Clinical Trial Result Information

Protocol number
M37081

Title of Study
Cardiovascular risk reduction evaluation in obese or overweight patients with mild or moderate hypertension after taking orlistat for 9 months – multicenter and open-label study

Sponsor
Produtos Roche Químicos e Farmacêuticos S.A.

Company division
Pharmaceutical

Product name
Xenical

Generic name
orlistat

Therapeutic area
Weight Loss

Clinical study summary
This was a multi-center, open-label, non-comparative, controlled study in overweight or obese patients with mild to moderate hypertension, to evaluate cardiovascular risk reduction and efficacy of orlistat (Xenical) treatment.

Study center(s)
14 centers in Brazil.

Phase of development
IV

Objectives
Primary: (1) To determine cardiovascular risk reduction in overweight or obese patients with mild to moderate hypertension after treatment with Xenical for 36 weeks. Secondary: (1) To determine the effect of Xenical after a 36-week treatment period on the following parameters: weight, blood pressure, lipid levels and glycemic control, visceral adiposity, and waist circumference.

Methodology
After screening and baseline measurements, eligible patients were instructed to take Xenical 120mg three times daily with major meals. After 36 weeks of treatment, cardiovascular and biochemical parameters were evaluated, and patients were weighed and measured.

Number of patients (planned/analyzed)
195 evaluable.

Diagnosis and main criteria for inclusion
Overweight or obese patients, with mild to moderate hypertension.

Test product, dose and mode of administration or test procedure
Xenical 120 mg/po/tid.

Duration of treatment
36 weeks

Reference therapy, dose and mode of administration or reference procedure
Not applicable

Criteria for evaluation (efficacy, safety)
Primary efficacy parameter: cardiovascular risk reduction.
American Heart Association (AHA) cardiovascular risk categories based on total score table (AHA-E1) and cardiovascular risk factors, including risk factors associated with the metabolic syndrome based on cardiovascular risk total score (MSR-E2). The 6 risk categories are no risk, potential risk, moderate risk, high risk, dangerous zone and maximum danger.

Secondary efficacy parameters: (1) AHA-E1 and MSR-E2 total scores evaluated; (2) Weight (kg); (3) Systolic and diastolic blood pressure (mmHg); (4) Body mass index (BMI; kg/m2); (5) Waist circumference (cm); (6) Glycemic variables: fasting glucose and 120-minute oral glucose tolerance test (OGTT 120); (7) Lipid parameters: total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density (LDL) lipoprotein cholesterol, and triglycerides; and (8) Visceral and subcutaneous adiposity.

Statistical methods
The Cochran-Mantel-Haenszel statistic, controlling by study center, was used to compare baseline and Week 36 distributions in the risk categories, for both total risk scores. Association analyses were developed using the Cochran-Mantel-Haenszel statistic, based on ridit scores, controlling by study center.

Linear model analyses for continuous response variables were developed with AR(1) covariance structure and using the restricted maximum likelihood (REML) estimation method or minimum variance quadratic unbiased estimator (MIVQUE) method when convergence criteria were not met. These analyses took into account the repeated measures of the observations over time. Multiple comparisons were carried out with Tukey-Kramer adjustment for significance levels when the interaction was not significant. When the interaction was significant, a descriptive analysis was carried out by study center.

OGTT 120 association analysis between baseline and Week 36 results, without last observation carried forward, was developed using the Cochran-Mantel-Haenszel statistic (based on ridit scores), controlling by study center.

Visceral and subcutaneous fat percent changes after 36 treatment weeks were correlated with AHA-E1, MSR-E2, and OGTT 120 percent changes in 36 weeks of treatment. Data were available for 93 patients, measured in centimeters.

The calculations were made using the SAS System, version 8.2.

Summary (efficacy, safety, other results)
Efficacy – No relevant differences between ITT and PP populations were observed.

