Orlistat (Xenical, Roche Laboratories) was approved by the Food and Drug Administration in 1999. It differs from the agents previously discussed as its mechanism of action does not exert effects in the central nervous system. Orlistat exerts its activity in the lumen of the stomach and small intestine by forming a covalent bond with the active serine residue site of gastric and pancreatic lipases. It is a reversible lipase inhibitor that decreases the absorption of dietary fats by approximately 30%. These unabsorbed triglycerides are eliminated, resulting in caloric deficit leading to weight loss.

The mechanism of action of orlistat allows it to be considered as a potential weight loss agent for patients on therapies contraindicated with sibutramine or other amphetamine-like anorexiants. Of particular concern are those patients for who are taking serotonergic agents. Orlistat offers the advantage of increasing weight loss without precipitating the serotonin syndrome as would sibutramine. Research is underway to determine if orlistat might be an alternative to sibutramine in obese patients on atypical antipsychotic agents.

The effect of orlistat on obese hypertensive patients was studied in a 1-year, prospective, randomized, double-blind, placebo-controlled multicenter trial. The study examined patients taking orlistat and adhering to a reduced calorie diet with no more than 30% of the calories from fat with patients on placebo with the same dietary restrictions. The researchers monitored the patients for weight loss, decline in body mass index (BMI), diastolic blood pressure, and plasma lipids. The orlistat group demonstrated a greater weight loss and decline in BMI than the placebo group. The treatment group also demonstrated a greater reduction in diastolic blood pressure with significant reductions in plasma cholesterol. The results demonstrated that orlistat causes weight loss and reduces cardiovascular risk.

As the site of action of orlistat is the gastrointestinal tract, there is little systemic absorption and exposure to orlistat. Plasma levels after a single dose were near the limits of detection (<5ng/mL). Metabolism of orlistat likely occurs within the gastrointestinal tract. Orlistat undergoes fecal and biliary excretion. About 97% of orlistat is excreted in the feces, with 83% as unchanged orlistat. Renal elimation of orlistat is less than 2%. The therapeutic dose of orlistat is 120mg three times daily.

Orlistat is contraindicated in patients with chronic malabsorption syndrome or cholestasis. Hypersensitivity to orlistat is also a contraindication to its use. Orlistat does exhibit a potential for misuse by patients with anorexia nervosa or bulimia. Precautions to be taken with administration of orlistat are related to its mechanism of action. Patients who do not adhere to a reduced fat diet may experience an increase in gastrointestinal adverse drug reactions if orlistat is taken with a high fat diet. Dietary fat should be distributed over three meals. If one meal is particularly high in fat, there may be gastrointestinal side effects. To ensure adequate nutrition, patients taking orlistat should be advised to take a multiple vitamin that includes fat-soluble vitamins once daily at a time when orlistat is not taken, such as bedtime. As some patients develop increased levels of urinary oxalate following treatment, orlistat should be employed with caution in patients with a history of hyperoxaluria or nephrolithiasis. Patients with diabetes mellitus may experience enhanced metabolic control which may warrant the reduction in dose of oral medications for diabetes mellitus (sulfonylureas, metformin, thiazolidinediones) and insulin.

Orlistat may cause up to one-third reduction in cyclosporine absorption. Changes in cyclosporine absorption occur with changes in dietary fat intake. Caution is to be employed in the concomitant use of cyclosporine and orlistat. As vitamin K is fat-soluble and its absorption may be decreased with concomitant orlistat use, patients on warfarin therapy and orlistat should be monitored for changes in coagulation monitoring parameters. As was previously mentioned, orlistat may potentially reduce the absorption of fat-soluble vitamins (vitamins A, D, E, and K) and beta-carotene. Co-administration of orlistat with pravastatin demonstrated an increase in pravastatin levels.

