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Cornell University Medical College New York, New York 10021
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Introduction |
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The recent association of fenfluramine and dexfenfluramine with valvular heart disease (2) dealt a blow to the popularization of pharmacotherapy for obesity. What, if any, role should pharmacotherapy play in the treatment of obesity? At the present time, pharmacotherapy has a limited role. Drug treatment of obesity is only appropriate in individuals who are at medical risk from their level of obesity, have not responded to more traditional, conservative management such as diet and exercise, have no contraindications to the use of the pharmacologic agent, and who understand the risks, likelihood of success, and possible need for long-term treatment to maintain lost weight. Pharmacotherapy is not appropriate for cosmetic weight loss.
Much of the criticism leveled at the medical treatment of obesity has been justified. Until recently, there have been no long-term studies of medical treatment proving efficacy and health benefit. Thus, the treatment of obesity with medication is in many ways similar to the treatment of hypertension in the 1960’s.
In the early 1950’s it was known that malignant hypertension was a rapidly fatal illness associated with accelerated vascular disease, but it was not known whether treatment would improve outcome. By the late 1950’s it was shown that malignant hypertension had a 20% survival rate at one year, which could be improved to 66% with medical therapy, even though such treatment was fraught with complications. Nonmalignant hypertension, on the other hand, caused no immediate, dramatic complications, and was thought of more as a behavioral disorder, exacerbated by excessive salt intake and stress. By the early 1960’s it was not known whether treatment of nonmalignant hypertension could improve the cardiovascular complications, which by that time had been shown to be associated with moderate levels of hypertension. Behavioral treatments did not work well, and medical treatments were not believed to be indicated because of their side effects and lack of proven benefit. In 1964, a small, properly controlled trial showed a marked decrease in complications over a 2–6 yr interval between 31 untreated and 26 effectively treated patients (3). In 1967, the Veterans Administration Cooperative Study (4) provided the first definitive proof that antihypertensive therapy reduced morbidity and mortality in cooperative men with initial diastolic blood pressures between 115–129 mm Hg. The drugs used were hydrochlorthaizide, reserpine, and hydralazine. In 1970, another publication documented the benefit in patients with diastolic blood pressures between 90 and 114 mm Hg (5). It took only 1.5 yr of follow-up to see a significant difference in the first study, but far longer in the second group with moderate hypertension, on average 3.3 yr. Thus, in the early 1960’s the available treatments had many side effects and complications and no proven health benefit. As a result, only patients with malignant hypertension were treated. Guanethedine, reserpine, and later, hydralazine were associated with substantial side effects such as orthostatic hypotension, impotence, and depression. Hydralazine caused systemic lupus erythematosus in a small percentage of patients. Methyldopa (Aldomet Merk & Co., Inc.), besides diuretics the most popular antihypertensive drug from 1962 until the late 1970’s, caused a number of side effects. These included loss of mental alertness, drowsiness, and galactorrhea, as well as autoimmune phenomena including a positive Coombs test in 20% of treated patients, positive antinuclear antibodies in 13%, and abnormal liver function tests in 6.3%. Eighty-three cases of serious hepatotoxicity were described. Hemolytic anemia occurred in 15–30 patients per 1000 treated. Despite these relatively common, serious side effects, methyldopa was described as the drug that "most (physicians) found... to be the most effective and least objectionable drug for the majority of patients with moderate degrees of hypertension" (6).
The current treatment paradigm of inititiating pharmacotherapy in those patients with a blood pressure over 140/90 took years to prove beneficial even though patients had been treated in that manner for some time. Why treat someone with a blood pressure greater than 140/90? Because that is the point above which the risk of long-term complications becomes significant enough to justify treatment. Will some patients have a complication of the treatment and no benefit? It’s possible. Back in the 1960’s and 1970’s, side effects and complications were more likely to occur than they are now, when we have more than 100 antihypertensive agents available. Our improved understanding of the physiology of blood pressure has allowed us to control blood pressure through a much broader array of mechanisms with fewer side effects. At present, no antihypertensive needs to be tolerated that has substantial risk or side effects, as so many others are available.
