Weight Loss Drugs: What Works?

Laura A. Stokowski, RN, MS

December 13, 2010

Currently on the Market

Two classes of weight-loss agents are currently available by prescription: noradrenergic agents for short-term weight loss and a lipase inhibitor for long-term weight loss.

Phentermine

Phentermine is US Food and Drug Administration (FDA)-approved for short-term (up to 12 weeks) treatment of obesity and is the most widely prescribed weight-loss drug in the United States.^[4] Phentermine is an adrenergic reuptake inhibitor,^[5] stimulating the sympathetic nervous system to release norepinephrine, one of the neurotransmitters involved in modulating food intake. Phentermine suppresses appetite and induces satiety much like amphetamines, but has little effect on dopamine transmission, mitigating its abuse potential.^[1] Because its effects last about 12 hours, phentermine should be taken in the morning. When used in combination with diet and exercise, phentermine has produced an average 3.6 kg greater weight loss than placebo.^[6]

Phentermine is the relatively "safe half" of the formerly popular (but no longer on the market) weight-loss drug phentermine-fenfluramine (phen-fen). Fenfluramine (but not phentermine) was linked to pulmonary hypertension and valvular heart disease. Phentermine alone was found to be an effective anorectic, and it is still available as a prescription drug in 15 mg to 37.5 mg strengths^[7] (although many manufacturers discontinued it).

Adverse effects include irritability, nervousness, restlessness, dry mouth, insomnia, constipation, and headache, but it has also been associated with hypertension, tachycardia, and palpitations, so it should not be taken by patients with cardiovascular disease or significant hypertension. Blood pressure should be monitored during therapy.

Diethylpropion

Like phentermine, diethylpropion is a noradrenergic agent with a similar mechanism of action (releasing and inhibiting the uptake of neurotransmitters norepinephrine and dopamine). Diethylpropion is available in 25-mg standard or 75-mg extended-release formulations, and is approved for short-term treatment of obesity.

In a recent study, 69 obese healthy adults were treated with diet and diethylpropion or diet and placebo.^[8] After 6 months, the diethylpropion group lost an average of 9.8% of initial body weight vs 3.2% in the placebo group (P < .0001). In 1 year, the mean weight loss in patients taking diethylpropion was 10.6%. Dry mouth and insomnia were the most frequent adverse events.^[8]

Benzphetamine and Phendimetrazine

Two other sympathomimetic drugs benzphetamine and phendimetrazine are still available by prescription for short-term weight loss. These drugs also act centrally, releasing dopamine and norepinephrine, resulting in appetite suppression, increased blood pressure, and increased heart rate. As schedule III drugs, however, benzphetamine and phendimetrazine have more potential for addiction and therefore are prescribed less often.^[9]

All sympathomimetic drugs stimulate the central nervous system, and can increase blood pressure and heart rate, while releasing glycerol and free fatty acids.^[9]Still, in a recent survey of obesity specialists in the United States, these were among the most frequently prescribed drugs in the clinical treatment of obesity. Most respondents (97%) reported prescribing phentermine, 64% prescribed diethylpropion, and 60% prescribed phendimetrazine.^[4]

Orlistat

A gastrointestinal and pancreatic lipase inhibitor, orlistat was approved in 1999 as the first in a new class of anti-obesity agents. In the gastrointestinal tract, orlistat binds to gastric and pancreatic lipases, preventing these enzymes from hydrolyzing dietary fat into absorbable free fatty acids.^[1] When not absorbed, triglycerides are excreted in the feces, along with cholesterol and fat-soluble vitamins. Taken with meals, orlistat can block the absorption of 30% of ingested fat.^[5] In this manner, orlistat reduces caloric intake and may have additional benefits.

A Cochrane meta-analysis^[10]of 11 randomized controlled trials of orlistat found that overweight and obese individuals who took orlistat had a mean weight loss of 2.9 kg (2.9%) more than those who took placebo. Compared with placebo, orlistat also significantly reduced waist circumference, body mass index (BMI), blood pressure, fasting glucose, and hemoglobin A1c concentrations in patients with diabetes, as well as total cholesterol, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) concentrations.^[2]

Adverse effects of orlistat are fairly common, affecting 15%-30% of patients and considered unpleasant and unacceptable by some patients.^[2] These include steatorrhea, bloating, fecal urgency, fecal incontinence, and oily stools.^[5] Orlistat might also interfere with the absorption of fat-soluble vitamins, including vitamins A, D, E, and K, so it has been suggested that patients taking orlistat should also take a multivitamin supplement containing these micronutrients, at least 2 hours before or after the administration of orlistat.

