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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods and Procedures
  5. Results
  6. Discussion
  7. ACKNOWLEDGEMENT
  8. DISCLOSURE
  9. References

It is well established that abdominal obesity or upper body fat distribution is associated with increased risk of metabolic and cardiovascular disease. The purpose of the present study was to determine if a 24 week weight loss program with orlistat 60 mg in overweight subjects would produce a greater change in visceral adipose tissue (VAT) as measured by computed tomography (CT) scan, compared to placebo. The effects of orlistat 60 mg on changes in total fat mass (EchoMRI-AH and BIA), ectopic fat (CT) and glycemic variables were assessed. One-hundred thirty-one subjects were randomized into a multicenter, double-blind placebo controlled study in which 123 subjects received at least one post baseline efficacy measurement (intent-to-treat population). Both orlistat-and placebo-treated subjects significantly decreased their VAT at 24 weeks with a significantly greater loss of VAT by orlistat treated subjects (−15.7% vs. −9.4%, P < 0.05). In addition, orlistat-treated subjects had significantly greater weight loss (−5.93 kg vs. −3.94 kg, P < 0.05), total fat mass loss (−4.65 kg vs. −3.01 kg, P < 0.05) and trended to a greater loss of intermuscular adipose tissue and content of liver fat compared with placebo-treated subjects. This is the first study to demonstrate that orlistat 60 mg significantly reduces VAT in addition to total body fat compared to placebo treated subjects after a 24 week weight loss program. These results suggest that orlistat 60 mg may be an effective weight loss tool to reduce metabolic risk factors associated with abdominal obesity.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods and Procedures
  5. Results
  6. Discussion
  7. ACKNOWLEDGEMENT
  8. DISCLOSURE
  9. References

It is well established that abdominal obesity or upper body fat distribution is associated with increased risk of metabolic and cardiovascular disease (1,2,3,4). This association is primarily explained by its strong relationship to visceral or intra-abdominal adipose tissue. Excess visceral adipose tissue (VAT) is an important and independent predictor of metabolic risk factors for coronary heart disease, in particular dyslipidemia and type 2 diabetes (5). Increases in visceral fat are associated with impaired glucose tolerance, insulin resistance (IR), hypertension, and abnormal lipid values. The metabolic abnormalities associated with abdominal obesity appear to be related to the unique metabolic and inflammatory features of visceral fat (3,6). Emerging evidence suggests that other ectopic fat depots may be linked to metabolic risk and morbidity (7). Liver fat deposition is independently linked to dyslipidemia and IR (7,8,9) and intermuscular adipose tissue (IMAT) is associated with metabolic abnormalities related to muscle and glucose metabolism (10).

Orlistat is a weight loss drug which acts by inhibiting gastrointestinal (GI) lipase, reducing the absorption of ∼25–30% of the dietary fat consumed. Orlistat 120 mg capsules were introduced on the market as a prescription drug over 10 years ago. More recently, 60 mg capsules were approved as a nonprescription weight loss aid in over 30 countries including the United States and Europe. The 60 mg dose has been shown to have approx 85% the efficacy of the 120 mg dose (11,12). Some preliminary studies have examined the effect of orlistat 120 mg capsules on changes in body composition (13,14,15). In particular, Tiikkainen et al (13) showed that the 120 mg dose of orlistat was effective in reducing visceral fat greater than diet alone, despite similar weight loss. To date no studies have examined the effect of 60 mg orlistat on changes in total body fat mass or adipose tissue distribution.

The purpose of the present study was to determine if a 24 week weight loss program with orlistat 60 mg in overweight subjects would produce greater changes in abdominal visceral fat compared to placebo. We also examined the effect of orlistat 60 mg on changes in total fat mass, ectopic fat, including IMAT and liver fat content, and markers of insulin sensitivity.