The evolution of pharmacotherapy for obesity is in many ways similar to the evolution of pharmacotherapy for hypertension. At present, we are in an early phase of the process, with only limited treatment options available, but with our understanding of the problem developing rapidly. We do know that, when using medication, some patients will lose weight and maintain lost weight (7), that losing weight will improve comorbid conditions in at least some people (8, 9), and that improving comorbidities, such as hypertension, diabetes, and hyperlipidemia will in turn reduce the risk of the morbidity and mortality associated with these diseases. Can we conclude that using medication to ultimately improve or prevent the comorbidities will prolong life? It sounds plausible, but could be hard to prove—to obtain the proof will certainly require a large multicenter trial. The recognition that a weight loss of only 5–10% of total body weight is associated with health benefit allows us to direct our treatment towards health, rather than cosmetic goals.
However, one way in which the history of the treatment of obesity has not paralleled that of hypertension is the prevalence of patient-driven demand for treatment. Convincing patients to take medication for hypertension has often been a chore, though easier over the past few years thanks to once-a-day dosing and substantial improvements in the side-effect profile of antihypertensives. With obesity treatments, on the other hand, patients have been willing to subject themselves to almost any risk in an effort to lose just a few pounds. This propensity has been particularly acute lately when the demand for treatment has been driven by a body- and youth-conscious society, large commercial weight-loss organizations, physician advertising, and media hype.
Until recently, the only medical therapies available are sympathomimetic appetite suppressants, which are not tolerated by some patients and not effective in others. Although available for almost 40 years, there are no studies documenting long-term efficacy, safety, and benefit of any sympathomimetic agent.
The potential availability of a new medication, sibutramine, and the potential availability of a second, orlistat, will broaden the spectrum of treatments sufficiently to make pharmacotherapy of obesity part of the pharmacologic armamentarium of the many physicians who deliver care to patients at medical risk from obesity.
Orlistat (Xenical, Roche Pharmaceuticals, Nutley, NJ), an inhibitor of pancreatic lipase, reduces the absorption of dietary fat by 30% at its recommended dose of 120 mg po tid before meals (10, 11, 12). Analysis of patients completing a 1-yr long placebo-controlled trial demonstrated that 55% of patients treated with orlistat at the above dose lost more than 5% of their body weight compared with 33% in the placebo-treated group. Twenty-five percent of patients taking orlistat lost more than 10% of their body weight, compared with 15% in the placebo group. In addition, orlistat slowed down the rate of weight regain in the second year of treatment. Clinical trials have shown reductions in blood pressure, fasting insulin concentration, and low density lipoprotein cholesterol, an increase in high density lipoprotein cholesterol, and improved glycemic control in obese diabetics (13). Of great interest, in patients with an oral glucose tolerance test consistent initially with diabetes, 44% improved to impaired glucose tolerance after 2 yr treatment with orlistat compared with only 11% in a placebo treated group. Furthermore, 72% of those with impaired glucose tolerance improved to normal compared with 48% in the placebo treated group, and only 1.7% progressed to diabetes, compared with 7.5% in the control group (Data on file. Roche Laboratories). Thus, treatment with orlistat clearly improves this important comorbidity over a 2-yr period.
Orlistat did not significantly affect the pharmacokinetics of digoxin, warfarin, nifedipine, atenolol, captopril, furosemide, or glyburide (14). Studies of fat soluble vitamins in patients taking orlistat show that serum levels of vitamin D and beta carotene were mildly reduced in some patients, while vitamins A, E, and K activity were unchanged. It will be recommended that a multivitamin be taken daily at least 3 h before or after a dose of orlistat (15). Mineral imbalance, gallstone, or renal stone formation were not observed with orlistat use. Gastrointestinal side effects were common, but generally mild and transient in most patients studied (16). Clinical experience with orlistat suggests that it enhances patients’ compliance with a low-fat diet by providing negative feedback in the form of the gastrointestinal side effects associated with fat malabsorption if too much fat is consumed.
Sibutramine (Meridia, Knoll Pharmaceuticals, Mt Olive, NJ), a norepinephrine and serotonin reuptake inhibitor, was recently approved by the Food and Drug Administration. Originally developed as an antidepressant, sibutramine produces dose-related weight loss when given in the range of 5–15 mg as a single dose daily (17, 18). Analysis of patients completing a 1-yr placebo-controlled trial demonstrated that 65% of those receiving 15 mg of sibutramine daily lost more than 5% of their body weight compared with only 29% of placebo-treated patients, and that 39% of sibutramine-treated patients lost more than 10% of their body weight compared with 8% in the placebo-treated group. The weight loss achieved with sibutramine was similar to that achieved with dexfenfluramine over 12 weeks. Sibutramine-induced weight loss was accompanied by a significant reduction in waist-hip ratio, decreases in plasma triglycerides, total cholesterol and low density lipoprotein cholesterol, an increase in high density lipoprotein cholesterol, and improved glycemic control. The health benefits seen with sibutramine are consistent with the amount of weight lost, i.e. more subjects benefit in the drug treated group because more subjects lost more weight. Adverse events seen during randomized trials included dry mouth, anorexia, constipation, insomnia, increased appetite, dizziness, nausea, abdominal pain, and tachycardia (data on file, Knoll Pharmaceuticals). The use of 10–15 mg of sibutramine daily has been shown to cause a mean increase in heart rate of 3–6 beats/min and an average elevation in diastolic blood pressure of less than 4 mm Hg (19). Less than 1% of subjects on these doses discontinued the trial because of the development of hypertension, which resolved promptly once the drug was stopped. The safety of sibutramine in patients with cardiovascular disease is currently being investigated. An echocardiographic study has shown no relationship between the use of sibutramine and valvular heart disease after an average of 7 months of treatment (20).
