This article examines the transitions in pharmacological therapy for obesity. It reviews the current options approved by the Food and Drug Administration and several drugs approved for other indications that can be used to treat obesity as well. Because weight regulation is complex and redundant systems protect against perceived starvation, optimal treatment of obesity in individual patients will likely require different combinations of behavioral, nutritional, pharmacologic, endoscopic, and surgical therapies.
The development of effective pharmacologic therapies has been both the greatest hope and one of the greatest disappointments in the field of obesity. At its root, obesity is a complex metabolic and behavioral disorder that disrupts normal body weight regulatory mechanisms. Logically, both the metabolic and behavioral components of body weight regulation should be amenable to pharmacologic treatment, and several agents have been developed that influence eating behavior, food intake, nutrient absorption, and energy expenditure. These medications induce weight loss, but to a lesser extent and for a shorter period than would be considered ideal by either patients or physicians. Moreover, many of these agents have been associated with unacceptable adverse effects, in many cases as a direct result of their therapeutic mechanism of action. These side effects, including the euphoric and addictive effects of amphetamines, the hypertensive and arrhythmogenic effects of the adrenergic agents, the cardiac valvular effects of fenfluramine, and the steatorrhea associated with orlistat, have significantly curtailed the use of these drugs and, in some cases, required their complete withdrawal from the market.
Recent studies of the physiology of body weight regulation have demonstrated the complexity of this control system and have identified numerous novel targets for therapeutic intervention. These studies provide hope that new, more specific agents will provide more effective and durable treatment of obesity with fewer side effects. The very complexity of weight regulation, however, and the powerful systems to defend against real or perceived starvation, makes it unlikely that a single pathway, cell, or molecule will prove to be the Achilles heel of obesity. Thus, long-term effective treatment is likely to require a multimodal approach, with multiple drugs aimed at different targets or novel combinations of specific pharmacologic, nutritional, endoscopic, and surgical approaches.
Currently available pharmacologic therapies for obesity can be effective adjuncts to diet- and exercise-based behavioral therapies, typically increasing the amount of weight loss by 4% to 6% over 1 to 2 years (eg, from a weight loss of 4% to a weight loss of 8% during this time). In nearly all cases, however, the maximal effect appears to occur within the first year of therapy (often within the first 6 months) with partial regain of lost weight thereafter. In addition, the response to each medication varies widely from patient to patient, with a small number of patients (typically 2%–5%) exhibiting considerably more weight loss than average, and a significant portion experiencing no weight loss.
For the currently available weight loss medications (regardless of the mechanism of action), the criterion of a 4-pound weight loss in 4 weeks is a helpful guideline. Weight loss of lesser magnitude provides good evidence that the medication has little therapeutic value for the patient. Given the potential for adverse effects, such modest weight loss is a strong indication for stopping the drug. For patients who lose 4 or more pounds in the first month, it is not clear how much additional weight loss should occur for the drug to be continued. Many physicians require that patients lose 4 pounds per month for a minimum of 3 months (12 pounds total) to consider the medication clinically effective. Thereafter, if a patient maintains the lower weight, the drug is still considered effective, since it is preventing the weight regain that occurs in more than 90% of patients upon cessation of treatment. For each of these drugs, human and animal studies suggest that they work less by causing weight loss per se than by causing the patient (or animal) to seek a specific, lower weight. For each drug and for each patient, there appears to be a maximum achievable weight loss. Continuing the drug is usually necessary to maintain all or most of the lost weight, and cessation is almost always associated with rapid regain of the lost weight.
Weight loss medications are usually reserved for patients who have failed more standard behavioral interventions, including various combinations of diet- and exercise-based approaches. Box 1 shows the standard criteria for use of these agents.
