Xenical Studies
Observational epidemiologic studies have established a relationship between obesity and visceral fat and the risks for cardiovascular disease, type 2 diabetes, certain forms of cancer, gallstones, certain respiratory disorders, and an increase in overall mortality. These studies suggest that weight loss, if maintained, may produce health benefits for obese patients who have or are at risk of developing weight-related comorbidities. The long-term effects of
orlistat on morbidity and mortality associated with obesity have not been established.
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 the 4-year XENDOS study and in seven long-term (1- to 2-years duration) multicenter, double-blind, placebo-controlled clinical trials. During the first year of therapy, the studies of 2-year duration assessed weight loss and weight maintenance. 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 the XENDOS study, which included 3304 patients, the time to onset of type 2 diabetes was assessed in addition to weight management. In all these 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.
Table 1 Percentage of Patients Losing = 5% and =10% of Body Weight From Randomization After 1-Year Treatment*| Intent-to-TreatPopulation† |
|---|
| = 5% WeightLoss | = 10% WeightLoss |
|---|
| Study No. | Xenical | n | Placebo | n | p-value | Xenical | n | Placebo | n | p-value |
|---|
| The diet utilized during year 1 wasa reduced-calorie diet. |
|
| 14119B | 35.5% | 110 | 21.3% | 108 | 0.021 | 16.4% | 110 | 6.5% | 108 | 0.022 |
| 14119C | 54.8% | 343 | 27.4% | 340 | <0.001 | 24.8% | 343 | 8.2% | 340 | <0.001 |
| 14149 | 50.6% | 241 | 26.3% | 236 | <0.001 | 22.8% | 241 | 11.9% | 236 | 0.02 |
| 14161‡ | 37.1% | 210 | 16.0% | 212 | <0.001 | 19.5% | 210 | 3.8% | 212 | <0.001 |
| 14185 | 42.6% | 657 | 22.4% | 223 | <0.001 | 17.7% | 657 | 9.9% | 223 | 0.006 |
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.
Table 2 Mean Change in Risk Factors From Randomization Following1-Year Treatment* Population asa Whole| Risk Factor | Xenical
120 mg† | Placebo† |
|---|
|
| Metabolic: | | |
| Total Cholesterol | -2.0% | +5.0% |
| LDL-Cholesterol | -4.0% | +5.0% |
| HDL-Cholesterol | +9.3% | +12.8% |
| LDL/HDL | -0.37 | -0.20 |
| Triglycerides | +1.34% | +2.9% |
| Fasting Glucose, mmol/L | -0.04 | +0.0 |
| Fasting Insulin, pmol/L | -6.7 | +5.2 |
| Cardiovascular: | | |
| Systolic Blood Pressure, mm Hg | -1.01 | +0.58 |
| Diastolic Blood Pressure, mm Hg | -1.19 | +0.46 |
| Anthropometric: | | |
| Waist Circumference, cm | -6.45 | -4.04 |
| Hip Circumference, cm | -5.31 | -2.96 |
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.
Table3 Percentage of Patients Losing =5% and =10% of BodyWeight From Randomization After 2-Year Treatment*| Intent-to-TreatPopulation† |
|---|
| = 5% Weight Loss | | = 10% Weight Loss | |
|---|
| Study No. | Xenical | n | Placebo | n | p-value | Xenical | n | Placebo | n | p-value |
|---|
| The diet utilized during year 2 wasdesigned for weight maintenance and not weight loss. |
|
| 14119C | 45.1% | 133 | 23.6% | 123 | <0.001 | 24.8% | 133 | 6.5% | 123 | <0.001 |
| 14149 | 43.3% | 178 | 27.2% | 158 | 0.002 | 18.0% | 178 | 9.5% | 158 | 0.025 |
| 14161‡ | 25.0% | 148 | 15.0% | 113 | 0.049 | 16.9% | 148 | 3.5% | 113 | 0.001 |
| 14185 | 34.0% | 147 | 27.9% | 122 | 0.279 | 17.7% | 147 | 11.5% | 122 | 0.154 |
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.
Four-year Results: Long-term Weight Control and Risk Factors
In the 4-year double-blind, placebo-controlled XENDOS study, the effects of
orlistat in delaying the onset of type 2 diabetes and on body weight were compared to placebo in 3304 obese patients who had either normal or impaired glucose tolerance at baseline. Thirty-four percent of the 1655 patients who were randomized to the placebo group and 52% of the 1649 patients who were randomized to the
orlistat group completed the 4-year study.
At the end of the study, the mean percent weight loss in the placebo group was -2.75% compared with -5.17% in the
orlistat group (p<0.001) (see Figure 1). Forty-five percent of the placebo patients and 73% of the
orlistat patients lost = 5% of their baseline body weight, and 21% of the placebo patients and 41% of the
orlistat patients lost = 10% of their baseline body weight following the first year of treatment. Following 4 years of treatment, 28% of the placebo patients and 45% of the
orlistat patients lost= 5% of their baseline body weight and 10% of the placebo patients and 21% of the
orlistat patients lost = 10% of their baseline body weight.
The relative changes from baseline in risk factors associated with obesity following 4 years of therapy were assessed in the XENDOS study population (see Table 4).
