Xenical Clinical Studies

The effects of Xenical on weight loss, weight maintenance, and weight regain and on a number of comorbidities (eg, type 2 diabetes, lipids, blood pressure) were assessed in seven long-term (1- to 2-years duration) multicenter, double-blind, placebo-controlled clinical trials. During the first year of therapy, weight loss and weight maintenance were assessed. During the second year of therapy, some studies assessed continued weight loss and weight maintenance and others assessed the effect of orlistat on weight regain. These studies included over 2800 patients treated with Xenical and 1400 patients treated with placebo. The majority of these patients had obesity-related risk factors and comorbidities. In these 7 studies, treatment with Xenical and placebo designates treatment with Xenical plus diet and placebo plus diet, respectively.

During the weight loss and weight maintenance period, a well-balanced, reduced-calorie diet that was intended to result in an approximate 20% decrease in caloric intake and provide 30% of calories from fat was recommended to all patients. In addition, all patients were offered nutritional counseling.

One-year Results: Weight Loss, Weight Maintenance, and Risk Factors:   Weight loss was observed within 2 weeks of initiation of therapy and continued for 6 to 12 months.

Pooled data from five clinical trials indicated that the overall mean weight loss from randomization to the end of 6 months and 1 year of treatment in the intent-to-treat population were 12.4 lbs and 13.4 lbs in the patients treated with Xenical and 6.2 lbs and 5.8 lbs in the placebo-treated patients, respectively. During the 4-week placebo lead-in period of the studies, an additional 5 to 6 lb weight loss was also observed in the same patients. Of the patients who completed 1 year of treatment, 57% of the patients treated with Xenical (120 mg three times a day) and 31% of the placebo-treated patients lost at least 5% of their baseline body weight.

The percentages of patients achieving >/=5% and >/=10% weight loss after 1 year in five large multicenter studies for the intent-to-treat populations are presented in Table 1.

The relative changes in risk factors associated with obesity following 1 year of therapy with Xenical and placebo are presented for the population as a whole and for the population with abnormal values at randomization.

Population as a Whole:   The changes in metabolic, cardiovascular and anthropometric risk factors associated with obesity based on pooled data for five clinical studies, regardless of the patient's risk factor status at randomization, are presented in Table 2. One year of therapy with Xenical resulted in relative improvement in several risk factors.

Population With Abnormal Risk Factors at Randomization: The changes from randomization following 1-year treatment in the population with abnormal lipid levels (LDL >/=130 mg/dL, LDL/HDL >/=3.5, HDL <35 mg/dL) were greater for Xenical compared to placebo with respect to LDL-cholesterol (-7.83% vs +1.14%) and the LDL/HDL ratio (-0.64 vs -0.46). HDL increased in the placebo group by 20.1% and in the Xenical group by 18.8%. In the population with abnormal blood pressure at baseline (systolic BP >/=140 mm Hg), the change in SBP from randomization to 1 year was greater for Xenical (-10.89 mm Hg) than placebo (-5.07 mm Hg). For patients with a diastolic blood pressure >/=90 mm Hg, Xenical patients decreased by -7.9 mm Hg while the placebo patients decreased by -5.5 mm Hg. Fasting insulin decreased more for Xenical than placebo (-39 vs -16 pmol/L) from randomization to 1 year in the population with abnormal baseline values (>/=120 pmol/L). A greater reduction in waist circumference for Xenical vs placebo (-7.29 vs -4.53 cm) was observed in the population with abnormal baseline values (>/=100 cm).

Effect on Weight Regain:   Three studies were designed to evaluate the effects of Xenical compared to placebo in reducing weight regain after a previous weight loss achieved following either diet alone (one study, 14302) or prior treatment with Xenical (two studies, 14119C and 14185). The diet utilized during the 1-year weight regain portion of the studies was a weight-maintenance diet, rather than a weight-loss diet, and patients received less nutritional counseling than patients in weight-loss studies. For studies 14119C and 14185, patients' previous weight loss was due to 1 year of treatment with Xenical in conjunction with a mildly hypocaloric diet. Study 14302 was conducted to evaluate the effects of 1 year of treatment with Xenical on weight regain in patients who had lost 8% or more of their body weight in the previous 6 months on diet alone.

In study 14119C, patients treated with placebo regained 52% of the weight they had previously lost while the patients treated with Xenical regained 26% of the weight they had previously lost (p<0.001). In study 14185, patients treated with placebo regained 63% of the weight they had previously lost while the patients treated with Xenical regained 35% of the weight they had lost (p<0.001). In study 14302, patients treated with placebo regained 53% of the weight they had previously lost while the patients treated with Xenical regained 32% of the weight that they had lost (p<0.001).

