DM: Weight Management (2001)
1. Age between 30 to 70 years
2. Diagnosis of type 2 diabetes
3. Body weight 120% or more of ideal
4. Meal-stimulated serum C-peptide >0.50 pmol/ml
1. Current or previous use of fenfluramine or phentermine
2. Significant abnormalities in screening laboratory tests
3. Symptomatic or electrocardiographic evidence of coronary artery disease
4. Pregnancy or plans to become pregnant
5. Cancer, glaucoma, active psychiatric disorder, or any chronic disease that would make adherance to the study protocol difficult
Recruitment: Subjects were recruited from the University of Minnesota General Clinical Research Center and through advertisement in the local media.
Design: 44 overweight type 2 diabetic subjects were randomly assigned to 20mg of fenfluramine 3 times a day with meals and 37.5mg of phentermine once a day before breakfast or dual placebos that looked identical to the study drugs. According to pre-established protocols, medications for diabetes, antihypertensive, and antihyperlipemic medications were adjusted, added or stopped by the investigators. Diabetic medication was adjusted accordingly to meet each subject's glycemic goals (hypoglycemic medication was initiated or increased only if the subject was experiencing hyperglycemic symptoms or if HbA1C was >10.0% and was decreased or stopped if hypoglycemia occurred >2 times per week or if home blood glucose was often <100 mg/dl).
Blinding: Double-blinded.
Intervention: Subjects received instruction on a hypocaloric diet (500-1,000 kcal reduction each day) by a registered dietitian, an individualized exercise prescription (with a minimum of walking for 30 minutes 3 times a week) and instruction in behavior modification techniques. Follow-up visits were scheduled 1, 2, 4, 6, 8, 10 and 12 months after randomization.
Statistical Analysis:
- Baseline data and changes from baseline in study parameters were compared between treatment groups at each time point using t test for unpaired data.
- A p value < 0.01 was required to declare significance.
- A x2 test was used to determine if the frequency of medication adjustments differed by treatment group.
- All data was presented as mean + SEM
Timing of Measurements: At each follow-up visit, the subjects completed a questionnaire about symptoms and medications, received a clinical examination, had measurements for body weight, height, blood pressure and heart rate taken, and had blood samples taken for fasting plasma glucose, fasting plasma lipids, and HbA1C
Dependent Variables:
- Changes in oral hypoglycemic agents
- Weight
- Blood pressure
- BMI
- HbA1C
- Fasting plasma glucose and lipids
Independent Variables:
- 20 mg fenfluramine 3 x day and 37.5 mg phentermine daily or dual placebos
- hypocaloric diet (500-1,000 kcal/day)
- exercise prescription (min. of walking 30min. 3 times/week)
- behavior modification techniques
Initial N: 44 subjects, 23 in drug group, 21 in placebo group
Attrition: 41 subjects, 21 in drug group (12 females, 9 males), 20 in placebo group (11 females, 9 males)
Age: placebo group: 49 + 2 years, drug group: 51 + 2 years
Ethnicity: data not provided
Other Relevant Demographics:
Anthropometrics:
Baseline Demographic and Clinical Data
|
Parameter |
Placebo Group |
Drug Group |
| Weight (kg) | 107 + 4 | 108 + 4 |
| BMI (kg/m2) | 37.2 + 1.3 | 37.0 +1.1 |
| Fasting plasma glucose ( mg/dl) | 178 + 14 | 175 + 10 |
| HbA1C (%) | 8.5 + 0.3 | 8.3 + 0.3 |
| Total cholesterol ( mg/dl) | 191 + 4 | 220 + 20 |
| Fasting triglycerides (mg/dl) | 210 + 22 | 491 + 236 |
| HDL cholesterol (mg/dl) | 36 + 2 | 37 + 2 |
| LDL cholesterol (mg/dl) | 116 + 5 | 120 + 8 |
Location: University of Minnesota General Clinical Research Center
Only data obtained before the withdrawal of fenfluramine (September 1997) were included in the report of the study.
| Parameter | Placebo Group | Drug Group | P value |
| Changes in oral hypoglycemic agents | 5% taking less medication, 30% taking more medication | 52% taking less medication, 5 %taking more medication | P< 0.005 |
| Average weight loss after 6 months | -2.7 ±1.4 kg | -9.6 ±1.5 kg | P =0.003 |
| Average weight loss after 1 year | -2.5 ±2.5 kg | -8.1 ±1.6 kg | P =0.080 |
| Average weight loss (%) of initial weight after 1 year | 2.2 + 2.2 | 8.0 + 1.7 | P=0.055 |
| Fasting plasma glucose after 1 year | 6 ±9 mg/dl | -38 ±17 mg/dl | P =0.044 |
Other Findings:
Weight loss:
- The greatest weight loss was reported at 4 months in the drug treatment group (n=17) –10.3±1.7 kg and greatest at 6 months in the placebo group (n=13) –2.7±1.4 kg.
HbA1C:
- There were significant differences in HbA1C between groups at 2, 4, 6, 8 and 10 months but not at 12 months.
- The number of subjects also decreased over time, partly because the study was discontinued because fenfluramine was taken off the market during the study period.
- The number of subjects at each time point in months: 2: 39, 4: 34, 6: 26, 8: 24: 10: 22, 12: 16.
HbA1c (%)
| Time | Placebo | Drug | P value |
| 2 months | -0.4+0.1 | -1.7+0.2 | 0.001 |
| 4 months | -0.5+0.3 | -1.9+0.3 | 0.001 |
| 6 months | -0.3+0.2 | -1.6+0.3 | 0.002 |
| 8 months | -0.1+0.2 | -1.3+0.3 | 0.006 |
| 10 months | 0.1+0.2 | -0.9+0.3 | 0.016 |
| 12 months | -0.2+0.2 | -0.7+0.3 | 0.188 |
Fasting plasma glucose:
- Fasting plasma glucose was below baseline at each time point in the drug treatment group but only at 2 months in the placebo group.
Fasting plasma lipids:
- Plasma cholesterol and triglycerides both decreased in the drug treatment group.
- Only the differences in plasma triglycerides at 2 and 4 months between the 2 groups were significant.
- Decreases in LDL and HDL cholesterol were minor and not considered to be significant.
Although the study had to be terminated prematurely due to the withdrawal of fenfluramine from the U.S. market, the data from this study demonstrate that weight loss medications improve glycemia during periods of active weight loss and may produce sufficient weight loss to favorably affect long-term glycemic control.
The addition of weight loss drugs to a program of diet, exercise and behavior modification produced weight loss of 8% of intial weight at 1 yr, whereas the addition of placebo produced weight loss of only 2% of initial weight. In addition, 52% of the drug treatment group had decreased or stopped diabetes medications at study end.
The authors also noted that the subjects participating in this study had type 2 diabetes for a relatively short duration and only a few required insulin therapy for glycemic control. They suggested that these characteristics may predict a better response to weight loss than seen in patients with diabetes of a longer duration or with more advanced insulin deficiency.| Government: | NIH | ||
| Not-for-profit |
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Very clear inclusion and exclusion criteria.
Study protocol was very detailed.
Only 16 of the 41 subjects were able to complete the study before study termination as a result of fenfluramine being taken off the market.|
Quality Criteria Checklist: Primary Research
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| 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")? | Yes | |
| 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? | Yes | |
| 6.6. | Were extra or unplanned treatments described? | No | |
| 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? | Yes | |
| 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 | |