringing in doctors’ notes or simply increasing the seat sizes for everybody. For a full report on this story click here. If readers of this blog have any other suggestions – I’d love to hear them. AMS Edmonton, Alberta
A-Drop-In the Obesity Ocean?
BEST HEALTH BLOG FINALIST: The second round of voting is on – please vote AGAIN for your favourite health blog by clicking here Yesterday, I blogged about NAPEs, which are molecules secreted by the gut that affect food intake. Today, I draw attention to another newly discovered molecule called adropin (encoded by a gene called Enho), which is secreted by the liver in response to a high fat meal (adropin is also expressed in parts of the brain that regulate energy metabolism). In this study, just out in CELL METABOLISM, Ganesh Kumar and colleagues from the Pennington Biomedical Research Centre (PBRC), Baton Rouge, LA, fed mice with a high-fat diet, resulting in increased secretion of adropin. However, as animals gained weight on the high-fat diet and developed insulin resistance and fatty livers, adropin levels dropped. Interestingly, in genetically altered mice that expressed high levels of adropin or with administration of exogenous adropin, animals were less likely to develop insulin resistance and fatty livers. Together, the findings from this study suggest that adropin generation in the liver may play a role in the metabolic adaptation to high dietary fat intake. Previous studies have shown that obese individuals show impaired metabolic flexibility and do not efficiently match fat oxidation with consumption. If adropin is indeed a metabolic signal to adapt substrate metabolism with fat intake, then the decline in adropin synthesis with obesity may be a factor in the impaired ability to match lipid metabolism with dietary fat intake, leading to the development of fatty livers, dyslipidemia, and glucose intolerance. Given their findings, the authors conclude that adropin (or its target) may lead to new treatments for obesity-related metabolic disorders. Obviously, it is still a long way from these findings in mice to treatments that are safe and effective in humans. Nevertheless, this study could be another stepping stone towards better understanding obesity and finding treatments that work. AMS Edmonton, Alberta Hat Tip to Dennis Vance for bringing this study to my attention.
Another Gut Hormone Reduces Food Intake
BEST HEALTH BLOG FINALIST: The second round of voting is on – please vote AGAIN for your favourite health blog by clicking here Anyone, who is even vaguely familiar with gut physiology, by now knows that besides being an exocrine organ (=secreting digestive fluids into the gut lumen), the gut also secretes a vast array of molecules into the blood stream that act at remote areas – simply said, the gut is also an endocrine organ and the term “incretins” is often used to describe the various hormones secreted by the gut. In this week’s issue of CELL, Matthew Gillum and colleagues from Yale University School of Medicine, New Haven, CT, report that a relatively abundant group of plasma lipids molecules with the unpronounceable name N-acylphosphatidylethanolamines (or better called “NAPEs”) are secreted into the circulation from the small intestine in response to ingested fat and that systemic administration of the most abundant circulating NAPE, at physiologic doses, decreases food intake in rats. They also showed that NAPE enters the brain and is particularly concentrated in the hypothalamus (a key area in the regulation of hunger and satiety) and that intracerebroventricular infusions of nanomolar amounts of NAPE reduce food intake. Not surprisingly, chronic NAPE infusion in rats results in a reduction of both food intake and body weight, suggesting that NAPE and long-acting NAPE analogues may be novel therapeutic targets for the treatment of obesity. Thus, we can now add another molecule to the long list of gut-derived hormones that have been shown to affect food intake. While this discovery emphasizes the importance of better understanding gut physiology and how it interacts with the regulation of food intake, we must be cautious of jumping to conclusion that this is the new “magic bullet” for obesity. The history of obesity pharmacology is littered with promising lead compounds and targets that failed to deliver safe drugs that work – however, every new avenue that holds promise is welcome – if NAPE analogues can be developed and prove to be safe and effective even in a subset of obese individuals, it would represent a major leap forward in our ability to treat this chronic and debilitating condition. AMS Edmonton, Alberta
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