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Hoffmann-LaRoche, which makes orlistat, funded the study. The company expects to fulfill the requirements for final FDA approval during the first quarter of 1999.Aronne, Louis J. Modern medical management of obesity: the role of pharmaceutical intervention.Journal of the American Dietetic Association v98 n10 (Oct, 1998):S23 (4 pages).COPYRIGHT 1998 American Dietetic Association
The medical treatment of obesity has been a topic of controversy for many years.
The popularity, and overuse, of the combination of medications phentermine and fenfluramine (phen-fen), combined with the introduction of several new medications and withdrawal of others has fueled the fire. Rapid advances in our understanding of the weight-regulating mechanisms make it likely that in 10 or 20 years the use of medication will be as standard in the treatment of obesity as the use of medication is now in the treatment of hypertension, diabetes, or hyperlipidemia. In fact, the treatment of obesity could supplant the treatment of many of the comorbidities of obesity, on which Americans currently spend billions of dollars per year. Medication will be used in conjunction with behavior, diet, and exercise programs as part of a standard regimen of treatment. No single component of treatment will dominate this regimen, but it will be common for all components to be used to varying degrees in different patients.
OBESITY AS A CHRONIC DISEASE
When considering the current medical treatment model, it is important to emphasize that obesity is a lifelong chronic disease that has responded poorly to behavioral management. Indeed, guidelines from the National Institutes of Health and the National Heart, Lung, and Blood Institute (1; see page 1177 of the October Journal for the Executive Summary of this report) will recommend that obesity be considered and managed as a chronic illness. Short-term or intermittent treatment like that used for patients with asthma may work in some patients, but for many with serious obesity, the problem needs to be viewed more like hypertension or diabetes. Many patients with adult onset type 2 diabetes, for example, are treated with medication on a daily basis. If patients stop taking their medication, the physician or Certified Diabetes Educator asks why they are not complying; the regular use of the medication is expected, even though many patients with diabetes could probably manage their blood glucose level by watching their diet more carefully and exercising more frequently. Obesity, which is believed to cause most cases of diabetes, should be regarded in the same way. In the case of an obese person with adult onset type 2 diabetes, if the addition of medication to treat the obesity also treats the diabetes, chronic treatment of the obesity makes sense. A different treatment model is the example of a patient with asthma who may take 2 medications for a few weeks and then taper down to I medicine, but the asthma may subsequently worsen and require the strongest treatment, corticosteroids. Similarly, for some obese patients, as willpower, stress, physical activity, and other factors wax and wane, the optimal treatment of their disorder may require intermittent, rather than continuous, treatment with medications.
Short-term solutions have proven ineffective in the long-term management of obesity, and they simply do not exist in the chronic disease treatment model any more than a simple cure for hypertension exists. A long-term approach to managing obesity is needed, because the disease will recur after the treatment is withdrawn or if the patient does not follow the treatment plan. This treatment failure should not be considered the patient's fault. It is clear that there are powerful physiologic mechanisms that drive weight back up following weight loss (2). The regulation of body weight is complex and only partially understood. Body weight seems to be regulated in much the same way that blood glucose levels, blood pressure, and body temperature are regulated; the mechanisms appear to be complex and to involve redundant feedback loops and other mechanisms that are not yet clearly understood.
THE PHYSIOLOGY OF WEIGHT CONTROL
The challenge of managing obesity will continue to perplex health care professionals until the body's weight-control mechanism is better understood. Why do people only lose 10% or 15% of their body weight? A possible answer may be illustrated with a simplified feedback loop based on information taken from animal studies (Figure). As weight is lost by reducing food intake, which involves the efferent portion of the weight-control feedback loop (ie, between the brain and its effect on the fat cell), the fat cells shrink, reducing expression of the ob gene and its hormone product, leptin. As a result of the decrease in leptin levels in the blood and brain, metabolic rate decreases, appetite increases, and other hormonal changes associated with weight loss are observed. Replacing leptin to achieve original levels of leptin does not completely normalize appetite and prevent weight regain in animals, however, suggesting that other hormones or neuropeptides are involved in this feedback mechanism. The net result is that weight loss ceases at a weight for which the effect of the leptin replacement is counterbalanced by an increase in appetite and a reduction in metabolic rate induced by the shrinking fat cell.
If this hypothesis, which illustrates only part of the mechanism found thus far in animals, is correct and applies to human beings as well, the concept of a weight plateau makes perfect sense. Until scientists can intervene at the level of the afferent limb of the weight-control feedback loop (between the fat cell and its hormonal effect on the brain), a body weight loss of 5% to 15% may be the best, on average, that can be achieved before adaptive counterregulatory systems are activated to an extent that results in weight being regained. We should not, however, dismiss the benefits of modest weight loss: there is compelling evidence (1) that even a small amount of weight loss, as little as 5%, is associated with significant improvements in health status. At present, the criteria for success in weight management, given the tools currently available, is to achieve and maintain even small weight loss (3).
