FDA Declines Approval for Contrave as Latest Weight Loss Therapy Drug

Despite a recommendation by the Endocrine and Metabolic Drugs Advisory Committee in December, the US Food and Drug Administration has denied approval for Orexigen Therapeutics and Takeda Pharmaceutical Co’s weight loss drug Contrave (naltrexone/bupropion). The agency is requesting another clinical trial due to concerns about the cardiovascular safety profile.

FDA Requests Further Studies on Cardiovascular Safety

Specifically, the FDA requested that a study be conducted “of sufficient size and duration” to demonstrate that the drug does not increase the risk of heart attack or stroke.
Contrave combines an antidepressant – bupropion, brand name Wellbutrin – and a drug used for addiction called naltrexone. In clinical studies, 35% of patients who took Contrave lost at least 5% of their body weight, a level that measures successful weight loss.
The major complications found in patients on Contrave were increased blood pressure and heart rate. Two patients were also noted to have seizures during the studies and the FDA is reviewing a case of fatal heart attack.
Orexigen has argued that the ingredients that comprise Contrave have been on the market for 20 years and have not shown any major cardiovascular-safety problems. The company had already agreed to a large post-approval study to test the risk of stroke and heart attack and proposed that limitations be set to exclude patients with high cardiovascular risk from being placed on Contrave for weight loss.
Had it been approved, Contrave would be the first new diet pill in a decade. Two other weight loss therapy drugs were rejected last year, including Lorquess (lorcaserin hydrochloride) and Qnexa (phentermine/topiramate). A previously approved diet drug, Meridia, was removed from the market last year due to cardiovascular safety concerns.

Yale Targets Weight Loss Pill

Researchers from Yale University may be close to finding a weight loss pill that boosts energy, and reduces the risk of type 2 diabetes. The scientist found that lowering a key enzyme in the brain, prolylcarboxypeptidase (PRCP), can decrease appetite and improve energy, resulting in weight loss.
The study, published in the Journal of Clinical Investigation was performed on mice. The researchers found that PRCP controls another essential hormone that regulates energy expenditure and inhibits food intake. The result of targeting PRCP was weight loss and decreased risk of type 2 diabetes.
Senior author Sabrina Diano, associate professor in the Departments of Obstetrics, Gynecology and Reproductive Sciences, and Neurobiology says, "Our research provides the first evidence that breaking down molecules in the brain that regulate metabolism is an important component of weight control.”
The molecule, alpha-melanocyte stimulating hormone (alpha-MSH) remained higher when PRCP was blocked, providing a new target for weight loss pills.
The study was conducted on mice that were naturally lean and then on mice that had PRCP removed. They ate less and lost weight. The mice had lower alpha-MSH, a hormone produced in the hypothalamus.
The mice were even able to lose weight when given a “fast food” type diet, containing forty five percent fat. Blocking PRCP in the brain resulted in less weight gain compared to mice given a regular diet. The findings could result in new and improved weight loss pills to treat escalating rates of obesity and type 2 diabetes. The study is considered a major advance in weight loss and obesity research.

