From "Challenges in Obesity Management"

Published in the Southern Medical Journal, 1999

The Problem of Obesity

Obesity has reached epidemic proportions in the U.S., and obesity is associated with increased risk of mortality and numerous other medical and health hazards, including hypertension, dyslipidemia, coronary heart disease, non-insulin-dependent diabetes mellitus (NIDDM), gallbladder disease, sleep apnea, ostearthritis, and several forms of cancer. Solomon and colleagues (1995) conclude that "the preponderance of evidence suggest that even mild overweight is probably associated with some increase in mortality risk." Obesity is also associated with increased health and socioeconomic costs. Colditz (1994) estimated the direct and indirect health care costs associated with obesity totaled $3.8 billion in 1990. The costs of obesity are not only economic. There are socioeconomic and personal tolls involved in the increasing prevalence of obesity, and obese women suffer the brunt of these costs. Obese individuals tend to receive lower salaries and lower attainment of social class, regardless of their level of education or intelligence test scores. This data led Wolf and Colditz to conclude that a body mass index (BMI) greater than 25 has immense economic and social costs.

Given these significant costs, it is not surprising that substantial efforts have been made to develop effective approaches to weight management. It is clear that there is a strong, positive relationship between BMI and risk for all-cause and some forms of cause-specific mortality. Even small therapeutic weight losses of 10-15% of initial body weight produce short-term improvements in several important risk factors, including NIDDM, dyslipidemia and hypertension. Intentional weight loss is associated with substantial reductions in all-cause mortality and mortality due to obesity-related cancers, diabetes and cardiovascular disease. These data give a clear rationale for pursuing effective methods for treating obesity.

Current Trends in Obesity Management Medical Treatment

Psychological Interventions

Psychological interventions, primarily in the form of lifestyle programs that include cognitive-behavioral methods for modifying diet, physical activity, and psychological functioning, are effective at producing gradual and moderate short-term weight losses. In most studies with extended follow-up, patients gradually return to baseline within a few years after treatment termination unless some form of maintenance program with sustained contact is implemented.

Current Adjunctive Pharmacotherapies

Early pharmacological interventions for obesity produced temporary weight losses, but sometimes were associated with aversive side effects, health risks and abuse. Progress in the development of new obesity drugs has been hindered by several factors including the unfortunate history of amphetamine abuse, the perception that obesity is a disorder of willpower, and the belief that drugs are not an appropriate treatment approach since they must be taken indefinitely.

Surgical Treatment

Surgical approaches are one of the most successful treatments for obesity if the person is morbidly obese (i.e., with a BMI of 40 or with medical problems and approximately 80 pounds overweight.) It should be considered after failure of medical and behavioral intervention of severe comorbid condition or lack of motivation, support or other psychological factors. Even if surgery is undertaken this does not preclude the use of medication and psychological intervention. This must be available and provided as early as possible for those patients because the patients regain weight which places them at risk for medical conditions related to obesity. The research at Weight Loss for Life shows that 80% of patients are successful and lose 60% of their excess body weight within a year. The literature and research at Weight Loss for Life shows an 80% long-term weight loss for 3-5 years. This compares to Weintraub's classic study with Phen-Fen of only 25% and long-term weight loss of 25 pounds.

Psychological Interventions

The average weight loss across studies for medical behavioral intervention is 8.4 kg. If long-term contact is maintained the patients maintain, on average, about two-thirds of their initial weight loss 9 to 10 months after treatment termination. If some form of maintenance program with sustained contact is implemented, this means monthly contact to support and motivate the patient to continue to exercise. 70% of patients, when exercising, maintain weight loss. Only 30% who do not continue to exercise succeed in maintaining weight loss. If an individual gains more than 5 pounds, they need counseling or a return to active treatment to insure long-term weight loss.

Current Adjunctive Pharmacotherapies

Progress has been hindered by the perception that obesity is a disorder of willpower, and the belief that drugs are not an appropriate treatment approach since they must be taken indefinitely. Interest in pharmacological approaches has increased due to the recognition that obesity is a chronic disease, which cannot be cured, but can be managed. This is similar to the results of other chronic diseases such as diabetes and hypertension treatment.

Fenfluramine - a serotonergic agent (recently withdrawn from the market) for treatment of obesity in 1973. Patients in these studies lost 15.3 plus/minus 1.2 kg (33 pounds) in combined treatment groups, and 10.9 plus/minus 1.0 kg (22 pounds) in the behavior therapy group, while patients in the control group gained 1.3 plus/minus 1.3 kg. Patients in both drug conditions experienced greater than 50% weight regain within one year after drug withdrawal. A subsequent study found that patients in all groups regained a substantial portion of their weight after the withdrawal of all treatment if they did not have a maintenance program, which includes at least a monthly follow-up with professional support. Medication gives a "jump start" to minimize the appetite. However, it is a comprehensive medical program of social and behavioral strategies that leads to long-term weight management.