Methods and Procedures

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods and Procedures
  5. Results
  6. Discussion
  7. ACKNOWLEDGEMENT
  8. DISCLOSURE
  9. References

Study design

This study was a multicenter, randomized, double-blind, placebo controlled, study in overweight and obese subjects which was conducted at three academic investigational sites, two in the United States and one in Sweden. All subjects signed a consent form that was reviewed and approved by local ethics or institutional review boards. Following consent, subjects participated in an initial screening assessment. Subjects who met the inclusion and exclusion criteria returned for a baseline visit at which time they were randomized and baseline measurements were collected. Subjects were provided a 4 week supply of orlistat (60 mg) or placebo capsules, educational materials, and received dietary counseling. Study visits were conducted at baseline and weeks 2, 4, 8, 12, 16, 20, and 24. All unused medications were returned at each visit. Any remaining capsules were counted to check compliance with the study medication. At the baseline visit, anthropometric and vital signs were measured. Body composition was measured in all subjects. Total fat mass (kg) was measured by Echo MRI-AH, and % body fat was assessed using bioelectrical impedance analysis (BIA). Regional fat areas (abdominal VAT, IMAT, and liver fat content (Hounsfield units (HU)) were measured by computed tomography (CT). All body composition measurements were repeated at 12 weeks and the end of the 24 week weight loss period. Total fat mass and % body fat also were measured at 2 and 4 weeks.

At baseline and week 24, fasting blood samples were collected for assessment of glucose and insulin. At screening and week 24 a fasting sample also was collected for safety labs. Females took a pregnancy test at screening and before each CT scan (baseline, week 12, and week 24).

Vital signs, body weight and waist circumference were measured at each visit and adverse events (AEs) were assessed and collected throughout the study.

Study population

Inclusion and exclusion criteria. Inclusion criteria included an age range of 18–60 years, normal eating habits, BMI 25–34.9 kg/m2, and a waist circumference for females >88 cm (35 inches) or for males >102 cm (40 inches). Exclusion criteria included pregnancy, a recent history of weight loss, taking any prescription drugs that could interfere with body weight or intestinal transit time, currently taking cyclosporine, warfarin, or amiodarone HCL, and a history of GI diseases, type 1 and 2 diabetes, uncontrolled hypertension, or heart disease.

Treatment

Subjects who met eligibility criteria were randomized to either orlistat 60 mg or placebo in a 1:1 manner. After the baseline measurements were completed, subjects met with a registered dietitian for nutrition counseling. They were instructed to consume a hypocaloric, low-fat diet containing 50% carbohydrate, 30% fat and 20% protein for the duration of the study and encouraged to exercise (e.g., 30–45 min walk, five times weekly). The estimated caloric requirement was based upon a 500 kcal daily deficit determined from the subject's current weight and activity level (16). Subjects received a 4-week supply of study medication and alli (alli is a registered trademark of GlaxoSmithKline Consumer Healthcare) educational materials or comparable dietary and usage information. These materials included a booklet which reinforced lifestyle changes and a guide to determine the calorie and fat content of meals. All subjects were instructed to take one capsule with each main meal (breakfast, lunch, and dinner) three times a day, to distribute their fat grams evenly across the three main meals, and to take a multivitamin daily at least 2 h before or after taking the study medication.

Body weight (kg) and waist circumference (cm) were measured at each visit and compared with height (cm) measured at screening. Waist circumference was measured in the standing position at the level midway between the lateral lower rib margin and the iliac crest.

Body composition measurements

Visceral fat, liver fat, and IMAT evaluation by CT. Eight slice CT scans were used to report abdominal VAT mass (kg) and liver fat (HU) as previously described (17). All sites used the same scanner model and software (GE LightSpeed; General Electric, Milwaukee, WI). All CT scans were performed with the participant lying in the supine position with the arms over the head. The L4–5 region was defined as “zero” with two slices taken below that location and five slices taken above. A single slice CT of the thigh region was used to measure IMAT (cm2) as described by Goodpaster (18). All CT scans were transferred and analyzed at one site (Pennington Biomedical Research Center) using commercially available software (Analyze; Analyze Direct, Rochester, MN). Only one individual, with an average reproducibility of ∼0.05%, analyzed all radiographic evaluations. The reader was blinded to test medication and the date of the testing.