Adverse drug reactions associated with orlistat are primarily gastrointestinal due to its activity in the gastrointestinal tract and minimal systemic exposure. Gastrointestinal effects include abdominal pain, diarrhea, fecal urgency, oily spotting, flatus with discharge, fecal incontinence, increased defecation, nausea, vomiting, and rectal pain. Although other adverse drug reactions may occur with orlistat, intolerance of the gastrointestinal effects was the most common reason cited for discontinuation of therapy. Central nervous system adverse drug reactions are headache, dizziness, and anxiety. Respiratory effects are upper and lower respiratory tract infections, influenza and ear, nose and throat symptoms. Musculoskeletal effects of back pain, arthritis, myalgia, and joint disorder have been reported. Female reproductive effects were menstrual irregularity and vaginitis. Miscellaneous adverse drug reactions included urinary tract infection, fatigue, otitis, pedal edema, and sleep disorder.

Summary

In light of the behavior modification, caloric restriction, and medications that are employed to help reduce weight, an important aspect of managing overweight and obesity is prevention. Scientists have predicted an increase in obesity worldwide, along with an increase in the health risks associated with the condition. Of parti cular concern are industrializing nations, whose abilities to handle existing health problems in their own population is limited. An increase in obesity-related disabilities will weaken the currently overwhelmed health care systems. Programs aimed at prevention may be more effective against obesity than weight loss programs.

After review of the pharmacologic agents for weight loss, several key points are evident. First, appropriate use of prescription agents in overweight patients with risk factors or obese patients is as an adjunct to behavior modification and dietary changes. Second, adherence to diet and exercise programs as well as compliance to medication regimens is critical to the patient’s achievement of weight loss goals. Finally, health care professionals (pharmacists, physicians, and nurses), motivational support groups, and family members all play important supportive roles for the patient to achieve not only weight loss, but to improve overall health.

Sibutramine (Meridia, Knoll Pharmaceuticals), approved by the Food and Drug Administration in 1997, is a newer agent that differs in mechanism of action from the anorexiant agents. The mechanism of action of sibutramine involves inhibiting the reuptake of the neurotransmitters norepinephrine and serotonin to stimulate the satiety center in the brain. Sibutramine does, however, share the recommendations for use with the previously discussed anorexiants. Patients taking sibutramine should be those with body mass index (BMI)>30kg/m and concurrently adhering to a reduced calorie diet and exercise program. Patients with risk factors and a BMI>27kg/m, are also potential candidates for sibutramine therapy.

Wirth and Krause conducted a randomized, double-blind, parallel-group, placebo-controlled trial, to study long term weight loss with sibutramine from April 1997 to September 1998 in Germany. A total of 1,102 obese adults with BMI 30-40kg/m entered a four week period of open label 15mg sibutramine daily. The patients with weight loss of 2% or 2 kilograms (1,001 patients), were then moved into the 44 week randomized treatment period. The patients were divided into three groups: 1) 405 patients received continuous sibutramine therapy 15mg/day weeks 1-48; 2) 395 patients received intermittent sibutramine therapy at 15mg/ day weeks 1-12, 19-30, and 37-48 with placebo during all other weeks; or, 3) 201 patients on placebo for weeks 5-48. Mean weight loss in the continuous therapy group during the 44-week random period was 3.8 kg, compared 3.3 kg mean weight loss in the intermittent therapy group. The difference between the mean weight loss between the continuous and intermittent therapy groups was not found by the researchers to be statistically significant. The patients receiving placebo for weeks 5-48 demonstrated a mean weight gain of 0.2kg. The researchers also found that waist circumference and triglyceride levels were reduced, and high-density lipoprotein levels were elevated as a result of sibutramine therapy. The incidence of adverse effects to sibutramine was lower in the intermittent therapy group than in the continuous therapy group. The researchers concluded that continuous and intermittent therapy of sibutramine were equivalent with respect to therapeutic response.

Obesity is Undertreated in the U.S. Today

An article in the November 2002 issue of JAMA reported on the growing epidemic of obesity in the U.S., and reported a troubling trend. Despite the growing awareness in the medical community of the dangers of obesity over the course of the past decade, only 42% of obese adults who visited a primary care physician in 1996 were counseled about weight loss. (While this study relied exclusively on self-reported data from patients, several other studies have come to similar conclusions.) It has been shown that patients who are counseled on weight loss and urged to shed pounds by a physician are much more likely to attempt to do so than those who receive no such advice. One reason for the undertreatment of obesity could be that the most appropriate interventions in most cases – lifestyle modifications (i.e., diet and exercise) and in some cases pharmacotherapy – generally result in a mere 5%-10% weight loss maintained over a maximum period of one to two years. Additionally, 95% of patients who undergo weight reduction regain lost weight within seven years. Nevertheless, it is still extremely important for obese patients to be given the information they need to understand the serious medical risks of overweight and obesity, as well as the methods available to treat it. Even minor weight losses of 5%-10% can improve glycemic control, blood pressure, and lipid profiles.