Fenfluramine-Phentermine - Although withdrawn from the market, several studies have examined the effectiveness of treatment with drug combinations along with a behavior modification component. Smaller doses of each medication can be effective, thus reducing adverse side effects, resulting in an overall 9.4 plus/minus 0.8 kg (20 pounds) weight loss after 3 years, with a plateau in weight loss at 18-20 weeks.

This is consistent with the recent open label trials at M.D. Weight Care done by Leo J. Borrell, M.D., with over 2000 patients in Houston enrolled in a comprehensive behavioral pharmacotherapy obesity treatment program. They reported average weight losses of 16.5 kg at 6 months and weight loss maintenance for 18 months, which shows the intensity of psycho-social contact correlated directly with weight (i.e., 2-4 pounds/month/visit).

At M.D. Weight Care this observation is substantiated by our cohort, in which the most frequently reported side effects at the follow-up were dry mouth (73%), drowsiness (22%), and constipation (16%) or diarrhea (16%). By the sixth follow-up, these complaints dropped to 55%, 5%, 10% and 2%, respectively. If the patient is informed of this, they are well-tolerated and attrition decreases.

Fluoxetine (Prozac) - Evaluated in several clinical trials, although it is not approved by the FDA for the treatment of obesity, Fluoxetine treatment produces significant initial weight losses up to 24 weeks.

The combination of fluoxetine and Prozac has been used to enhance dietary restraint and reduce hunger in daytime, while the addition of dexfenfluramine at dinner might effectively control binging. Fluoxetine-dexfenfluramine combination lost significantly more weight than patients who received fluoxetine (13.4 plus/minus 6.3 kg vs. 6.2 plus/minus 2.8 kg, respectively). This combination is more effective at producing short-term weight loss than either fluoxetine or dexfenfluramine alone. The addition of dexfenfluramine appeared to prevent weight gain during active treatment reported in previous fluoxetine studies.

Sertraline - a serotonin inhibitor used in the treatment of depression, following a very low calorie diet (VLCD) demonstrated some long-term advantage over placebo.

Ephedrine-Caffeine - Several randomized, double-blind, placebo-controlled trials of ephedrine, a stimulant anorexiant, usually in combination with caffeine and aspirin, produced greater weight loss than dietary restriction alone (no more than 4 kg/10 pounds after 24 weeks). The ephedrine-caffeine combination is not approved for the treatment of obesity and the FDA recently has expressed serious concerns about the safety of ephedrine.

Other Drugs - Anorexiant medications, including mazindol, diethylpropion, and phenylpropanolamine have produced modest weight loss of 4-10 pounds over 6 to 12 months.

Recently Approved and Future Drugs

New pharmacotherapies (i.e., Xenical) can reduce energy intake, reduce nutrient absorption, or increase energy expenditure. It is due to be released in 1998.

New Behavioral Applications

A greater emphasis must be placed on regular physical activity in weight management programs, as both an intervention and a treatment outcome, since 70% who exercise or participate in a structured exercise program maintain weight loss. It is an important predictor of weight maintenance. Further, it was found that moderately and highly-fit men, irrespective of BMI, experienced significantly lower age-adjusted risk for all-cause mortality compared to sedentary or low fit men.

Moderate-intensity, home-based exercise programs have been shown to improve functional capacity and adherence, particularly when combined with brief instruction and regular telephone contacts. Long-term adherence rates for home-based programs can be greater than for group-based exercise, and they can provide superior weight losses if there is professional contact and monitoring and enhancement of motivation.

Reduce Energy Intake

Dexfenfluramine - (Redux) Dexfenfluramine was approved by the FDA for the treatment of obesity in 1996, but has a longer history of use in Europe. It has since been taken off the market. Patients treated with dexfenfluramine lost 9.82 plus/minus .50 kg (20 pounds), while the placebo group lost 7.2 plus/minus 8.6 kg. Treatment with dexfenfluramine can lead to significant reductions in visceral adipose tissue, which results in improvements in insulin sensitivity, and may be particularly helpful for obese patients with (Non-Insulin Dependent) Diabetes.

Once patients are taken off medication for obesity, they regain most or all of their lost weight. They regained approximately 60% of their initial weight loss within 5 months after drug withdrawal, and approximately 110% three years after withdrawal. This demonstrates that medications, exercise and motivational counseling needs to be used for extended periods of time (3-5 years). Long-term success is best provided by a multidisciplinary team and/or coordinated and supervised by a physician with a special interest in this area.

Sibutramine - (Meridia) a noradrenergic and serotonin reuptake inhibitor that has both satiating and thermogenic effects, produced weight losses of 4.7-7.6 kg in several clinical trials. Doses of 10 and 15 mg per day produced weight losses that were 3-5 kg better than placebo and tended to plateau by 24 weeks. It is to be available in 1998.

