Effectiveness of Pharmacotherapy

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Multiple randomized controlled trials (RCT) of sibutramine and orlistat used as adjuncts to a therapeutic lifestyle change (TLC) have shown them to increase the amount of weight loss or to be effective for long-term weight maintenance treatment. The most recent summary of the RCT studies regarding this effectiveness was published by the US Preventive Services Task Force (USPSTF) called "Summary of the Evidence: Screening and Interventions for Obesity in Adults" [2]. This report was published in late 2003. As part of the report there is a summary of the RCTs on obesity pharmacotherapy published in 2001 by Arterburn and Noel [3]. Therefore, before looking at the 2003 report, here is a brief review of the 2001 data.

The Arterburn and Noel report classifies medications used to treat obesity into three categories: a trade-off between benefits and harms, unknown effectiveness, or likely to be ineffective or harmful. Medications in the category of tradeoff between benefits and harms include sibutramine, phentermine, mazindol, and orlistat. Medications in the unknown effectiveness category are dietlyproprion and fluoxetine. The likely to be ineffective or harmful group of medications includes dexfenfluramine, fenfluramine, fenfluramine plus phentermine, and phenylpropanolamine [3]. It is strongly suggested physicians not prescribe medications in the second or third category for weight loss until there is clinical evidence that supports the benefit of using medications in either of these two groups. This chapter will focus on medications in the first category to help the physician make the best clinical decision between benefits and harms when prescribing medication for weight loss.

Before discussing the effectiveness of each medication listed in Arterburn and Noel's first category, it is helpful to understand the pharmacokinetics of sibutramine, orlistat, and phentermine. First, sibutramine and its active metabolites, M1 and M2, act in the brain as a reuptake inhibitor of norepinephrine, serotonin, and dopamine. Sibutramine does not actively release monoamines [4], rather it inhibits the monoamine's degradation which causes central nervous system (CNS) suppression of appetite. In addition to the anorectic effect of sibutramine, it may also create a thermogenic effect of consuming calories by activating the beta3-system in brown adipose tissue [5].

The benefit of using sibutramine has been studied for up to 2 years. The 2003 USPSTF summary of the Arterburn and Noel report states that sibutramine is more effective than placebo in promoting modest weight loss (range 6.2 to 9.2 lb in seven RCTs over 5 to 24 months) in healthy adults with controlled hypertension. Once the medication was stopped, weight regain occurred [2]. This might suggest that to maintain weight loss attributed to the use of the medication the patient must remain on the medication indefinitely. From management of a chronic disease perspective, daily use of a medication in order to help control the disease is acceptable. How many patients with diabetes, hypertension, or hyperlipidemia start medication and then at some point in time are able to stop taking the medication completely? It may occur in rare situations where the patient makes a dramatic change in lifestyle, but for most patients with a chronic disease, once on a medication, always on a medication. This may be true for long-term obesity treatment as well.

Orlistat is a gastric and pancreatic lipase inhibitor. The blockage of the lipase enzymes leads to the inhibition of digesting triglycerides and cholesterol. This results in preventing the absorption of about 30% of a patient's dietary fat [5]. For example, a patient who consumes 2000 calories per day, of which 30% or a total of 600 calories is from fat, will reduce caloric intake by 200 calories per day by taking the medication. Over time this gradual but cumulative reduction in calories results in weight loss.

The USPSTF report summarizing Arterburn and Noel's review of the orlistat studies states there was a modest weight loss compared to placebo while using the medication (average of 7.7-lb loss in 10 RCTs). However, the actual report summarizes results from the 10 studies in one sentence. It is difficult to understand the effectiveness of the medication compared to the control. For instance, meta-analysis of 5 of the 10 RCTs compared a group using orlistat combined with a low-calorie diet (LCD), which at one year showed a weight loss of 13.4 lb, to the placebo plus LCD group, which averaged a loss of 5.7lb [3].

Phentermine resembles amphetamine with a noradrenergic effect that decreases appetite [5]. It does not impact dopamine levels, is a Drug Enforcement Agency (DEA) schedule IV medication, and has little addictive potential. For years physicians have prescribed phentermine with minimal serious adverse reactions reported [3]. Like phentermine, mazindol is a sympathomimetic amine that stimulates the CNS to decrease appetite. Arterburn and Noel's analysis found only one case report of pulmonary hypertension diagnosed one year after stopping the medication [3]. Mazindol is a DEA schedule IV medication.