Body mass index (BMI)>30 kg/m 2 or BMI>27 kg/m 2 in association with significant medical complications
Failure of behavioral approaches, including diet and exercise regimens
No strong contraindications to the medication used
For continued treatment, weight loss of≥4 pounds per month for each of the first three months
Medications approved for the treatment of obesity
Table 1 lists the medications most commonly used for the treatment of obesity. These drugs are specifically approved by the US Food and Drug Administration (FDA) for this indication. Table 2 lists medications approved for other indications that have been found in one or more clinical studies to generate a significant weight loss effect. Three drugs, diethylpropion, phendimetrazine, and benzphetamine, are approved by the FDA but classified as Schedule III drugs by the Drug Enforcement Administration because of their high potential for abuse. These drugs have little or no role in the routine management of obesity and are not considered further here.
| Medication | Typical Dosing | Classification | Common Adverse Effects |
|---|---|---|---|
| Phentermine , a | 15–37.5 mg/d | Adrenergic agent | Tachycardia, hypertension |
| Sibutramine , a,b | 10-15 mg/d | Serotonergic or adrenergic | Hypertension, tachycardia |
| Orlistat | 120 mg tid | Lipase inhibitor | Malabsorption, steatorrhea |
a Phentermine is approved by the FDA for 3 months’ use and sibutramine and orlistat are each approved for one year’s use. Use in clinical practice varies widely.
b Use of sibutramine in patients taking serotonin-selective reuptake inhibitors (SSRI) is relatively contraindicated because of the risk of serotonin syndrome.
| Medication | Typical Dosing a | Primary Indications | Common Adverse Effects |
|---|---|---|---|
| Bupropion , b | 150-300 mg/d | Depression | Anticholinergic, agitation |
| Metformin | 500-1000 mg/d | Type 2 diabetes | Hepatic oxidative injury |
| Exenatide | 5–10 mcg bid | Type 2 diabetes | Nausea |
| Topiramate | 50-100 mg/d | Seizure disorder Migraine headaches | Cognitive impairment, peripheral neuropathy |
| Zonisamide | 400-600 mg/d | Seizure disorder | Cognitive impairment |
a Typical dosing for use as a weight loss agent. Dosing for primary indication may be higher.
b Use of phentermine, sibutramine or bupropion in patients taking monoamine oxidase (MAO) inhibitors is strongly contraindicated because of the risk of severe cardiovascular events. Bupropion is contraindicated in patients with bipolar disease.
Phentermine
Phentermine is an adrenergic reuptake inhibitor that augments adrenergic signaling in the brain and peripheral tissues. It is therefore thought to promote weight loss by activation of the sympathetic nervous system with resulting decrease in food intake and increased resting energy expenditure.
Phentermine is the safe half of the phentermine-fenfluramine (phen-fen) combination therapy introduced in the 1990s. Unlike fenfluramine, phentermine has no known effects on cardiac valves. As a adrenergic agonist, however, it can be associated with tachycardia and, less commonly, hypertension. Thus, phentermine should be used with caution in people at significant risk for hemodynamic or cardiovascular complications of tachycardia and those with uncontrolled hypertension. It is good practice to monitor the pulse and blood pressure of patients closely during the first few weeks of phentermine therapy.
Because phentermine is no longer covered by patent protection and there are several proprietary and generic formulations available, it is the least expensive and most commonly prescribed medication for weight loss. It comes in two major forms, phentermine resin (Ionamin) and phentermine-HCl. Normal dosing is 15 to 30mg/d for phentermine resin and 18.75 to 37.5mg/d for phentermine-HCl. An acceptable therapeutic response is considered as 4 pounds per 4 weeks for at least the first 8 to 12 weeks of therapy, when given with or without associated dietary and exercise counseling.
Although approved by the FDA for only 3 months’ use, many experts advocate longer-term use in patients who demonstrate a good therapeutic response during the first 3 months. As with other weight loss medications, the weight loss generally stops within 3 to 6 months of initiation. For patients who have lost a significant amount of weight during this time, continuation of the drug is nonetheless valuable to prevent weight regain.
Phentermine
Phentermine is an adrenergic reuptake inhibitor that augments adrenergic signaling in the brain and peripheral tissues. It is therefore thought to promote weight loss by activation of the sympathetic nervous system with resulting decrease in food intake and increased resting energy expenditure.
Phentermine is the safe half of the phentermine-fenfluramine (phen-fen) combination therapy introduced in the 1990s. Unlike fenfluramine, phentermine has no known effects on cardiac valves. As a adrenergic agonist, however, it can be associated with tachycardia and, less commonly, hypertension. Thus, phentermine should be used with caution in people at significant risk for hemodynamic or cardiovascular complications of tachycardia and those with uncontrolled hypertension. It is good practice to monitor the pulse and blood pressure of patients closely during the first few weeks of phentermine therapy.