Total fat mass by Echo-MRI-AH. Quantitative magnetic resonance-based method for measuring total fat mass (kg) directly (Echo MRI-AH, EchoMedical Systems, Houston, TX) uses the distinct resonance frequency of protons in lipid and water (19). Following training, all study sites used a common data acquisition consistent with the manufacturer's instructions manual. Since the EchoMRI machine uses a low field strength magnet (static magnetic field ∼0.0065 Tesla), the subject was screened for any conditions that would preclude safe MRI and to ensure that they did not contain ferromagnetic objects that could distort the magnetic field. External radio-frequency radiation was controlled by metal shielding and the use of Faraday netting. Subjects were fasted prior to the evaluation. After lying semi-recumbent on a sliding trolley, the subject was pushed into the bore of the magnet and radio-frequency spectra were acquired for ∼3 min.

Data acquisition was performed in triplicate in single minute, in-device scan time; the three data sets were then averaged.

Percent body fat by BIA. A bioelectric impedance analysis device (Quantum X; RJL Systems, Clinton twp, MI) was used to measure % body fat across all sites as previously described (20). The methodology was agreed to by all study sites, consistent with the manufacturer's instruction manual.

Homeostatic model assessment (HOMA)

HOMA, a method used to quantify IR (21), has been shown to be a reliable surrogate measure of insulin sensitivity, correlating with the euglycemic insulin clamp technique (22). HOMA was determined using the formula:

(Fasting insulin (µU/ml) × fasting glucose (mmol/l))/22.5

Selectivity index (SI)

The SI was used as a measure of orlistat's ability to target abdominal visceral adipose tissue loss compared to total adipose tissue lost. (23). The selectivity index was calculated using the following equation:

  • image

The percent change in VAT was measured in subjects using CT. The percent change in fat was calculated from total fat mass obtained by EchoMRI-AH.

Statistical methods

The null hypothesis tested was that there was no difference between the orlistat and the placebo treatment groups in the mean change in VAT from baseline to week 24. At 90% power, the sample size was determined to be 40 completed subjects per treatment arm to detect a 110 g difference between the treatment groups. In this study, there were 54 subjects in the orlistat group and 53 subjects in the placebo group who completed the study.

The primary efficacy analysis of the mean change in VAT from baseline to week 24, is based on last observation carried forward (LOCF) using the intent to treat (ITT) population. All other analyses use the ITT observed and completer populations.

For differences between the treatment groups, the tests were two-sided, at the 0.05 significance level. Normality assumptions were examined for all variables discussed. A repeated measures analysis was performed, with treatment group, center, visit, and treatment by visit interaction as main effects, and the baseline value as the covariate, in the model.

The primary efficacy variable, change in VAT from baseline to week 24 was analyzed by analysis of covariance, ANCOVA. The baseline value was included in the model as a covariate, and treatment group and center were added as main effects. Additional covariates, e.g., age, were investigated in separate models. Adjusted mean squares were provided and associated P values were generated.

Secondary efficacy variables, VAT at week 12, body weight, waist circumference, total fat mass, percent (%) body fat, liver fat content, fasting glucose, insulin, and HOMA were analyzed with ANCOVA, for change from baseline, similar to the week 24 VAT analysis.

AEs were summarized for all subjects in the safety population, using descriptive statistics (number and percent of subjects) by treatment group. The safety population included all randomized subjects who received at least one dose of medication.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods and Procedures
  5. Results
  6. Discussion
  7. ACKNOWLEDGEMENT
  8. DISCLOSURE
  9. References

Subject disposition

One hundred and thirty-one subjects were randomized to orlistat plus diet or placebo plus diet (Figure 1). There were 13 placebo subjects and 11 orlistat subjects who discontinued the study due to AEs, lost to follow up, withdrawal of consent or other reasons. Three subjects in the orlistat group (4.8%) and none in the placebo discontinued due to AEs.

image

Figure 1. Subject disposition.

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The ITT population, defined as subjects who had at least one post-treatment efficacy treatment, was comprised of 61 placebo and 62 orlistat subjects. The completer population included 93 subjects (43 placebo, 50 orlistat,) who completed the study, had VAT measured at week 24 and did not have any major protocol violations. The placebo group had more protocol violations associated with baseline and post CT scans performed outside of the defined window; the remaining number of protocol violations were similar between groups.

Demographic and baseline characteristics

Demographic and baseline characteristics were similar between orlistat and placebo groups in the ITT population (Table 1). Most subjects were female (83%), white (76%), with a mean age of 43.4 years and a mean BMI of 31.0 kg/m2.