High-fat diet can disrupt our biological clock

Indulgence in a high-fat diet can not only lead to overweight because of excessive calorie intake, but also can affect the balance of circadian rhythms – everyone’s 24-hour biological clock, Hebrew University of Jerusalem researchers have shown.
The biological clock regulates the expression and/or activity of enzymes and hormones involved in metabolism, and disturbance of the clock can lead to such phenomena as hormone imbalance, obesity, psychological and sleep disorders and cancer.
While light is the strongest factor affecting the circadian clock, Dr. Oren Froy and his colleagues of the Institute of Biochemistry, Food Science and Nutrition at the Hebrew University’s Robert H. Smith Faculty of Agriculture, Food and Environment in Rehovot, have demonstrated in their experiments with laboratory mice that there is a cause-and-effect relation between diet and biological clock imbalance.
To examine this thesis, Froy and his colleagues, Ph.D. student Maayan Barnea and Zecharia Madar, the Karl Bach Professor of Agricultural Biochemistry, tested whether the clock controls the adiponectin signaling pathway in the liver and, if so, how fasting and a high-fat diet affect this control. Adiponectin is secreted from differentiated adipocytes (fat tissue) and is involved in glucose and lipid metabolism. It increases fatty acid oxidation and promotes insulin sensitivity, two highly important factors in maintaining proper metabolism.
The researchers fed mice either a low-fat or a high-fat diet, followed by a fasting day, then measured components of the adiponectin metabolic pathway at various levels of activity. In mice on the low-fat diet, the adiponectin signaling pathway components exhibited normal circadian rhythmicity. Fasting resulted in a phase advance. The high-fat diet resulted in a phase delay. Fasting raised and the high-fat diet reduced adenosine monophosphate-activated protein kinase (AMPK) levels. This protein is involved in fatty acid metabolism, which could be disrupted by the lower levels.
In an article soon to be published by the journal Endocrinology, the researchers suggest that this high-fat diet could contribute to obesity, not only through its high caloric content, but also by disrupting the phases and daily rhythm of clock genes. They contend also that high fat-induced changes in the clock and the adiponectin signaling pathway may help explain the disruption of other clock-controlled systems associated with metabolic disorders, such as blood pressure levels and the sleep/wake cycle.

Low-Calorie Sweeteners Can Help with Weight Loss

Some recent reports have questioned the weight loss and caloric control benefits of low-calorie sweeteners. A new study, however, supports the idea that low-calorie sweeteners can significantly reduce a person’s caloric intake and the tendency to overeat and thus help with weight loss.
Despite ongoing concerns and debates about any harm artificial and other low-calorie sweeteners such as aspartame and stevia may cause, millions of people turn to these products as table sweeteners and to the low-calorie and/or low-sugar foods that have them as ingredients as a way to control caloric intake and their weight.
Some concerns about low-calorie sweeteners are that individuals who use them may compensate for the lower caloric intake by eating more of other foods, and that they may feel less satisfied after consuming sugar substitutes and feel hungry, which could lead them to overeat.
In a new study, published in the journal Appetite, researchers gave study participants (both healthy and overweight adults) a pre-meal that contained either sucrose (table sugar), aspartame, or stevia (a low-calorie herbal sweetener). Participants who received the aspartame or stevia consumed significantly fewer calories overall, did not overeat, and did not say they had increased feelings of hunger.
The results of this study support the findings of a 2009 meta-analysis in which investigators evaluated 224 studies. In that report, published in the American Journal of Clinical Nutrition, the researchers concluded that while there were concerns that including non-nutritive sweeteners in the diet promoted an increase in caloric intake and contributed to obesity, “most of the purported mechanisms by which this occurs are not supported by the available evidence.”
Beth Hubrich, a dietitian with the Calorie Control Council, noted that when low-calorie sweeteners are “used as part of an overall healthy diet,” both as a table sweetener and in low-calorie products, they “can be beneficial tools in helping people control caloric intake and weight.”