Two-year Results:  Long-term Weight Control and Risk Factors: The treatment effects of Xenical were examined for 2 years in four of the five 1-year weight management clinical studies previously discussed (see Table 1). At the end of year 1, the patients' diets were reviewed and changed where necessary. The diet prescribed in the second year was designed to maintain patient's current weight. Xenical was shown to be more effective than placebo in long-term weight control in four large, multicenter, 2-year double-blind, placebo-controlled studies.

Pooled data from four clinical studies indicate that 40% of all patients treated with 120 mg three times a day of Xenical and 24% of patients treated with placebo who completed 2 years of the same therapy had >/=5% loss of body weight from randomization. Pooled data from four clinical studies indicate that the relative weight loss advantage between Xenical 120 mg three times a day and placebo treatment groups was the same after 2 years as for 1 year, indicating that the pharmacologic advantage of Xenical was maintained over 2 years. In the same studies cited in the One-year Results (see Table 1), the percentages of patients achieving a >/=5% and >/=10% weight loss after 2 years are shown in Table 3.

The relative changes in risk factors associated with obesity following 2 years of therapy were also assessed in the population as a whole and the population with abnormal risk factors at randomization.

Population as a Whole:    The relative differences in risk factors between treatment with Xenical and placebo were similar to the results following 1 year of therapy for total cholesterol, LDL-cholesterol, LDL/HDL ratio, triglycerides, fasting glucose, fasting insulin, diastolic blood pressure, waist circumference, and hip circumference. The relative differences between treatment groups for HDL cholesterol and systolic blood pressure were less than that observed in the year one results.

Population With Abnormal Risk Factors at Randomization: The relative differences in risk factors between treatment with Xenical and placebo were similar to the results following 1 year of therapy for LDL- and HDL-cholesterol, triglycerides, fasting insulin, diastolic blood pressure, and waist circumference. The relative differences between treatment groups for LDL/HDL ratio and isolated systolic blood pressure were less than that observed in the year one results.

Study of Patients With Type 2 Diabetes:    A 1-year double-blind, placebo-controlled study in type 2 diabetics (N=321) stabilized on sulfonylureas was conducted. Thirty percent of patients treated with Xenical achieved at least a 5% or greater reduction in body weight from randomization compared to 13% of the placebo-treated patients (p<0.001). Table 4 describes the changes over 1 year of treatment with Xenical compared to placebo, in sulfonylurea usage and dose reduction as well as in hemoglobin HbA1c, fasting glucose, and insulin.

In addition, Xenical (n=162) compared to placebo (n=159) was associated with significant lowering for total cholesterol (-1.0% vs +9.0%, p</=0.05), LDL-cholesterol (-3.0% vs +10.0%, p</=0.05), LDL/HDL ratio (-0.26 vs -0.02, p</=0.05) and triglycerides (+2.54% vs +16.2%, p</=0.05), respectively. For HDL cholesterol, there was a +6.49% increase on Xenical and +8.6% increase on placebo, p>0.05. Systolic blood pressure increased by +0.61 mm Hg on Xenical and increased by +4.33 mm Hg on placebo, p>0.05. Diastolic blood pressure decreased by -0.47 mm Hg for Xenical and by -0.5 mm Hg for placebo, p>0.05.

Glucose Tolerance in Obese Patients:   Two-year studies that included oral glucose tolerance tests were conducted in obese patients not previously diagnosed or treated for type 2 diabetes and whose baseline oral glucose tolerance test (OGTT) status at randomization was either normal, impaired, or diabetic.

The progression from a normal OGTT at randomization to a diabetic or impaired OGTT following 2 years of treatment with Xenical (n=251) or placebo (n=207) were compared. Following treatment with Xenical, 0.0% and 7.2% of the patients progressed from normal to diabetic and normal to impaired, respectively, compared to 1.9% and 12.6% of the placebo treatment group, respectively.

In patients found to have an impaired OGTT at randomization, the percent of patients improving to normal or deteriorating to diabetic status following 1 and 2 years of treatment with Xenical compared to placebo are presented. After 1 year of treatment, 45.8% of the placebo patients and 73% of the Xenical patients had a normal oral glucose tolerance test while 10.4% of the placebo patients and 2.6% of the Xenical patients became diabetic. After 2 years of treatment, 50% of the placebo patients and 71.7% of the Xenical patients had a normal oral glucose tolerance test while 7.5% of placebo patients were found to be diabetic and 1.7% of Xenical patients were found to be diabetic after treatment.