Table 1.  Demographics and baseline characteristics, ITT population
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Visceral Adipose Tissue

Both groups had a significant decrease in VAT from baseline to week 24 (P < 0.001), but the orlistat group had a significantly greater mean reduction in VAT as compared to placebo (ITT LOCF, P < 0.05, Figure 2), corresponding to a relative mean change of −9.4% in the placebo group as compared to −15.7% in the orlistat group. Figure 3 illustrates visceral fat CT images at baseline and week 24 in an orlistat 60 mg female subject with a relative mean change of 15.2%.

image

Figure 2. Mean changes from baseline visceral adipose tissue (VAT) at week 12 and 24 by treatment group. Mean ± s.e.m., ITT LOCF (baseline to week 24) and ITT observed (baseline to week 12) *P < 0.05 orlistat vs. placebo. ITT, intent to treat; LOCF, last observation carried forward.

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image

Figure 3. Visceral fat computed tomography (CT) images at baseline and week 24. Images of representative female orlistat subject; baseline of BMI 34.4 kg/m2; % change in visceral adipose tissue (VAT) of 15.2%, and change in body weight of 5.6%.

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Results for changes in VAT were similar at 12 weeks. Both groups had significant decreases from baseline to week 12 (P < 0.001), and the orlistat group had a significantly greater mean reduction in VAT as compared to the placebo group (ITT observed, P < 0.05, Figure 2). This translated to a relative mean change of −8.3% in placebo as compared to −12.0% in the orlistat group.

Figure 2 shows the adjusted mean changes from baseline to week 12 and 24 for the placebo and orlistat groups in the ITT population.

Similar results were observed at both the 12 and 24 weeks in the completer population (week 12: −0.48 ± 0.06 kg vs. −0.25 ± 0.06 kg, P < 0.01; week 24: − 0.63 ± 0.08 kg vs. −0.28 ± 0.09 kg P < 0.01, orlistat, placebo respectively).

A significantly greater percent of subjects on orlistat achieved a ≥10% loss in VAT as compared to those on placebo at week 24, with 63.0% in the orlistat group vs. 43.4% in placebo, P < 0.05).

Body weight and waist circumference

There was a significant decrease in the adjusted mean weight change from baseline to week 24 in both groups. The orlistat group had a significantly greater mean reduction in body weight as compared with the placebo group (−5.93 ± 0.63 kg vs. −3.94 ± 0.64 kg, P < 0.05) corresponding to a relative mean change in the orlistat group of −6.6% as compared to −4.3% in the placebo group. Results for body weight in the completer population were −6.32 ± 0.64 kg vs. −4.05 ± 0.72 kg, orlistat, placebo, respectively P < 0.05.

A significantly greater proportion of subjects using orlistat 60 mg lost ≥5% of their body weight as compared to those on placebo (orlistat 31/54 = 57.4%, placebo 19/53 = 35.8%, P < 0.05).

Figure 4 shows the mean % change from baseline for VAT and body weight over time (ITT population). Starting at 12 weeks, the mean change in body weight was significantly greater in the orlistat group (−4.63 ± 0.44 kg vs. −3.32 ± 0.44 kg, orlistat, placebo respectively, P < 0.05). The mean change in VAT was significantly greater at 24 weeks; at 12 weeks a similar trend was observed (P = 0.06). The changes in VAT and body weight correlated across time for both groups (0.76 and 0.80 for orlistat and 0.82 and 0.85 for placebo at weeks 12 and 24, respectively; P < 0.001).

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Figure 4. Mean percent change in visceral adipose tissue and body weight over time. Mean ± s.e.m., ITT observed. *P < 0.05; **P < 0.01 orlistat vs. placebo. ITT, intent to treat.

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The change in VAT from baseline to week 24 was examined in subjects with ≥5% weight loss and those that lost <5%. In subjects with >5% weight loss, a significant decrease from baseline to week 24 was observed in both treatment groups (P < 0.001); there was a significant decrease from baseline for subjects with <5% weight loss in the orlistat group (P < 0.01), whereas no significant change was observed in the placebo group. For subjects with ≥5% weight loss, no difference between treatment groups was observed; in subjects with <5% weight loss, the orlistat group showed a significantly greater decrease as compared to placebo (−0.320 ± 0.098 kg vs. −0.003 ± 0.080 kg, orlistat, placebo, respectively P < 0.05).

