EAL

DM: Prevention of Type 2 Diabetes (2007)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To determine the long-term effect of orlistat, a gastrointestinal lipase inhibitor, in combination with lifestyle changes in reducing progression to type 2 diabetes and body weight over 4 years in obese, non-diabetic patients who had either normal glucose tolerance (NGT) or impaired glucose tolerance (IGT). Secondary aims were to determine the effect of orlistat treatment on weight-related metabolic abnormalities associated with increased risk for cardiovascular disease and the safety and tolerability of orlistat over 4 years.

Inclusion Criteria:

30-60 years of age
BMI ≥ 30kg/m²
nondiabetic glucose tolerance
Patients with IGT were eligible for inclusion. The criteria for IGT were fasting whole blood glucose < 6.7mmol/l and 2-h whole blood glucose 6.7-10.0mmol/l.

Exclusion Criteria:

Diabetes and ongoing and active cardiovascular and gastrointestinal disease.

Description of Study Protocol:

Recruitment

The system for centralized patient recruitment and scheduling of patients were described in a previous study by Torgerson in Control Clin Trials 2001;22:515-525.

Design

After screening subjects were randomized according to sex and OGTT results to receive either placebo or orlistat in a one-to-one ratio, using a centralized randomization procedure and schedule.

Blinding used (if applicable)

Matching placebo and oristat capsules were used. The investigators received sealed envelopes for each patient that contained the identity of the study medication.

Intervention (if applicable)

All patients were prescribed a reduced-calorie diet (~800 kcal/d deficit) containing 30% of calories from fat and not more than 300 mg of cholesterol per day. Energy intake was readjusted every 6 months to account for any weight lost during the preceding months. Participants received dietary counseling every 2 weeks for the first 6 months and monthly thereafter. Patients were encouraged to walk at least 1 extra kilometer a day in addition to their usual physical activity. All patients kept physical diaries.

Statistical Analysis

The intent-to-treat population consisted of all randomized patients who received at least one dose of study drug and had at least one follow-up efficacy assessment. Cumulative incidence rates of type 2 diabetes were calculated using a Kaplan-Meier estimate-of-survival function with partitions at 6-month intervals.
Statistical significance of differences between treatment groups for the primary end point of time to onset of diabetes were determined by the log-rank test. If significant, hazard ratios were determined as an estimate of relative risk of developing diabetes. Age and BMI subgroups were categorized at baseline as above or below the median to determine the effect of age and BMI on the relative risk of developing type 2 diabetes.
Quantitative changes in primary and secondary efficacy parameters were analyzed at yearly timepoints using an ANCOVA model. Baseline values were used as covariates. Lipid parameters were analyzed using percent change. Body weight changes were analyzed categorically. Descriptive statistics for all secondary parameters involving changes over time used observed data. Descriptive statistics for change in body weight and categorical body weight changes used last observations forward (LOCF) data unless otherwise noted. Observed, LOCF, and baseline observation carried forward (BLCF) methods were used for hypothesis testing of quantitative parameters.

Data Collection Summary:

Timing of Measurements

Dietary counseling was provided every 2 weeks for the first 6 months then monthly thereafter.
Body weight was recorded every 3 months.
Waist circumfernece was assessed at baseline, 3 and 6 months and every 6 months tereafter.
Standard laboratory parameters as well as plasma levels of the fat-soluble vitamins were assessed every 6 months.
A 75-g OGTT was performed at baseline and then at every 6 months.

Dependent Variables

Time to onset of type 2 diabetes
Change in body weight
Change from baseline in anthropometric measurements, metabolic profile, and in time to onset of IGT.

Independent Variables

Lifestyle changes and 120 mg of orlistat or
Lifestyle changes and placebo

Control Variables

Baseline variables were used as covariates in analyzing the quantitative changes in primary and secondary efficacy parameters at yearly timepoints.

Description of Actual Data Sample:

Initial N: 3,305 participants were randomized to treatment with orlistat plus lifestyle changes (n = 1,650) or placebo plus lifestyle changes (n = 1,655), of which 3,304 were treated.

Attrition (final N): 1,414 with 850 of 1,650 [52%] of the orlistat-treated group and 564 of 1,655 [34%] of the placebo group completing the treatment.

