Expert Panel Advises FDA Approve Qnexa for Obesity Treatment
Yesterday, the US FDA Endocrinologic and Metabolic Drugs Advisory Committee voted 20 to 2 in favour of approving Qnexa, a low-dose controlled-release formulation of phentermine and topiratmate, for the medical treatment of obesity. This is the first positive vote for a new anti-obesity drug by the FDA committee in 13 years. As I pointed out in my presentation (on behalf of the sponsor) to the Advisory Committee , Qnexa has the potential to address an important unmet clinical need – both the degree of weight loss (just over 10% on average) and the favourable trends in cardiovascular risk factors (with the exception of heart rate) have the potential of making this a significant advance in our ability to medically manage obesity. As I told the Committee, “Back in medical school, I was taught that when the risk of not treating a condition exceeds the risk of treating, then you treat.” As readers of these pages know, there are indeed substantial health risks with not treating obesity in those who have evident obesity related health problems. Not that there are no risks with treatment – based on the experience with the use of topiramate as an anti-epileptic drug and for the prevention of migraines, there is a likelihood that the topiratmate component in Qnexa (although contained at a lower dose) can increase the risk of orofacial clefts if taken during the first trimester of pregnancy – this is why, it is likely that the drug will not be freely available and there will be strict measures in place to minimize exposure in women, who may become pregnant. (discussion around this issue included a rather funny moment, when one of the panel members, asked how often you could expect the average ‘Joe’ to take a pregnancy test – this was quickly corrected to average ‘Jane’) But there are also other risks like kidney stones, tingling in hands and feet, and perhaps some psychiatric issues that may need to be carefully monitored. In this context it is important to remember, that at the recommended dose, Qnexa contains only about a quarter of the maximum dose of phentermine (30 mg) and less than one-eight of the maximum dose of topiramate (400 mg). The lower risk for side effects with these substantially lower doses is additionally mitigated by the controlled-release formulation. This is probably why many of the common ‘side effects’ commonly associated with topiramate… Read More »
FDA To Discuss Obesity Drug Qnexa
This morning, the US FDA Endocrinologic and Metabolic Drugs Advisory Committee will discuss the safety and efficacy of new drug application (NDA) 22-580, proposed trade name QNEXA (phentermine/topiramate) Controlled-Release Capsules, manufactured by VIVUS, Inc., as an adjunct to diet and exercise for weight management in patients with a body mass index (BMI) equal to or greater than 30 kilograms (kg) per square meter or a BMI equal to or greater than 27 kg per square meter if accompanied by weight-related comorbidities. Background material for this hearing are available here. More details on this meeting are available here. It will be of interest to see how the panel decides to vote. AMS Washington, DC
Does Skin Fat Protect From Diabetes?
Regular readers will be aware that there is a rather poor relationship between the total amount of body fat and health, which, indecently, is why I am not a big fan of the term ‘healthy weight’ and why we had to come up with the Edmonton Obesity Staging System. In fact, we have known for a long time that it is visceral fat or the fat deposited ‘ectopically’ in organs like the liver, pancreas, heart, or skeletal muscle that tends to cause the cardiometabolic problems. Indeed, there are good reasons to believe that the safest place to store any excess calories is in your subcutaneous or skin fat. This notion is once again supported by new data by Smith and colleagues published in the latest issue of the Journal of Clinical Endocrinology and Metabolism, suggesting that skin fat may, at least in women, reduce the risk of developing diabetes. Thus, data from the The INternational Study of Prediction of Intra-abdominal adiposity and its RElationships with cardioMEtabolic risk/Intra-Abdominal Adiposity (INSPIRE ME IAA), a cross-sectional computed tomography imaging study with data collected from 4144 (51.8% men) in 29 countries, shows that while cardiovascular disease increased with visceral adiposity tertles, diabetes risk was inversely related with subcutaneous adipose tissue in women [0.76] and not associated with type 2 diabetes in men [0.97]. Good enough to remind us that using rather crude measures of obesity like weight, BMI, or even total body fat, is certainly not enough to decide on who needs obesity treatment and who doesn’t. AMS Washington, DC Smith JD, Borel AL, Nazare JA, Haffner SM, Balkau B, Ross R, Massien C, Alméras N, & Després JP (2012). Visceral Adipose Tissue Indicates the Severity of Cardiometabolic Risk in Patients with and without Type 2 Diabetes: Results from the INSPIRE ME IAA Study. The Journal of clinical endocrinology and metabolism PMID: 22337910 .