Both treatment groups showed a decrease in waist circumference at 24 weeks. The mean change for the orlistat group was −6.7 ± 0.7 cm and −5.0 ± 0.7 cm in placebo (P < 0.001). The orlistat group showed greater improvements as compared to placebo. This difference was not significant in the ITT population (P = 0.085), whereas there was a significant treatment difference in the completer population (−7.0 ± 0.7 cm vs. −4.9 ± 0.8 cm, P < 0.05).

Total fat mass, % body fat, and selectivity index

Both treatment groups had significant decreases (P < 0.001) in total fat mass from baseline to week 24 as shown in Table 2. At 24 weeks the orlistat group had a significantly greater mean reduction as compared to the placebo group (P < 0.05).

Table 2.  Total fat mass, percent body fat, liver fat content and IMAT results at week 24, ITT observed population
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There was a significantly greater reduction in % body fat in the orlistat group at 24 weeks as compared to placebo (Table 2, P < 0.05), and only the orlistat group had a significant decrease from baseline to week 24 (P < 0.01).

The selectivity index for the orlistat group was 1.2 at week 12 and 1.2 at week 24 for the ITT population. The index was similar for orlistat males and females at the post baseline visits. For subjects who lost ≥5% weight loss, SI was 1.1 whereas SI for those who lost <5% was 1.5.

Liver fat content and IMAT

Changes for liver fat content (HU) from baseline to week 24 are shown in Table 2. Both groups showed improvements at week 24, but only the orlistat group had a significant change over time (P < 0.01). No significant differences were observed between treatment groups.

There were significant changes in IMAT (mm2) from baseline to week 24 in both treatment groups (Table 2, P < 0.001). Mean changes corresponded to a mean percent reduction of 12.2% and 7.8%, orlistat and placebo, respectively. The orlistat group had a greater reduction in IMAT compared to placebo; there was a trend in the difference between treatment groups. (Table 2, P = 0.081).

Fasting glucose, insulin, and HOMA

The adjusted mean change in fasting glucose (mmol) from baseline to week 24 was −0.23 ± 0.04 and −0.11 ± 0.04 for orlistat and placebo, respectively. Both placebo (P < 0.05) and orlistat (P < 0.0001) had significant decreases in fasting glucose from baseline to week 24. There was a greater mean reduction in fasting glucose from baseline to week 24 in the orlistat group, but the difference between groups was of marginal significance (P = 0.051).

There were no significant changes in fasting insulin levels (pmol/l) from baseline to week 24, either within or between treatment groups (−1.5 ± 4.8 and 6.3 ± 5.1, orlistat and placebo, respectively).

Mean HOMA values at baseline and week 24 were 3.70 and 3.34 in the orlistat group and 3.79 and 3.74 in the placebo group. The adjusted mean change from baseline to week 24 showed a decrease of −0.241 ± 0.201 in the orlistat group and an increase of 0.165 ± 0.210 in the placebo group. There were no significant changes, either within or between treatment groups.

Safety

At least one adverse event was reported by 52 (81.3%) placebo subjects and 57 (90.5%) orlistat subjects. There were no differences in AEs between the orlistat and placebo groups for all body systems with the exception of the GI system. Consistent with previous controlled studies conducted with orlistat (11,24,25) the most commonly observed AE's were GI disorders, with an incidence of 51.6% in the placebo group and 76.2% in the orlistat group. The higher incidence in the orlistat group was associated with treatment-related GI AEs, 42 (66.7%) in the orlistat group as compared to 17 (26.6%) in placebo subjects. Almost all the treatment-related GI AEs occurred in less than 12% of subjects with the exception of oily (34.9%) and soft stools (22.2%). Most of the GI-AEs were rated as mild in both groups. Six serious AEs (SAE's) were reported by three subjects (one placebo and two orlistat). One orlistat subject, reported four events, including severe exacerbation of gallstones treated with cholecystectomy, moderate cystic duct leak, severe abdominal infection, and moderate kidney stone exacerbation treated with lithotripsy. Only exacerbation of gallstones was considered possibly related to study drug. The other two SAE's included severe worsening of gallstones treated with cholecystectomy (placebo) and blurry vision of mild intensity (orlistat). Both of these events were classified as unlikely related, and study treatment was interrupted for a short time. All SAE's resolved.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods and Procedures
  5. Results
  6. Discussion
  7. ACKNOWLEDGEMENT
  8. DISCLOSURE
  9. References

