Obesity

OB/GYN News, Sept 1, 2004 by Mitchel L. Zoler, Sharon Worcester

Withdrawal of the popular obesity drugs fenfluramine and dexfenfluramine (Redux) from the U.S. market in 1997 left Americans hungry for new obesity drugs with long-term efficacy. They're still waiting, as their waistlines continue to grow.

In other words, there's no weight-loss drug now available that's close to ideal. Obesity plus overweight remains the most common nutritional disorder in the United States, with a prevalence that has ballooned by 75% since 1980. Available pharmacologic agents are rarely effective for weight loss or for improving obesity-related conditions unless they're used as part of a comprehensive approach that also includes dietary and lifestyle changes and behavioral therapy. Patients often regain weight after stopping treatment. But despite these shortcomings, some type of drug therapy is recommended for patients with a body mass index of 27 kg/[m.sup.2] or higher and obesity-related morbidity, and for everyone with a BMI of 30 kg/[m.sup.2] or higher.

Orlistat and sibutramine are the newest obesity drugs and are the only ones approved for long-term use. Both have been studied for at least 2 years. Along with behavioral interventions, these drugs are generally modestly effective for weight loss and maintenance, compared with placebo.

Behavioral interventions--which can be as simple as support group participation or consulting a registered dietitian--enhance the effects of treatment. In one study with 57 patients, loss of at least 15% of body weight was the benchmark for success. This goal was reached by 15% of patients treated with a drug only, 25% of those treated with a drug plus participation in a lifestyle intervention group, and 60% of patients who got the drug and participated in both lifestyle and behavioral intervention groups.

With the exception of orlistat, which is not absorbed into the systemic circulation, obesity drugs should be avoided by women who are pregnant or breast-feeding. A number of experts also don't prescribe orlistat during pregnancy.

Several other drugs are in development. Cannabinoid receptor blockers, now in phase III trials, may become the first approved appetite-reducing drugs that are not stimulants. Topiramate and other antiepileptics are being studied for obesity and may be particularly good for patients with bingeing disorders.

Drug             AWC/day*              Dosage

LIPASE INHIBITOR
orlistat         no generic available  120 mg b.i.d.
 [Xenical]       [$2.76]

MIXED NORADRENERGIC-SEROTONERGIC AGENT
sibutramine      no generic available  5-15 mg/day
 [Meridia]       [$4.16 (15 mg/day)]

NORADRENERGIC AGENTS
All agents in class are appetite suppressants. The four drugs listed
here are on the DEA's schedule of controlled substances, so all are
considered to have some potential for abuse. Few have been studied for
longer than 6 months; all are approved for short-term use only (assumed
to be less than 12 weeks). All are contraindicated in patients with
moderate to severe hypertension, cardiovascular disease, or a history
of drug abuse.
phentermine      $1.02 (37.5 mg/day)   18.5-37.5
 [Adipex-P]      [$1.67]               mg/day
 [Atti-Plex P]   [$0.65]
 [Pro-Fast SR]   [$0.89]
benzphetamine    no generic available  25-50 mg/day
 [Didrex]        [$1.07 (50 mg/day)]
phendimetrazine  $0.36 (35 mg b.i.d.)  17.5-70 mg
 [Bontril]       [$0.80]               b.i.d or t.i.d.
 [Obezine]       [$0.10]
 [Phendiet]      [$0.08]
diethylpropion   $0.72                 25 mg t.i.d.
 [Tenuate]       [$1.62]

Drug             What the Experts Say**

LIPASE INHIBITOR
orlistat         Available in trade formulation only. The single Food
 [Xenical]       and Drug Administration-approved obesity drug that
                 works by blocking nutrient absorption. Inhibits
                 pancreatic lipases, blocking absorption of about
                 one-third of fat consumed. Approved for long-term use
                 for weight loss and maintenance. Modestly effective; no
                 abuse potential. Recently approved for use in
                 adolescents. Taken during a fat-containing meal or
                 within 1 hour after meal is over. Labeled dosage is 120
                 mg t.i.d., but most use it b.i.d. with lunch and dinner
                 and eat a low-fat breakfast. Mild to moderate
                 gastrointestinal upset can occur if too much fat is
                 consumed. GI effects can be ameliorated with a nightly
                 dose of psyllium fiber, which binds to the oils that
                 are not absorbed. A daily multivitamin can help
                 counteract decreased absorption of fat-soluble
                 vitamins.