PHARMACOLOGIC TREATMENTS FOR OBESITY
Until September 1997, the combination of phentermine and fenfluramine (phen-fen) was the most popular treatment for obesity. The rationale behind it was reasonable: a low-dose combination of drugs affecting different central nervous system mechanisms could be clinically effective with fewer adverse effects than either drug alone at higher doses. Results in a small number of uncomplicated patients treated with phentermine and fenfluramine demonstrated that together they were the most successful medical treatment for obesity yet devised, and in some persons the combination helped maintain weight loss for up to 4 years.
Unfortunately, fenfluramine (Pondimin) and dexfenfluramine (Redux) have been associated with the development of primary pulmonary hypertension and a valvular heart disease characterized by mild aortic regurgitation, moderate mitral regurgitation, or both (4). Other pathologic manifestations have been described (5), including a thickening of the cardiac valves with an exudate similar to that seen in carcinoid syndrome, in which blood serotonin levels are elevated. As a result, fenfluramine and dexfenfluramine have been withdrawn from the market. The mechanism by which these serotonin-releasing agents might cause valvular damage is not understood.
New options for the pharmacologic treatment of obesity are available, and more will continue to be introduced. Sibutramine (Meridia) is a serotonin and norepinephrine reuptake inhibitor. It is similar in certain ways to the selective serotonin reuptake inhibitors that have been available for more than 10 years for the treatment of depression. Orlistat (Xenical) is a gastrointestinal lipase inhibitor that works by a novel mechanism of action (6). It is nonsystemic, has no central nervous system effects, and does not affect appetite. Rather, orlistat reduces the absorption of dietary fat by roughly 30% by inhibiting gastrointestinal lipase activity.
Medication should only be considered for patients with a body mass index (BMI) greater than 30, or greater than 27 if they have 2 or more comorbidities and have failed to lose weight on a program of diet, exercise, and behavior therapy (1).
Sibutramine
Sibutramine is the first reuptake inhibitor to have been approved as an appetite suppressant. Sibutramine reduces appetite, enhances satiety and, in animals, increases metabolic rate. It has fewer and less severe side effects than older appetite suppressants, which work by causing norepinephrine release. The metabolic studies performed thus far on human beings are not definitive about the effect of sibutramine on energy expenditure, although in animal studies that effect is clear (7). Sibutramine proved ineffective for its original purpose as an antidepressant (8), although it was noted in these early trials that patients lost weight while taking it. Sibutramine is similar to venlafaxine (Effexor) in its mechanism of action (9), although it has a greater effect on norepinephrine and a smaller effect on serotonin than does venlafaxine.
Studies lasting as long as 1 year have been conducted to examine the effect of sibutramine on weight loss (8,9). In a study of patients with a starting body mass index (BMI, measured as kg/[m.sup.2]) of 33, a daily dose of 10 mg sibutramine resulted in a mean weight loss of 4.8 kg, and a 15-mg daily dose resulted in a mean weight loss of 6.1 kg, whereas patients receiving a placebo lost a mean of 1.8 kg. Body weight reached a plateau after about 6 months (8,9). A categorical, or responder, analysis of the efficacy of sibutramine in this study looked at those patients receiving sibutramine for 1 year who achieved [greater than] 5% or [greater than]10% weight loss. Of patients involved in the study for 1 year 29% of those in the placebo group achieved [greater than] 5% weight loss, compared with 56% of those in the sibutramine group receiving a daily dose of 10 mg, and 66% of those in the sibutramine group receiving a daily dose of 15 mg. On the other hand, weight loss [greater than] 10% of initial weight was achieved by 6% in the placebo group, 30% in the sibutramine at 10 mg group and 39% in the sibutramine at 15 mg group (10).
The most common adverse effects of sibutramine include constipation, dry mouth, headache, and insomnia. Sibutramine may also increase blood pressure and heart rate. The average increase in blood pressure is 4 mm Hg (9), and the more weight patients lose, the less likely they are to have an increase in blood pressure. However, 1 in 8 patients may have an increase in blood pressure of 15 mm Hg or greater, and blood pressure and pulse must be monitored regularly. Blood pressure returns to normal when the medication is stopped. Only 0.8% of patients had to be withdrawn from the clinical trials for either hypertension or tachycardia, compared with 0.5% in the placebo-treated group. Sibutramine must be used cautiously in patients with hypertension, and its use is not recommended in patients with coronary artery disease, arrhythmias, congestive heart failure, or stroke.