Analysis according to AHA-E1 and MSR-E2 scores - When patients were assessed by AHA-E1 scores, a significant shift to lower-risk categories occurred (P<0.0001). At baseline, 77.9% of patients were categorized as moderate risk. After 36 weeks of treatment, the number of patients initially categorized as moderate risk decreased by 26.5%. Of patients categorized as moderate risk at the beginning of treatment, 38.3% were categorized as potential risk at the end of study. Of patients who began treatment categorized as potential risk, 12.8% finished the study in the range of no risk at all.

A significant shift to lower-risk categories also occurred for MSR-E2 scores (P<0.0001). After a 36-week treatment period, the number of patients categorized as high risk at the beginning of the study decreased by 8.9%, and the number categorized as moderate risk decreased by 21.5%. Of patients who began treatment at high risk, 87.5% were in the moderate risk category by the end of study. Of patients who began treatment at moderate risk, 34.9% were in the potential risk category by the end of study.

AHA-E1 scores decreased by 4.6 units (least squares means) (P<0.0001) from Week 0 to Week 8. After 36 weeks of treatment, AHA-E1 scores decreased by 5.6 units (least squares means) (P<0.0001). MSR-E2 scores decreased by 4.1 units (least squares means from Week 0–8) (P<0.0001). After 36 weeks of treatment, MSR-E2 scores decreased (least squares means) by 5.3 units (P<0.0001).

Weight, blood pressure, lipid levels, OGTT improvement analyses – After 36 weeks of treatment, highly significant decreases were observed for weight (7.0 kg; P<0.0001), systolic blood pressure (8.8 mmHg; P=0.0002), BMI (2.8 kg/m2; P<0.0001), and waist circumference (6.9 cm; P<0.0001) (least squares means). For lipid levels, a significant reduction was observed for total cholesterol from Week 0 to Week 8 (6.9%; P<0.0001) (least squares means). However, no additional significant decreases were observed from Week 8 compared with subsequent weeks until the end of study. LDL cholesterol decreased by 5.9% from Week 0 to Week 8 (P=0.0101), and no additional significant percentage changes were observed from Week 8 compared with subsequent weeks; triglyceride reduction was 9.6% after 36 weeks of treatment (P=0.0203) (least squares means). After 36 weeks of treatment, OGTT 120 categories were associated with OGTT categories at Week 0 (P=0.0005). Of patients who began treatment with OGTT 120 ≥200 mg/dL, by the end of the study 50% had OGTT 120 ≥140 mg/dL but <200 mg/dL; 33.3% had OGTT 120 <140 mg/dL. At the beginning of the study (Week 0), 62.5% of patients with OGTT 120 ≥140 mg/dL but <200 mg/dL finished the study with OGTT 120 <140 mg/dL at Week 36. Of patients with a OGTT 120 <140 mg/dL at Week 0, 84% remained in this category.

Visceral fat analysis – Visceral fat percent change correlates weakly with percent changes for AHA-E1 total score, MSR-E2 total score, and OGTT 120. However, subcutaneous fat percent change correlates significantly with total score percent changes for AHA-E1 and MSR-E2. The subgroup of patients with fasting glucose >110 mg/dL or OGTT 120 ≥140 mg/dL was analyzed with respect to the primary efficacy variables and physical examination variables. Results were analogous to those obtained for the ITT population.

Safety – Thirty-six patients (18.75%) had no adverse events, and 156 (81.25%) had ≥1 episode. Gastrointestinal disorders were the most frequently reported adverse event (57.6%). The vast majority of adverse events were of mild intensity. Five serious adverse events were reported, 4 not related to study drug and 1 of unknown relationship to treatment.

Conclusions
: The results of this study corroborate previous findings that Xenical is effective not only for weight reduction but also for the improvement of risk factors associated with cardiovascular disease. Overweight/obesity is a feature of the metabolic syndrome and is usually seen along with several other components of the syndrome (such as hypertension, dyslipidemia, and glucose intolerance); treatment with Xenical improved all risk factors associated with the metabolic syndrome and reduced the risk of cardiovascular disease, as assessed by AHA-E1 and MSR-E2 scores.

Publications (references, if available)
International Journal of Obesity 2002; 26 (Suppl 1):S152

Date of report
3/24/2004