Table 4 Mean Change in Risk FactorsFrom Randomization Following 4-Years Treatment*| Risk Factor | Xenical
120 mg† | Placebo† |
|---|
|
| Metabolic: | | |
| Total Cholesterol | -7.02% | -2.03% |
| LDL-Cholesterol | -11.66% | -3.85% |
| HDL-Cholesterol | +5.92% | +7.01% |
| LDL/HDL | -0.53 | -0.33 |
| Triglycerides | +3.64% | +1.30 |
| Fasting Glucose, mmol/L | +0.12 | +0.23 |
| Fasting Insulin, pmol/L | -24.93 | -15.71 |
| Cardiovascular: | | |
| Systolic Blood Pressure, mm Hg | -4.12 | -2.60 |
| Diastolic Blood Pressure, mm Hg | -1.93 | -0.87 |
| Anthropometric: | | |
| Waist Circumference, cm | -5.78 | -3.99 |
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 5 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.
Table 5 Mean Changes inBody Weight and Glycemic Control From Randomization Following 1-YearTreatment in Patients With Type 2 Diabetes | Xenical
120 mg*
(n=162) | Placebo*
(n=159) | Statistical Significance |
|---|
| Statistical significance based on intent-to-treatpopulation, last observation carried forward. |
| ns nonsignificant, p>0.05 |
|
| % patients who discontinued dose of oralsulfonylurea | 11.7% | 7.5% | † |
| % patients who decreased dose of oralsulfonylurea | 31.5% | 21.4% | |
| Average reduction in sulfonylurea medicationdose | -22.8% | -9.1% | † |
| Body weight change (lbs) | -8.9 | -4.2 | † |
| HbA1c | -0.18% | +0.28% | † |
| Fasting glucose, mmol/L | -0.02 | +0.54 | † |
| Fasting insulin, pmol/L | -19.68 | -18.02 | ns |
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.
Onset of Type 2 Diabetes in Obese Patients
In the XENDOS trial, in the overall population,
orlistat delayed the onset of type 2 diabetes such that at the end of four years of treatment the cumulative incidence rate of diabetes was 8.3% for the placebo group compared to 5.5% for the
orlistat group, p=0.01 (see Table 6 ). This finding was driven by a statistically-significant reduction in the incidence of developing type 2 diabetes in those patients who had impaired glucose tolerance at baseline (Table 6 and Figure 2).
Orlistat did not reduce the risk for the development of diabetes in patients with normal glucose tolerance at baseline.
The effect of
Xenical to delay the onset of type 2 diabetes in obese patients with IGT is presumably due to weight loss, and not to any independent effects of the drug on glucose or insulin metabolism. The effect of
orlistat on weight loss is adjunctive to diet and exercise.
Table 6 Incidence Rate of Diabetes at Year 4by OGTT Status at Baseline*| OGTT at baseline | Normal | Impaired | All |
|---|
|
| Treatment | Placebo | Orlistat | Placebo | Orlistat | Placebo | Orlistat |
| Number of patients* | 1148 | 1235 | 324 | 337 | 1472 | 1572 |
| # pts developing diabetes | 16 | 21 | 62 | 48 | 78 | 69 |
| Life table rate† | 2.1% | 1.7% | 27.2% | 18.7% | 8.3% | 5.5% |
| Observed percent | 1.4% | 1.7% | 19.1% | 14.2% | 5.3% | 4.4% |
| Absolute risk reduction | | | |
| Life table | 0.4% | 8.5% | 2.8% |
| Observed | -0.3% | 4.9% | 0.9% |
| Relative risk reduction‡ | 8% | 42% | 34% |
| p-value | 0.79 | <0.01 | 0.01 |
Pediatric Clinical Studies
The effects of
Xenical on body mass index (BMI) and weight loss were assessed in a 54-week multicenter, double-blind, placebo-controlled study in 539 obese adolescents (357 receiving
Xenical 120 mg three times a day, 182 receiving placebo), aged 12 to 16 years. All study participants had a baseline BMI that was 2 units greater than the US weighted mean for the 95th percentile based on age and gender. Body mass index was the primary efficacy parameter because it takes into account changes in height and body weight, which occur in growing children.
During the study, all patients were instructed to take a multivitamin containing fat-soluble vitamins at least 2 hours before or after ingestion of
Xenical. Patients were also maintained on a well-balanced, reduced-calorie diet that was intended to provide 30% of calories from fat. In addition, all patients were placed on a behavior modification program and offered exercise counseling.
Approximately 65% of patients in each treatment group completed the study.
Following one year of treatment, BMI decreased by an average of 0.55 kg/m2 in the
Xenical-treated patients and increased by an average of 0.31 kg/m2 in the placebo-treated patients (p=0.001).
The percentages of patients achieving = 5% and= 10% reduction in BMI and body weight after 52 weeks of treatment for the intent-to-treat population are presented in Table 7.
Table 7 Percentages of Patients with = 5% and = 10%Decrease in Body Mass Index and Body Weight After 1-Year Treatment* (Protocol NM16189)| Intent-to-TreatPopulation† |
|---|
| = 5% Decrease | = 10% Decrease |
|---|
| Xenical | n | Placebo | n | Xenical | n | Placebo | n |
|---|
|
| BMI | 26.5% | 347 | 15.7% | 178 | 13.3% | 347 | 4.5% | 178 |
| Body Weight | 19.0% | 348 | 11.7% | 180 | 9.5% | 348 | 3.3% | 180 |