Low-Dose Orlistat Effects on Body Weight of Mildly to Moderately Overweight Individuals:  A 16 Week, Double-Blind, Placebo-Controlled Trial

Background:  Currently there are no studies evaluating low dose orlistat in mildly or moderately overweight patients.  As the number of mildly to moderately overweight patients increases, low dose orlistat may be an option to aid in weight loss when lifestyle modifications are ineffective. 

 

Objective:  The purpose of this study was to determine if orlistat 60 mg 3 times daily is safe and effective for weight loss in overweight individuals (BMI 25-28 kg/m²). 

 

Methods:  This was a randomized, double-blind, placebo-controlled, parallel group study.  It was conducted for a 16 week treatment period at 20 primary care centers in the US.  Three hundred ninety-one patients were randomized to receive placebo (195 patients) or orlistat 60 mg (196 patients) 3 times daily with meals.  The inclusion criteria consisted of men or women greater than or equal to 18 years of age, with BMI at least 25 and less than 28 kg/m², and willing to lose 10% of body weight.  Exclusion criteria included pregnant or lactating women, weight loss of at least 3 kg in the previous 3 months, significant cardiovascular disease, gastrointestinal surgery for obesity, use of pharmacologic agents affecting body weight in the previous 6 months, and use of any drugs that might interact with Orlistat.  Patients were instructed to maintain a nutritionally balanced, energy-restricted diet.  After the baseline assessment, subjects returned at 2, 4, 8, 12, and 16 weeks.  The primary objectives were changes in body weight, safety, and tolerability.  The secondary objectives were effects on risk factors for cardiovascular disease.  An intent-to-treat (ITT) and per protocol analysis were utilized.  Efficacy variables were analyzed as absolute change and relative change from baseline.  An 80% power was calculated for the difference in weight change. 

 

Results:  Two hundred ninety-two patients completed the study with 140 (72%) in the placebo group and 152 (78%) in the orlistat group.  Results for weight loss were all statistically significant.  In the intention to treat analysis, weight loss was 1.90 kg in the placebo group and 3.05 in the orlistat group (mean difference 1.15 kg; 95% CI 0.54 to 1.76; p < 0.001).  For participants that completed the 16 week treatment, weight reductions were 2.22 kg for placebo and 3.55 kg for orlistat (mean difference 1.33 kg; 95% CI 0.61 to 2.05; p < 0.001).  In the per protocol analysis, patients receiving orlistat, compared to those receiving placebo, had greater reductions from baseline in fasting serum cholesterol (-4.4% vs. 0.0%; p = 0.004), LDL cholesterol levels (-7.2% vs. –0.6%; p = 0.005), and systolic and diastolic blood pressure (-4.7% vs. –1.8%; p = 0.004 and –7.2% vs. –0.6%; p = 0.001, respectively).  There were no significant changes in HDL cholesterol, triglycerides, or fasting plasma glucose levels.  Gastrointestinal adverse events were significantly more common in the orlistat-treated patients.  The authors concluded that 60 mg orlistat 3 times daily in mildly to moderately overweight individuals produced significant weight loss in addition to reductions in total cholesterol, LDL cholesterol, and systolic and diastolic blood pressure compared to placebo. 

 

Strengths:  The study design was optimal since a placebo-controlled, double-blind, and randomized design is best in determining the true efficacy of a drug.  The use of both intent-to-treat and per protocol analysis provided insight to the effects of patient dropout on the treatment results. 

 

Weaknesses:  Unblinding was not assessed or reported even though it was likely to occur when patients in the orlistat group experienced GI side effects.  A treatment duration of 16 weeks was insufficient to determine the long-term effects of orlistat on weight loss, and a large dropout rate occurred.  Patient were instructed to take regularly scheduled doses even if meals were missed, which is not consistent with the approved dosing of orlistat that recommends a dose be taken only with fat containing meals.  Based upon the objective of the study, the authors should have collected and reported the results from the food diaries that they disseminated to the patients.  It is unknown whether diet and exercise were similar between the groups, which were important to consider in a study that examined weight loss and risk factors for cardiovascular disease.  In addition, all baseline characteristics were not given.  Potential conflicts of interest existed, and bias appeared to influence the study by the presentation of results in a manner that underestimated the actual occurrence of GI side effects and overestimated the clinical importance of the results.  Standard error instead of standard deviation was utilized for most results. 

 

Conclusion:  Based on the study’s results and limitations, orlistat 60 mg 3 times daily does not produce clinically significant reductions in weight loss or cardiovascular risk factors.  Further evidence remains to be established in supporting over-the-counter use of orlistat that will consider a longer treatment duration and diet and exercise as modifying factors.  This product should not be recommended to patients without evidence that the benefits in weight loss outweigh the prominent GI side effects.  Lifestyle modifications in diet and exercise still appear to be the best treatment and prevention of weight gain in the population. 

 

Anderson JW, Schwartz SM, Hauptman J, et al.  Low-dose orlistat effects on body weight of mildly to moderately overweight individuals:  a 16 week, double-blind, placebo-controlled trial.  Ann Pharmacother 2006;40:1717-23.

 

Lucy A. Dalzot, Pharm.D. Candidate