The purpose of the present study was for the first time to investigate whether 60 mg orlistat results in a significantly greater change in visceral adipose tissue following 24 weeks of treatment as compared to placebo. In addition, we examined changes in total fat mass, ectopic fat, and insulin sensitivity. The results demonstrate that subjects on orlistat 60 mg along with a reduced calorie, low fat diet have a greater reduction in visceral fat at both 12 and 24 weeks as compared to placebo subjects on diet alone. A significantly greater weight loss was observed in the orlistat group starting at 12 weeks, consistent with results from previous orlistat trials (11,24,25). Changes in VAT generally corresponded to changes in body weight across time in both groups. Subjects on orlistat had a significantly greater reduction in total fat mass and % body fat at 24 weeks, consistent with previous results on 120 mg orlistat (26,27). There was a trend in IMAT and liver fat content towards a greater reduction in the orlistat group at 24 weeks.

When changes in VAT were examined in weight responders and nonresponders, orlistat subjects who lost <5% of their body weight showed significantly greater reductions in VAT as compared to placebo whereas no treatment difference was observed in subjects who lost ≥5% body weight. Based on a systematic review of weight loss interventions, Chaston and Dixon (28) have shown that VAT is lost preferentially with modest weight loss, but the effect diminishes with greater weight loss. The current results suggest that orlistat may have a preferential effect on VAT, which is masked with greater changes in weight loss. In a study of 47 obese female subjects, Tiikkainen et al (13) found similar changes in weight loss and reductions in VAT and subcutaneous adipose tissue in the orlistat and placebo groups, but only orlistat was effective in significantly reducing the ratio of visceral fat to subcutaneous or total adipose tissue. The authors suggest that lowering fat absorption or altering the composition of fatty acids may have favorable effects on the ratio of VAT to subcutaneous or total fat.

Generally, the proportion of VAT change with weight loss is greater than the percent change in total body fat. In a survey of the literature, Smith and Zachwieja (23) addressed the issue of selective reduction of fat by assessing the percent of VAT lost to the percent of total fat mass lost. Termed the selectivity index, the authors reported that most weight loss interventions had a ratio of 1.4 to 1.8. Since an equal loss of VAT and total body fat has a SI of 1, it would appear that weight loss with orlistat, with a SI of 1.2, does not cause a selective reduction in VAT. In addition, since women have a lower SI than men (23), the high proportion of women in this study may explain the lower SI. However, the SI in those that lost <5% weight loss was 1.5 as compared with 1.1 in subjects who lost ≥5%, supporting the hypothesis that orlistat may have a preferential effect on VAT, which is masked with greater changes in weight loss.

There was a trend towards a reduction in IMAT in the orlistat group at week 24; this may be due to the variability in the measurement. In the current study, IMAT was determined by one CT slice at the mid-thigh, which has been shown to have the highest correlation to total body IMAT volume (29). However, adding a second and third slice to the location increases the predictive value. Since the exact location of each slice is influenced by the height (and hence BMI) of the subject, each slice may not be anatomically identical across subjects, which may explain the high variability (29).

Although the orlistat group showed a significant improvement at 24 weeks in liver fat content, as measured by CT (HU), this difference was not significantly different from placebo. Recently, an open label, 3 month study using orlistat 60 mg was conducted to examine changes in fat distribution. The authors reported decreases in VAT and body weight at 12 weeks which were similar to the current results (14). Using proton magnetic resonance spectroscopy (1H-MRS), a 43% reduction in intra-hepatocellular lipids was observed; in the current study, there was a 27% reduction in liver fat, based on CT. Hepatic measurements obtained by CT and liver biopsy correlate well with intra-hepatocellular lipids as measured by 1H-MRS (30,31). The latter provides a quantitative assessment of fatty infiltration of the liver whereas CT provides an accurate visualization of the whole liver, including both diffuse and focal fatty filtrations of the parenchyma.

