BBI Contributing Editor

FORT LAUDERDALE, Florida The North American Association for the Study of Obesity (NAASO; Silver Spring, Maryland) annual meeting, held here last fall, was attended by a diverse group of healthcare professionals, including clinicians, dieticians, surgeons, psychologists and psychiatrists. Obesity is considered to be at epidemic levels and is of heightened concern due to the increased risk of diabetes, heart disease, osteoarthritis, depression and also an increased risk of cancer.

The correlation of excessive weight and Type 2 diabetes is especially strong, thus the meeting's co-sponsorship by the American Diabetes Association (Alexandria, Virginia). An estimated 25% increase in the incidence of Type 2 diabetes in the U.S. in the last 20 years has been attributed to the marked increase in the prevalence of obesity. Overweight is defined as having a BMI (Body Mass Index) of 25 to 29.9 kg/m² and obese is defined as having a BMI of 30 kg/m² and greater.

More than 64% of adults in the U.S. are either overweight or obese, up from 56% in a 1988-1994 study, according to a 1999-2000 National Health and Nutrition Examination survey that was published in the Journal of the American Medical Association. Data from this survey confirms that there has been nearly a two-fold increase in the number of obese Americans in the last two decades. The number of overweight children in the U.S. also is growing. The National Center for Health Statistics reported that 15% of children ages 6 to 18 were overweight in 2000, up from 6% in 1980, and 10.4% of preschoolers are obese. There are 5,000 deaths each week due to adipocity.

The Rand Corporation (Santa Monica, California) reported that the number of severely obese people (100 or more pounds overweight) has increased from one out of 200 in 1986 to one out of 50 in 2000. Dr. John Foreyt at Baylor College of Medicine (Houston, Texas) predicted that by 2040, only 5% to 15% of Americans will maintain a healthy weight

While trailing the U.S., the trend in Europe also is moving toward increased obesity. The percentage of obese adults in Britain has tripled in the past 20 years, and for children has tripled in the past decade, the fastest rates of increase in Western Europe. This rise has been attributed to consumption of oversized portions and greater patronage of fast-food outlets.

Principal factors that are generally considered as contributing to obesity are excessive caloric consumption and a sedentary lifestyle. Dr. Lee Kaplan of the Massachusetts General Hospital Weight Center (Boston, Massachusetts) has identified three causes of obesity: genetics, environment and an imbalance of energy within the body (when energy consumed from food exceeds the energy expended in daily activities). A recent study by economists at Harvard University (Cambridge, Massachusetts) found that people are not consuming more calories at mealtime but the increase in daily caloric intake comes from snacking between meals, which has risen 60% since the late 1970s.

Prescription drugs for weight loss

In obese patients, weight loss by lifestyle management alone, such as diet and exercise, is often not effective, and the use of pharmaceuticals has become a standard of treatment. In past years, the diet drugs fenfluramine (Pondimin) and dexfenfluramine (Redux) were withdrawn due to reports of valvular heart disease. Three weight-loss drugs are currently approved in the U.S. Xenical (orlistat), which prevents the body from absorbing fat, is sold by Hoffmann-La Roche (Nutley, New Jersey) and Meridia (sibutramine) which inhibits serotonin uptake is marketed by Abbott Laboratories (Abbott Park, Illinois). Phentermine (one-half of the notorious fen-phen drug) is a generic drug and is sold by several companies under various brand names (Adipex-P, Plegine, Prelu-2 and X-Trozine). These drugs are orally administered. Xenical and Meridia are for long-term use and phentermine is for short-term use. Both Xenical and Meridia are indicated for patients with a BMI of at least 30 or for patients with a co-morbidity (e.g., hypertension or diabetes) having a BMI of 27. They are detailed to primary care physicians, internists, cardiologists and gastroenterologists.

The drugs have different modes of action. Xenical works by reducing the body's ability to absorb dietary fat by about one-third and Meridia functions as an appetite suppressant. Maximum weight loss usually occurs within six months of starting medication. Sales of Xenical and Meridia have tailed off after a strong start. Xenical can cause severe diarrhea and Meridia attracted the FDA's attention after several patients died. Sales of prescription anti-obesity drugs in the U.S. were $344 million in 2002, a decline of 18% from $420 million in 2001.

Regeneron Pharmaceuticals (Tarrytown, New York) conducted a 2,000-patient Phase III trial at 65 sites in the U.S. on Axokine, a ciliary neurotrophic factor that is administered by subcutaneous self-injection for the treatment of obesity. Results of this trial, reported earlier in 2003, were disappointing. Axokine produced only a small weight loss, and two-thirds of the patients developed antibodies that attacked and neutralized the drug. However, the company is continuing to test this drug on a broad range of overweight and obese individuals in an open label Phase III study. Also, it was reported that significant weight loss was achieved in a Phase II study using Axokine in overweight and obese Type 2 diabetic patients.

