Weight Management

Citation:

Miles JM, Leiter L, Hollander P, Wadden T, Anderson JW, Doyle M, Foreyt J, Aronne L and Klein S. Effect of orlistat in overweight and obese patients with type 2 diabetes treated with metformin. Diabetes Care 2002;25(7):1123-1128.

PubMed ID: 12087008
 
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:
The purpose was to assess effect of a gastrointestinal lipase inhibitor (orlistat) on body weight, glycemic control, and cardiovascular risk factors in patients with type 2 diabetes who are treated with metformin.
Inclusion Criteria:
  • diagnosis of type 2 diabetes
  • 40 to 65 years of age
  • BMI 28 to 43 kg/m2
  • stable weight maintained for > 3 months
  • HbA1c between 7.5 and 12.0%
  • received metformin treatment at 1,000-2,550 mg/day for > 6 weeks prior to the study
  • patients who received sulfonylurea therapy in addition to metformin were permitted as long as the sulfonylurea dose was stable for 12 weeks before study entry
  • informed consent given.
Exclusion Criteria:
  • receiving insulin, thiazolidinediones or alpha glucosidase inhibitors
  • any clinical condition that might affect study end points including renal, hepatic or endocrine disorders, poorly controlled hypertension (systolic blood pressure > 160 mm Hg or diastolic blood pressure > 100 mg Hg), active gastrointestinal disease, previous bariatric surgery, a history of bulimia, substance abuse, or use of any weight loss medications
  • pregnancy, lactation or women of child-bearing potential.
Description of Study Protocol:

Recruitment: 34 centers in the U.S. and 6 centers in Canada

Design: Multi-center, randomized, double-blind, placebo-controlled trial

  • 2-week screening phase followed by randomization to 52-week control or treatment phase
  • patients were stratified into two groups based on HbA1c levels (< 10% or > 10%)
  • reduced calorie diet
    • 600 kcal/day deficit (calculated with Harris-Benedict equation and designed to promote weight loss of 0.25-0.5 kg/week)
    • after 6 months, daily energy intake reduced by additional 200 kcal/day to compensate for reduced energy needs due to weight loss
    • minimum calorie intake 1,200 kcal/day
    • energy distribution: 30% as fat, 50% as carbohydrate, and 20% as protein
    • maximum cholesterol content of 300 mg/day.
    • all patients received dietary counseling at baseline and regular interals (not describesd)
  • all patients encouraged to increase physical activity
  • daily multivitamin tablet prescribed

Blinding used: double blinding

Intervention:

  • Patients randomized received 52 weeks treatment with 120 mg orlistat or placebo three times daily with main meals

Statistical Analysis

  • Power analysis assumed 35% drop out rate. Alpha level of 0.025 used in sample size estimations; sample size estimated to provide 80% power to detect differences in primary dependent variables of body weight and HbA1C
  • Intent-to-treat analysis on 254 patients in placebo group and 250 patints in orlista group who had at least one efficacy follow-up visit
  • tested significance of treatment differences (weight and HbA1c) by ANCOVA models including fixed effects for treatment, center, treatment by center interaction HbA1c stratum, treatment by HbA1c stratum interaction and baseline covariate
  • ANCOVA also used for secondary efficacy variables (fasting serum glucose and lipids, blood pressure, dose of diabetes medications, hypertension and waist circumference
  • Placebo-adjusted 95% CIs of orlistat treatment effect were determined for all primary and secondary dependent (efficacy) variables
  • Cochran Mantel-Haenszel test used for frequency distributions of proportions of patients in each treatment group with decreases in body weight of > 0.5% and > 1.0%
Data Collection Summary:

Timing of Measurements

  • clinic visits at weeks 0,2,4,8,12,16, 20, 24, 30, 36, 42, 48 and 52
  • baseline screening at week 0 included: medical history, physical examination, electrocardiogram, standard laboratory assessments, vital signs, body weight, HbA1c, serum lipids
  • serum glucose measured at weeks 0, 2, 4, 8, 12, 16, 20, 24, 30, 36, 42, 48 and 52)
  • HbA1c measured at weeks 0, 12, 24, 36 and 52
  • Serum lipids (triglycerides, total-, LDL- and HDL-cholesterol, LDL/HDL ratio) measured at weeks 0, 24 and 52
  • measured waist circumference at weeks 0, 24 and 52

Dependent Variables

  • Primary:
    • body weight
    • HbgA1c
  • Secondary
    • fasting serum lipids
    • blood pressure (measured in sitting position)
    • waist circumference (measured midway between lateral lower rib margin and the iliac crest)

Independent Variables

  • orlistat treatment (120 mg three times daily at main meals)

Control Variables

  • placebo for subjects in control group
  • patients were stratified into two groups based on HbA1c levels (< 10% or > 10%)
Description of Actual Data Sample:

Initial N:  516

  • Placebo: n=261 (52% males)
  • 120 mg orlistat treatment n=255 (52% males)

Attrition: 311 patients completed 1 year of treatment

Age: mean ages 43.7 ± 0.4 and 52.5 ± 0.4 years for placebo and treatment groups, respectively

Ethnicity: for placebo and treatment groups, respectively:

  • caucasian: 79% and 84%
  • black: 36% and 24%
  • other: 17% and 15%

Other relevant demographics:

Anthropometrics: at baseline, no significant differences between placebo and treatment groups in sex, age, race, weight, height, BMI, HbA1c or fasting glucose levels.

  • mean weight 101.5 kg
  • mean BMI: 35.4 kg
  • mean fasting glucose 11.3 mmol/L
  • mean HbA1c 8.8%

Location: 34 centers in the United States and 6 in Canada

 

Summary of Results:

 

Variables

Orlistat Group

 

Placebo group

 

Statistical Significance of Group Difference

Weight

4.7 ± 0.3 kg

1.8 ± 0.3 kg

P < 0.0001

Reduction in HbA1c (adjusted for sulfonylurea)

-0.90 ± 0.08 %

-0.61 ± 0.08 %

 P=0.014

Reduction in fasting serum glucose

-2.0 ± 0.2 mmol/L

-0.7 ± 0.2 mml/L

P=0.001

Patients in orlistat group lost weight more rapidly than those in the placebo group. More than twice as many patients in the treatment group lost > 5% of baseline body weight (P=0.008); more patients in treatment group lost > 10% of baseline body weight (P=0.003) .

Other Findings

 

Reason for drop-out Placebo Treatment
treatment refusal 57 36
loss to follow-up 35 25
adverse events 12 25
protocol violations 5 0
treatment failure 2 0

Author Conclusion:
Obese patients with type 2 diabetes who are treated with metformin may benefit from adjunctive orlistat thereapy.
Funding Source:
Industry:
Hoffman LaRoche
Pharmaceutical/Dietary Supplement Company:
Reviewer Comments:
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? 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? Yes
  6.6. Were extra or unplanned treatments described? Yes
  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? Yes
  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? Yes
10. Is bias due to study's funding or sponsorship unlikely? Yes
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.2. Was the study free from apparent conflict of interest? Yes