Weight Management

Citation:
Kelley DE, Bray GA, Pi-Sunyer FX, Klein S, Hill J, Miles J, Hollander P. Clinical efficacy of orlistat therapy in overweight and obese patients with insulin-treated type 2 diabetes:  a 1-year randomized controlled trial. Diabetes Care 2002;25:1033-1041.  PubMed ID: 12032111
 
Study Design:
Randomized Controlled Trial
Class:
A - Click here for explanation of classification scheme.
Quality Rating:
Positive POSITIVE: See Quality Criteria Checklist below.
Research Purpose:
To assess the effect of orlistat on weight loss, glycemic control and cardiovascular risk factors in overweight or obese insulin-treated type 2 diabetic patients.
Inclusion Criteria:
  • Aged 40 - 65 years
  • Overweight or obese adults (BMI 28 - 43)
  • Stable weight (< 3 kg weight change) for 3 months before study entry 
  • Type 2 diabetes treated with insulin alone or combined with oral agents
  • Suboptimal metabolic control (HbA1c 7.5 - 12.0%)
Exclusion Criteria:
  • If diabetes treatment included a thiazolidinedione or if diabetic medications had changed during the 12 weeks before screening
  • Medical history or presence of renal, hepatic, or endocrine disorders that could affect the results of the study
  • Previous bariatric surgery
  • Use of approved or experimental weight reduction medications or treatments
  • Presence of malabsorption syndrome
  • Presence of bulimia or laxative abuse
  • Presence of disorders that could affect compliance with requirements of study
Description of Study Protocol:

Recruitment

Methods not described.

Design:  Multicenter, randomized placebo-controlled trial, patients stratified based on HbA1c levels <10 or >10%

Blinding used (if applicable):  Double blind

Intervention (if applicable)

  • Orlistat (120 mg 3 x day) or placebo combined with reduced calorie diet 
  • Medication compliance assessed by capsule counting
  • Patients considered compliant if at least 70% of prescribed dose taken, withdrawn from study if compliance <60%
  • Dietary compliance monitored by dietary intake records
  • Patients encouraged to participate in physical activity 

Statistical Analysis

Groups were compared using Holm's sequential rejection procedure.  Number of subjects enrolled was estimated to be sufficient to provide a statistical power of at least 80% to detect differences between treatment groups of a 2.1 kg change in body weight and 0.5% change in HbA1c.  Intent to treat analysis conducted using data from all patients who had at least 1 postbaseline efficacy observation.  Differences between groups in the frequency distributions of weight loss, changes in HbA1c and changes in diabetes medications were tested using Cochran-Mantel Haenszel method.

Data Collection Summary:

Timing of Measurements

Study consisted of a 2 week screening phase followed by 52 week treatment phase.  Subjects were seen every 2-4 weeks for study assessments, procedures and dietary instruction.  Fasting serum glucose measured at each visit, HbA1c measured at baseline and at weeks 12, 24, 36 and 52.  Serum lipids and waist circumference measured at weeks 24 and 52.

Dependent Variables

  • Body weight
  • Glycemic control:  HbA1c, fasting serum glucose, dosage of diabetes medications 
  • Blood pressure
  • Serum lipids:  total, LDL and HDL cholesterol, triglycerides, and LDL/HDL ratio
  • Waist circumference measured with calibrated measuring tape 

Independent Variables

  • Orlistat (120 mg 3 x day) or placebo combined with reduced calorie diet 
  • Medication compliance assessed by capsule counting
  • Patients considered compliant if at least 70% of prescribed dose taken, withdrawn from study if compliance <60%
  • Dietary compliance monitored by dietary intake records
  • Patients encouraged to participate in physical activity 

Control Variables

 

Description of Actual Data Sample:

Initial N: 550 patients enrolled and randomized. (274 in orlistat group, 276 in placebo)

Attrition (final N):  Intent-to-treat population consisted of 266 in orlistat group (116 males, 150 females) and 269 in placebo group (118 males, 151 females).  Overall, 54% of placebo-treated and 50% of orlistat-treated patients withdrew prematurely.

Age:  orlistat group:  57.8 +/- 0.5 years, placebo group:  58.0 +/- 0.5 years 

Ethnicity:  orlistat group:  71% Caucasian, 17% African-American, 2% Asian, 10% Other; placebo group:  73% Caucasian, 16% African-American, 1% Asian, 10% Other 

Other relevant demographics:

Anthropometrics:  Baseline characteristics similar between groups; groups well-matched for sex and distribution of racial/ethnic groups

Location:  43 centers in the United States

 

Summary of Results:

 

Variables

Placebo (n=276)

Orlistat (n=266)

P value

Change in SBP (mmHg) -0.9 +/- 1.0 -1.2 +/- 1.0

0.948

Change in DBP (mmHg)

-1.0 +/- 0.5

-2.3 +/- 0.7

0.075

Change in total cholesterol (mmol/l) 0.08 +/- 0.07 -0.30 +/- 0.07 0.002
Change in LDL cholesterol (mmol/l) -0.08 +/- 0.05 -0.38 +/- 0.05 0.001
Change in HDL cholesterol (mmol/l) 0.05 +/- 0.01 0.02 +/- 0.01 0.247
Change in LDL/HDL ratio -0.25 +/- 0.06 -0.50 +/- 0.07 0.013

Change in triglycerides (mmol/l)

0.31 +/- 0.13

0.18 +/- 0.16

0.421

Other Findings

After 1 year, the orlistat group lost significantly more weight (-3.89 +/- 0.27 kg of baseline body weight) than the placebo group (-1.27 +/- 0.28 kg, P < 0.001).

Orlistat treatment, compared with placebo, produced greater decreases in HbA1c (-0.62 +/- 0.08% vs -0.27 +/- 0.08%, P = 0.002), fasting serum glucose (-1.63 +/- 0.3 vs -1.08 +/- 0.3 mmol/l, P = 0.02) and the required doses of insulin and other diabetic medications.

Orlistat also produced greater improvements than placebo in serum total cholesterol (P = 0.0002) and LDL cholesterol concentrations (P = 0.001) and LDL/HDL ratio (P = 0.01).  

Author Conclusion:
Orlistat therapy produces clinically significant weight loss, with improvements in glycemic control and cardiovascular disease risk factors, in overweight or obese patients with type 2 diabetes who have suboptimal metabolic control with insulin therapy. 
Funding Source:
Industry:
Hoffman LaRoche
Pharmaceutical/Dietary Supplement Company:
Reviewer Comments:
Recruitment methods not described.  Some statistical methods uncommon. Study sponsored by Hoffman-La Roche.
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) ???
  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? No
  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? N/A
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? N/A
  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? ???
  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? ???
  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? ???
  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? Yes
9. Are conclusions supported by results with biases and limitations taken into consideration? ???
  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? Yes
  10.2. Was the study free from apparent conflict of interest? ???