Orlistat
A promising antiobesity medication on the horizon is orlistat. Orlistat is a gastrointestinal lipase inhibitor that competes with dietary fat for sites on the lipase molecules in the gastrointestinal tract. Only trace amounts of orlistat are absorbed through the gastrointestinal tract, and orlistat has been shown to have no systemic effects. It blocks the absorption of about 30% of dietary fat at a therapeutic oral dose of 120 mg three times a day. It has no apparent effect on appetite.
In addition to preventing the absorption of fat, orlistat may enhance dietary compliance with a low-fat diet. It gives patients a strong gastrointestinal feedback message if they eat too much fat in their diet. In our clinical experience with this drug, some patients tested its efficacy by eating more fat than recommended. If they experienced side effects such as oily stools, they adjusted their dietary fat intake accordingly to prevent the side effects.
In a 1-year trial (11) of patients prescribed a dietitian-supervised low-fat, energy-restricted diet and either 120 mg orlistat 3 times a day or placebo, a mean weight loss of 9% was found in the patients who received orlistat vs a mean weight loss of 5.8% in the placebo group (P [less than].05). In a responder analysis, 33% of patients receiving placebo vs 55% of patients in the orlistat group lost more than 5% of their initial body weight. Fifteen percent of the patients in the placebo group vs 25% of patients in the orlistat group lost [greater than] 10% of their initial body weight.
HEALTH BENEFITS ASSOCIATED WITH MEDICAL MANAGEMENT
Weight loss is not the only goal of obesity treatment. Improvement in the comorbidities associated with obesity is an important endpoint in current clinical trials. With sibutramine, there is evidence that some of the comorbidities associated with obesity improve: metabolic parameters such as uric acid concentration, glucose levels, and lipid levels improve in direct relationship to the amount of weight lost (10,12).
In addition to the health benefits brought on by weight loss, orlistat induced a further 8% reduction in low-density lipoprotein cholesterol independent of weight loss. Other health improvements include decreased blood pressure, improved fasting insulin levels, and improved glycemic control in study patients with diabetes.(13).
An improvement in glucose tolerance status is among the most exciting findings of the orlistat clinical studies. In addition to helping patients comply with a low-fat weight loss diet, orlistat may help to improve impaired glucose tolerance and thus prevent diabetes. The pooled clinical data indicate that of patients whose initial oral glucose tolerance test results showed diabetes in the diet alone (placebo) condition, 15% improved to normal glucose tolerance and 15% improved to impaired glucose tolerance (14). In the patients who received orlistat, of those who tested positive for diabetes at baseline, 25% improved to normal, and 43% improved from diabetic to impaired glucose tolerance. Two thirds of patients receiving orlistat improved their glucose tolerance, compared to less than one third on diet alone, a strikingly better result with orlistat compared with placebo. This is a substantial improvement in health outcome, and in view of the economic burden of diabetes, this finding has important public health implications.
Of the patients who had impaired glucose tolerance at baseline, 10% of those receiving a placebo progressed to diabetes, while the glucose tolerance of only 2.6% of those receiving orlistat worsened, a 4-fold difference in outcome. Of the patients with impaired glucose tolerance at baseline, 46% of those in the placebo group and 72% of those receiving orlistat shifted to having normal glucose tolerance at 1 year.
The frequency of gastrointestinal side effects was 41% greater in those receiving orlistat than in the placebo group, although few patients dropped out as a result of side effects. Of interest, 82.3% of patients receiving orlistat completed 1-year trials, compared with only 75.1% of those receiving a placebo, suggesting that the gastrointestinal side effects of orlistat were not great enough to dissuade them from taking the drug. During the second year of the 2-year trials, the number of gastrointestinal side effects decreased substantially, so that there were only 17% more side effects in the patients receiving orlistat than in those receiving a placebo. In general, the gastrointestinal side effects were described as being mild to moderate, occurred early in treatment and resolved spontaneously. Our own personal experience, based on anecdotal evidence from patients, suggested that they tested the drug by eating a high-fat food to see what happened. If they experienced a gastrointestinal side effect, they would cut back on the portion size, or try a low-fat alternative. Patients learned how much fat they could tolerated while on the medication and kept their fat intake to a level slightly below this threshold. It is the consumption of excess dietary fat, not the drug, that triggers the gastrointestinal side effects. Thus, patient education will be crucial to prevent gastrointestinal side effects when prescribing a drug such as orlistat.
SUMMARY
In conclusion, obesity is an epidemic in our society. It is associated with at least 1 comorbidity in most patients with a BMI of 27 or greater. Dietitians, as well as physicians, play an integral role in the management of obesity. As better medical treatments for obesity become available, the focus in dietary prescription may shift away from reducing energy and fat intake toward healthier eating for disease prevention. A comprehensive approach, which, in some patients, may include medical therapy as an adjunct, is necessary to treat obesity effectively. Candidates for treatment with medication include patients with a BMI greater than 30, or greater than 27 if they have comorbidities. Antiobesity agents with novel mechanisms of action will supply