Muscle Hormone Irisin Stimulates Fat Browning?
Exercise is by far one of the most powerful medicines – except that we know very little about how it actually works. So, how does exercise induce all of its many health benefits, especially in tissues and organs that are not even directly involved in this activity? Surprising new insights into how exercise works come from a paper by Pontus Boström and colleagues from the Dana-Farber Cancer Institute and Harvard Medical School, published in a recent issue of NATURE, reporting the discovery of a new hormone secreted by skeletal muscle in response to exercise. In their experiments in mice and humans, the researchers show that exercise induces the production and secretion of a ‘myokine’ they call irisin. They also show that irisin (encoded by the FNDC5 gene), surprisingly, acts on white adipose cells in culture and in vivo to stimulate expression of uncoupling protein 1 (UCP1), a molecule characteristic of brown fat and non-activity thermogenesis. In mice, increased levels of irisin did indeed result in higher energy expenditure with no changes in movement or food intake. “Nanomolar levels of this protein increase UCP1 in cultures of primary white fat cells by 50 fold or more, resulting in increased respiration. Perhaps more remarkable, viral delivery of irisin that causes only a moderate increase (~3 fold) in circulating levels stimulates a 10–20 fold increase in UCP1, increased energy expenditure and an improvement in the glucose tolerance of mice fed a high fat diet.” As the authors do not fail to note, “Irisin could be therapeutic for human metabolic disease and other disorders that are improved with exercise.” Certainly, the notion that exercise can stimulate the secretion of a hormone from skeletal muscle, that appears to have multiple metabolic benefits, is a big step forward in our understanding of exactly why exercise has the many benefits that it does. AMS Washington, DC Boström P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC, Rasbach KA, Boström EA, Choi JH, Long JZ, Kajimura S, Zingaretti MC, Vind BF, Tu H, Cinti S, Højlund K, Gygi SP, & Spiegelman BM (2012). A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature, 481 (7382), 463-8 PMID: 22237023 .
Weekend Roundup, February 17, 2012
As not everyone may have a chance during the week to read every post, here’s a roundup of last week’s posts: The Cure For Everything – Or Not? Personalizing Exercise Protocols Based on Genetics? What Does Adult Obesity Teach Us About Childhood Obesity? Ergonomic Office Furniture For Obese Employees Asthma and Airway Symptoms Improve After Bariatric Surgery Have a great Sunday! (or what is left of it) AMS Fort Lauderdale, FL You can now also follow me and post your comments on Facebook
Hindsight: Obesity And Cardiovascular Hemodynamic Function
A common strategy to quickly get your name into the literature on a topic you know little about is to publish a thorough literature review. Having decided to move my career from a focus on hypertension to a broader interest in obesity, in 1999, Rainer Koch (a young medical intern at the time) and I, wrote a paper for Current Hypertension Reports, in which we summarized what was known at the time about the typical cardiovascular problems in obese patients. The paper described the characteristic excentric left ventricular hypertrophy and left atrial dilatation, suggesting cardiac volume overload in obese patients, a finding that largely distinguished it from the more hypertension that was generally found in learner patients (albeit with abdominal adiposity), which is characterized by increased peripheral resistance and concentric hypertrophy. We also reviewed the accumulating evidence showing marked improvement of ventricular dimensions and cardiac function in patients undergoing massive weight reduction following bariatric surgery. Thus, long before I ever saw or began managing bariatric patients, I was already quite aware of the potential cardiovascular benefits of surgery in these patients. According to Google Scholar, this paper has been cited 23 times. AMS Fort Lauderdale, FL
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