- Click here for explanation of classification scheme.

The aim of the present study was to evaluate critically, in the pooled multicenter orlistat clinical trial population, the hypothesis that relatively small long-term body weight loss significantly improves glucose tolerance and reduces the rate of diabetes onset in obese subjects.

• >18 years of age
• BMI: 30 to 43
• Adequate contraception in women of childbearing age
• Absence of weight loss (>4 kg) in the previous 3 months

• Stopped smoking in the past 6 months
• Significant cardiac, renal, hepatic, GI, psychiatric or endocrine disorders
• Had drug-treated type 2 diabetes
• History or presence of substance abuse 
• Excessive intake of alcohol
• Taking medications that altered appetite or lipids

Recruitment: Subjects were recruited at 39 clinical research centers in the U.S. and Europe between 1992 and 1995.

Design:  Meta-analysis of pooled data from three 2-year, double blinded RCTs. Individuals assigned to receive either orlistat, 120 mg 3 times daily, or placebo for 2 full years were included. All individuals were placed on a low energy diet during yr 1 on the basis of estimated maintenance requirements: (1.3 x calculated BMR) – (500 to 800 kcal/d) and a maintenance diet during year 2. A 4-wk lead in period used to evaluate potential to lose weight and were stratified into 2 groups: <2 kg vs. 2 kg and then were randomized to placebo or Orlistat group.

Blinding used (if applicable): pooled data from double-blinded studies

Intervention: 120-mg capsules 3 times per day with their 3 main meals for 52 or 104 weeks

Statistical Analysis: Analysis of variance models were used to test the hypothesis that changes in baseline body weight and oral glucose tolerance were greater in the Orlistat group than in the placebo group. Categorical analysis of frequency distributions of weight loss and shift in OGTT status were performed using X² analysis. The glucose and insulin AUCs were compared across the treatment groups by 2-way analyses of covariance using treatment and diabetes status as group variables.

Timing of measurements: 

• Baseline screening included medical history, physical exam, weight, EKG, thyroid function, hematology, blood chemistries, urinalysis and 3-hr OGTT with 75 g glucose load; criteria used at 2-hr for evaluation:  Normal: <140 mg/dL,  Impaired: 140 to 199 mg/dL, Diabetes: >=200 mg/dL
• 3-hour oral glucose tolerance test (OGTT) with a 75-g oral glucose load was performed at randomization (day 1), 26 weeks (one study only), 52 weeks, and/or 104 weeks.
• Body weight was measured every 2 weeks until week 16, every 4 weeks until year 1, and every 8 weeks thereafter in the 2-year studies.

Dependent variables:

• Oral glucose tolerance status
• Body weight
• Glucose and insulin area under the curve (AUC)

Independent variables:

• Orlistat treatment or placebo

Control variables: 

 

Initial N: 675 participants completed the 4-week placebo lead-in period and were randomized to receive double-blind treatment with placebo or Orlistat

Attrition (Final N):  675 participants, 316 in Placebo, 359 in Orlistat

Age:  Mean age = 44.3 ± 0.7 for Placebo group; 43.9 ± 0.6 for Orlistat group

Ethnicity: Primarily Caucasian with some African Americans, Hispanics and Asians

Other relevant demographics: none

Anthropometrics:  Mean length of follow-up was 582 days. 

Characteristics at randomization:

Characteristic	Placebo	Orlistat
	(n=316)	(n=359)
Weight, mean  ± SEM, kg	99.8  ± 0.9	99.0  ± 0.6
Body mass index, mean  ± SEM kg/m2	36.0  ± 0.9	35.6  ± 0.1

Location: 39 clinical centers in the U.S. and Europe

Other Findings

Participants who were treated with Orlistat lost more weight than those on placebo (-6.72 ±0.41 kg vs. –3.79 ±0.38 kg, (P<0.001)).

Those with IGT at baseline and on Orlistat were more likely to return to normal glycemia (71.6%) than those on placebo (49.1%) (P<0.04).

A smaller percentage of subjects with IGT at baseline progressed to diabetic status in the Orlistat group (3.0%) vs. the placebo group (7.6%); the difference was not statistically significant.

Fasting glucose decreased significantly more in both the normal (P<0.02) and impaired (P<0.02) groups treated with Orlistat compared with placebo, while the glucose under the curve decreased significantly more only in the normal group treated with Orlistat vs. placebo (P<0.001).

Partial inhibition of fat absorption by orlistat in obese subjects produces sustained weight loss, significantly impacts glucose and insulin metabolism, and can significantly diminish the risk of deterioration of glucose tolerance.

A limitation of the study was that the OGTT was done on day 1 after the 4 wk lead-in period after the subjects had followed an energy restricted diet (-500 to -800 kcal below estimated maintenance energy requirements).

 

Industry:

Hoffman LaRoche Pharmaceutical/Dietary Supplement Company:

Only 3 studies included and protocols differed minimally.  The weight loss in the placebo group was ~50% of the that lost by the Orlistat group (~15 pounds over the 2 yr period).