Following oral administration, sibutramine is rapidly absorbed from the gastrointestinal tract, with peak plasma concentration occurring within 3-4 hours. Bioavailability is about 77% of a single dose of the agent. Plasma protein binding of sibutramine is 94%-97%. Sibutramine undergoes hepatic metabolism by the cytochrome P-450 (3A₄) isoenzyme. Elimination of sibutramine is 85% combined urinary and fecal elimination, with the majority of elimination being renal (77%). Contraindications to sibutramine are numerous. Obviously, concurrent use of other centrally acting appetite suppressants is to be avoided. Use of sibutramine is to be avoided in the following cardiovascular conditions: moderate to severe hypertension, history of coronary artery disease, congestive heart failure (CHF), arrhythmias or stroke. Other contraindications include anorexia nervosa, co-administration or within 14 days of MAO inhibitor use, severe hepatic dysfunction, glaucoma (particularly narrow angle glaucoma), and history of drug abuse. As a component of sibutramine mechanism of action is the inhibition of serotonin reuptake, concomitant administration of selective serotonin reuptake inhibitors (fluoxetine, paroxetine, sertraline, nefazodone, citalopram) should be avoided due to the risk of development of serotonin syndrome (increased blood pressure, flushing, tachycardia).

Precautions of sibutramine use are renal or hepatic impairment, concomitant cardiovascular disease, history of seizures, gallstones, and glaucoma. Sibutramine is a pregnancy category C drug.

Adverse drug reactions of sibutramine that affect the cardiovascular system are tachycardia, vasodilation, hypertension, and palpitations. The central nervous system side effects include headache, nervousness, anxiety, depression, emotional lability, insomnia, agitation. Gastrointestinal system effects are dry mouth, anorexia, constipation, dyspepsia, diarrhea, and flatulence. Dysmenorrhea, urinary tract infection, vaginitis, and menorrhagia are side effects of the genitourinary system. Respiratory system effects. Dermatologic effects of rash, sweating, acne and pruritus may occur. Miscellaneous effects are back, neck or chest pain, allergic reactions, edema, arthralgia, fever, and leg cramps.

Table 3. Agents Associated with Serotonin Syndrome
Drug Category	Agents
MAO Inhibitors	Tranylcypromine Phenelzine Isocarboxazid
Serotonin Receptor Agonists	Sumatriptan Naratriptan Rizatriptan Zolmitriptan
Selective Serotonin Reuptake Inhibitors	Fluoxetine Paroxetine Fluvoxamine Sertraline Citalopram
Tricyclic Antidepressants	Amitriptyline Nortriptyline Imipramine Doxepin Trimipramine Amoxapine Desipramine Protriptyline Clomipramine
Miscellaneous	Meperidine Bupropion

Drug interactions associated with sibutramine involve primarily agents that affect the neurotransmitter serotonin. Concurrent use with monoamine oxidase inhibitors may precipitate hypertensive crisis. The serotonin syndrome may be precipitated through concomitant use of sibutramine with serotonin receptor agonists, selective serotonin reuptake inhibitors, tricyclic antidepressants, bupropion, and meperidine. (For a summary of these agents see Table 3). Additive anorectic effects occur when sibutramine is combined with other centrally acting appetite suppressants. Augmentation of the cardiovascular adverse drug reactions associated with sibutramine (tachycardia, increased blood pressure) may occur with concurrent administration of systemic sympathomimetic agents (pseudoephedrine, ephedra). Dosing of sibutramine should be initiated at 10 mg daily. After four weeks of therapy and inadequate weight loss, the dose may be increased to 15 mg daily. For patients who have difficulty tolerating a 10 mg daily dose of sibutramine, a dosage regimen of 5 mg daily may be considered. Monitoring of cardiovascular status should play a pivotal role in decisions regarding dosage adjustment.