MIXED NORADRENERGIC-SEROTONERGIC AGENT
sibutramine      Available in trade formulation only. Inhibits
 [Meridia]       norepinephrine, serotonin, and dopamine reuptake. A
                 Drug Enforcement Administration (DEA) schedule IV
                 substance, which means abuse potential is similar to
                 phentermine's. Best taken in the morning. Usually
                 started at 10 mg/day; titrated to 15 mg/day after 4
                 weeks if necessary; 5 mg/day an option for those who
                 don't tolerate a higher dosage. Maintenance of weight
                 loss was shown optimal with 15-mg/day dosage. Approved
                 for long-term use. Modestly effective. Good for those
                 who often feel hungry and report frequent cravings;
                 tends to make patients feel full sooner and reduces
                 cravings. Often prescribed for younger, healthier
                 patients. Increases in pulse and blood pressure lead to
                 discontinuation in about 5%; regular blood pressure
                 monitoring necessary.

NORADRENERGIC AGENTS
All agents in class are appetite suppressants. The four drugs listed
here are on the DEA's schedule of controlled substances, so all are
considered to have some potential for abuse. Few have been studied for
longer than 6 months; all are approved for short-term use only (assumed
to be less than 12 weeks). All are contraindicated in patients with
moderate to severe hypertension, cardiovascular disease, or a history
of drug abuse.
phentermine      Available in generic and trade formulations. By far the
 [Adipex-P]      most commonly prescribed drug for weight loss. The
 [Atti-Plex P]   "phen" half of the "fen-phen" combination that became
 [Pro-Fast SR]   unavailable when fenfluramine was pulled by the FDA in
                 1997. Phentermine remains available; never implicated
                 in causing valvular heart disease. Long-term studies
                 lacking. DEA schedule IV drug, which means it has less
                 abuse potential than some other drugs in class listed
                 here. Experts consider it a second-line drug. Sometimes
                 used long term, but this needs patient's informed
                 consent. Also available in sustained-release
                 formulation.
benzphetamine    Available in trade formulation only. DEA schedule III
 [Didrex]        drug; abuse potential rated higher than phentermine's.
                 Approved for short-term use for obesity. Used once
                 daily or divided as b.i.d. or t.i.d. Dosage can be
                 increased to maximum of 50 mg t.i.d. Rarely used,
                 because of abuse potential and risk of cardiovascular
                 effects.
phendimetrazine  Available in generic and trade formulations. DEA
 [Bontril]       schedule III drug; abuse potential rated higher than
 [Obezine]       phentermine's. Also available in sustained-release
 [Phendiet]      formulation. Approved for short-term use for obesity.
                 Rarely used, because of potential for abuse and risk of
                 cardiovascular effects. Additional brand-name
                 formulations are Melfiat and Prelu-2, but these are not
                 available for indicated dosage.
diethylpropion   Available in generic and trade formulations. DEA
 [Tenuate]       schedule IV drug; abuse potential similar to
                 phentermine's. Rarely used. Like the other
                 noradrenergics, approved for short-term use only, but
                 occasionally used for long-term treatment. Taken 1 hour
                 before meals. Also available in an extended-release
                 formulation.

* Average wholesale cost/day is based on the average wholesale price for
a 100-unit container, or closest size, in the 2003 Red Book.
**Comments reflect the opinions and expertise of the following sources:
* Dr. Louis J. Aronne, clinical professor of medicine and director of
the Comprehensive Weight Control Program at Weill Medical College of
Cornell University, New York; president-elect of the North American
Association for the Study of Obesity.
* Gerald G. Briggs, B. Pharm., pharmacist clinical specialist, Women's
Hospital, Long Beach (Calif.) Memorial Medical Center. Source on drug
safety in pregnant and nursing women.
* Dr. Jack A. Yanovski, head, unit on growth and obesity, developmental
endocrinology branch, National Institute of Child Health and Human
Development, Bethesda, Md.
* Dr. Susan Z. Yanovski, codirector, Office of Obesity Research,
National Institute of Diabetes and Digestive and Kidney Diseases,
Bethesda, Md.