Sanofi-Synthelabo (Paris) is conducting an international Phase III trial on more than 6,000 obese patients with Rimonabant, its weight loss drug that functions by blocking the cannabinoid receptors in the brain that stimulate hunger. The company plans to submit a new drug application to the FDA at the end of 2004 or early in 2005.

Manhattan Pharmaceuticals (New York) is developing oleoyl estrone as a weight-loss drug. Oleoyl estrone, which occurs naturally in our blood, has been shown in preclinical studies to effect significant weight loss without rebound weight gain after treatment was discontinued and without the need for dietary modifications.

Phytopharm (Godmanchester, UK) had licensed to Pfizer (New York) its appetite suppressant, P57, that was shown to reduce caloric intake in overweight subjects. Earlier this year, Pfizer discontinued clinical development of P57 and another corporate partner is being sought. At least a dozen other weight-loss drugs are in the pipelines of pharmaceutical companies that have not yet progressed to the Phase III trial stage.

Gut hormones

Many papers at the NAASO meeting presented data from preclinical and human studies on gut hormones that stimulate or reduce food intake. Some experts believe that there are two dozen gut hormones that control appetite and energy metabolism, among them PYY3-36 (PYY), ghrelin, glucagon-like peptide-1 (GLP-1), Apo A IV, gastric inhibitory polypeptide (GIP), cholecystokinin and oxymodulin.

Nastech Pharmaceutical (Bothell, Washington) presented safety and preclinical data on its PYY nasal spray. It uses a formulation that increases the delivery of peptides by more than 100-fold. PYY, a satiety hormone, is produced by endocrine cells in the gut and signals to the brain when a stomach is full, thereby switching off the appetite after a meal. The hormone is naturally produced in proportion to the amount of calories ingested. After nasal administration, PYY was detected in the plasma within about five minutes and reached peak effect in 15 to 30 minutes, simulating to the brain the normal release kinetics of having eaten a meal. A Phase I trial of the PYY nasal spray for the treatment of obesity is under way with Dr. Stephen Bloom at the Imperial College of Medicine (London). In a previous study published in the New England Journal of Medicine, it was reported that the intravenous administration of PYY reduces caloric intake.

Bloom, a leading researcher in appetite control and natural hormones, noted that PYY interacts with two types of neurons in the brain, one that stimulates appetite and one that inhibits appetite. Obese people have low levels of PYY and are sensitive to its effect. It is not known whether low PYY levels initiate the development of obesity or whether PYY levels are reduced as a result of obesity.

Leptin also regulates fat in the body. It is produced by the obese gene and is released in proportion to the amount of fat present. Thus, unlike PYY, high levels of leptin occur in obese people and an injection of additional leptin does result in less eating. Amgen (Thousand Oaks, California) had previously sought to develop leptin as a treatment for obesity, but the trial patients lost very little weight.

Supplements, herbal remedies, etc.

Numerous non-prescription dietary supplements and herbal remedies are sold for weight loss, although they typically lack clinical proof of efficacy and received little attention at NAASO. Kemin Consumer Care (Des Moines, Iowa), a manufacturer of nutritional ingredients, featured proteinase inhibitor II. It is extracted from potatoes and has been shown in clinical test to be a safe and effective satiety agent. It works by enhancing the body's natural release of the satiety hormone cholecystokinin.

Exhibitors of meal replacements for weight loss at NAASO were Slim-Fast Foods (West Palm Beach, Florida), a subsidiary of the Anglo-Dutch Unilever, and Optifast and Optisource from Novartis Nutrition (St. Louis Park, Minnesota), which are medically supervised diets. Optisource is for use by patients after bariatric surgery. Medifast (Owings Mills, Maryland) competes in this market and uses physicians to sell its meal supplements. A new entrant is Shape Up!, a retail line of nutritional supplements for weight loss launched by Phil McGraw, a psychologist, author and host of the Dr. Phil television program. Slim-Fast sponsored several posters at the meeting that provided results of clinical studies that showed short and long-term evidence of weight loss and reduced cardiovascular risk from their portion-controlled soy meal replacement plan.