Because phentermine is no longer covered by patent protection and there are several proprietary and generic formulations available, it is the least expensive and most commonly prescribed medication for weight loss. It comes in two major forms, phentermine resin (Ionamin) and phentermine-HCl. Normal dosing is 15 to 30mg/d for phentermine resin and 18.75 to 37.5mg/d for phentermine-HCl. An acceptable therapeutic response is considered as 4 pounds per 4 weeks for at least the first 8 to 12 weeks of therapy, when given with or without associated dietary and exercise counseling.
Although approved by the FDA for only 3 months’ use, many experts advocate longer-term use in patients who demonstrate a good therapeutic response during the first 3 months. As with other weight loss medications, the weight loss generally stops within 3 to 6 months of initiation. For patients who have lost a significant amount of weight during this time, continuation of the drug is nonetheless valuable to prevent weight regain.
Sibutramine
Sibutramine, a monoamine reuptake inhibitor, enhances adrenergic, serotonergic and dopaminergic signaling in the brain. Thus, it has pharmacologic characteristics that are similar to, if weaker than, those of phen-fen. Unlike fenfluramine, which has been withdrawn because of the risk of carcinoid-like cardiac valvular disease, sibutramine’s serotonergic effects have not been associated with valvular abnormalities.
Sibutramine treatment is associated with an average weight loss of approximately 5% to 8%, as compared with 2% to 4% in participants receiving placebo. Most of the randomized, controlled trials include dietary or exercise counseling for participants in both the treatment and placebo groups, which likely accounts for the weight loss in the placebo group. Thus, sibutramine itself appears to be associated with an average weight loss of approximately 3% to 4% during the first 6 to12 months of treatment. Extension of therapy for up to 2 years is associated with an average regain of approximately half of the weight lost initially. However, in one large trial, of the participants who experienced greater than or equal to 5% weight loss on sibutramine, more than 25% maintained the full weight loss when sibutramine treatment was continued for an additional year. As with other therapies for obesity, there is a wide patient-to-patient variation in response. A small percentage of patients exhibits dramatic weight loss, and a significant number experience no weight loss benefit at all. To date, no clinically relevant predictors of outcome after sibutramine or other weight loss medications have been identified.
The normal dosing for sibutramine in adults is 10 to 15 mg/d taken once daily. Many physicians prefer to start with 10 mg/d and increase to 15 mg/d as clinically required. Doses higher than 15 mg/d have not been demonstrated to have increased efficacy, and they are associated with a greater risk of side effects. Patients who lose greater than or equal to 4 lb/mo for at least 3 months are considered clinical responders and are good candidates for continuation of this treatment. As with other pharmacologic therapies, weight loss generally stops after approximately 3 to 6 months. Nonetheless, for patients who have lost a significant amount of weight by this time, continuing treatment appears to decrease the rate and magnitude of weight regain. Sibutramine is currently approved by the FDA for up to 1 year of treatment. However, many specialists use it in clinical responders for as long as it appears effective in preventing weight regain.
In most patients, the major side effects of sibutramine relate to its adrenergic properties. Approximately 10% to 15% of patients experience hypertension that can be managed by antihypertensive therapy or discontinuing the sibutramine; fewer than 3% of patients need to discontinue this drug because of uncontrolled hypertension. Patients with preexisting hypertension undergoing sibutramine therapy need to be monitored closely for exacerbation of their hypertension and their antihypertensive regimen adjusted as required. A small number of patients exhibit tachycardia with sibutramine, and this drug should be avoided in patients who are at elevated risk for life-threatening tachyarrhythmias and those who are unlikely to tolerate tachycardia of any cause. Other, generally less severe and dangerous side effects include anticholinergic-like effects.
Use of sibutramine in patients taking serotonin-selective reuptake inhibitors (SSRIs) is relatively contraindicated because of an increased risk of serotonin syndrome, which is marked by some combination of flushing, diarrhea, and hypotension. As a result, sibutramine should only be prescribed to patients on SSRIs when both agents are strongly indicated and the patient is closely supervised by a physician well versed in the use of these agents alone and in combination.
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The Surgical Treatment of Metabolic Disease and Morbid Obesity
Short- and Long-Term Surgical Follow-Up of the Postbariatric Surgery Patient
Gastrointestinal Symptoms and Diseases Related to Obesity: An Overview
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