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 if chronic treatment of insulin resistance can preserve ß-cell function and delay or prevent type 2 diabetes.

Inclusion Criteria:

Participants were:

≥ 18 years of age
had gestational diabetes mellitus (GDM) in the previous 4 years
were willing to use effective contraception

Exclusion Criteria:

no evidence of chronic disease
serum alanine aminotransferase concentration < 1.5 times the laboratory upper normal
no diabetes
sum of five oral glucose tolerance test (OGTT) plasma glucose concentrations ≥ 625 mg/dl, predicting a 70% risk of diabetes in the next 5 years

Description of Study Protocol:

Recruitment Between August 1995 and May 1998, chart reviews and patient interviews identified women from Los Angeles County Women's and Children's Hospital.

Design

Women with previous gestational diabetes were randomized to placebo or the insulin-sensitizing drug troglitazone administered in a double-blind fashion.

Blinding used (if applicable)

Participants were randomized to receive troglitazone 400 mg/d or placebo in a double-blind fashion.

Intervention (if applicable)

Subjects recieved dietary advice and were advised to walk for 30 min 3 days each week. Subjects had a frequently sampled intravenous glucose tolerance test (IVGTT) within 4 weeks of the screening OGTT, then randomized to receive troglitazone 400 mg/day or placebo in a double-blind fashion. Follow-up visits were scheduled every 3 months for pill counts and measurements of fasting plasma glucose. OGTTs were scheduled annually. Diet and exercise recommendations were repeated at OGTTs. IVGTTs were scheduled 3 months after randomization.

Statistical Analysis

Statistical analyses addressed four questions:

1) Did troglitazone reduce the incidence of diabetes?

2) What early metabolic changes were associated with protection from diabetes?

3) Did troglitazone prevent or only mask deterioration to diabetes?

4) Did troglitazone preserve ß-cell function?

All analyses were conducted with subjects assigned to their initial treatemnt group, using available data for the period of follow-up relevant to the particular analysis.

Continuous variables were compared between treatment groups or subgroups by t tests if normally distributed, otherwise, nonparametric Wilcoxon tests were used.
Changes between baseline and follow-up measurements were compared between groups by Wilcoxon's nonparametric methods
Categorical variables were compared by χ² or Fisher's exact test.
Cumulative diabetes incidence rates were calculated by life table analysis
Average annual diabetes incidence rates were calculated by person-years
Incidence rates were compared between treatment groups or subgroups by long-rank tests.
Hazard ratios (HR) of diabetes were calculated by Cox proportional hazards regression analysis without and with adjustment for differences (p < 0.15) in baseline variables and four on-trial variables - rate of weight change, average pill compliance, pregnancy (yes/no), and fraction of months on hormonal contraception.
All statistical tests were two-sided, and statistical significance was accepted for α< 0.05.

Data Collection Summary:

Timing of Measurements

Fasting blood glucose was measured every 3 months, and oral glucose tolerance tests (OGTTs) were performed annually. Intravenous glucose tolerance tests (IVGTTs) were performed at baseline and 3 months later to identify early metabolic changes associated with any protection from diabetes.

Dependent Variables

Diagnosis of Diabetes according to the American Diabetes Assocation criteria
OGTT measured by fasting glucose (mg/dl) and 2-h glucose
IVGTT measured as fasting glucose (mg/dl), fasting insulin, whole body insulin sensitivity (S₁), Glucose disappearance (K_g), insulin area, acute insulin response to intravenous glucose (AIRg), and the dispostion index (DI) (the product of AIRg and S₁).
BMI (kg/m²)
Waist-to-hip circumference ratio
Use of hormonal contraceptives

Independent Variables

400 mg troglitazone and lifestyle changes
placebo and lifestyle changes

Control Variables

Adjustments were made for differences in baseline and on-trial characteristics.

Description of Actual Data Sample:

Initial N: 266 women, 133 women were randomized to each group - troglitazone and placebo.