Low-carbohydrate vs. low-fat

Penelope Greene of the Harvard School of Public Health (Boston, Massachusetts) presenting intriguing results from her 12-week study which provided evidence that people eating an extra 300 calories per day on low-carbohydrate diets lost the same amount of weight as those on standard low-fat plans. This suggests that not all calories count equally towards weight gain.

Barbara Rolls from Penn State University (State College, Pennsylvania) reported that weight gain is determined by the energy density of foods consumed and not the amount of food we eat or the total fat content. Foods that are bulked up with fiber and water have low energy density and contain few calories relative to their weight. The consumption of salad at the start of a meal was suggested for reducing the overall caloric intake.

Surgical approaches, devices

Americans having a BMI greater than 40 and are candidates for bariatric surgery. According to the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (Bethesda, Maryland), more than 10 million Americans, or 4.7% of the population, are eligible for this procedure. The number of bariatric surgeries has increased in recent years from 4,000 in 2001 to 86,000 in 2002 and an estimated 120,000 in 2003. The risks in bariatric surgery are subsequent weight gain, poor nutrition and possible death. It must be followed by adherence to a strict diet to maintain nutrition.

A special session at NAASO was devoted to bariatric surgery. Roux-en-Y is the most commonly performed surgical procedure for the morbidly obese, representing about 75% of these procedures. It entails creating a gastric bypass by using a stapler to make a small pouch (about the size of a walnut) at the top of the stomach. The small intestine is then shortened by up to four feet and then attached to the pouch thereby shunting food to the bottom of the digestive tract. Food bypasses the main part of the stomach, but the digestive juices from the stomach enter the intestine as usual. Food preferences change after gastric bypass surgery.

Dr. Alison Hoppin of the Massachusetts General Hospital Weight Center (Boston, Massachusetts) reported that people undergoing Roux-en-Y surgery lose their taste for buttery or fatty foods and develop cravings for fruits and vegetables, thereby maintaining a healthy diet and suggesting that the surgery may produce hormonal changes enabling people to lose weight.

Gastric banding is performed laparoscopically. It amounts to 15% of surgeries for obesity and is gaining popularity. The Lap-Band gastric banding system from Inamed (Santa Barbara, California) received market clearance from the FDA in June 2001 and is the only product currently marketed in this country for gastric banding. It has been sold in Europe for the past 10 years, where it competes with the Swedish Adjustable Gastric Band from Switzerland's Obtech Medical, owned by Johnson & Johnson (New Brunswick, New Jersey). Importantly, it is adjustable and reversible and has a much lower mortality rate (one in 10,000) than the Roux-en-Y procedure (one in 200). The duodenal switch procedure accounts for the remaining 10% of bariatric surgery procedures. It entails removal of most of the lateral curved portion of the stomach in a procedure known as a biliopancreatic diversion. The lumen is transected and an anastomosis is performed between the proximal duodenum and the proximal ileum.

Bariatric surgery on adolescents is gaining in popularity and was featured in a recent report in The Wall Street Journal. However, many insurers refuse to cover this surgery. It was noted that the problem of obese children is so severe that "their generation could be the first in American history with a shorter life expectancy than their parents."

Attracting much media attention at the NAASO meeting was the presentation by Dr. Scott Shikora, the lead researcher in a study conducted at Tufts-New England Medical Center (Boston, Massachusetts). He reported on the Transcend Gastric Stimulation System for helping severely obese people to lose weight. Unlike other surgeries for treating morbidly obese patients, this device does not alter gastrointestinal anatomy. It has been shown to be safe in a series of studies conducted worldwide on 450 subjects.

The system uses an implantable electronic pulse generator to deliver electrical stimulation to the stomach that causes feelings of fullness. In a 30-patient study, two leads were implanted in the muscular wall of the stomach using a laparoscopic procedure. The leads were connected to an electrical generator that is placed under the abdominal skin (similar to a pacemaker). There were no complications reported by any patients, of whom 80% lost weight after eight to nine months and 60% lost more than 10% of their excess weight.

Monitoring aids for weight loss

Several products were exhibited at NAASO that can assist a patient during a weight-loss regimen. The Actical physical activity monitor from Mini Meter (Bend, Oregon) is a light (17 grams) and compact accelerometer that is used to collect activity data from children that can be transferred via telemetry to a reader. Actical monitors can be worn on the wrist, waist or ankle.

The MedGem indirect calorimeter from Health-eTech (Golden, Colorado) is a hand-held device that is used to determine the number of calories utilized in a day at rest. A breath test is employed to accurately measure oxygen consumption for calculating resting metabolic rate and enabling patients to determine if their metabolism is normal, fast or slow. Knowing one's metabolic rate eliminates the guesswork out of cutting calories.