Concerns about a link between orlistat and colon cancer, as well as possible liver damage, are currently being investigated.^[11] Orlistat may also interfere with the absorption, and therefore the effectiveness, of other drugs the patient is taking, such as amiodarone and cyclosporine, and through its effect on vitamin K, it can prolong bleeding in patients taking warfarin.^[11] This class of drug should probably be avoided in patients with gastrointestinal disease or malabsorption syndromes.^[2]

Orlistat is currently available as a prescription drug (Xenical^® 120 mg) or an over-the-counter weight loss supplement (Alli^® 60 mg). Although it is approved for long-term weight loss, orlistat's somewhat low tolerability and high cost may limit its long-term use.

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Cite this: Laura A. Stokowski. Weight Loss Drugs: What Works? - Medscape - Dec 13, 2010.

The Weight-Loss Imperative

The classifications of "overweight" and "obese" are defined by BMI, calculated from a patient's weight and height. A person with a BMI ≥ 25 kg/m² is considered "overweight" and someone with a BMI ≥ 30 k/m²is considered^, "obese." Using these definitions, 68% of the adults in the United States are overweight, and 34% are obese.^[36]

The days when obesity was considered primarily a cosmetic problem are long gone. We now know that obesity is a complex disease that develops from a combination of genetic and environmental factors, and that the health implications of obesity are vast (see Table). In addition to elevated rates of type 2 diabetes, cardiovascular disease, and cancer, obesity can make surgical management more difficult and result in more postoperative complications.^[37,38]

Evidence of a survival benefit for obesity in select clinical situations is not enough to compensate for the overwhelming health risks, including death, associated with excessive body weight.^[4]

Table. Diseases Associated With Obesity^[39]

Organ System	Conditions
Cardiovascular	Hypertension, peripheral vascular disease, myocardial infarction, cerebral vascular accidents, peripheral venous insufficiency, thrombophlebitis, pulmonary embolism
Respiratory	Asthma, obstructive sleep apnea, obesity-hypoventilation syndrome
Metabolic	Type 2 diabetes mellitus, impaired glucose tolerance, hyperlipidemia
Musculoskeletal	Back strain/disc disease, osteoarthritis
Gastrointestinal	Cholelithiasis, gastrointestinal reflux disease, nonalcoholic fatty liver disease, hepatic cirrhosis, hepatic carcinoma, colorectal carcinoma
Urologic	Stress incontinence
Endocrine/Reproductive	Polycystic ovary syndrome, pregnancy/fetal abnormalities, male hypogonadism, endometrial, breast, ovary, prostate cancer, pancreatic cancer
Dermatologic	Intertriginous dermatitis
Neurologic	Pseudotumor cerebri, carpal tunnel syndrome
Psychologic	Depression, eating disorders, body image disturbance

Clinical Interventions for Obesity

The chief clinical intervention for obesity is lifestyle change, which usually involves counseling and behavioral therapy for reducing caloric intake and increasing physical activity. For patients who fail to lose weight with lifestyle intervention, pharmacotherapy and surgical approaches may be indicated.

The benefits of weight reduction, even on a fairly modest scale (5%-10% of body weight) are well documented. Among other benefits, weight loss is associated with a lower incidence of diabetes, hypertension, and dyslipidemia,^[40]improved urinary incontinence,^[41]and reduced inflammation in osteoarthritis.^[42]Patients with diabetes who lose even small amounts of weight have better metabolic control, fewer cardiovascular risk factors, and lower mortality rates.^[43,44] Continually losing and regaining weight (weight cycling), however, might be worse than maintaining a stable excessive weight. The evidence on weight cycling and threats to health is inconsistent, but raises the question of its safety.^[45]

Unfortunately, the degree of weight loss that is usually achieved with lifestyle intervention alone is insufficient. Efforts to lose weight are often thwarted by a compensatory slowing of the metabolism and high rates of recidivism.^[2]

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