Attrition (final N): 30 women failed to return for follow-up, 11 in the placebo group and 19 in the troglitazone group for a total of 236 participants (122 in the placebo group and 114 in the troglitazone group)

Age:

Placebo group: 34.3 years ± 6.5

Troglitazone group: 34.9 years ± 6.6

Ethnicity: Hispanic

Other relevant demographics:

BMI: Placebo group: 30.3 kg/m² ± 5.3, troglitazone group: 30.6 kg/m²± 6.1

Waist-to-hip circumference ratio: Placebo group: 0.86 ± 0.05, troglitazone group: 0.85 ± 0.06

Using hormonal contraceptives: Placebo group: 48%, troglitazone group 43%

Anthropometrics Randomized groups were balanced for all variables

Location:

Los Angeles County Women's and Children's Hospital, Los Angeles, CA

Summary of Results:

Average annual diabetes incidence rates in women who returned for follow-up

Variables	Placebo group	Troglitazone group	Statistical Significance of Group Difference
Average annual diabetes incidnece rates	12.1%	5.4%	< 0.01

Metabolic parameters from IVGTTs at baseline and 3 months on trial

Variables	Placebo group Baseline	Placebo group 3 months	p	Troglitazone group Baseline	Troglitazone group 3 months	p
Fasting glucose (mg/dl)	94.3 ± 10.4	97.2 ±14.5	0.009	94.5 ±10.0	91.0 ±10.4	<0.0001
K_g(min^-1 x 100)	1.49± 0.40	1.48 ±0.41	0.99	1.43 ±0.41	1.46 ±0.48	0.53
S₁(min^-1 per µU/ml x 10^-4)	2.34 ±1.80	2.17 ±1.48	0.17	2.60 ±1.67	3.76 ±2.27	<0.0001
Insulin area (µU/ml x min)	10518 ±5544	10701 ±5673	0.90	9402 ± 5504	6551 ±3644	<0.0001
AIRg (µU/ml x min)	542 ±499	534 ±460	0.91	461 ±357	406 ±294	0.10
DI	995 ±709	969 ±720	0.35	987 ± 720	1321 ±852	<0.0001

Protection from diabetes required an increase in S₁ early on but was most prominent in women who responded to that increase with a large reduction in insulin output from ß-cells.

Other Findings

Average annual incidence rates of diabetes during the postrial perid was 21.2% for the placebo group and 3.1% for the troglitazone group (p = 0.03). The placebo group had incresaing glucose levels and decreasing ß-cell compensation for increasing insulin resistance. The troglitazone group had stable ß-cell compensation for stable insulin resistance.

Author Conclusion:

A 50% reduction in the incidence of type 2 diabetes was seen in young Hispanic women with recent GDM who were treated with troglitazone. Protection from diabetes was observed for 8 months after the drug was stopped and it was associated with preservation of ß-cell compensation for stable insulin resistance. Protection required an improvement in S₁ soon after initiation of treatment, but most closely linked to a reduction in the amount of insulin required from ß-cells.

Funding Source:

Reviewer Comments:

Whether differences in drug metabolism, peroxisome proliferator-activated receptor-γ, or the etiology of insulin resistance could distinguish between these groups remains to be determined. A prevention strategy in which high-risk people are prescribed behavioral interventions initially and advanced to pharmacological treatment if their plasma glucose concentrations continue to increase is suggested. Interventions may be most beneficial before clinical hyperglycemia develops as hyperglycemia serves as a chronic stimulus to insulin secretion. Identification of the underlying genetic variations should provide important insights into the pathogenesis of ß-cell failure in type 2 diabetes. Genetic information should also allow the development of individually targeted and early interventions to preserve ß-cell functions.

Study was terminated early when troglitazone was withdrawn from the market after reports of hepatotoxicity in patients taking the drug.

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?	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?	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?	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