Leptin - is a protein that may inhibit Neuropeptide Y (NPY) gene expression and appears to increase satiety and energy expenditure. Defects in the ob gene are rare in humans. A lack of the ob protein is probably not a primary cause of human obesity, but the possibility that obese individuals are insensitive to endogenous leptin production. Human leptin clinical trials are currently underway.

Brain & Gut Peptides - important for potential drug development in the areas of peptide agonists and antagonists. Studies have found elevated levels of beta-endorphin (an opiate peptide that stimulates feeding) in obese individuals. Opiate peptide antagonists are now being investigated for application to obesity and binge eating. For example, naloxone, an opiate blocker, has been shown to supress desire for and consumption of sweet, high-fat foods in both obese and normal-weight binge eating women, but not in non-bingers.

Other Peptides - Cholecystokinin (CCK) & NPY - there are no known defects in the CCK responses of obese individuals. B-3 antagonists are currently not approved by the FDA for the treatment of obesity.

Focus on Clinical Issues

The Limits of Drug Therapies - There is the Myth of the magic bullet. The reality is that a comprehensive coordinated medical care program produces superior results and is less costly because of the long-term effectiveness.

Studies of single drugs and drug combinations, usually in conjunction with psychosocial lifestyle modification programs, have shown modest weight loss when compared to lifestyle change and placebo. Potential and significant adverse effects include depression, neurotoxicity, primary pulmonary hypertension (pph), and the potential for abuse or the development of tolerance. PPH occurs at an annual rate of 1 to 2 cases per million in the general population, but recent estimates suggest the rate may be as high as 23 to 46 cases per million for patients using anorexiants. The recent report from the Mayo Clinic raises additional concerns about valvular heart disease, but their advice is prudent: "Remain calm." More comprehensive study is necessary since this was an observational study. (Other side effects include diarrhea, polyuria, dry mouth, sleep disturbance, nervousness, sexual dysfunction, and increased blood pressure, but these effects are geberally mild to moderate, and tend to ameliorate with continued treatment.)

Attrition and Adherence - Poor adherence is common and it is a routine dilemma in the management of many chronic diseases. For example, in weight loss, 85% attrition in 96 weeks, 57% of patients dropped out over 3.5 years, 57% attrition at 1 year, and 30% in 30 days was reported. If attrition can be this high in controlled clinical trials, it is likely to be a greater problem in clinical settings. Attrition appears to be related to motivation that is maintained by intensity of professional contact independent of amount of weight loss necessary. Emotional factors are significant since stress is responsible for 80% of weight gain. To place this risk in perspective, the risk of anphylatic shock or stroke while using oral contraceptives and smoking are 40 per million. Death from an automobile accident is 200 per million.

Factors Influencing Attrition & Adherence

Expectation

It is difficult to understand compliance problems. Financial and real life demands are as difficult to assess in research situations. Satisfaction with the result may be a more useful measure. This requires assessment of motivations, expectations, intensity of treatment and severity of problems, not just weight. A clue is available from research which shows that there is a large gap between how much weight patients expect to lose and how much they really lose; they drop out due to disappointment with the treatment. In one of the few studies on this issue, only 9% of the participants achieved their "dream" weight, only 25% made it to their "happy" weight, and 25% reached their "acceptable" weight. 67% achieved only their "disappointed" weight or below. This gap between their weight loss expectations and reality may be an important factor in early treatment withdrawal. Also, research shows that the more severe the weight problem, the more intense treatment needs to be to be effective. The role of the physician and professional is to help individuals to continue to perservere when they reach less than their ideals, appreciated their successes and set realistic goals. This will allow continuing effort as the resources of the individual and the program allow.

Cost-Effectiveness

Short-term obesity treatment does not have good outcomes. It is not unreasonable that obese patients should receive long-term, continuous interventions, including extended drug therapy, similar to the treatment of hypertension or diabetes, continued support and therapist contact, and continuous drug therapy. This data provides preliminary evidence that long-term comprehensive obesity treatment could be delivered in a cost effective manner by physicians who see the patient 10-20 minutes at each visit 1-2 times per month.

Reality of Real World Reimbursement and Support for Weight Loss Treatment

It is important that obesity treatments receive parity with regards to insurance reimbursement since it is a proven effective preventive intervention. The treatment of at-risk individuals (i.e., obese individuals without current comorbid medical or psychological conditions that are reimbursable) is essential since the risk of significant morbidity and mortality have been demonstrated. In addition, weight loss has also been shown to minimize those risks.

Public Policy

Finally, the most effective programs should be targeted at obesity prevention for young children. Further research is needed to determine the acceptability of incentives-based measures to the general public, as well as how they might positively and negatively impact businesses, schools and governmental bodies.

Conclusions: Beyond Weight Loss

It is likely that overweight individuals will need motivational counseling, medical evaluation, long-term management programs and extended pharmacotherapy. These programs require not only physical activity and nutrition management, but concern about the quality of life, since long-term weight loss is strongly influenced by emotions, stress and coping skills.