Thus, both of these medications have been shown to not only reduce weight, but to also reduce the severity of certain comorbidities over the 1- to 2-yr time frame. Like other chronic diseases, obesity does not always respond to conservative treatments such as diet, exercise, and behavior change. What is the patient to do if he or she does not respond to the method and is not obese enough to warrant surgery, the only treatment proven to be effective in the long term? What about the patient with complications of obesity? Should treatment of the obesity be tried as a first line treatment to "kill two birds with one stone"? The medical treatment paradigm works for other chronic diseases: why shouldn’t it work for obesity? One of the most important recent papers in the obesity treatment literature comes from Dr. Thomas Wadden and his colleagues at the University of Pennsylvania (21). In this trial, they randomized 26 women to one of two treatment groups: ten 15- to 20-min visits over a 1-yr period with a physician in a protocol-based weight reduction program or 32 75-min behavior modification sessions led by a master’s or doctoral level nutritionist. Both groups received phentermine 15 mg per day and fenfluramine 60 mg per day. After one year, both groups had lost the same amount of weight, 15%. Treatment was associated with a highly significant improvement in blood lipids, mood, and appetite. The 10-visit-per-year treatment paradigm could be reproduced in any doctor’s office and could even be trimmed a bit with the help of interested support staff such as dietitians. This pilot study suggests that the treatment paradigm that currently works for other chronic diseases such as hyperlipidemia, diabetes, and hypertension will work for obesity. As medications that help manage obesity improve, it is only a matter of time before pharmacotherapy becomes a standard part of the medical armamentarium.
At the present time, pharmacotherapy for obesity should be considered in patients who have a BMI greater than 30, and in those with a BMI greater than 27 if they have comorbidities. Every patient with a BMI in those ranges, however, should not be on medication. All patients to whom medication is prescribed should be making their best effort to moderately reduce caloric intake and exercise regularly. Evaluation and follow-up by a registered dietician is an excellent way to accomplish this. The effect of the treatment should be continually re-evaluated to determine if it is, in fact, effective. If a patient does not get medical benefit from the treatment, it should be discontinued. If the patient develops side effects but is losing weight, the risk of the side effects must be weighed against the benefit of the weight loss. This is particularly important in patients with comorbidities such as sleep apnea or arthritis of the weight-bearing joints, which in many cases are best managed by weight reduction. In the obese patient with comorbidities, management of the obesity should be taken into consideration and may take precedence over the management of the comorbidity, particularly if other comorbid conditions are present that might benefit from weight loss. Treatments for the comorbidity that worsen the obesity should be avoided if other options are available. For example, in most obese type 2 diabetics, metformin and acarbose should be used as first-line treatment, with consideration given to the new weight-loss drugs because of improvement in lipids that may accompany the weight loss. In obese patients with hypertension, weight loss may reduce blood pressure; this is true even if sibutramine, which may increase blood pressure in some patients, is used. Drugs that are known to cause weight gain, such as steroids, progestins, antidepressants, and antipsychotics may exacerbate obesity, and their use should be monitored carefully in the obese patient.
Obesity will shorten the lives of some people, but not others. The use of medication to treat obesity is an extension of our approach to the management of the chronic diseases such as diabetes, hypertension, and hyperlipidemia, which occur much more commonly in obese individuals. If we could effectively treat obesity, we could prevent a substantial proportion of these comorbidities before they occur, thus saving the enormous health related costs associated with their treatment. As our understanding of the weight regulating mechanism progresses, in years to come, the pharmacologic treatment of obesity may supplant the treatment of these and other disorders, which are a direct result of an accumulation of excess body fat.
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