Arterburn and Noel found only one RCT study for phentermine and one for mazindol. In each study, the use of medication appeared to be more effective than placebo. The phentermine study involved only 108 patients. Both the intervention and placebo groups were placed on an LCD of 1000 calories per day. After 9 months, the phentermine group lost 27.5 lb whereas the placebo group lost 10.5 lb, with an average difference between the two groups of 16 lb. In the mazindol study, a total of 65 people who were more than 15% overweight were followed for 3 months. The intervention group lost an average of 8.4lb more than the placebo group. When treatment ended, weight regain occurred [3].

Though both phentermine and mazindol have been prescribed for years, both medications have serious scientific limitations when considered for treating a chronic disease. Neither has any other RCT studies to justify its use other than the one just discussed. Neither medication is FDA-approved for long-term treatment, nor has long-term safety been determined. Anecdotal results coupled with the absence of published serious side effects do not justify the cost and potential risk to the patient. More RCT studies are needed to determine effectiveness and safety before a physician can confidently prescribe either medication for long-term weight control.

The 2003 USPSTF found 13 RCTs that met their criteria from studies published since 1996 and not reviewed by Arterburn and Noel. Six studies evaluated sibutramine, six reviewed orlistat, and one covered metformin. The analysis considered the duration of the study, the difference in weight loss compared to placebo, and percentage of patients who lost 5% and 10% of their weight, which can have a meaningful impact on the presence of other chronic diseases, as shown by the Diabetes Prevention Program [6].

Of the six sibutramine studies for weight loss, five spanned 6 to 12 months. Patients treated with sibutramine experienced a range of 6.2lb to 10.5 lb more weight loss than patients in the placebo group. Four studies compared what percentage of the sibutramine-treated group lost 5% or 10% of body weight compared to the placebo group. The sibutramine-treated group lost 5% of their weight in 19% to 57% more patients compared to the placebo group, and 5% to 27% of the sibutramine-treated patients lost 10% of their weight compared to placebo. Results depended on dosage of the medication [2].

James et al. published a weight maintenance study called the sibutramine trial of obesity reduction and maintenance (STORM). A total of 605 obese participants received sibutramine 10 mg per day along with an LCD for 6 months during the weight loss phase of the study. Patients with greater than 5% weight loss were randomized to continue receiving sibutramine 10 mg per day compared to the placebo group for 18 months. At the end of the study, 43% of the intervention group maintained at least 80% of their weight loss compared to 16% in the control group [7].

Of the six orlistat studies reviewed by the USPSTF, five covered 6 to 12 months' duration. Orlistat recipients lost an average of 6.1 lb to 9.9lb more than the placebo group. The frequency of response was recorded in only two trials. A 10% weight loss occurred in up to 38% of the orlistat-treated patients, and in 9% to 19% more orlistat-treated patients than the control group [2].

Two RCTs focused on use of orlistat for weight loss maintenance. The study by Hill et al. enrolled patients who lost 8% or more over 6 months on a conventional weight loss program without pharmacotherapy. Participants were randomly assigned to receive a placebo, orlistat 30mg, 60 mg, or 120 mg three times per day for one year. At the end of the study, 47.5% of the group taking orlistat 120mg regained less than one-quarter of the lost weight compared to 29.9% of the placebo group [8].

In a 2-year weight maintenance study from Finland, which started with 96 obese patients and finishing with 72 participants, patients received orlistat for 2 years, placebo for 2 years, or 1 year of orlistat followed by 1 year of placebo. Patients treated with orlistat for both years sustained greater weight loss than those who had placebo both years or orlistat the first year and placebo the second [9].

In another weight maintenance study with 796 obese patients involving 17 primary care centers in the United States, 1-year weight loss was greater with orlistat 60mg three times per day (15.4lb) and orlistat 120mg three times per day (17.5 lb) compared to placebo (9.1 lb). The positive effect of orlistat compared to placebo was sustained through the 24 months of the study. At the end of the 2 years, 34% of the orlistat group maintained a 5% or greater weight loss compared to 24% of the placebo group [10].

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