Pharmacotherapy

Drug therapy has undergone radical changes in the last 2 years. With the publication of the trials with phentermine and fenfluramine by Weintraub in 1992 (210 weeks), drug therapy began to change from short-term to long-term use. Both dexfenfluramine and fenfluramine alone, as well as the combination of phentermine/fenfluramine, were used long term. However, concerns about recently reported unacceptable side effects, such as valvular lesions of the heart causing significant insufficiency of the valves (658), have led to the withdrawal of the drugs dexfenfluramine and fenfluramine from the market in September 1997 (761).  No drugs remained that were approved by the Food and Drug Administration (FDA) for use longer than 3 months. In November 1997, the FDA approved a new drug, sibutramine, for use in obesity. In April 1999, orlistat was approved by FDA for weight loss.

Rationale: The purpose of weight loss and weight maintenance is to reduce health risks. If weight is regained, health risks increase once more. The majority of persons who lose weight regain it (585), so the challenge to the patient and the practitioner is to maintain the weight loss. Because of the tendency to regain weight after weight loss, the use of long-term medication to aid in the treatment of obesity may be indicated in carefully selected patients.

The drugs used to promote weight loss have been anorexiants or appetite suppressants. Three classes of anorexiant drugs have been developed, all of which affect neurotransmitters in the brain: those that affect catecholamines, those that affect serotonin, and those that affect both. They work by increasing the secretion of dopamine, norepinephrine, or serotonin into the synaptic neural cleft, or by inhibiting the reuptake of these neurotransmitters back into the neuron, or by both mechanisms. The new agent sibutramine has norepinephrine and serotonin effects. Another new agent, orlistat, has a different mechanism of action, the blockage of fat absorption.

Very few trials longer than 6 months have been done with any drug. The ones tested for at least 1 year that received FDA approval for long-term use are shown in the table below. These drugs are effective but modest in their ability to produce weight loss. Net weight loss attributable to drugs generally has been reported to be in the range of 2 to 10 kg (4.4 to 22 lb), although some patients lose significantly more weight. It is not possible to predict how much weight an individual may lose. Most of the weight loss usually occurs in the first 6 months of therapy.

+ Ephedrine and caffeine, and fluoxetine have also been tested for weight loss, but are not approved for use in the treatment of obesity. Mazindol, phentermine, benzphetamine, and phendimetrazine are approved for only short-term use for the treatment of obesity.
* FDA approval withdrawn

Adverse effects include primary pulmonary hypertension with fenfluramine and dexfenfluramine (395, 586, 587), valvular heart disease with dexfenfluramine and fenfluramine (658), and increases in blood pressure and pulse with sibutramine (510).   With orlistat, there is a possible decrease in the absorption of fat-soluble vitamins; overcoming this may require vitamin supplementation. People with a history of high blood pressure, CHD, congestive heart failure, arrhythmias, or history of stroke should not take sibutramine, and all patients taking the medication should have their blood pressure monitored on a regular basis. Depression has been described with the serotonergic drugs but it is generally not clinically significant. Neurotoxic effects with neuronal atrophy have been described with high doses of dexfenfluramine in rats and primates, but not in humans (588).  The risks for using appetite suppressant drugs during pregnancy are unknown.

Evidence Statement: Weight loss drugs approved by the FDA for long-term use may be useful as an adjunct to diet and physical activity for patients with a BMI of 30 with no concomitant obesity-related factors or diseases, and for patients with a BMI of 27 with concomitant obesity-related risk factors or diseases. Evidence Category B.

Rationale: If after at least 6 months on a weight loss regimen of an LCD, increased physical activity, and behavior therapy, the patient has not lost the recommended 1 lb/week, careful consideration may be given to pharmacotherapy. There are few long-term studies evaluating the safety or effectiveness of many currently approved weight loss medications. At present, sibutramine and orlistat are available for long-term use. Their risk/benefit ratio is such that they can be recommended for use with the degree outlined above (589).