Weight Loss Study Compares Low Carbohydrate/High Protein Diets

A widely reported Israeli study, published in the New England Journal of Medicine, compared three popular weight loss diets – low fat, which was attributed to the American Heart Association, low carbohydrate/high protein based on the Atkins diet, and Mediterranean style. The researchers found that people on the low carbohydrate/high protein diet lost slightly more weight over a two year period. Does that mean that people who are trying to lose weight should adopt a low carbohydrate/high protein diet?
An important point to clarify is that the Israeli researchers began their study in 2005, before the association’s dietary recommendations were revised in 2006. Therefore, the diet identified as being low-fat and based on American Heart Association guidelines is no longer recommended by the association, which does not currently advocate restricting total fat intake to less than 30 percent for weight loss.
In the American Heart Association’s 2006 dietary recommendations, the association stresses the importance of limiting “bad fats,” and says that saturated fats should be less than seven percent of calories consumed daily, and trans-fats should be less than one percent. A range between 25 – 35 percent for total fat consumption is suggested for most people, not just those trying to lose weight. Saturated fats are typically found in meat products and in tropical oils, such as coconut and palm oil. Trans-fat is man-made, and is also known as partially-hydrogenated fat – it is found mainly in commercially baked goods.
Just as importantly, the 2006 recommendations focus on what people should eat more of — fruits, vegetables, low-fat dairy products, lean-meats, poultry and fish twice a week. These recommendations were developed by internationally recognized experts, who based their recommendations on hundreds of published studies that looked at the relationship between what people eat and the development of heart disease and stroke.
The diet identified as Mediterranean in the study was high in fiber and vegetables and low in red meat (a major source of saturated fat), with no more than 35 percent of total calories coming from fat. This pattern reflects the current recommendations from the American Heart Association.
Multiple studies have shown that diets high in saturated and trans fats are strongly associated with the development of heart disease, and that diets rich in fruits, vegetables and whole grains are strongly associated with a lower risk of heart disease.
Robert H. Eckel, M.D., a former president of the American Heart Association and a professor of medicine at the University of Colorado Denver School of Medicine cautions the public about jumping to conclusions about the results of the Israeli study.
“Although the people who ate the low carbohydrate/high protein diet lost more weight, it is crucial to consider what diets high in saturated fats might do to your blood vessels and heart over time. The scientific evidence strongly indicates that this type of diet could put people at higher risk of developing heart disease.”
While the weight loss was moderately different between all three groups, the clinical difference was marginal. The American Heart Association stands behind its dietary guidelines as an effect way of losing weight and keeping it off.
The American Heart Association’s No Fad Diet book provides an individualized weight loss program that offers three different strategies for people to choose from, including a low-carb option.
What you need to know right now:
* Eighty-six percent of the participants in the Israeli study were men, and it is unknown how the study’s results apply to women
* The low fat diet used in the study was based on the American Heart Association’s dietary guidelines issued in 2000. Subsequently, the association issued revised recommendations in 2006, which are similar to the Mediterranean dietary pattern in the study, emphasizing high fiber foods, vegetables and limits for foods high in saturated fat, such as red meat
* The Israeli study demonstrates that there are several effective ways to lose weight – people on all three dietary patterns lost weight – but the health effects of eating a high-protein/low carbohydrate Atkins style diet over time are not known
* If you have heart disease, you should avoid any diet that emphasizes eating foods high in saturated or trans fats. A large body of scientific research strongly associates such diets with an increased risk of heart disease.

Majority of Americans Fail to Maintain Weight Loss

Findings from Penn State College of Medicine researchers show that only one in six obese or overweight Americans are able to maintain weight loss. The scientists say the findings are important. Targeting individuals who are successful at keeping weight off could help others.
The researchers say the only way to reduce the number of obese American is by making weight loss programs available to more people and more effective. They note that obesity rates in America doubled between 1980 and 2004.
Jennifer Kraschnewski, M.D., M.P.H., assistant professor of medicine and public health sciences says, "It is important for health professionals to understand the true prevalence of long-term weight loss, as it may help to change the underlying beliefs and influence clinical practice. Studies have shown that physicians may not believe offering weight loss advice and counseling is a worthwhile activity in clinical practice. An awareness of our findings may encourage health professionals to pursue weight loss counseling for overweight patients."
The study sample included an analysis of 14,306 people from the National Health and Nutrition Examination Survey, from 1999 to 2006. The findings showed that after a year, thirty six percent of individuals maintained five percent weight loss.
Other findings revealed that women were more likely than men to keep off ten percent of weight. Sixteen percent of diabetics, compared to non diabetics were able to maintain weight loss. Partnered or married individuals had a lower prevalence of long-term weight loss success.
If researchers could identify those who have success with maintaining weight loss, Kraschnewski says the impact on public health would be significant, even though reducing five percent of body weight seems modest. “Particularly, those individuals who have lost at least five percent and kept it off -- one in three Americans who have ever been overweight -- may represent a unique opportunity to reach a target population who has had some success but could benefit from greater weight loss efforts."
Sixty nine percent of those studied said weight loss of at least 10 pounds the previous year was intentional. Long-term weight loss was most successful among younger people, females, non-Hispanic whites and those with higher education and better overall health. The findings show Americans can lose weight – the problem is finding ways to keep it off.