EAL

DM: Prevention and Treatment of CVD (2007)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To compare the effect of a conservative versus an intensive approach (addition of a thiazolidinedione) of managing diabetes on blood thrombgenicity of patients with type 2 diabetes mellitus.

Inclusion Criteria:

history of diabetes for >1 year
age 20-70 y
HbA1c greater-than-or-equal-to 7.5%
current treatment with insulin or a sulfonylurea

Exclusion Criteria:

contraindication to the use of thiazolidinediones
baseline transaminase levels > 2 times the upper normal limit
fasting C-peptide levels < 0.1 ng/ml
treatment with troglitazone or metformin in the prior three months
history of acute coronary syndrome or revascularization in the past three months
malignant diseases
concurrent anticoagulant or antiplatelet therapy (other than aspirin)

Description of Study Protocol:

Recruitment : not specified

Design : Randomized Controlled Trial. Subjects were randomized to receive placebo or 600 mg troglitazone once a day for three months. Subjects continued with current hypoglycemic therapy.

Blinding used (if applicable): study was double-blinded; placebo tablets matched intervention tablets

Intervention (if applicable): 600 mg troglitazone or placebo given to randomized subjects

Statistical Analysis

baseline differences between the two groups were assessed using non-paired Student t test or Mann-Whitney U test when distribution was not normal
repeated measures analysis of variance (RM-ANOVA) was used to test the effect of treatment on the HbA1c and thrombus formation-dependent measures
RM-ANOVA also used to test treatment and/or glycemic improvement effects; Geisser-adjusted Fs are reported for these analyses
Post hoc tests of time x glycemic improvement group were conducted by testing the slopes of each improvement group by an unpaired Student t test.
repeated measures multivariate analysis of variance conducted for all other exploratory dependent measures and Wilk's lambda values were reported for these analyses
sub-group analyses were performed by RM-ANOVAs. Follow-up Pearson correlations between delta scores were conducted.

Data Collection Summary:

Timing of Measurements: measurements taken at baseline and after 3 months

Dependent Variables

lipid profile
fibrinogen
blood cell count
glucose
routine biochemical parameters
creatinine
HbA1c
urine analysis
urine albumin/creatinine
total plasma insulin
C-peptide level
C-reactive protein
HbA1c
blood thrombogenicity, assessed as the change in the thrombus area formed in an ex vivo perfusion chamber at baseline and at 3 months after randomization

Independent Variables

600 mg troglitazone or placebo given to randomized subjects

Control Variables

Description of Actual Data Sample:

Initial N: 40, 24 men and 16 women

Attrition (final N): 40

Age: 57.1 ± 1.2 y

Ethnicity: not specified

Other relevant demographics: 25% of group members were smokers, 5 members in each group

Anthropometrics :BMI 31.0 ± 1.4

Location: United States

Summary of Results:

Results from subjects showing glycemic improvement

Variables	Conservative Treatment		Treatment with Troglitazone
	Baseline	3-month post	Baseline	3-month post
BMI	33.8±3	30.7±3	30.5±2	30.6±2
Thrombus, mg/dl	15188±1210	12065±862	15607±1705	11728±866
Glucose, %	171±9	161±14	153±15	119±13
HbA1c, mg/dl	9.3±0.2	8±0.2	9.1±0.4	7.6±0.2
C-reactive protein, mg/dl	7.18±3.06	5.98±3.06	5.06±1.29	2.97±0.90
Fibrinogen, mg/dl	301±19	277±17	308±39	247±20
C-peptide, ng/dl	3.48±0.67	3.59±0.46	1.86±0.23	1.96±0.25
sP-selectin, ng/dl	215±21	135±19	142±19	120±11

Other Findings

There were no significant differences between the control and intervention groups at baseline.
At the end of the study patients were divided into groups based on glycemic improvement: 14 patients from the intensively treated group and 10 patients from the conservatively treated group showed a reduction in baseline HbA1c greater than or equal to 0.5% and a significant reduction in mean HbA1c levels (9.2% to 7.8% at baseline and 3 months, respectively, p<0.01.
There were not significant differences in baseline characteristics for any of the biological variables between the glycemic improvement and no improvment groups
A t test of changes in thrombus formation across the study revealed that patients with glycemic improvement had significantly less thrombus formation compared with those without improvement, p< 0.01.
A significant correlation was observed between thrombus formation changes and HbA1c changes (r = 0.47, p<0.01), demonstrating that the more HbA1c was reduced, the more thrombus formation was reduced.
Subjects without improvement in glucose control (from either treatment group) failed to show improvement in hypercoagulability

Author Conclusion:

The study demonstrated an association between glycemic control improvement and blood thrombogenicity reduction in patients with poorly controlled type 2 diabetes.

Even placebo-treated patients who achieved a reduction in HbA1c demonstrated a significant reduction in thromobogenicity. Subjects without improvement in glucose cotnrol failed to show improvement in hypercoagulability.

Funding Source:

Reviewer Comments:

Authors note that a non-glucose-mediated effect of troglitazone may have contributed to the improvement in thrombogenicity.

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?	No
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?	N/A
	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%.)	N/A
	4.3.	Were all enrolled subjects/patients (in the original sample) accounted for?	Yes
	4.4.	Were reasons for withdrawals similar across groups?	N/A
	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?	N/A
	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)?	N/A
	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?	No
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