Weight Management

Study Design:
- Click here for explanation of classification scheme.
Quality Rating:
Research Purpose:

To assess the impact of treatment with orlistat, a pancreatic lipase inhibitor, on weight loss, glycemic control, and serum lipid levels in obese patients with type 2 diabetes on sulfonylurea medications.

Inclusion Criteria:

1.Completion of the placebo during the 5-week lead-in period with a drug compliance of at least 70% based on counting placebo tablets.

2. >18 years of age

3. BMI: 28-40 kg/m2

4. Oral hypoglycemic drug therapy for at least 6mo before the study

5. Stable plasma glucose level on a second-generation sulfonylurea agent as the only hypoglycemic agent at entry into the trial.

Exclusion Criteria:

1. Pregnant, lactating, or of childbearing potential and not taking adequate contraceptive measures.

2. Clinically relevant condition that would interfere with the outcome of the study: psychiatric disorders, substance abuse, cholecystitis, pancreatic disease, uncontrolled hypertension.

3. Significant complications associated with diabetes.

4. Weight loss >4 kg in the previous 3 months.

5. History of recurrence of nephrolithiasis or symptomatic cholelithiasis, or GI surgery for weight loss, history of bulimia or laxative abuse.

6. Had taken medication that could influence body weight or plasma lipids during the 8 weeks before the study.

Description of Study Protocol:

Recruitment: A multicenter double-blind randomized placebo-controlled trial was conducted in 12 centers in the U.S.  Specific recruitment methods not specified. 

Design: Randomized controlled trial.  After lead-in period, patients who were receiving oral sulfonylurea medications for 6 months prior, were prescribed a nutritionally balanced weight-loss diet comprising 30% of calories from fat, 50% calories from CHO, and 20% calories from protein.  For 2 weeks prior to randomization, subjects were maintained on a constant dose of oral hypoglycemic agent for the remainder of the lead-in period.

Blinding Used:  Double-blind

Intervention: Study tablets were to be taken with meals and along with a hypocaloric diet ( -500 kcal/day deficit) for 52 weeks.

Randomization to Orlistat (120 mg or placebo TID) was stratified according to weight loss and glucose control as during the 4 week lead-in period as follows:

a. weight loss < 2 kg, glucose 5.6 to 8.9 mmol/L

b. weight loss < 2 kg, glucose 9.0-12.2 mmol/L

c. weight loss > 2 kg, glucose 5.6 –8.9 mmol/L

d. weight loss > 2 kg, glucose 9.0 –12.2 mmol/L

Statistical Analysis:

Patients were included in the safety analysis if they had received one dose of trial medication after randomization and had a subsequent safety observation.  The null hypothesis that the expected mean weight change from baseline to the end of 1 year of double-blind treatment did not differ significantly between the placebo and orlistat treatment was tested using ANOVA and ANCOVA models.  The placebo adjusted 95% CI of orlistat treatment effect, based on the least-squares mean was also determined.

Data Collection Summary:

Timing of Measurements:

Assessments were conducted at weeks 1 and 2 and then every 2-4 weeks for the remainder of the 52 weeks.

  • fasting glucose was measured at each visit
  • HbA1C was measured at baseline and at weeks 12, 24, 36, and 52 weeks.
  • insulin levels were assessed at bseline and at 24 and 52 weeks. 

Dependent Variables:

  • glycemic control ( changes from baseline in fasting plasma glucose, HbA1C, and insulin)
  • lipid levels ( changes from baseline to weeks 24 and 52 for: total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, LDL-to-HDL ratio, VLDL cholesterol, and apolipoprotein B) 
  • waist circumference (measured baseline and at 24 and 52 weeks)
  • tolerability to orlistat
  • body weight

  • Independent Variables:

  • weight loss
    • orlistat 120mg TID
    • hypocaloric diet ( -500 kcals/d)

    Control Variable:

    • placebo TID


  • Description of Actual Data Sample:

    Initial N: 391 patients were enrolled. 322 completed the 5 week lead-in and were randomized to double-blind treatment. Orlistat group comprised of 163 subjects and 159 in placebo group.