Age: Orlistat plus lifestyle changes 43.0 years ± 8.0 and in the placebo plus lifestyle chagnge group 43.7 years ± 8.0

Ethnicity: Not described by author

Other relevant demographics: Orlistat plus lifestyle group 905 (55.2%) female, 735 (44.8%) male. Placebo group 905 (55.3%) female, 732 (44.7%) male.

Anthropometrics: No signficant difference

Location:

22 Swedish medical centers between 1997 and 2002

Summary of Results:

The effect of baseline strata on the relative risk of developing type 2 diabetes over 4 years in patients, irrespective of treatment.

Variables	Hazard ratio	95% CI	p
Treatment group: orlistat vs placebo	0.63	(0.46-0.87)	0.0052
Glucose tolerance: impaired vs normal	10.60	(7.30-15.40)	<0.0001
Sex: male vs female	1.41	(1.02-1.96)	0.0390
Age (years): > 44 vs ≤ 44	1.44	(1.02-2.04)	0.0383
BMI (kg/m²): ≥ 37 vs < 37	1.36	(0.97-1.91)	0.0726

Mean change from baseline of cardiovascular risk factors at years 1 and 4 in all patients (observed data)

Variables	Year 1 Placebo + lifestyle	Year 1 Orlistat + lifestyle	Year 1 p between treatments	Year 4 Placebo + lifestyle	Year 4 Orlistat + lifestyle	Year 4 p between treatments
n	1,295	1,487		567	851
Diastolic BP (mmHg)	-2.6	-3.6	<0.01	-1.9	-2.6	<0.01
Systolic BP (mmHg)	-5.2	-7.3	<0.01	-3.4	-4.9	<0.01
Total Cholesterol (%)	-1.3	-8.8	<0.01	-2.3	-7.9	<0.01
LDL cholesterol (%)	-1.6	-11.4	<0.01	-5.1	-12.8	<0.01
HDL cholesterol (%)	8.5	3.4	<0.01	9.1	6.5	<0.01
LDL-to-HDL ratio	-0.3	-0.5	<0.01	-0.4	-0.6	<0.01
Triglycerides (%)	-6.3	-6.2	<0.05	2.9	2.4	NS
Waist Circumference (cm)	-7.0	-9.6	<0.01	-4.4	-6.4	<0.01
Venous fasting whole blood glucose (mmol/l)	0.2	0.1	<0.01	0.2	0.1	<0.01
Serum fasting insulin (pmol/l)	-17.0	-26.5	<0.01	-20.6	-32.0	<0.01
Fibrinogen (µmol/l)	0.1	0.2	NS	-0.5	-0.4	<0.05
Plasminogen activator inhibitor-1 (U/ml)	-3.0	-7.1	<0.01	0.1	-3.0	<0.01

Other Findings

During 4 years of treatment, orlistat plus lifestyle changes signficantly decreased the progression to type 2 diabetes compared with placebo plus lifestyle changes (log-rank p = 0.0032). Cumulative incidence rates were 6.2 vs 9.0%. The hazard ratio (0.627 [95% CI 0.455-0.863]) corresponds to a 37.3% decrease in the risk of developing diabetes with orlistat compared with placebo.

Mean weight loss was significantly greater with orlistat than placebo at 1 year (10.6 vs 6.2 kg; p < 0.001) and remained significanlty greater at the end of the 4 year study (5.8 vs 3.0 kg;p < 0.001).

There were statistically significant decreases in the orlistat group compared with the placebo group after 4 years of treatment for all assessed fat-soluble vitamins, however the mean level of each assessed vitamin remained well within its reference range at all times during the 4 year study for both the orlistat and placebo group.

Author Conclusion:

The addition of orlistat to lifestyle changes significantly reduces the incidence of type 2 diabetes in obese subjects over 4 years. In addition, orlistat significantly inceases weight loss in obese subjects with either imparied glucose tolerance or normal glucose tolerance and improves other cardiovascular risk factors.

Funding Source:

Reviewer Comments:

The study was not powered to detect treatment differences in the subgroup with NGT at baseline for which the progression rate to type 2 diabetes turned out to be very low. The proportion of patients who discontinued treatment prematurely was similar to other studies with up to two years' duration. A limitation was that repeat testing of patients with a positive OGTT result was not instituted until the majority of patients had completed the 6-month examination. Some repeat tests were not captured.

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?	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?	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