Weight loss medications should be used only by patients who are at increased medical risk because of their weight and should not be used for "cosmetic" weight loss. The risk factors and diseases considered serious enough to warrant pharmacotherapy at BMI of 27 to 29.9 are hypertension, dyslipidemia, CHD, type 2 diabetes, and sleep apnea.

Not every patient responds to drug therapy. Tests with weight loss drugs have shown that initial responders tend to continue to respond, while initial nonresponders are less likely to respond even with an increase in dosage (395, 507).  If a patient does not lose 2 kg (4.4 lb) in the first 4 weeks after initiating therapy, the likelihood of long-term response is very low (507).  This finding may be used as a guide to treatment, either continuing medication in the responders or stopping it in the nonresponders. If weight is lost in the initial 6 months of therapy or is maintained after the initial weight loss phase, this should be considered a success, and the drug may be continued.

It is important to remember that the major role of medications should be to help patients stay on a diet and physical activity plan while losing weight. Medication cannot be expected to continue to be effective in weight loss or weight maintenance once it has been stopped (590, 591).  The use of the drug may be continued as long as it is effective and the adverse effects are manageable and not serious. There are no indications for specifying how long a weight loss drug should be continued. Therefore, an initial trial period of several weeks with a given drug or combination of drugs may help determine their efficacy in a given patient. If a patient does not respond to a drug with reasonable weight loss, the physician should reassess the patient to determine adherence to the medication regimen and adjunctive therapies, or consider the need for dosage adjustment. If the patient continues to be unresponsive to the medication, or serious adverse effects occur, the physician should consider its discontinuation (592).

Rationale: The potential for side effects from the use of weight loss drugs is of great concern. Adverse effects with sibutramine include increased blood pressure and tachycardia (590).  With orlistat, there are oily and loose stools and some fat-soluble vitamin malabsorption (389).  Thus, a multivitamin supplement is recommended. Side effects are generally mild and may improve with continued use, although their persistence may result in discontinuation of the drug.

There is a great interest in weight loss drugs among consumers. Because of the possibility of serious adverse effects, it is incumbent on the practitioner to use drug therapy with caution. Practitioners should be sure that patients are not taking drugs that have been withdrawn from the market for safety reasons, and herbal medications are not recommended as part of a weight loss program. These preparations have unpredictable amounts of active ingredients and unpredictable and potentially harmful effects. In those patients with a lower level of obesity risk, nonpharmacological therapy is the treatment of choice. It is important for the physician to monitor both the effectiveness and the side effects of the drug.

Rationale: Given the fact that adverse events may increase in association with combination drug therapy, it seems wise that, until further safety data are available, using weight loss drugs singly (not in combination) would be more prudent. Some patients will respond to lower doses, so that full dosage is not always necessary. The short-term use of drugs ( 3 months) has not generally been found to be effective.

Drugs should be used only as part of a comprehensive program that includes behavior therapy, diet, and physical activity. Appropriate monitoring for side effects must be continued while drugs are part of the regimen. Patients will need to return for follow-up in 2 to 4 weeks, then monthly for 3 months and then every 3 months for the first year after starting the medication. After the first year, the doctor will advise the patient on appropriate return visits. The purpose of these visits is to monitor weight, blood pressure, and pulse, discuss side effects, conduct laboratory tests, and answer questions. 

Since obesity is a chronic disorder, the short-term use of drugs is not helpful. The health professional should include drugs only in the context of a long-term treatment strategy (593). The risk/benefit ratio cannot be predicted at this time, since not enough long-term data (> 1 year) are available on any of the available drugs.

Recommendation: Weight loss drugs approved by the FDA may only be used as part of a comprehensive weight loss program, including dietary therapy and physical activity, for patients with a BMI of 30 with no concomitant obesity-related risk factors or diseases, and for patients with a BMI of 27 with concomitant obesity-related risk factors or diseases. Weight loss drugs should never be used without concomitant lifestyle modifications. Concomitant assessment of drug therapy for efficacy and safety is necessary. If the drug is efficacious in helping the patient lose and/or maintain weight loss and there are no serious adverse effects, it can be continued.  If not, it should be discontinued. Evidence Category B.