    Attrition (Final N): 254 completed the study: 73% in placebo group & 85% in Orlistat group.  Reasons for premature withdrawal included adverse effects, loss to follow-up, noncompliance, administrative, protocol violations and treatment failure.  79% dropout rate.

    Age / Ethnicity / Demographics / Anthropometrics:

    Parameter Placebo Orlistat
    n 159 162
    Sex (M/F) 85/74 79/83
    Age (years) 54.7 + 9.7 55.4 + 8.8
    White 140 141
    Black 9 13
    Hispanic 6 4
    Other 4 4
    Weight (kg) 99.7 + 15.4 99.6 + 14.5
    Height (cm) 170.9 + 9.5 169.6 + 9.5
    BMI (kg/m2) 34.0 + 3.4 34.5 + 3.2
    Fasting plasma glucose (mmol/l) 9.09 + 1.87 8.85 + 1.68
    HbA1c ( %) 8.2 + 1.07 8.05 + 0.98

    Location: U.S.

    Summary of Results:
    • After 1 yr of treatment, the Orlistat group lost 6.2 + 0.45% of initial body weight compared to 4.3 + 0.49% in the placebo group (P<0.001).  Twice as many patients receiving Orlistat (49% vs 23%) lost > 5% of initial body weight (P<0.001).
    • Orlistat treatment + diet compared with placebo + diet was associated with a significant improvement in glycemic control as reflected in decreased HbA1c and fasting glucose (P<0.001).

    Parameter Placebo Group Orlistat Group p value
    weight loss in kg(after 1 yr) 6.19 + 0.51 4.31 + 0.57 P<0.001
    weight loss of 5% of initial body weight 22.6% 48.8% P<0.001
    weight loss > 10% of initial body weight 8.8% 17.9% P=0.017
    mean fasting plasma glucose (mmol/l) after 1yr.

     increase 0.54 + 0.15

    decrease 0.02 + 0.14 P<0.001
    mean HbA1c increase 0.18 + 0.11% decrease 0.28 + 0.09% P<0.001
    decrease in mean waist circumference after 1 yr (cm) -2.0 + 0.5 -4.8 + 0.5 P<0.01
    oral sulfonylurea medication decrease 9% decrease 23% P=0.0019

    Orlistat treatment also improved serum lipids compared to placebo group as shown in below table.

    serum lipids p value
    T-Chol <0.001
    LDL-C <0.001
    TG <0.05
    Apolipprotein B <0.001
    LDL/HDL ratio <0.001

    Other Findings:

    • A total of 43.2% of orlistat treated patients decreased the amount of oral sulfonylureas, compared to 28.9% of the placebo group.
    • 11.7% of orlistat treated patients discontinued sulfonylurea medication
    • 15 placebo treated patients ( 8.8%) withdrew from the trial prematurely due to  elevated plasma glucose levels on three or more occasions despite maximal doses of sulfonylurea medication compared to only 5 patients (2.5%) in the orlistat group. 
    • 79% of patients in the orlistat group complained of at least one GI event compared to 59% in the placebo group.
    • 7 patients in the orlistat group withdrew due to the GI events compared to 2 in the placebo group.
    • After 52 weeks of treatment, mean vitamin E and beta-carotene levels were significantly lower in the orlistat group vs. placebo ( P <0.001). However, no significant change in the E-to-LDL ratio in either group.
    Author Conclusion:

    Orlistat is an effective treatment modality in obese patients with type 2 diabetes with respect to clinically meaningful weight loss and maintenance of weight loss, improved glycemic control, and improved lipid profile.