Significant decreases in fasting glucose levels were observed at 24 weeks, with a greater reduction in the orlistat group. As the mean baseline values for both groups were within the normal range (normal range: 3.9–5.5 mmol/l) the decrease in glucose was relatively small.

In examining the HOMA results, a recent study, including 2,321 euglycemic hyperinsulinemic clamps (2,138 nondiabetic), developed decision rules to diagnose cutoffs for the diagnosis of IR. The authors suggested that a HOMA score of > 4.65, or BMI >27.5 kg/m2 and a HOMA value >3.6 indicated IR (31). Since most subjects in the current study had a BMI >27.5 and a mean HOMA value >3.6 at baseline, both groups would be considered IR (HOMA >3.6). At week 24, the mean HOMA value was 3.3 in the orlistat group, which is below the proposed IR cutoff, whereas in placebo subjects, the mean value remained above 3.7.

Consistent with previous studies (11,24,25), the most commonly observed AEs in both groups occurred in the GI system reflecting the higher incidence of selected GI events associated with orlistat's mechanism of action. Most of these GI-AE's were mild in intensity, and with the exception of fatty/oily stool and soft stools, the occurrence of these specific events was less than 20%.

There were several strengths to the current study. This was a longitudinal multi-center study which examined changes in total fat mass, VAT, IMAT, and liver fat in response to a reduced calorie low fat diet with orlistat or placebo. Variability in imaging across sites was minimized; all sites used the same scanner model and software, CT scans were transferred and analyzed at one site, and the reader for all radiographic evaluations was blinded to both medication and date of the testing. Second, to our knowledge this is the first trial in which EchoMRI-AH has been used successfully across multiple sites. This technology has several advantages to other methods of whole body composition in that it is noninvasive and radiation free; more accurate and precise than other methods; allows for fast data acquisition, and ideally suited for studies which track small changes in total body composition over time (18,33).

One limitation of the current study was the assessment of insulin sensitivity. Although a change in insulin sensitivity was not a primary endpoint of the study, better conclusions could have been drawn with more direct measures of metabolic changes during the course of the study.

In summary, this is the first placebo-controlled, randomized, study on 60 mg orlistat to demonstrate a significantly greater reduction in visceral adipose tissue as compared to placebo over 6 month duration. Consistent with previous orlistat studies, the nonprescription dose resulted in significantly greater changes in body weight, total fat mass, and percent body fat. The data also demonstrate that weight loss achieved with orlistat 60 mg positively impacts changes in VAT and, to a lesser degree IMAT and liver fat content, which are associated with improved insulin sensitivity. Taken together, these findings suggest that orlistat 60 mg may be an effective weight loss tool that can help reduce cardiometabolic risk associated with upper body adiposity.

ACKNOWLEDGEMENT

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods and Procedures
  5. Results
  6. Discussion
  7. ACKNOWLEDGEMENT
  8. DISCLOSURE
  9. References

This study was supported by GlaxoSmithKline Consumer Healthcare. The sponsor had primary responsibility for designing the study protocol, receiving and managing study data and planning statistical analyses. The authors from the academic sites collaborated with the sponsor on aspects of study design and assessed and treated all study participants. S.S. and S.M.S. wrote the first draft of the manuscript, which was revised with input from all of the authors. The authors thank all the individuals who generously shared their expertise in the design, planning, and conduct of the study. We also acknowledge all the subjects who participated in this study. Some data from this study were presented at the 1st International Congress on Abdominal Obesity, January 2010, and the International Congress of Obesity, July 2010.

DISCLOSURE

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods and Procedures
  5. Results
  6. Discussion
  7. ACKNOWLEDGEMENT
  8. DISCLOSURE
  9. References

All academic authors received research grants from GlaxoSmithKline (GSK) Consumer Healthcare (to their respective institutions) to conduct the study. F.G. and J.M. have served as paid consultants to the company. E.B, S.M.S., and V.B-D are employees of and S.M.S. and V.B.-D. hold stock in the company. R.K. is a contract employee of GSK Consumer Healthcare. F.P. is currently an employee for R & D, Gilead Sciences.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods and Procedures
  5. Results
  6. Discussion
  7. ACKNOWLEDGEMENT
  8. DISCLOSURE
  9. References
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