    Funding Source:
    F Hoffmann-La Roche, Novo-Nordisk, Boots, Sandoz, Parke-Davis, Boehringer Mannheim, Eli Lilly
    Pharmaceutical/Dietary Supplement Company:
    University/Hospital: Baylor Medical Center, VA Hospital, University of Utah, University of Washington Medical Center, University of Pittsburgh Medical School, Washington University Medical School, Georgetown University Medical School, San Diego Endocrine and Medical Clinic, East Bay Clinical Trial Center, Florida Hospi
    Reviewer Comments:

    Well-designed study with well defined inclusion and exclusion criteria.  There was no behavioral component or physical activity reported in this study.

    The results of this study are somewhat disappointing; the mean weight loss in the Orlistat group was 13.5 lb & 10lb in the placebo group.

    Quality Criteria Checklist: Primary Research
    Relevance Questions
      1. Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies) Yes
      2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about? Yes
      3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice? Yes
      4. Is the intervention or procedure feasible? (NA for some epidemiological studies) Yes
    Validity Questions
    1. Was the research question clearly stated? Yes
      1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? Yes
      1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? Yes
      1.3. Were the target population and setting specified? Yes
    2. Was the selection of study subjects/patients free from bias? Yes
      2.1. Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study? Yes
      2.2. Were criteria applied equally to all study groups? Yes
      2.3. Were health, demographics, and other characteristics of subjects described? Yes
      2.4. Were the subjects/patients a representative sample of the relevant population? Yes
    3. Were study groups comparable? Yes
      3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) Yes
      3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? Yes
      3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) Yes
      3.4. If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis? N/A
      3.5. If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.) N/A
      3.6. If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? N/A
    4. Was method of handling withdrawals described? Yes
      4.1. Were follow-up methods described and the same for all groups? Yes
      4.2. Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.) Yes
      4.3. Were all enrolled subjects/patients (in the original sample) accounted for? Yes
      4.4. Were reasons for withdrawals similar across groups? Yes
      4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study? N/A
    5. Was blinding used to prevent introduction of bias? Yes
      5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? Yes
      5.2. Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.) Yes
      5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? N/A
      5.4. In case control study, was case definition explicit and case ascertainment not influenced by exposure status? N/A
      5.5. In diagnostic study, were test results blinded to patient history and other test results? Yes
    6. Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described? Yes
      6.1. In RCT or other intervention trial, were protocols described for all regimens studied? Yes
      6.2. In observational study, were interventions, study settings, and clinicians/provider described? N/A
      6.3. Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect? Yes
      6.4. Was the amount of exposure and, if relevant, subject/patient compliance measured? Yes
      6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? ???
      6.6. Were extra or unplanned treatments described? N/A
      6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? Yes
      6.8. In diagnostic study, were details of test administration and replication sufficient? N/A
    7. Were outcomes clearly defined and the measurements valid and reliable? Yes
      7.1. Were primary and secondary endpoints described and relevant to the question? Yes
      7.2. Were nutrition measures appropriate to question and outcomes of concern? Yes
      7.3. Was the period of follow-up long enough for important outcome(s) to occur? Yes
      7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? Yes
      7.5. Was the measurement of effect at an appropriate level of precision? Yes
      7.6. Were other factors accounted for (measured) that could affect outcomes? N/A
      7.7. Were the measurements conducted consistently across groups? Yes
    8. Was the statistical analysis appropriate for the study design and type of outcome indicators? Yes
      8.1. Were statistical analyses adequately described and the results reported appropriately? Yes
      8.2. Were correct statistical tests used and assumptions of test not violated? Yes
      8.3. Were statistics reported with levels of significance and/or confidence intervals? Yes
      8.4. Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)? Yes
      8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? Yes
      8.6. Was clinical significance as well as statistical significance reported? Yes
      8.7. If negative findings, was a power calculation reported to address type 2 error? N/A
    9. Are conclusions supported by results with biases and limitations taken into consideration? Yes
      9.1. Is there a discussion of findings? Yes
      9.2. Are biases and study limitations identified and discussed? No
    10. Is bias due to study's funding or sponsorship unlikely? ???
      10.1. Were sources of funding and investigators' affiliations described? No
      10.2. Was the study free from apparent conflict of interest? ???